ECR 2021 – Volume 16 by Radcliffe Cardiology

Volume 16 • 2021

www.ECRjournal.com

Official journal of

Cardiology

Lifelong Learning for Cardiovascular Professionals

28: 1279– 1289

www.ECRjournal.com

Volume 16 • 2021

Official journal of

Editor-in-Chief Juan Carlos Kaski

St George’s University of London, London, UK

Associate Editor Pablo Avanzas

University Hospital of Oviedo, Oviedo, Spain

Richard Conti

Wolfgang Koenig

University of Florida, Gainesville, US

Technical University of Munich, Munich, Germany

Section Editors

Basil Lewis

Lady Davis Carmel Medical Center and Technion-IIT, Haifa, Israel

Giuseppe Mancia

Mario Marzilli

University of MilanoBicocca, Milan, Italy

University of Pisa, Pisa, Italy

Hiroaki Shimokawa Tohoku University, Sendai, Japan

International Advisers Cardiac Imaging

Biomarkers of CV Risk

Environmental Issues for CV Health

Royal Brompton Hospital, London, UK

Karolinska Institute, Solna, Sweden

Center for Cardiology, University Medical Center Mainz, Mainz, Germany

Pharmacogenomics

Ischaemic Heart Disease

Hospital Universitario Central de Asturias, Spain

St George’s University of London, London, UK

Catholic University of the Sacred Heart, Rome, Italy

Genetics and Cardiovascular Disease

Cardiovascular Disease in Women

Genética Molecular-Laboratorio Medicina, HUCA, Oviedo, Spain

Radboud University, Nijmegen, Netherlands

Cardio-oncology

Cardiomyopathies and Athletes Heart Disease

John Baksi

Thomas Münzel

Bruna Gigante

Arrhythmias

David Calvo

Eliecer Coto

Rebecca Dobson

Azara Janmohamed

Giampaolo Niccoli Telemedicine

Angela Maas

Fausto J Pinto

Santa Maria University Hospital (CHULN), CCUL, Lisbon School of Medicine, University of Lisbon, Portugal

Heart Failure

Gianluigi Savarese

University of Liverpool Heart & Chest Hospital, Liverpool, UK

St George’s University of London, London, UK

Aneil Malhotra

Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden

Structural Heart Disease: Cardiac Intervention

Maria Lorenza Muiesan

Hypertension

Pharmacotherapy

University of Brescia, Brescia, Italy

Universidad Complutense, CIBERCV, Madrid, Spain

Giuseppe Ferrante

Humanitas Research Hospital, Humanitas University, Milan, Italy

Juan Tamargo

Regional Editors Asia

Shao-Liang Chen

North America

Nanjing First Hospital, Nanjing Medical University, Nanjing, China

Libin Cardiovascular Institute, University of Calgary, Calgary, Alberta, Canada

South America

Alberto Lorenzatti Hospital Córdoba, Cordoba, Argentina

Australasia

Carlos Morillo

Christopher Zeitz

University of Adelaide, Adelaide Medical School; Central Adelaide Local Health Network, Adelaide, Australia

Europe

Peter Ong

Robert-Bosch-Krankenhaus, Stuttgart, Germany

Editorial Board Dominick Angiolillo

University of Florida College of Medicine, Jacksonville, FL, US

Ramón Arroyo-Espliguero

Hospital General Universitario, Guadalajara, Spain

Lina Badimon

Research Institute-Hospital de la Santa Creu i Sant Pau, IIBSant Pau, CiberCV, Barcelona, Spain

Debasish Banerjee

Vinayak Bapat

Columbia University Medical Centre, New York, US

Antoni Bayés-Genís

William Boden

Sandwell & West Birmingham Hospitals NHS Trust, Birmingham, UK

Christopher Cannon

Haukeland University Hospital and Department of Clinical Science, University of Bergen, Bergen, Norway

Hospital Germans Trias i Pujol, Barcelona, Spain

Harvard Medical School, Boston, US

John Beltrame

University of Bologna, Bologna, Italy

University of Adelaide, Adelaide, Australia

Natalia Berry

St George’s University of London, London, Mid Atlantic Permanente Medical Group, Washington DC, US UK

Derek Connolly

VA Boston Healthcare System; Boston University School of Medicine, Boston, MA, US

Edina Cenko Peter Collins

Imperial College, London, UK

Clea Colombo

São Leopoldo Mandic Medical School, São Paulo, Brazil

Dana Cramariuc

Alberto Cuocolo

University of Naples Federico II, Naples, Italy

Gheorghe Andrei Dan

Colentina University Hospital, Bucharest, Romania

www.ECRjournal.com

Volume 16 • 2021

Ranil de Silva

Imperial College, London, UK

Marcelo Di Carli

Brigham and Women’s Hospital, Harvard Medical School, Boston, US

Carlo Di Mario

Careggi University Hospital, Florence, Italy

Polychronis Dilaveris

Hippokration General Hospital, Athens, Greece

Natalia Docheva

Heart and Brain Center of Excellence University Hospital, Pleven, Bulgaria

Ingrid Dumitriu

Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK

Dirk Duncker

Editorial Board (cont.)

Kim Greaves

Sunshine Coast University Hospital, Queensland, Australia

Eileen Handberg

University of Florida, Florida, US

Koji Hasegawa

National Hospital Organization Kyoto Medical Center, Kyoto, Japan

Melina Huerin

Lezica Cardiovascular Institute, Buenos Aires, Argentina

Marjan Jahangiri

St George’s Hospital, London, UK

Victoria Jowett

Great Ormond Street Hospital, London, UK

Thomas Kahan

Danderyd University Hospital, Danderyd, Sweden

Koichi Kaikita

Thoraxcenter, Cardiovascular Research School COEUR, University Medical Centre Rotterdam, Rotterdam, Netherlands

Kumamoto University, Kumamoto, Japan

Perry Elliott

Centre for Inherited Cardiovascular Diseases, UCL, London, UK

University College, London, UK

Christine Espinola-Klein

Johannes Gutenberg University Mainz, Mainz, Germany

Giulia Ferrannini

Karolinska Institutet, Stockholm, Sweden

Albert Ferro

King’s College London, London, UK

Juan-Pablo Kaski Mike G Kirby

Valeria Gaudieri

University Federico II, Naples, Italy

Robert Gerber

Conquest Hospital, Hastings, UK

Eva Gerdts

University of Bergen, Bergen, Norway

Bernard Gersh

Mayo Clinic, Minnesota, US

David Goldsmith

St George’s University of London, London, UK

Tommaso Gori

Johannes Gutenberg University Mainz, Mainz, Germany

Diana Gorog

University of Hertfordshire, Hatfield, Hertfordshire, UK

Anastasia Mihailidou

St George’s University of London, London, UK

Haukeland University Hospital, Bergen, Norway Kolling Institute, Royal North Shore Hospital and Macquarie University, Sydney, Australia

Kavitha Muthiah

Univ University of New South Wales, Sydney, Australia

Carmela Nappi

University Federico II, Naples, Italy

Amalia Peix

Institute of Cardiology and Cardiovascular Surgery, Havana, Cuba

Denis Pellerin

St Bartholomew’s Hospital, London, UK

Carl Pepine

Patrizio Lancellotti

Wroclaw Medical University, Wroclaw, Poland

Ben Freedman

Ente Ospedaliero Cantonale, Bellinzona, Switzerland

Imperial College, London, UK

Hospital Universitario La Paz, Madrid, Spain

Università Cattolica del Sacro Cuore, Rome, Italy

Augusto Gallino

Helga Midtbø

Sreenivasa Rao Kondapally Seshasai

Royal Bournemouth Hospital, Bournemouth, UK

Silvia Maffei

Olivia Manfrini

University of Bologna, Bologna, Italy

Axel Pries

Valentina Puntmann

Goethe University Hospital Frankfurt, Frankfurt, Germany

Hari Raju

Macquarie University, Sydney, Australia

Robin Ray

Felipe Martinez

UICE-HP Cardiología, HU Virgen Macarena, Seville, Spain

Antoni Martínez-Rubio

IBFM CNR, Segrate, Italy

University Hospital of Sabadell, Sabadell, Barcelona, Spain

John McNeill

Monash University, Melbourne, Australia

Puja Mehta

Emory Women’s Heart Center and Emory Clinical Cardiovascular Research Institute, Emory University School of Medicine, Atlanta, GA, US

Lilia Sierra-Galan

American British Cowdray Medical Center, Mexico City, Mexico

Iana Simova

National Cardiology Hospital, Sofia, Bulgaria

Isabella Sudano

University of Athens, Athens, Greece

St George’s University of London, London, UK

National University of Cordoba, Cordoba, Argentina

Rosa Sicari

Italian National Research Council, Rome, Italy

Eva Prescott

María Martin

Central University Hospital of Asturias, Oviedo, Asturias, Spain

Vinoda Sharma

Sandwell and West Birmingham Hospitals NHS Trust Birmingham, UK

National Heart Centre Singapore, Singapore

Charité Universitätsmedizin, Berlin, Germany

National Research Council, Pisa, Italy

Sanjay Sharma

St George’s University of London, London, UK

Piotr Ponikowski

Amir Lerman

Jiunn-Lee Lin

Nesan Shanmugam

University Hospital and University of Zurich, Zurich, Switzerland

Bispebjerg Hospital, Copenhagen, Denmark

Taipei Medical University Shuang-Ho Hospital, Taipei, Taiwan

Roxy Senior

Esther Perez-David

Gaetano Lanza

Mayo Clinic, Minnesota, US

Anne Grete Semb

Diakonhjemme Hospital, Oslo, Norway

University of Florida, Florida, US

University of Liège, Liège, Belgium

Heart Research Institute, Charles Perkins Centre, University of Sydney, Sydney, and Concord Hospital, Concord, NSW, Australia

Noel Bairey Merz

Ignacio J Amat Santos

Hospital Clínico Universitario de Valladolid, Spain

Cedars-Sinai Heart Institute, Los Angeles, US

University of Hertfordshire, Hatfield, UK

Michael Fisher

Royal Liverpool University Hospital, Liverpool, UK

Guiomar Mendieta

Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain

Alejandro Recio Ornella Rimoldi

Helen Routledge

Worcestershire Royal Hospital, Worcester, UK

Magdi Saba

St George’s University of London, London, UK

Antonia Sambola

Hospital Vall d’Hebron, Barcelona, Spain

Jack Wei Chieh Tan

Konstantinos Toutouzas Isabella Tritto

University of Perugia, Perugia, Italy

Dimitrios Tziakas

Democritus University of Thrace, Xanthi, Greece

Moises Vasquez

Hospital Rafael Angel Calderon Guardia, C.C.S.S., San Jose, Costa Rica

Ilais Moreno Velasquez

Istituto Conmemorativo Gorgas de Estudios de la Salud, Panama

Inga Voges

University Medical Center of SchleswigHolstein, Kiel, Germany

Mauricio Wajngarten University of São Paulo, São Paulo, Brazil

Hiroshi Watanabe

Hamamatsu University School of Medicine, Hamamatsu, Japan

Carolyn Webb

National Heart & Lung Institute, Imperial College London, London, UK

Matthew Wright

St Thomas’ Hospital, London, UK

José Luis Zamorano

Hospital Ramón y Cajal, Madrid, Spain

www.ECRjournal.com

Volume 16 • 2021

Editorial Publishing Director Leiah Norcott Head of Print Design Tatiana Losinska | Production Editors Aashni Shah, Bettina Vine Editorial Coordinator Calum White | Peer Review Editor Nicola Parsons Contact leiah.norcott@radcliffe-group.com

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Published by Radcliffe Cardiology. All information obtained by Radcliffe Cardiology and each of the contributors from various sources is as current and accurate as possible. However, due to human or mechanical errors, Radcliffe Cardiology and the contributors cannot guarantee the accuracy, adequacy or completeness of any information, and cannot be held responsible for any errors or omissions, or for the results obtained from the use thereof. Published content is for information purposes only and is not a substitute for professional medical advice. Where views and opinions are expressed, they are those of the author(s) and do not necessarily reflect or represent the views and opinions of Radcliffe Cardiology. Radcliffe Cardiology, Unit F, First Floor, Bourne End Business Park, Cores End Road, Bourne End, Buckinghamshire SL8 5AS, UK © 2021 All rights reserved • ISSN: 1758-3756 • eISSN: 1758-3764

Volume 16 • 2021

Aims and Scope

• European Cardiology Review is an international, English language, peer-reviewed, open access journal that publishes articles continuously on www.ECRjournal.com. • European Cardiology Review aims to assist time-pressured physicians to stay abreast of key advances and opinions in cardiology medicine and practice. • European Cardiology Review comprises balanced and comprehensive articles written by leading authorities, addressing the most pertinent developments in the field. • European Cardiology Review provides comprehensive updates on a range of salient issues to support physicians in developing their knowledge and effectiveness in day-to-day clinical practice.

Structure and Format

• European Cardiology Review publishes review articles, original research, expert opinion articles, guest editorials and letters to the editor. • The structure and degree of coverage assigned to each category of the journal is the decision of the Editor-in-Chief, with the support of the Section Editors and Editorial Board.

Abstracting and Indexing

E uropean Cardiology Review is abstracted, indexed and listed in PubMed, Crossref, Embase, Scopus, Emerging Sources Citation Index, Google Scholar and Directory of Open Access Journals. All articles are published in full on PubMed Central a month after publication. Radcliffe Group is an STM member publisher.

Editorial Expertise

E uropean Cardiology Review is supported by various levels of expertise: • Overall direction from an Editor-in-Chief, supported by the Associate Editor, Section Editors and an Editorial Board comprising leading authorities from a variety of related disciplines. • Invited contributors who are recognised authorities in their fields. • Peer review – conducted by experts appointed for their experience and knowledge of a specific topic. • An experienced team of editors and technical editors.

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The journal follows guidance from the International Committee of Medical Journal Editors and the Committee on Publication Ethics. We expect all parties involved in the journal’s publication to follow these guidelines. All authors must declare any conflicts of interest.

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Articles published within this journal are open access, which allows users to copy, redistribute and make derivative works for noncommercial purposes, provided the original work is cited correctly. The author retains all non-commercial rights for articles published herein under the CC-BY-NC 4.0 License (https://creativecommons. org/licenses/by-nc/4.0/legalcode). Radcliffe Medical Media retains all commercial rights for articles published herein unless otherwise stated. Permission to reproduce an article for commercial purposes, either in full or in part, should be sought from the publication’s Managing Editor. To support open access publication costs, Radcliffe charges an Article Publication Charge (APC) to authors upon acceptance of an unsolicited paper as follows: £1,050 UK | €1,200 Eurozone | $1,369 all other countries. Waivers are available, as specified in the ‘Instructions to authors’ section on www.ECRjournal.com.

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• On submission, all articles are assessed by the Editor-in-Chief to determine their suitability for inclusion. • Suitable manuscripts are sent for double-blind peer review. • The Editor-in-Chief reserves the right to accept or reject any proposed amendments. • Once a manuscript has been amended in accordance with the reviewers’ comments, it is assessed to ensure it meets quality expectations. • The manuscript is sent to the Editor-in-Chief for final approval.

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European Cardiology Review is an online publication. Articles are published continuously on www.ECRjournal.com. The journal is free to read online and PDF downloads are available for registered users.

Online

All published manuscripts are free to read at www.ECRjournal.com. They are also available at www.radcliffecardiology.com, along with articles from the other journals in Radcliffe Cardiology’s cardiovascular portfolio – Arrhythmia & Electrophysiology Review, Cardiac Failure Review, Interventional Cardiology: Reviews, Research, Resources and US Cardiology Review.

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Contents The EXCEL Trial: The Interventionalists’ Perspective

George William Hunter, Vinoda Sharma, Chetan Varma and Derek Connolly DOI: https://doi.org/10.15420/ecr.2020.32

2020 Asian Pacific Society of Cardiology Consensus Recommendations on the Use of P2Y12 Receptor Antagonists in the Asia-Pacific Region

Jack WC Tan, Derek P Chew, Muhamad Ali SK Abdul Kader, Junya Ako, Vinay K Bahl, Mark Chan, Kyung Woo Park, Praveen Chandra, I-Chang Hsieh, Do Quang Huan, Sofian Johar, Dafsah Arifa Juzar, Byeong-Keuk Kim, Cheol Whan Lee, Michael Kang-Yin Lee, Yi-Heng Li, Wael Almahmeed, Eric Oliver Sison, Doreen Tan, Yu-Chen Wang, Shiuan Jong Yeh and Gilles Montalescot DOI: https://doi.org/10.15420/ecr.2020.40

Coronavirus Disease 2019: Cardiac Complications and Considerations for Returning to Sports Participation Daniel X Augustine, Tracey Keteepe-Arachi and Aneil Malhotra DOI: https://doi.org/10.15420/ecr.2020.36

Pharmacotherapy in Stable Coronary Artery Disease: Historical Perspectives and New Insights from the ISCHEMIA Trial Jonathan Yap, Derek P Chew, Gregg W Stone and Jack Wei Chieh Tan DOI: https://doi.org/10.15420/ecr.2020.48

Bridging the Gap in a Rare Cause of Angina Sumanth Khadke, Jovana Vidovic and Vinod Patel DOI: https://doi.org/10.15420/ecr.2020.33

Atrial Fibrillation in Congenital Heart Disease Irene Martín de Miguel and Pablo Ávila DOI: https://doi.org/10.15420/ecr.2020.41

The Renin–Angiotensin–Aldosterone System and Coronavirus Disease 2019 Eliecer Coto, Pablo Avanzas and Juan Gómez DOI: https://doi.org/10.15420/ecr.2020.30

Deferred Stenting for Heavy Thrombus Burden During Percutaneous Coronary Intervention for ST-Elevation MI Akshyaya Pradhan, Monika Bhandari, Pravesh Vishwakarma and Rishi Sethi DOI: https://doi.org/10.15420/ecr.2020.31

Editorial: The EXCEL Trial

Pablo Avanzas and Juan Carlos Kaski DOI: https://doi.org/10.15420/ecr.2021.02

The ISCHEMIA Trial: And the Winner Is… the Patient Pablo Avanzas and Juan Carlos Kaski

DOI: https://doi.org/10.15420/ecr.2021.03

A Practical Guide for Cardiologists to the Pharmacological Treatment of Patients with Type 2 Diabetes and Cardiovascular Disease Tariq Ahmad, Ralph J Riello and Silvio E Inzucchi DOI: https://doi.org/10.15420/ecr.2020.01.R1

Novel Pharmacological Treatment of Patients with Type 2 Diabetes and Cardiovascular Disease: What Cardiologists and Diabetologists Should Know Felipe Martínez

DOI: https://doi.org/10.15420/ecr.2020.38

Role of Inflammation in Coronary Epicardial and Microvascular Dysfunction Shigeo Godo, Jun Takahashi, Satoshi Yasuda and Hiroaki Shimokawa DOI: https://doi.org/10.15420/ecr.2020.47

Consensus Recommendations by the Asian Pacific Society of Cardiology: Optimising Cardiovascular Outcomes in Patients with Type 2 Diabetes

Jack Wei Chieh Tan, David Sim, Junya Ako, Wael Almahmeed, Mark E Cooper, Jamshed J Dalal, Chaicharn Deerochanawong, David Wei Chun Huang, Sofian Johar, Upendra Kaul, Sin Gon Kim, Natalie Koh, Alice Pik-Shan Kong, Rungroj Krittayaphong, Bernard Kwok, Bien J Matawaran, Quang Ngoc Nguyen, Loke Meng Ong, Jin Joo Park, Yongde Peng, David KL Quek, Ketut Suastika, Norlela Sukor, Boon Wee Teo, Chee Kiang Teoh, Jian Zhang, Eugenio B Reyes and Su Yen Goh DOI: https://doi.org/10.15420/ecr.2020.52

Anti-inflammatory Treatment and Cardiovascular Outcomes: Results of Clinical Trials Alberto J Lorenzatti

DOI: https://doi.org/10.15420/ecr.2020.51

Management of Dyslipidaemia in Real-world Clinical Practice: Rationale and Design of the VIPFARMA ISCP Project Ricardo Lopez Santi, Felipe Martinez, Adrian Baranchuk, Alvaro Sosa Liprandi, Daniel Piskorz, Alberto Lorenzatti, Maria Pilar Lopez Santi and Juan Carlos Kaski; on behalf of the VIPFARMA ISCP Investigators DOI: https://doi.org/10.15420/ecr.2020.42 © RADCLIFFE CARDIOLOGY 2021 Access at: www.ECRjournal.com

Contents Optimal Prognostication of Patients with Coronary Stenoses in the Pre- and Post-PCI setting: Comments on TARGET FFR and DEFINE-FLOW Trials Presented at TCT Connect 202 Andreas Seitz, Stefan Baumann, Udo Sechtem and Peter Ong DOI: https://doi.org/10.15420/ecr.2021.04

Atherosclerotic Cardiovascular Disease in Rheumatoid Arthritis: Impact of Inflammation and Antirheumatic Treatment Anne Mirjam Kerola, Silvia Rollefstad and Anne Grete Semb DOI: https://doi.org/10.15420/ecr.2020.44

The Association Between Psoriasis and Cardiovascular Diseases Ahmed Zwain, Mohanad Aldiwani and Hussein Taqi DOI: https://doi.org/10.15420/ecr.2020.15.R2

Inflammation and Cardiovascular Disease: The Future

Natalie Arnold, Katharina Lechner, Christoph Waldeyer, Michael D Shapiro and Wolfgang Koenig DOI: https://doi.org/10.15420/ecr.2020.50

Mapping Technologies for Catheter Ablation of Atrial Fibrillation Beyond Pulmonary Vein Isolation

Giulio La Rosa, Jorge G Quintanilla, Ricardo Salgado, Juan José González-Ferrer, Victoria Cañadas-Godoy, Julián Pérez-Villacastín, Nicasio Pérez-Castellano, José Jalife and David Filgueiras-Rama DOI: https://doi.org/10.15420/ecr.2020.39

TCT Connect 2020 Trial Update: FORECAST, COMBINE OCT-FFR and DEFINE-PCI Kevin Cheng and Ranil de Silva

DOI: https://doi.org/10.15420/ecr.2021.07

The ISCHEMIA Trial: What is the Message for the Interventionalist? Emmanuel Ako, Sukhjinder Nijjer, Abtehale Al-Hussaini and Raffi Kaprielian DOI: https://doi.org/10.15420/ecr.2020.37

Asian Pacific Society of Cardiology Consensus Recommendations on the Use of MitraClip for Mitral Regurgitation

Khung Keong Yeo, Jack Wei Chieh Tan, David WM Muller, Darren L Walters, JoAnn Lindenfeld, Michael Kang Yin Lee, Angus Shing Fung Chui, Sai Satish, Teguh Santoso, Shunsuke Kubo, John Chan Kok Meng, Kenny YK Sin, See Hooi Ewe, David Sim, Edgar Tay, Krissada Meemook, Shih-Hsien Sung, Quang Ngoc Nguyen, Xiangbin Pan, Makoto Amaki, Masaki Izumo, Kentaro Hayashida, Jung Sun Kim, Do-Yoon Kang, Gregg Stone and Takashi Matsumoto DOI: https://doi.org/10.15420/ecr.2021.01

2020 Asian Pacific Society of Cardiology Consensus Recommendations on Antithrombotic Management for High-risk Chronic Coronary Syndrome

Jack Wei Chieh Tan, Derek P Chew, David Brieger, John Eikelboom, Gilles Montalescot, Junya Ako, Byeong-Keuk Kim, David KL Quek, Sarah J Aitken, Clara K Chow, Sok Chour, Hung Fat Tse, Upendra Kaul, Isman Firdaus, Takashi Kubo, Boon Wah Liew, Tze Tec Chong, Kenny YK Sin, Hung-I Yeh, Wacin Buddhari, Narathip Chunhamaneewat, Faisal Hasan, Keith AA Fox, Quang Ngoc Nguyen and Sidney TH Lo DOI: https://doi.org/10.15420/ecr.2020.45

Invasive Diagnosis of Coronary Functional Disorders Causing Angina Pectoris

Sascha Beck, Valeria Martínez Pereyra, Andreas Seitz, Johanna McChord, Astrid Hubert, Raffi Bekeredjian, Udo Sechtem and Peter Ong DOI: https://doi.org/10.15420/ecr.2021.06

The Role of C-reactive Protein in Patient Risk Stratification and Treatment

Ramón Arroyo-Espliguero, María C Viana-Llamas, Alberto Silva-Obregón and Pablo Avanzas DOI: https://doi.org/10.15420/ecr.2020.49

New Challenging Scenarios in Transcatheter Aortic Valve Implantation: Valve-in-valve, Bicuspid and Native Aortic Regurgitation Sandra Santos-Martínez and Ignacio J Amat-Santos DOI: https://doi.org/10.15420/ecr.2021.12

Pathophysiology and Diagnosis of Coronary Functional Abnormalities

Jun Takahashi, Akira Suda, Kensuke Nishimiya, Shigeo Godo, Satoshi Yasuda and Hiroaki Shimokawa DOI: https://doi.org/10.15420/ecr.2021.23

The Fourth Trimester: Pregnancy as a Predictor of Cardiovascular Disease Pensée Wu, Ki Park and Martha Gulati DOI: https://doi.org/10.15420/ecr.2021.18

Contents

Timing of Intervention in Asymptomatic Patients with Aortic Stenosis Teresa Sevilla, Ana Revilla-Orodea and J Alberto San Román DOI: https://doi.org/10.15420/ecr.2021.11

Coronavirus Disease 2019: Psychological Stress and Cardiovascular Diseases Maki Komiyama and Koji Hasegawa

DOI: https://doi.org/10.15420/ecr.2021.10

ISCHEMIA Trial: Key Questions and Answers Jose Lopez-Sendon, Raúl Moreno and Juan Tamargo DOI: https://doi.org/10.15420/ecr.2021.16

Transcatheter Aortic Valve Implantation and Subclinical and Clinical Leaflet Thrombosis: Multimodality Imaging for Diagnosis and Risk Stratification María Martín, Javier Cuevas, Helena Cigarrán, Juan Calvo and César Morís DOI: https://doi.org/10.15420/ecr.2021.09

Novel Cardiovascular Biomarkers Associated with Increased Cardiovascular Risk in Women With Prior Preeclampsia/HELLP Syndrome: A Narrative Review Esmee ME Bovee, Martha Gulati and Angela HEM Maas DOI: https://doi.org/10.15420/ecr.2021.21

The Role of Mental Stress in Ischaemia with No Obstructive Coronary Artery Disease and Coronary Vasomotor Disorders Roos ET van der Meer and Angela HEM Maas DOI: https://doi.org/10.15420/ecr.2021.20

Hypertension in Women: Should There be a Sex-specific Threshold? Eva Gerdts and Giovanni de Simone

DOI: https://doi.org/10.15420/ecr.2021.17

Association Between Colchicine Treatment and Clinical Outcomes in Patients with Coronary Artery Disease: Systematic Review and Meta-analysis

Francesco Condello, Matteo Sturla, Bernhard Reimers, Gaetano Liccardo,Giulio G Stefanini, Gianluigi Condorelli and Giuseppe Ferrante DOI: https://doi.org/10.15420/ecr.2021.31

Women and Diabetes: Preventing Heart Disease in a New Era of Therapies Giuseppe Galati, Pierre Sabouret, Olga Germanova and Deepak L Bhatt DOI: https://doi.org/10.15420/ecr.2021.22

Secondary Prevention of Cardiovascular Disease in Women: Closing the Gap Aarti Thakkar, Anandita Agarwala and Erin D Michos DOI: https://doi.org/10.15420/ecr.2021.24

Levosimendan in Europe and China: An Appraisal of Evidence and Context

Xiangqing Kong, Xinqun Hu, Baotong Hua, Francesco Fedele, Dimitrios Farmakis and Piero Pollesello DOI: https://doi.org/10.15420/ecr.2021.41

2021 Asian Pacific Society of Cardiology Consensus Recommendations on the Use of P2Y12 Receptor Antagonists in the Asia-Pacific Region: Special Populations

Jack Wei Chieh Tan, Derek P Chew, Kin Lam Tsui, Doreen Tan, Dmitry Duplyakov, Ayman Hammoudeh, Bo Zhang, Yi Li, Kai Xu, Paul J Ong, Doni Firman, Habib Gamra, Wael Almahmeed, Jamshed Dalal, Li-Wah Tam, Gabriel Steg, Quang N Nguyen, Junya Ako, Jassim Al Suwaidi, Mark Chan, Mohamed Sobhy, Abdulla Shehab, Wacin Buddhari, Zulu Wang, Alan Yean Yip Fong, Bilgehan Karadag, Byeong-Keuk Kim, Usman Baber, Chee Tang Chin and Ya Ling Han DOI: https://doi.org/10.15420/ecr.2021.35

Asian Pacific Society of Cardiology Consensus Recommendations for Pre-participation Screening in Young Competitive Athletes

Luokai Wang, Tee Joo Yeo, Benedict Tan, Bernard Destrube, Khim Leng Tong, Swee Yaw Tan, Gregory Chan, Zijuan Huang, Frankie Tan, Yu Chen Wang, Jong-Young Lee, Erik Fung, Gary Yiu Kwong Mak, Raymond So, Chaisiri Wanlapakorn, Ade Meidian Ambari, Lucky Cuenza, Choong Hou Koh and Jack Wei Chieh Tan DOI: https://doi.org/10.15420/ecr.2021.26

Palpitations in the Cancer Patient Hani Essa and Gregory YH Lip

DOI: https://doi.org/10.15420/ecr.2021.44

Microvascular Angina: Diagnosis and Management

Haider Aldiwani, Suzan Mahdai, Ghaith Alhatemi and C Noel Bairey Merz DOI: https://doi.org/10.15420/ecr.2021.15

The Female Athlete’s Heart: Overview and Management of Cardiovascular Diseases Silvia Castelletti and Sabiha Gati

DOI: https://doi.org/10.15420/ecr.2021.29

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Coronary Artery Disease in Chronic Kidney Disease: Need for a Heart–Kidney Team-Based Approach Gautam R Shroff, Michelle D Carlson and Roy O Mathew DOI: https://doi.org/10.15420/ecr.2021.30

Coronary Artery Disease in Patients with Aortic Stenosis and Transcatheter Aortic Valve Implantation: Implications for Management Antonio FB de Azevedo Filho, Tarso AD Accorsi and Henrique B Ribeiro DOI: https://doi.org/10.15420/ecr.2021.27

Definitions and Epidemiology of Coronary Functional Abnormalities Andreas Seitz, Johanna McChord, Raffi Bekeredjian, Udo Sechtem and Peter Ong DOI: https://doi.org/10.15420/ecr.2021.14

Why We Need Specialised Centres for Women’s Hearts: Changing the Face of Cardiovascular Care for Women Martha Gulati, Cara Hendry, Biljana Parapid and Sharon L Mulvagh DOI: https://doi.org/10.15420/ecr.2021.49

Neuromodulatory Approaches for Atrial Fibrillation Ablation

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Asian Pacific Society of Cardiology Consensus Recommendations on Dyslipidaemia

Natalie Koh, Brian A Ference, Stephen J Nicholls, Ann Marie Navar, Derek P Chew, Karam Kostner, Ben He, Hung Fat Tse, Jamshed Dalal, Anwar Santoso, Junya Ako, Hayato Tada, Jin Joo Park, Mei Lin Ong, Eric Lim, Tavin Subramaniam, Yi-Heng Li, Arintaya Phrommintikul, SS Iyengar, Saumitra Ray, Kyung Woo Park, Hong Chang Tan, Narathip Chunhamaneewat, Khung Keong Yeo and Jack Wei Chieh Tan DOI: https://doi.org/10.15420/ecr.2021.36

2021 ESC Guidelines on Cardiac Pacing and Cardiac Resynchronisation Therapy Gheorghe-Andrei Dan

DOI: https://doi.org/10.15420/ecr.2021.51

25th Annual Scientific Meeting of the International Society of Cardiovascular Pharmacotherapy Jack Wei Chieh Tan

DOI: https://doi.org/10.15420/ecr.2021.16.POGE

Compound A, a Ginger Extract, Significantly Reduces Pressure Overload-induced Systolic Heart Failure in Mice

Yuto Kawase, Kana Shimizu, Masafumi Funamoto, Yoichi Sunagawa, Yasufumi Katanasaka, Yusuke Miyazaki, Satoshi Shimizu, Koji Hasegawa and Tatuya Morimoto DOI: https://doi.org/10.15420/ecr.2021.16.PO1

β3 Adrenergic Receptors in the Sinoatrial Node for Heart Rate Regulation Shu Nakao, Kazuki Yanagisawa, Tomoe Ueyama, Koji Hasegawa and Teruhisa Kawamura DOI: https://doi.org/10.15420/ecr.2021.16.PO2

Polysaccharide Peptide of Ganoderma lucidum Reduces Endothelial Injury in Stable Angina and High-risk Patients Eliana Susilowati, Djanggan Sargowo and Nadia Ovianti DOI: https://doi.org/10.15420/ecr.2021.16.PO3

Clinical Efficacy of Intracoronary Papaverine After Nicorandil Administration for Safe and Optimal Fractional Flow Reserve Measurement Shinjo Sonoda

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Prevalence of CYP2C19 Gene Polymorphism in Patients with Coronary Artery Disease Undergoing Percutaneous Coronary Intervention Maya Rosana Amalia and Susi Herminingsih DOI: https://doi.org/10.15420/ecr.2021.16.PO5

Retrospective Study to Assess the Effect of Telmisartan on Urine Albumin to Creatinine Ratio in Indian Hypertensive Patients Balram Sharma, Hanmant Barkate, Sachin Suryawanshi, Mayur Jadhav, Obaidullah Khan and Gauri Dhanaki DOI: https://doi.org/10.15420/ecr.2021.16.PO7

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The Role of Isocitrate Dehydrogenases in Direct Reprogramming to Cardiomyocytes Tomoaki Ishida, Tomoe Ueyama, Ai Baba, Koji Hasegawa and Teruhisa Kawamura DOI: https://doi.org/10.15420/ecr.2021.16.PO8

Chrysanthemum morifolium Extract Prevents the Development of Doxorubicin-induced Heart Failure Masaya Ono, Yoichi Sunagawa, Yasufumi Katanasaka, Koji Hasegawa and Tatsuya Morimoto DOI: https://doi.org/10.15420/ecr.2021.16.PO9

Discovery of Novel Small Molecules for Heart Failure Therapy Using Cultured Cardiomyocyte by High Throughput Screening Assay

Satoshi Shimizu, Miho Yamada, Takahiro Katagiri,Yoichi Sunagawa, Yasufumi Katanasaka, Yusuke Miyazaki, Masafumi Funamoto, Sari Nurmila, Kana Shimizu, Naohisa Ogo, Akira Asai, Koji Hasegawa and Tatsuya Morimoto DOI: https://doi.org/10.15420/ecr.2021.16.PO10

Early Initiation of Tolvaptan is Associated with Early Discharge in Elderly Heart Failure Patients Shunsuke Kiuchi, Shinji Hisatake, Yoshiki Murakami, Takahide Sano and Takanori Ikeda DOI: https://doi.org/10.15420/ecr.2021.16.PO11

The Polyunsaturated Fatty Acids EPA and DHA Prevent Myocardial Infarction-induced Heart Failure by Inhibiting p300-HAT Activity in Rats

Yoichi Sunagawa, Ayumi Katayama, Masafumi Funamoto, Kana Shimizu, Satoshi Shimizu, Yasufumi Katanasaka, Yusuke Miyazaki, Koji Hasegawa and Tatsuya Morimoto DOI: https://doi.org/10.15420/ecr.2021.16.PO12

A Novel Curcumin Formulation, ASD-Cur, Suppressed the Development of Systolic Dysfunction After Myocardial Infarction in Rats

Hidemichi Takai, Yoichi Sunagawa, Masafumi Funamoto, Kana Shimizu, Satoshi Shimizu, Yasufumi Katanasaka, Yusuke Miyazaki, Atsusi Imaizumi, Tadashi Hashimoto, Hiromichi Wada, Koji Hasegawa and Tatsuya Morimoto DOI: https://doi.org/10.15420/ecr.2021.16.PO13

The Natural Product Zerumbone Suppresses Pressure Overload-Induced Cardiac Dysfunction by Inhibiting Cardiac Hypertrophy and Fibrosis Mikuto Tojima, Yasufumi Katanasaka, Yoichi Sunagawa, Koji Hasegawa and Tatsuya Morimoto DOI: https://doi.org/10.15420/ecr.2021.16.PO14

Evaluation of β-blocker Dose Optimisation Among Patients Attending Heart Failure Clinic at Sarawak Heart Centre, Malaysia Yii Ching Wong, Tiong Kiam Ong and Yee Ling Cham DOI: https://doi.org/10.15420/ecr.2021.16.PO15

Prevalence of Aspirin and Clopidogrel Resistance in Patients with Recurrent Ischaemic Cerebrovascular Disease Niyata Hananta Karunawan and Rizaldy Taslim Pinzon DOI: https://doi.org/10.15420/ecr.2021.16.PO16

EXCEL Trial

The EXCEL Trial: The Interventionalists’ Perspective George William Hunter, Vinoda Sharma , Chetan Varma and Derek Connolly Department of Cardiology, Sandwell and West Birmingham Hospitals NHS Trust, Birmingham, UK

Abstract

Left main stem (LMS) disease is identified in up to 5% of diagnostic angiography cases, and is associated with significant morbidity and mortality due to the proportion of myocardium it subtends. In the past 10 years, there has been a significant change in the way we contemplate treating lesions in the LMS due to evolving experience and evidence in percutaneous coronary intervention (PCI) strategies and technologies. This has been reflected in recent changes in European and International guidance on managing patients with this lesion subset. Here, the authors provide an overview of the current literature regarding the management of LMS disease using PCI in light of new developments and emerging concepts in this field, specifically looking at the recent EXCEL trial.

Keywords

Left main stem, percutaneous coronary intervention, coronary artery bypass grafting, EXCEL, major adverse cardiovascular events, target lesion revascularisation, MI Disclosure: The authors have no conflicts of interest to declare. Received: 4 September 2020 Accepted: 20 October 2020 Citation: European Cardiology Review 2021;16:e01. DOI: https://doi.org/10.15420/ecr.2020.32 Correspondence: George William Hunter, Cardiology Department, Birmingham City Hospital, Dudley Rd, Birmingham B18 7QH, UK. E: g.hunter4@nhs.net Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Left main stem (LMS) disease is identified in up to 5% of diagnostic angiography cases, and is associated with significant morbidity and mortality due to the proportion of myocardium at risk, carrying large prognostic significance.1 Treatment strategies for combating LMS disease must therefore be efficacious and robust. Initial experience with percutaneous coronary intervention (PCI) in treating LMS disease using older-generation stents and limited use of contemporary imaging modalities had demonstrated poorer outcomes, leading to coronary artery bypass grafting (CABG) being considered the gold-standard therapy.2 However, newer-generation drug-eluting stents (DESs), more advanced intravascular imaging modalities, and a better understanding of patient selection, have meant that PCI is now considered to be a viable alternative to CABG, and its use is increasing in patients with LMS disease. The past 5–10 years of research in this field has given rise to a new evidence base, some of which has been controversial, and has led to a change in the way we think about managing LMS disease. We summarise this evidence base with the followup data from the most recent large randomised controlled trials (RCTs).

Evidence from Early Registry Data

Evidence for LMS intervention, both with PCI and CABG, started with early registry data. Initial data from the Coronary Artery Surgical Study registry demonstrated the importance of recognising the prognostic significance of LMS disease and the need for intervention.3 The results from the study showed a 5-year mortality reduction from 43% to 16% in symptomatic patients with LMS disease with CABG compared with medical therapy alone with medical therapy alone, with a median survival of 6.6 years. Decreased mortality peri- and post-CABG has also been documented.4 Registries comparing CABG with PCI strategies using contemporary devices have demonstrated similar findings in the majority of cases. These findings

included equivalent major adverse cardiovascular and cerebrovascular events (MACCE) rates, but also a higher risk of peri-procedural cerebrovascular accident in CABG groups, and a higher incidence in the need for future target lesion revascularisation (TLR) in PCI groups.5–7 Given the suggestions provided by early registry data sets, it was apparent that more powerful data were needed in the form of RCTs to confirm these findings.

Evidence from Randomised Controlled Trials

The first large RCT comparing PCI to CABG in LMS disease was the SYNTAX trial, in which 1,800 patients were randomised to receive either the first-generation TAXUS (Boston Scientific) DES or CABG.8 Prior to randomisation, diagnostic angiograms were scored based on the SYNTAX score, which was originally developed to objectively quantify anatomical and lesion complexity.9 Cases were then divided into tertiles (SYNTAX score of 0–22, 23–32 and >32) based on lesion complexity. It became apparent that CABG was superior when treating complex disease (i.e. SYNTAX score of >32), with equivalent MACCE in the lower two tertiles.8 The 5-year follow-up data demonstrated MACCE rates of 36.9% in the PCI group versus 31% in the CABG group (p=0.12), with higher rates of stroke with CABG (1.5% versus 4.3%, p=0.03) and higher rates of repeat revascularisation with PCI (26.7% versus 15.5%, p<0.01). CABG had better outcomes in both high and intermediate tertiles at 5 years.10 The 10-year follow-up results in the LMS subgroup have since been published and demonstrate a similar trend in MACCE to the 1-year follow-up data (n=16,89, 26% mortality with PCI versus 28% with CABG, p=0.019), with similar outcomes across the whole cohort, but a statistically greater benefit of CABG in the highest risk group based on lesion complexity (28% mortality in three-vessel disease with PCI versus 21% with CABG).8,11

EXCEL Trial: The Interventionalists’ Perspective Other smaller RCTs that have assessed the non-inferiority of LMS PCI to CABG include the LE MANS and PRECOMBAT trials, as well as a trial by Boudriot et al.12–14 These studies had different endpoints and were also limited by sample size, older-generation stents and the lack of recommended intracoronary imaging. More recently, the 5-year follow-up data from the Evaluation of XIENCE versus Coronary Artery Bypass Graft Surgery for Effectiveness of Left Main Revascularizaton (EXCEL) and the NOBLE trials have been published.15,16 NOBLE was a non-inferiority trial that randomised 1,201 patients with LMS disease to either PCI using DESs (BioMatrix Flex stent) or CABG.17 Interestingly, this trial demonstrated inferiority in the PCI-treated group at 5-year followup (p=0.0002). This was driven by higher MACCE (all-cause mortality, nonprocedural MI, repeat revascularisation or stroke) rates in the PCI group (28.4% versus 19%; 95% CI [1.24–2.01]), caused by higher rates of nonprocedural MI (7.6% versus 2.7%; 95% CI 1.66-5.39) and repeat revascularisation (17.1% versus 10.2%; 95% CI [1.25–2.40]). There were no significant differences in all-cause mortality (9.4% versus 8.7%; 95% CI [0.74–1.59]) or stroke (4% versus 2%; 95% CI [0.86–3.55]).17 The EXCEL trial was also a non-inferiority trial, in which 1,905 patients with LMS disease of low or intermediate complexity (as assessed by the SYNTAX score, i.e. <32) to either PCI using a second-generation Xience fluoropolymerbased cobalt-chromium everolimus DES (948 patients) or CABG (957 patients).18 The primary endpoint was a composite of death from any cause, stroke or MI at 3 years. The secondary endpoints were a composite of death from any cause, stroke or MI at 30 days, and a composite of death, stroke, MI or ischaemia-driven revascularisation at 3 years. We used the Society of Cardiovascular Angiography and Interventions (SCAI) definition of MI after PCI or CABG, which included three main criteria.19 First, in patients with normal baseline creatine kinase-MB (CKMB), the definition of MI is based on when the peak CK-MB (measured within 48 hours) of the procedure rises to ≥10 times the local laboratory upper limit of normal (ULN) or to ≥5 times the local laboratory ULN with new pathological Q-waves in ≥2 contiguous leads or new persistent left bundle branch block (LBBB), or in the absence of CK-MB measurements, and a normal baseline cardiac troponin (cTn), a cTn (I or T) level (measured within 48 hours of the PCI) rises to ≥70 times the local laboratory ULN, or ≥35 times the local laboratory ULN with new pathological Q-waves in ≥2 contiguous leads, or new persistent LBBB. Second, in patients with already elevated baseline CK-MB (or cTn) in whom the biomarkers are stable or falling, the definition of MI is based on the rise of CK-MB (or cTn) by an absolute increment equal to those levels recommended above from the most recent pre-procedure level. Third, in patients with elevated baseline CK-MB (or cTn) in whom the biomarker levels have not been shown to be stable or falling, the definition of MI is based on the rise in CK-MB (or cTn) by an absolute increment equal to those levels recommended above plus new ST-segment elevation or depression plus signs consistent with a clinically relevant MI, such as new-onset or worsening heart failure or sustained hypotension.19 This is in contrast with the use of the third and fourth universal definition of MI specifically for type 4a for PCI-related MI and type 5 for CABG-related MI.20,21 The reasons for utilising the SCAI definition (for MI) that have been cited are based on the best available evidence linking biomarker abnormalities to subsequent mortality in large clinical trials, it avoids ascertainment bias and uses the same criteria for PCI and CABG. It is also said to avoid the pitfall of tabulating MI events that are small enough not to have clinical

impact and instead permits assessment of MI events that are likely to be clinically relevant.22 At 3 years, the primary endpoint occurred in 15.4% of patients in the PCI group and in 14.7% of patients in the CABG group (difference: 0.7% points, upper 97.5% confidence limit: 4% points, p=0.02 for non-inferiority; HR: 1.00, 95% CI [0.79–1.26], p=0.98 for superiority). The secondary endpoint at 30 days occurred in 4.9% of patients in the PCI group and 7.9% in the CABG group (p<0.001 for non-inferiority, p=0.008 for superiority). The secondary endpoint at 3 years occurred in 23.1% of patients in the PCI group and 19.1% in the CABG group (p=0.01 for non-inferiority, p=0.10 for superiority). The 5-year outcomes of the EXCEL trial were presented at the Transcatheter Cardiovascular Therapeutics (TCT) conference in 2019.15 At 5 years, the primary outcome occurred in 22% of patients in the PCI group and in 19.2% of patients in the CABG group (difference 2.8% points, 95% CI [−0.9, 6.5], p=0.13).15 The incidence of cardiovascular death (5% and 4.5%, respectively; difference 0.5%, 95% CI [−1.4, 2.5]) and MI (10.6% and 9.1%, respectively; difference 1.4% points, 95% CI [−1.3, 4.2]) was similar in the PCI and CABG arms. Ischaemia-driven revascularisation was also more frequent in the PCI arm compared with the CABG arm (16.9% versus 10%; difference, 6.9% points; 95% CI [3.7–10.0]). Death due to any cause occurred more frequently in the PCI arm compared with the CABG arm (13% versus 9.9%, difference: 3.1% points, 95% CI [0.2–6.1]). Eighteen of 30 deaths due to any cause in the PCI arm were adjudicated as non-cardiovascular deaths; five were definite cardiovascular deaths and seven had an undetermined cause. There was a non-significant increase in stroke rate in the CABG treatment group. No significant difference was found between PCI and CABG in the composite outcome of death, stroke or MI at 5 years for patients with LMS disease with low or intermediate anatomical complexity, as assessed by the SYNTAX score. There were three distinct intervals of relative efficacy between PCI and CABG. From 0 to 30 days, there were a greater number of events (death, stroke or MI) in the CABG group (8%) than in the PCI group (4.9%). From 30 days to 1 year, event rates were similar for PCI (4.1%) and CABG (3.8%), but between 1 and 5 years, PCI patients experienced a higher rate of events than their CABG counterparts (15.1% and 9.7%, 95% CI [1.23–2.12], with curves continuing to diverge over time. This is similar to the 10-year followup in the SYNTAX trial, which demonstrated a clear benefit for CABG in the higher SYNTAX tertiles, based on complexity, even at 10 years.11 Following the EXCEL and NOBLE trials, in 2018 the European Society of Cardiology–European Association for Cardio-Thoracic Surgery (ESC/EACTS) jointly published the guidelines on myocardial revascularisation, in which LMS revascularisation with low SYNTAX LMS CAD was considered a class I level of evidence A for both PCI and CABG, and intermediate SYNTAX LMS CAD as a class IIa level of evidence A for PCI (IA for CABG).23

Controversies

Following the TCT presentation of the 5-year EXCEL data, there has been significant controversy regarding the use of the SCAI definition of MI, rather than the universal definition, being implemented. The SCAI definition of MI includes clinically relevant MIs, rather than basing the diagnosis mainly on biomarker elevation, which is the case in the universal definition.24 In December 2019, the EACTS withdrew its support from the chapter of the joint ESC/EACTS practice guidelines for myocardial revascularisation in LMS disease due to concerns regarding misleading results from the EXCEL trial because of the use of the SCAI definition for

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EXCEL Trial: The Interventionalists’ Perspective MI.25 There was also concern regarding the underrepresentation of the higher rate of all-cause mortality detected within the PCI arm of the trial. The authors of the EXCEL trial responded and stated that this was an underpowered secondary endpoint, and therefore, was statistically uncertain; the clinical events committee adjudicated the excess to be due to non-cardiovascular causes. The EXCEL trial data are currently undergoing independent review by the New England Journal of Medicine and the Cardiovascular Research Foundation, which should clarify the published findings.

Stent Technologies

As with any PCI therapy, especially LMS PCI, it is important to minimise the need for further revascularisation. It is therefore vital to reduce the incidence of in-stent restenosis (ISR) and stent thrombosis (ST). Newer stent technology has led to improvements in restenosis, with data demonstrating that DESs are associated with a better outcome than bare metal stents, and same-generation DESs have shown similar clinical and angiographic outcomes.26–28

Evidence Assessing the Impact of Lesion Location

Previous registry data have shown that approximately two-thirds of significant unprotected LMS disease involves the distal bifurcation.6 MACCE and target-vessel revascularisation are more prevalent in distal LMS disease compared with ostial or shaft disease, as shown by Naganuma et al. in the DELTA registry.29 An analysis of the cohort from the ISAR-LEFTMAIN study has also shown the need for multiple stents as an independent predictor of adverse MACCE.30 Similar outcomes were seen in a subset of the SYNTAX and EXCEL trials.29,31 The DELTA registry demonstrated worse outcomes for PCI of distal LMS versus ostial/midshaft LMS. Overall, CABG was better for repeat revascularisation compared with PCI.27

Evidence for the Use of Intravascular Imaging

Intravascular ultrasound (IVUS) has been given a level IIa (B) indication by the ESC for use in LMS PCI to assess stenosis severity.23 IVUS guidance for LMS PCI has never been formally investigated in an RCT, but registry data suggest improved outcomes.32,33 In the EXCEL trial, 290 of the 948 patients randomised to PCI had both pre- and post- PCI IVUS. However, IVUS guidance was used in 722 of the 948 patients at some stage of the procedure, and it was strongly recommended to optimise stenting. In a substudy of these 722 patients, it was found that a small final minimal stent area (MSA), measured by IVUS after LMS PCI, was associated with adverse events (including death, MI and stent thrombosis) during long-term follow-up.32 Three MSA tertiles were assessed as small (4.4–8.7 mm2), intermediate (8.8–10.9 mm2) and large (11–17.8 mm2), with a primary endpoint of all-cause mortality, MI or stroke. A graded relationship was found between MSA tertiles with an improved primary endpoint and increasing MSA size (19.4%, n=32/172 in the smallest tertile; 16.1%, n=26/169 in the intermediate tertile; and 9.6%, n=15/163) in the largest tertile; p=0.01 for smallest versus largest tertile). A substudy in the NOBLE trial also demonstrated a significant reduction in TLR (5.1% versus 11.6%, p=0.01) with IVUS-guided stent optimisation for LMS PCI, but no difference in MACCE was found.34

Guidelines on LMS Revascularisation

European and US societies have issued guidelines on revascularisation of patients with LMS disease.23,35–37 CABG maintains a class 1 indication across all anatomical subgroups. It is interesting to note that PCI assumes a stronger position in the ESC guidelines, with a class 1 recommendation in patients with a low SYNTAX score and 2A for an intermediate score. In

contrast, the American College of Cardiology (ACC) guidelines give only a 2A recommendation for PCI for low scores and a 2B for intermediate scores. Both societies are in agreement about the superiority of CABG for patients with a high SYNTAX score.23,38–40

Published European and US Guidelines for the Follow-up of Patients after Myocardial Revascularisation, Including LMS Intervention

In all studies to date on the optimal follow-up after PCI, the gain from discovering patients with restenosis is obscured by the high rate of falsepositive exercise ECG tests indicating ischaemia. Therefore, simple exercise ECG testing is not recommended for follow-up, and a noninvasive imaging approach is preferred.23 Specific studies clarifying which subset of patients benefit more from a specific follow-up approach are missing. The ESC guidelines for the follow-up for patients receiving revascularisation give a class 1C level of guidance to following patients up for symptomatic review after 3 months.23 If patients remain symptomatic, then a class 1C level of guidance is given to suggest further coronary angiography for these patients. If patients remain asymptomatic following high-risk PCI (including LMS PCI), then a level of evidence of IIb C is given for routine coronary angiography, or non-invasive stress testing at 6 months, 1 year and 5 years following PCI. In the past, follow-up angiography was recommended (class IIa) between 2 and 6 months after PCI in patients who underwent unprotected left main revascularisation based on the 2005 ACC/American Heart Association PCI guidelines.35 This recommendation was removed in the 2009 focused update.36

Conclusion

Following the recent publication of outcome data from large RCTs, there is now evidence to demonstrate equipoise between PCI and CABG management in patients with LMS disease with a low-to-intermediate SYNTAX score. As well as new-generation DES technologies and more advanced intravascular imaging modalities, this may lead to a change in practice with regard to treating these patients with PCI. This is especially important for the discussion of treatment options with the patient. It is important to consider that we do not have any longer follow-up data from these trials, and this these will be anticipated in the coming years. There is, however, an increase in spontaneous MI seen in PCI patients (both in the NOBLE and EXCEL trials), which at 5 years was balanced by an increase in procedural MIs in CABG patients (in the EXCEL trial), as well as consistent observations of increased repeat revascularisation in PCI patients (in all three trials: SYNTAX, NOBLE and EXCEL). The EXCEL trial is undergoing independent review following the controversy discussed earlier. This controversy has led to loss of patient and public trust, and wide publication and escalation of the concerns in the media. It has also led to a deterioration in the relationship between the PCI community and the cardiothoracic surgical community. With the findings of the independent reviews, it is hoped that these relationships can be restored and strengthened. From the viewpoint of the PCI community, the EXCEL trial has demonstrated significant advances in the outcomes of patients undergoing revascularisation for LMS disease with PCI, and this should still be considered within the forum of the multidisciplinary heart team when discussing optimal revascularisation within this patient group on an individualised basis and with patient involvement.

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EXCEL Trial: The Interventionalists’ Perspective 1. DeMots H, Rösch J, McAnulty JH, Rahimtoola SH. Left main coronary artery disease. Cardiovasc Clin 1977;8:201–11. PMID: 302748. 2. O’Keefe JH Jr, Rutherford BD, McConahay DR, et al. Early and late results of coronary angioplasty without antecedent thrombolytic therapy for acute myocardial infarction. Am J Cardiol 1989;64:1221–30. https://doi.org/10.1016/00029149(89)90558-4; PMID: 2589185. 3. Myers WO, Davis K, Foster ED, et al. Surgical survival in the Coronary Artery Surgery Study (CASS) registry. Ann Thorac Surg 1985;40:245–60. https://doi.org/10.1016/S00034975(10)60037-9; PMID: 3876085. 4. Yusuf S, Zucker D, Peduzzi P, et al. Effect of coronary artery bypass graft surgery on survival: overview of 10-year results from randomised trials by the Coronary Artery Bypass Graft Surgery Trialists Collaboration. Lancet 1994;344:563–70. https://doi.org/10.1016/S0140-6736(94)91963-1; PMID: 7914958. 5. Biondi-Zoccai GG, Lotrionte M, Moretti C, et al. A collaborative systematic review and meta-analysis on 1278 patients undergoing percutaneous drug-eluting stenting for unprotected left main coronary artery disease. Am Heart J 2008;155:274–83. https://doi.org/10.1016/j.ahj.2007.10.009; PMID: 18215597. 6. Lee MS, Kapoor N, Jamal F, et al. Comparison of coronary artery bypass surgery with percutaneous coronary intervention with drug-eluting stents for unprotected left main coronary artery disease. J Am Coll Cardiol 2006;47:864–70. https://doi.org/10.1016/j.jacc.2005.09.072; PMID: 16487857. 7. Seung KB, Park DW, Kim YH, et al. Stents versus coronaryartery bypass grafting for left main coronary artery disease. N Engl J Med 2008;358:1781–92. https://doi.org/10.1056/ NEJMoa0801441; PMID: 18378517. 8. Serruys PW, Morice MC, Kappetein AP, et al. Percutaneous coronary intervention versus coronary-artery bypass grafting for severe coronary artery disease. N Engl J Med 2009;360:961–72. https://doi.org/10.1056/NEJMoa0804626; PMID: 19228612. 9. Sianos G, Morel MA, Kappetein AP, et al. The SYNTAX score: an angiographic tool grading the complexity of coronary artery disease. EuroIntervention 2005;1:219–27. PMID: 19758907. 10. Morice MC, Serruys PW, Kappetein AP, et al. Five-year outcomes in patients with left main disease treated with either percutaneous coronary intervention or coronary artery bypass grafting in the Synergy Between Percutaneous Coronary Intervention with Taxus and Cardiac Surgery trial. Circulation 2014;129:2388–94. https://doi. org/10.1161/CIRCULATIONAHA.113.006689; PMID: 24700706. 11. Thuijs DJFM, Kappetein AP, Serruys PW, et al. Percutaneous coronary intervention versus coronary artery bypass grafting in patients with three-vessel or left main coronary artery disease: 10-year follow-up of the multicentre randomised controlled SYNTAX trial. Lancet 2019;394:1325–34. https:// doi.org/10.1016/S0140-6736(19)31997-X; PMID: 31488373. 12. Buszman PE, Kiesz SR, Bochenek A, et al. Acute and late outcomes of unprotected left main stenting in comparison with surgical revascularization. J Am Coll Cardiol 2008;51:538–45. https://doi.org/10.1016/j.jacc.2007.09.054; PMID: 18237682. 13. Park SJ, Kim YH, Park DW, et al. Randomized trial of stents versus bypass surgery for left main coronary artery disease. N Engl J Med 2011;364:1718–27. https://doi.org/10.1056/ NEJMoa1100452; PMID: 21463149. 14. Boudriot E, Thiele H, Walther T, et al. Randomized comparison of percutaneous coronary intervention with sirolimus-eluting stents versus coronary artery bypass grafting in unprotected left main stem stenosis. J Am Coll Cardiol 2011;57:538–45. https://doi.org/10.1016/j. jacc.2010.09.038; PMID: 21272743. 15. Stone GW, Kappetein AP, Sabik JF, et al. Five-year outcomes after PCI or CABG for left main coronary disease. N Engl J Med 2019;381:1820–30. https://doi.org/10.1056/

NEJMoa1909406; PMID: 31562798. 16. Holm NR, Mäkikallio T, Lindsay MM, et al. Percutaneous coronary angioplasty versus coronary artery bypass grafting in the treatment of unprotected left main stenosis: updated 5-year outcomes from the randomised, non-inferiority NOBLE trial. Lancet 2020;395:191–9. https://doi.org/10.1016/ S0140-6736(19)32972-1; PMID: 31879028. 17. Mäkikallio T, Holm NR, Lindsay M, et al. Percutaneous coronary angioplasty versus coronary artery bypass grafting in treatment of unprotected left main stenosis (NOBLE): a prospective, randomised, open-label, non-inferiority trial. Lancet 2016;388:2743–52. https://doi.org/10.1016/S01406736(16)32052-9; PMID: 27810312. 18. Stone GW, Sabik JF, Serruys PW, et al. Everolimus-eluting stents or bypass surgery for left main coronary artery disease. N Engl J Med 2016;375:2223–35. https://doi. org/10.1056/NEJMoa1610227; PMID: 27797291. 19. Moussa ID, Klein LW, Shah B, et al. Consideration of a new definition of clinically relevant myocardial infarction after coronary revascularization: an expert consensus document from the Society for Cardiovascular Angiography and Interventions (SCAI). J Am Coll Cardiol 2013;62:1563–70. https://doi.org/10.1016/j.jacc.2013.08.720; PMID: 24135581. 20. Thygesen K. ‘Ten commandments’ for the fourth universal definition of myocardial infarction 2018. Eur Heart J 2019;40:226. https://doi.org/10.1093/eurheartj/ehy856; PMID: 30649367. 21. Thygesen K, Alpert JS, Jaffe AS, et al. Third universal definition of myocardial infarction. Circulation 2012;126:2020–35. https://doi.org/10.1161/ CIR.0b013e31826e1058; PMID: 22923432. 22. Moussa ID, Stone GW. Myocardial infarction after percutaneous coronary intervention and coronary artery bypass graft surgery: time for a unifying common definition. JACC Cardiovasc Interv 2017;10:1508–10. https://doi. org/10.1016/j.jcin.2017.06.048; PMID: 28797426. 23. Neumann FJ, Sousa-Uva M, Ahlsson A, et al. 2018 ESC/ EACTS guidelines on myocardial revascularization. Eur Heart J 2019;40:87–165. https://doi.org/10.1093/eurheartj/ehy394; PMID: 30165437. 24. Genereux P, Gersh BJ, Gershlick A, et al. Official response from EXCEL leadership. 12 December 2019. https://www. tctmd.com/slide/official-response-excel-leadership (accessed 29 January 2021). 25. Pagano D. EACTS responds to BBC Newsnight’s investigation on the EXCEL trial. 2019 December. https:// www.eacts.org/eacts-responds-to-bbc-newsnightsinvestigation-on-the-excel-trial (accessed 29 January 2021) 26. Pandya SB, Kim YH, Meyers SN, et al. Drug-eluting versus bare-metal stents in unprotected left main coronary artery stenosis a meta-analysis. JACC Cardiovasc Interv 2010;3:602– 11. https://doi.org/10.1016/j.jcin.2010.03.019; PMID: 20630453. 27. Mehilli J, Richardt G, Valgimigli M, et al. Zotarolimus- versus everolimus-eluting stents for unprotected left main coronary artery disease. J Am Coll Cardiol 2013;62:2075–82. https:// doi.org/10.1016/j.jacc.2013.07.044; PMID: 23973699. 28. Mehilli J, Kastrati A, Byrne RA, et al. Paclitaxel- versus sirolimus-eluting stents for unprotected left main coronary artery disease. J Am Coll Cardiol 2009;53:1760–8. https://doi. org/10.1016/j.jacc.2009.01.035; PMID: 19422982. 29. Naganuma T, Chieffo A, Meliga E, et al. Long-term clinical outcomes after percutaneous coronary intervention for ostial/mid-shaft lesions versus distal bifurcation lesions in unprotected left main coronary artery: the DELTA registry (Drug-Eluting Stent for Left Main Coronary Artery Disease): a multicenter registry evaluating percutaneous coronary intervention versus coronary artery bypass grafting for left main treatment. JACC Cardiovasc Interv 2013;6:1242–9. https://doi.org/10.1016/j.jcin.2013.08.005; PMID: 24355114. 30. Tiroch K, Mehilli J, Byrne RA, et al. Impact of coronary anatomy and stenting technique on long-term outcome after drug-eluting stent implantation for unprotected left main coronary artery disease. JACC Cardiovasc Interv

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2014;7:29–36. https://doi.org/10.1016/j.jcin.2013.08.013; PMID: 24332416. 31. Gershlick AH, Kandzari DE, Banning A, et al. Outcomes after left main percutaneous coronary intervention versus coronary artery bypass grafting according to lesion site: results from the EXCEL trial. JACC Cardiovasc Interv 2018;11:1224–1233. https://doi.org/10.1016/j.jcin.2018.03.040; PMID: 29976358. 32. Maehara A, Mintz G, Serruys P, et al. Impact of final minimal stent area by IVUS on 3-year outcome after PCI of left main coronary artery disease: the EXCEL trial. J Am Coll Cardiol 2017;69(11 Suppl):963. https://doi.org/10.1016/S07351097(17)34352-8. 33. Mintz GS, Nissen SE, Anderson WD, et al. American College of Cardiology clinical expert consensus document on standards for acquisition, measurement and reporting of intravascular ultrasound studies (IVUS). A report of the American College of Cardiology Task Force on Clinical Expert Consensus Documents. J Am Coll Cardiol 2001;37:1478–92. https://doi.org/10.1016/S07351097(01)01175-5; PMID: 11300468. 34. Ladwiniec A, Walsh SJ, Holm NR, et al. Intravascular ultrasound to guide left main stem intervention: a NOBLE trial substudy. EuroIntervention 2020;16:201–9. https://doi. org/10.4244/EIJ-D-19-01003; PMID: 32122821. 35. Smith SC, Feldman TE, Hirshfeld JW, et al. ACC/AHA/SCAI 2005 guideline update for percutaneous coronary intervention--summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/SCAI Writing Committee to Update the 2001 Guidelines for Percutaneous Coronary Intervention). Circulation 2006;113:156–75. https:// doi.org/10.1161/CIRCULATIONAHA.105.170815; PMID: 16391169. 36. Kushner FG, Hand M, Smith SC, et al. 2009 focused updates: ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction (updating the 2004 guideline and 2007 focused update) and ACC/ AHA/SCAI guidelines on percutaneous coronary intervention (updating the 2005 guideline and 2007 focused update): a report of the American College of Cardiology Foundation/ American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2009;54:2205–41. https://doi. org/10.1016/j.jacc.2009.10.015; PMID: 19942100. 37. Fihn SD, Gardin JM, Abrams J, et al. 2012 ACCF/AHA/ACP/ AATS/PCNA/SCAI/STS guideline for the diagnosis and management of patients with stable ischemic heart disease: a report of the American College of Cardiology Foundation/ American Heart Association Task Force on Practice Guidelines, and the American College of Physicians, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. J Am Coll Cardiol 2012;60:e44–164. https://doi.org/j.jacc.2012.07.013; PMID: 2318215. 38. Hillis LD, Smith PK, Anderson JL, et al. 2011 ACCF/AHA guideline for coronary artery bypass graft surgery: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 2011;124:2610–42. https://doi. org/10.1161/CIR.0b013e31823b5fee; PMID: 22064600. 39. Hillis LD, Smith PK, Anderson JL, et al. 2011 ACCF/AHA guideline for coronary artery bypass graft surgery: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 2011;124:e652–735. https://doi.org/10.1161/ CIR.0b013e31823c074e; PMID: 22064599. 40. Spertus JA, Winder JA, Dewhurst TA, et al. Development and evaluation of the Seattle Angina Questionnaire: a new functional status measure for coronary artery disease. J Am Coll Cardiol 1995;25:333–41. https://doi.org/10.1016/07351097(94)00397-9; PMID: 7829785.

APSC Consensus Statements

2020 Asian Pacific Society of Cardiology Consensus Recommendations on the Use of P2Y12 Receptor Antagonists in the Asia-Pacific Region Jack WC Tan,1,2 Derek P Chew,3 Muhamad Ali SK Abdul Kader,4 Junya Ako,5 Vinay K Bahl,6 Mark Chan,7 Kyung Woo Park,8 Praveen Chandra,9 I-Chang Hsieh,10 Do Quang Huan,11 Sofian Johar,12 Dafsah Arifa Juzar,13 Byeong-Keuk Kim,14 Cheol Whan Lee,15 Michael Kang-Yin Lee,16 Yi-Heng Li,17 Wael Almahmeed,18 Eric Oliver Sison,19 Doreen Tan,20 Yu-Chen Wang,21 Shiuan Jong Yeh22 and Gilles Montalescot23,24,25 1. National Heart Centre, Singapore; 2. Sengkang General Hospital, Singapore; 3. College of Medicine and Public Health, Flinders University, Adelaide, Australia; 4. Hospital Pulau Pinang, Penang, Malaysia; 5. Kitasato University and Hospital, Tokyo, Japan; 6. All India Institute of Medical Sciences, New Delhi, India; 7. National University Hospital, Singapore; 8. Seoul National University Hospital Internal Medicine, Seoul, South Korea; 9. Medanta – The Medicity, Gurgaon, India; 10. Chang Gung Memorial Hospital, Taoyuan City, Taiwan; 11. Heart Institute of Ho Chi Minh City, Ho Chi Minh, Vietnam; 12. Ripas Hospital, Brunei; 13. Universitas Indonesia, Jakarta, Indonesia; 14. Yonsei University College of Medicine, Seoul, South Korea; 15. Asan Medical Center, University of Ulsan, Seoul, South Korea; 16. Queen Elizabeth Hospital, Hong Kong, China; 17. National Cheng King University Hospital, Tainan, Taiwan; 18. Cleveland Clinic Abu Dhabi, United Arab Emirates; 19. University of the Philippines-Philippine General Hospital, Manila, Philippines; 20. Khoo Teck Puat Hospital, Singapore; 21. China Medical University Hospital, Taichung City, Taiwan; 22. Taipei Medical University, Taipei, Taiwan; 23. Sorbonne University, Paris, France; 24. ACTION Study Group, France; 25. Pitié-Salpêtrière Hospital (AP-HP), Paris, France

Abstract

The unique characteristics of patients with acute coronary syndrome in the Asia-Pacific region mean that international guidelines on the use of dual antiplatelet therapy (DAPT) cannot be routinely applied to these populations. Newer generation P2Y12 inhibitors (i.e. ticagrelor and prasugrel) have demonstrated improved clinical outcomes compared with clopidogrel. However, low numbers of Asian patients participated in pivotal studies and few regional studies comparing DAPTs have been conducted. This article aims to summarise current evidence on the use of newer generation P2Y12 inhibitors in Asian patients with acute coronary syndrome and provide recommendations to assist clinicians, especially cardiologists, in selecting a DAPT regimen. Guidance is provided on the management of ischaemic and bleeding risks, including duration of therapy, switching strategies and the management of patients with ST-elevation and non-ST-elevation MI or those requiring surgery. In particular, the need for an individualised DAPT regimen and considerations relating to switching, de-escalating, stopping or continuing DAPT beyond 12 months are discussed.

Keywords

P2Y12 inhibitors, Asia-Pacific, acute coronary syndrome, consensus, aspirin, bleeding Disclosure: This work was funded through the Asian Pacific Society of Cardiology by unrestricted educational grants from Abbott Vascular, Amgen, AstraZeneca, Bayer and Roche Diagnostics. JWCT has received honoraria from AstraZeneca, Bayer, Amgen, Medtronic, Abbott Vascular, Biosensors, Orbus Neich, Boehringer Ingelheim and Pfizer; and research grants from Medtronic, Abbott Diagnostics and Beckmann. DPC reports consulting fee from Asian Pacific Society of Cardiology; support for travel to meetings for the study or otherwise from Asian Pacific Society of Cardiology; grants/grants pending from Roche Diagnostics; and payment for development of educational presentations including service on speakers’ bureaus from AstraZeneca. JA reports honoraria from AstraZeneca, Daiichi Sankyo, Bayer and Sanofi; and grants/grants pending from Daiichi Sankyo. MC reports consulting fee/honorarium from AstraZeneca. KWP reports consulting fee from Arnold & Porter LLP. DQH reports consulting fee or honorarium from AstraZeneca; and support for travel to meetings for the study or otherwise from AstraZeneca. SJ reports honorarium from Medtronic; and travel/accommodation expenses from Medtronic and Edward Lifesciences. DAJ reports board membership at Menarini; honorarium from AstraZeneca; and travel/ accommodation expenses from Boston Scientific. DT reports honorarium from The Meeting Lab; and travel/accommodation expenses paid to institution from The Meeting Lab. GM reports research grants to the institution or consulting/lecture fees from Abbott, Amgen, Actelion, American College of Cardiology Foundation, AstraZeneca, Axis-Santé, Bayer, Boston-Scientific, Boehringer Ingelheim, Bristol-Myers Squibb, Beth Israel Deaconess Medical, Brigham Women’s Hospital, Idorsia, Elsevier, Fédération Française de Cardiologie, Frequence Medicale, ICAN, Lead-Up, Medtronic, Menarini, MSD, Pfizer, Quantum Genomics, Sanofi, SCOR global life, Servier and WebMD. All other authors have no conflicts of interest to declare. Acknowledgement: Medical writing support was provided by Ivan Olegario of MIMS Pte Ltd. Received: 20 October 2020 Accepted: 4 November 2020 Citation: European Cardiology Review 2021;16:e02. DOI: https://doi.org/10.15420/ecr.2020.40 Correspondence: Jack Wei Chieh Tan, National Heart Centre, 5 Hospital Dr, Singapore 169609, Singapore. E: jack.tan.w.c@singhealth.com.sg Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

2020 APSC Consensus Recommendations on P2Y12 Inhibitor Use The management of acute coronary syndrome (ACS) varies across the Asia-Pacific region.1 In particular, there is significant heterogeneity regarding the use of reperfusion techniques and pharmacological management.1 For example, thrombolysis is commonly used for reperfusion in China, India and parts of South-East Asia, whereas percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) are more common in Japan, Korea, Taiwan, Australia and New Zealand.1 Dual antiplatelet therapy (DAPT) with a P2Y12 inhibitor and aspirin is generally recommended for at least 1 year following an ACS, or longer for patients with a high ischaemic/low bleeding risk.2,3 However, there is considerable variation in DAPT duration across Asia and a one-size-fits-all approach based on Western guidelines may not be appropriate for Asian populations.4 For example, genetic polymorphisms (i.e. polymorphisms affecting CYP2C19 function) associated with a slower rate of bioactivation of clopidogrel have a substantially higher prevalence in Asian people (29–60%) than Caucasian people (15%).5 Furthermore, the ‘East Asian paradox’ results in a different benefit–risk profile, where the risk of ischaemic events is lower, and bleeding higher, than Western populations, despite higher average on-treatment platelet reactivity.6,7 Nevertheless, data generated from Asian patients are limited and rarely incorporated into major international guidelines. Newer oral therapies have been developed offering faster onset, more potent platelet inhibition and lower response variability than clopidogrel. Ticagrelor, a cyclo-pentyl-triazolo-pyrimidine, has a reversible, directacting mechanism of action that is not impacted by CYP2C19 polymorphisms and prasugrel, a thienopyridine prodrug, is less susceptible to CYP2C19 polymorphisms than clopidogrel.8–11 We aim to summarise key evidence and provide recommendations on the use of P2Y12 inhibitors in Asian patients.

Methods

The Asian Pacific Society of Cardiology (APSC) convened a panel of 22 experts from 13 countries in Asia-Pacific with clinical and research expertise in the use of P2Y12 inhibitors, to develop consensus statements on the use of these class of drugs in ACS patients in the Asia-Pacific region. The experts were members of the APSC who were nominated by national societies and endorsed by the APSC consensus board. After a comprehensive literature search, with particular focus on Asian-centric studies, selected applicable articles were reviewed and appraised using the Grading of Recommendations Assessment, Development, and Evaluation system, as follows: 1. High (authors have high confidence that the true effect is similar to the estimated effect). 2. Moderate (authors believe that the true effect is probably close to the estimated effect). 3. Low (true effect might be markedly different from the estimated effect). 4. Very low (true effect is probably markedly different from the estimated effect).12 The available evidence was then discussed during two consensus meetings. Consensus statements were developed during these meetings, which were then put to an online vote. Each statement was voted on by each panel member using a three-point scale (agree, neutral or disagree). Consensus was reached when 80% of votes for a statement were agree or neutral. In the case of non-consensus, the statements were further

discussed using email, then revised accordingly until the criteria for consensus was reached.

Results and Discussion

The efficacy and safety of ticagrelor was demonstrated in the Study of Platelet Inhibition and Patient Outcomes (PLATO), which enrolled more than 18,500 patients with an ACS.13 The risk of cardiovascular (CV) death, MI or stroke with ticagrelor decreased by 16% compared with clopidogrel after 12 months, with benefit being observed within 30 days and accruing throughout the study period. Notably, ticagrelor reduced the risk of both CV death and recurrent non-fatal MI versus clopidogrel. The PEGASUS-TIMI 54 study subsequently demonstrated a benefit when extending ticagrelor-based DAPT for up to 3 years.14 No difference in PLATO- or TIMI-defined major bleeding was observed between ticagrelor or clopidogrel in the PLATO study, but non-CABGrelated and TIMI-defined major bleeding was significantly increased in PLATO and PEGASUS-TIMI 54, respectively.13,14 Ticagrelor was also associated with an increased risk of dyspnoea.13 No interaction between Asian/non-Asian ethnicity and efficacy was observed in PLATO.15 However, the overall event rate was higher in Asian patients, despite a similar bleeding risk.15 Southeast Asian patients also appeared to experience higher rates of ischaemic events and bleeding than East Asian patients.15 Two randomised but underpowered studies, PHILO and TICA KOREA, compared ticagrelor versus clopidogrel in Asian patients.16,17 The risk of bleeding and ischaemic events was increased among East Asian patients with ACS from Japan, Taiwan, and South Korea in PHILO.16 Likewise, in TICA KOREA, the incidence of clinically significant bleeding was significantly higher with ticagrelor versus clopidogrel among Koreans hospitalised for ACS with planned invasive management, while the incidence of CV death, MI, or stroke was also numerically higher in the ticagrelor arm.17 TRITON-TIMI 38 compared prasugrel with clopidogrel in patients with an ACS scheduled to undergo PCI; prasugrel reduced the risk of CV death, MI or stroke by 19% compared with clopidogrel, but the incidence of nonCABG-related TIMI major and life-threatening bleeding were significantly increased.18 As a result, a reduced 5 mg dose is indicated for patients aged ≥75 years or with body weight <60 kg, and prasugrel is contraindicated for those with a history of stroke or transient ischaemic attacks.8 The PRASFIT-ACS study on Japanese patients with ACS undergoing PCI is the only randomised trial comparing the outcomes with prasugrel and clopidogrel in an exclusively Asian population.19 Notably, patients were administered markedly lower doses of prasugrel (20 mg loading/3.75 mg daily maintenance dosing), yet the incidence of CV death, MI or stroke was reduced by 23% at 24 weeks without significantly increasing nonCABG-related major bleeding. While the reduced risk of ischaemic events was not statistically significantly different, the result was comparable with the TRITON-TIMI 38 trial, although follow-up was shorter.18,19 Only one randomised head-to-head comparison of prasugrel and ticagrelor has been performed – the Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment (ISARREACT) 5 trial.20 In this open-label study the risk of CV death, MI, or stroke was 36% higher with ticagrelor than prasugrel at 1 year (9.3% versus 6.9%;

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2020 APSC Consensus Recommendations on P2Y12 Inhibitor Use p=0.006), while rates of major bleeding were similar.20 However, this result must be interpreted with caution because of the open-label design, high rate of drug discontinuation, an unexpectedly low rate of MI in the prasugrel arm and allowance for telephone follow-up of participants.20 No head-to-head studies comparing ticagrelor and prasugrel have been performed in Asian patients. Overall, DAPT incorporating ticagrelor or prasugrel, instead of clopidogrel, reduces the risk of ischaemic events, but may increase the risk of bleeding.13,18 However, studies of ticagrelor and prasugrel have largely been performed in Western populations that may have a differing risk profile for both ischaemic and bleeding events versus Asian patients. Therefore, targeted guidance for physicians prescribing ticagrelor or prasugrel to Asian patients with an ACS are necessary.

Figure 1: Treatment Algorithm for Patients with STEMI STEMI patient eligible for reperfusion therapy

For thrombolysis

Take to cardiac catheterisation laboratory for primary PCI

DAPT regimen with aspirin and: First choice: ticagrelor/prasugrel Second choice: clopidogrel

If switching from clopidogrel to ticagrelor, delay for at least 8 hours, or until the next day

DAPT for 12 months

ST-elevation Acute Coronary Syndrome Statement 1. A 12-month duration of therapy for ticagrelor (180 mg loading and 90 mg twice-daily maintenance dose) and prasugrel (60 mg loading and 10 mg daily) are effective and safe in the prevention of adverse cardiovascular events among patients with ST-elevation MI (STEMI) and are recommended in patients who are undergoing primary PCI. Level of evidence: High. Level of agreement: 100% agree, 0% neutral, 0% disagree. Statement 2. If aspirin and clopidogrel are introduced early in thrombolysis, a switch to ticagrelor should be considered the next day or after 8 hours. Level of evidence: High. Level of agreement: 90.9% agree, 9.1% neutral, 0% disagree. Both ticagrelor and prasugrel significantly reduce the risk of CV death, MI or stroke in patients with an ST-elevation ACS (STE-ACS) versus clopidogrel.21,22 However, ticagrelor and prasugrel have not been extensively studied in Asian patients with STE-ACS, so the use of clopidogrel should not be disregarded. Antiplatelet therapy should be initiated upon diagnosis of STE-ACS, ideally before or while a patient is being transported to the hospital for primary PCI, in the absence of contraindications (e.g. severe bleeding; Figure 1).2,3 Prehospital administration of ticagrelor (i.e. in transit) to patients presenting with an STE-ACS is possible, but does not offer significant benefits beyond a reduced risk of stent thrombosis.23 Aspirin (300 mg or 325 mg loading dose and 75 mg or 81–100 mg maintenance dose) should be initiated for all STE-ACS patients prior to or at hospital presentation.2,3 For patients initially managed using thrombolysis, US and European guidelines recommend administering clopidogrel immediately, because ticagrelor was administered >24 hours after a STE-ACS in the PLATO study.2,24 The European guidelines note switching from clopidogrel to prasugrel or ticagrelor may be considered after 48 hours for patients who receive fibrinolysis and subsequently undergo PCI.24 No significant differences in the rate of TIMI major bleeding after 30 days in patients have been observed in STEMI patients treated with ticagrelor or clopidogrel after undergoing fibrinolysis in an approximately 8-hour/ next-day timeframe.25 Likewise, rates of major bleeding were similar after 12 months, indicating that early switching from clopidogrel to ticagrelor

Provide written and verbal information, advice, support and treatment on related conditions and secondary prevention (including lifestyle advice), as relevant. In select patients, consider extending DAPT. DAPT = dual antiplatelet therapy; PCI = percutaneous coronary intervention; STEMI = ST-elevation MI.

after fibrinolysis is feasible.26 The use of prasugrel after fibrinolysis for STEMI has not been well studied, so no recommendation is made.

Non-ST-elevation Acute Coronary Syndrome Statement 3. Ticagrelor (180 mg loading and 90 mg twice daily maintenance dose) is recommended in patients with non-STelevation ACS (NSTE-ACS). In patients receiving an early invasive strategy (<12 hours), pre-treatment may not be mandated. Level of evidence: High. Level of agreement: 100% agree, 0.0% neutral, 0.0% disagree. Statement 4. Prasugrel (60 mg loading and 10 mg daily) is recommended only in patients who have undergone percutaneous coronary intervention. In countries where a reduced loading or maintenance dose is approved, a reduced dose may be considered. Pre-treatment is not recommended. Level of evidence: High. Level of agreement: 100% agree, 0% neutral, 0% disagree. Statement 5. Unless bleeding risk is high, a minimum of 6 months of DAPT is recommended to reduce ischaemic risk in NSTE-ACS. Level of evidence: Moderate. Level of agreement: 86.4% agree, 4.5% neutral, 9.1% disagree. This consensus statement recommends the use of P2Y12 inhibitors as part of DAPT as a cornerstone intervention for NSTE-ACS (Figure 2), in a similar manner to Western guidelines.27 The efficacy and safety profile of ticagrelor in patients with NSTE-ACS is consistent with the overall PLATO study population.28 While a study in Chinese patients with NSTE-ACS undergoing PCI suggested that doubling the ticagrelor loading dose may achieve faster onset of platelet inhibition without an increase in adverse events, this is unlikely to be associated with a clinically meaningful benefit and is inconsistent with the approved ticagrelor label.9,10,29

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2020 APSC Consensus Recommendations on P2Y12 Inhibitor Use Figure 2: Treatment Algorithm for Patients with NSTEMI Patients with NSTEMI already initiated on aspirin

Ischaemia-guided strategy: • Ticagrelor*† • Clopidogrel† Prasugrel is not recommended

Early coronary angiography/ early invasive strategy: • First choice: ticagrelor*† • Second choice: prasugrel† • Third choice: clopidogrel†

Follow-up antiplatelet therapy: 1. Aspirin indefinitely 2. Discontinue ticagrelor or clopidogrel 5 days, and prasugrel 7 days, before CABG for patients undergoing revascularisation 3. Ticagrelor/prasugrel (or clopidogrel as second choice) for up to 12 months Prasugrel is not indicated for medically treated patients with ACS

*Recommendations for ticagrelor in patients with NSTEMI are based on the PLATO subgroup analysis examining patients presenting with NSTE-ACS, which included patients with NSTEMI and other ACS without ST-elevation.28 †Please refer to local prescribing information for dosing recommendations. ACS = acute coronary syndrome; CABG = coronary artery bypass graft; NSTE-ACS = non-ST-elevation ACS; NSTEMI = non-ST-elevation MI.

No benefit has been observed versus placebo when initiating P2Y12 antiplatelet therapy when invasive procedures for ACS are planned within 12 hours of presentation, so routine pre-treatment prior to early invasive intervention is not mandated.30 The efficacy and safety of prasugrel was only investigated in patients who underwent PCI in TRITON-TIMI 38, and the approved indication has been limited accordingly.8,11,18 Reduced prasugrel dosing (20 mg loading/3.75 mg daily maintenance dosing) has demonstrated improved efficacy compared with clopidogrel in Japanese patients with ACS without significantly increasing non-CABG-related major bleeding, supporting lower indicated dosing in some Asian countries.19 Prasugrel pre-treatment prior to invasive procedures is not recommended because of the increased risk of bleeding without reducing the risk of ischaemic events.31 A net clinical benefit is expected for all patient groups with at least 6 months of DAPT after an ACS.32 However, for patients with a high risk of bleeding, the reduced risk of ischaemic events needs to be weighed against the risk of bleeding after 6 months.32 Furthermore, as pointed out by some panellists, the DAPT study evaluated a treatment duration of at least 12 months.

Bleeding Risk Statement 6. There is no specific bleeding risk calculator recommended for use in Asian populations. Level of evidence: Very low. Level of agreement: 95.5% agree, 4.5% neutral, 0.0% disagree. Statement 7. Ticagrelor or prasugrel in combination with aspirin should be considered as first-line for NSTE-ACS patients at high risk of ischaemia, unless patient has prior history of bleeding or is above 85 years old. Adjust the duration of therapy based on bleeding risk. Level of evidence: Low. Level of agreement: 72.8% agree, 0.0% neutral, 13.6% disagree.

Statement 8. Proton pump inhibitors (PPIs) may be considered for use in patients with high risk of bleeding. However, other causes of bleeding or anaemia should be investigated. Level of evidence: Moderate. Level of agreement: 100.0% agree, 0.0% neutral, 0.0% disagree. Statement 9. A radial access should be considered as default strategy for patients undergoing catheterisation. Level of evidence: High. Level of agreement: 95.5% agree, 4.5% neutral, 0.0% disagree. Statement 10. Among patients on DAPT who are scheduled to undergo non-cardiac surgery, consider the risk associated with stopping DAPT or continuing aspirin alone versus delaying surgery until completion of 6 months of DAPT post-MI. A joint discussion between cardiologist and proceduralist regarding the risk of bleeding versus an ischaemic event following cessation of DAPT should be considered. Stop ticagrelor and clopidogrel 5 days, and prasugrel 7 days, prior to surgery. Level of evidence: Moderate. Level of agreement: 95.5% agree, 4.5% neutral, 0.0% disagree. A recommendation for a specific bleeding risk score was not recommended in Asia because there is no validated bleeding risk calculator for Asian patients. Post-ACS bleeding risk tends to be overestimated compared with ischaemic risk in Asian patients.33 Therefore, an individualised assessment of the benefit-risk ratio of DAPT should be performed on the basis of a patient’s medical history, physical examination, and laboratory parameters. Both ticagrelor and prasugrel have demonstrated improved efficacy versus clopidogrel in patients with ACS undergoing revascularisation, although some panellists have highlighted that the data for prasugrel is only for PCI.18,34,35 No difference in the risk of major bleeding was observed between ticagrelor and clopidogrel in the Asian subgroup analysis of the PLATO study or in several real-world comparisons in Asian populations.15,36–38 However, other studies have suggested there is an increased risk of major bleeding with ticagrelor compared with clopidogrel in East Asian patients.16,17,39–43 The risk of bleeding with prasugrel has also been reported to be higher than for clopidogrel in Korean patients.44 The risk of any bleeding has been reported as being comparable between ticagrelor and prasugrel in East Asian patients.43 Therefore, duration of therapy should be based on a perceived on-going net clinical benefit. No increase in the risk of bleeding or ischaemic events has been observed in patients administered ticagrelor or prasugrel versus clopidogrel alongside a PPI.45–47 However, PPI administration is associated with lower clopidogrel active metabolite levels and ex vivo-measured platelet inhibition.48 Bleeding complications may also be reduced with the use of a transradial access during PCI. A 2020 meta-analysis that included 18 randomised controlled trials (n=21,669) found that among patients with ACS who have undergone PCI, transradial access decreased the risk of major bleeding by 38% (p<0.001) compared to a transfemoral route.49 Radial access was also associated with a 25% lower risk of all-cause mortality (p=0.002). Both results were consistent across subgroups except in those that used bivalirudin as an anticoagulant, wherein no benefit was seen for major bleeding or mortality.

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2020 APSC Consensus Recommendations on P2Y12 Inhibitor Use DAPT should not be stopped within 4 weeks of stenting unless it is for critical surgery. The ischaemic versus bleeding risk in patients treated with DAPT undergoing surgery must be weighed during pre-surgery discussions between the cardiologist and the proceduralist. The Food and Drug Administration (FDA) and European Medicines Agency (EMA)-approved label states that ticagrelor should be stopped for up to 5 days prior to elective surgery.9, 10 While the European Society of Cardiology 2017 guidelines recommend stopping treatment up to 3 days prior to surgery based on the results of the ONSET/OFFSET study, the panel does not support this recommendation because it is based on a single study.3,50 Clopidogrel and prasugrel treatment should be stopped 5 and 7 days before surgery, respectively.3

Switching Antiplatelet Therapy Statement 11. Clinicians must evaluate reasons for de-escalation and weigh these against the risk of a possible ischaemic event. If de-escalation is necessary, this should be delayed for as long as possible (at least 1 month, but preferably >3 months after the ACS event) as risk of ischaemic events in revascularised patients decreases over time. Level of evidence: Low. Level of agreement: 86.4% agree, 13.7% neutral, 4.5% disagree. Statement 12. Regardless of time frame, reloading is required when switching from ticagrelor or prasugrel to clopidogrel unless there is on-going bleeding. Level of evidence: Very low. Level of agreement: 81.9% agree, 4.5% neutral, 13.6% disagree. DAPT should be continued for a minimum of 12 months, unless contraindicated or not tolerated.2,3 De-escalation (change from ticagrelor or prasugrel to clopidogrel) may be required due to major bleeding, ambiguity surrounding dose requirements for elderly patients/patients with low body weight using prasugrel, or cost.51–53 De-escalation of ticagrelor or prasugrel to clopidogrel may reduce the risk of bleeding without compromising efficacy.54 However, observational data from Asian patients have suggested that de-escalating DAPT in the absence of platelet-function-testing-guided clopidogrel dosing may increase the risk of ischaemic events without reducing bleeding risk.38,51,53,55 If de-escalation to clopidogrel is necessary, de-escalation should be delayed as long as possible, preferably until >3 months after an ACS, and avoided <1 month after the event,56 because of the time-dependent decrease in the risk of ischaemic events following an ACS. Data from patients who de-escalate DAPT is limited and a consensus on a de-escalation strategy has not been reached in the literature. To guide practice despite the lack of strong evidence, the panel consensus is to consider a 600 mg loading dose of clopidogrel when de-escalating from ticagrelor to clopidogrel, irrespective of time from ACS. However, directly de-escalating to a 75 mg daily maintenance dose of clopidogrel is reasonable when de-escalation is due to bleeding.57

Long-term Versus Short-term Dual Antiplatelet Therapy Statement 13. The standard duration of DAPT is 12 months after an ACS. Extension of DAPT beyond 1 year may be considered for high ischaemic-risk patients, such as those with high-risk stent anatomy, complex coronary anatomy or additional risk factors (e.g. diabetes). Clinicians must evaluate both ischaemic and bleeding risk. Level of evidence: High. Level of agreement: 85.5% agree, 0.0% neutral, 4.5% disagree. Continuing DAPT with clopidogrel beyond 12 months has been shown to decrease the risk of ischaemic events, including CV death, among highrisk patients with a history of MI versus aspirin alone, but is associated with an increased risk of major bleeding.58 Similar outcomes when continuing DAPT with ticagrelor (60 or 90 mg) beyond 12 months were reported in the PEGASUS-TIMI 54 trial, although there was no significant increase in the rate of fatal bleeding or intracranial haemorrhage.14 The FDA and EMA licensed the use of ticagrelor 60 mg from 12–36 months because of its comparable efficacy but lower risk of bleeding versus a 90-mg dose.9,10 DAPT using ticagrelor 60 mg beyond 12 months has also demonstrated a benefit compared with placebo in patients with concomitant multivessel disease or diabetes.59,60

Genotyping, CYP2C19 Polymorphisms and Platelet Function Testing Statement 14. Due to the lack of positive prospective trials in Asian patients, the routine use of point-of-care platelet function testing to guide decisions in antiplatelet therapy is not recommended. Level of evidence: Very low. Level of agreement: 100% agree, 0.0% neutral, 0.0% disagree. Patients with a CYP2C19 poor metaboliser phenotype may not achieve adequate platelet inhibition with the CYP219-dependent prodrug clopidogrel.5 In contrast, ticagrelor and prasugrel are not dependent on CYP2C19 bioactivation,5 but differences in bioactivation alone do not fully account for the reduced risk of ischaemic events with ticagrelor versus clopidogrel.61 CYP2C19 polymorphism-guided antiplatelet prescribing may improve clinical outcomes for patients with ACS and offers a cost-effective approach to treatment.62–64 Point-of-care platelet function testing may also act as a surrogate marker for CYP2C19 polymorphisms for patients administered clopidogrel.65 Nonetheless, despite the high prevalence of CYP2C19 polymorphisms in the Asia-Pacific region, routine use of genotype-guided DAPT is not recommended because of the lack of prospective randomised trials performed in the Asia-Pacific region demonstrating a clinical benefit, though further research is warranted.5,65,66

Special Populations Statement 15. Ticagrelor has been shown to be effective and safe among specific populations (diabetes, elderly and chronic kidney disease [CKD]) with ACS. Level of evidence: Moderate. Level of agreement: 89.9% agree, 9.1% neutral, 0.0% disagree.

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2020 APSC Consensus Recommendations on P2Y12 Inhibitor Use Caution and clinical judgment must be exercised when using DAPT in patients with comorbidities associated with an increased risk of ischaemic events and/or bleeding, such as diabetes or CKD, and in elderly patients (age >75 years).67–69 No dose adjustment is required for ticagrelor.9,10 A reduced 5 mg daily dose of prasugrel is required for patients weighing <60 kg and prasugrel is not recommended for patients aged ≥75 years.8,67–69

Future Directions

Spontaneous major bleeding and bleeding associated with urgent invasive procedures remain concerns for patients administered DAPT following an ACS. In particular, the antiplatelet effects of ticagrelor cannot be reversed with platelet transfusion.70 A candidate reversal agent is PB2452 (PhaseBio Pharmaceuticals), a monoclonal antibody fragment that binds ticagrelor, is under investigation and has demonstrated immediate and sustained reversal of the antiplatelet effects of ticagrelor in a phase 1 study.70 Efforts to prospectively investigate the efficacy and safety of CYP2C19 polymorphism-guided antiplatelet prescribing in Asia, and subsequent cost-effectiveness analyses, would be welcomed given the economic considerations that drive antiplatelet prescribing in the region. 1. Chan MY, Du X, Eccleston D, et al. Acute coronary syndrome in the Asia-Pacific region. Int J Cardiol 2016;202:861–9. https://doi.org/10.1016/j.ijcard.2015.04.073; PMID: 26476044. 2. Levine GN, Bates ER, Bittl JA, et al. 2016 ACC/AHA guideline focused update on duration of dual antiplatelet therapy in patients with coronary artery disease. Circulation 2016;134:e123–55. https://doi.org/10.1161/ cir.0000000000000404; PMID: 27026020. 3. Valgimigli M, Bueno H, Byrne RA, et al. 2017 ESC focused update on dual antiplatelet therapy in coronary artery disease developed in collaboration with EACTS: the Task Force for dual antiplatelet therapy in coronary artery disease of the European Society of Cardiology (ESC) and of the European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J 2018;39:213–60. https://doi.org/10.1093/ eurheartj/ehx419; PMID: 28886622. 4. Jeong YH. “East Asian Paradox”: challenge for the current antiplatelet strategy of “one-guideline-fits-all races” in acute coronary syndrome. Curr Cardiol Rep 2014;16:485. https://doi. org/10.1007/s11886-014-0485-4; PMID: 24668607. 5. Scott SA, Sangkuhl K, Gardner EE, et al. Clinical Pharmacogenetics Implementation Consortium guidelines for cytochrome P450-2C19 (CYP2C19) genotype and clopidogrel therapy. Clin Pharmacol Ther 2011;90:328–32. https://doi.org/10.1038/clpt.2011.132; PMID: 21716271. 6. Kang J, Park KW, Palmerini T, et al. Racial differences in ischaemia/bleeding risk trade-off during anti-platelet therapy: individual patient level landmark meta-analysis from seven RCTs. Thromb Haemost 2019;119:149–62. ttps:// doi.org/10.1055/s-0038-1676545; PMID: 30597509. 7. Misumida N, Ogunbayo GO, Kim SM, et al. higher risk of bleeding in asians presenting with ST-segment elevation myocardial infarction: analysis of the National Inpatient Sample Database. Angiology 2018;69:548-54. https://doi. org/10.1177/0003319717730168; PMID: 28905638. 8. EFFIENT (prasugrel) tablets. Highlights of prescribing information. FDA. 2009. https://www.accessdata.fda.gov/ drugsatfda_docs/label/2011/022307s003lbl.pdf (accessed 16 November 2020). 9. BRILINTA (ticagrelor) tablets, for oral use. Highlights of prescribing information. FDA. 2016. https://www.accessdata. fda.gov/drugsatfda_docs/label/2016/022433s020lbl.pdf (accessed 16 November 2020). 10. Brilique 60 mg film-coated tablets. Summary of product characteristics. European Medicines Agency. 2019. https:// www.ema.europa.eu/en/documents/product-information/ brilique-epar-product-information_en.pdf (accessed 16 November 2020). 11. Efient 10 mg film-coated tablets. Efient 5 mg film-coated tablets. Summary of product characteristics. European Medicines Agency. 2019. https://www.ema.europa.eu/en/ documents/product-information/efient-epar-productinformation_en.pdf (accessed 16 November 2020). 12. Balshem H, Helfand M, Schünemann HJ, et al. GRADE guidelines: 3. Rating the quality of evidence. J Clin Epidemiol 2011;64:401–6. https://doi.org/10.1016/j.jclinepi.2010.07.015; PMID: 21208779.

Limitations

The breadth of literature on the role of ticagrelor, prasugrel, and clopidogrel in ACS is diverse and these consensus recommendations are not exhaustive and are based on the best available evidence at the time of publication. The consensus statements are not intended to replace clinical judgement. Furthermore, the use of P2Y12 inhibitors in patients receiving oral anticoagulants due to concomitant AF was not discussed, and is discussed in another consensus document.

Conclusion

When managing Asian patients who have had an ACS with DAPT, there are different considerations compared with those for Western populations. While data from Asian populations comparing outcomes with ticagrelor, prasugrel, and clopidogrel are limited, there is evidence to suggest that ticagrelor or prasugrel should be preferred over clopidogrel for most patients with ACS, particularly those who have undergone PCI. The decision on duration of DAPT – including the need to de-escalate, stop or continue therapy beyond 12 months – should be individualised, considering both the ischaemic and bleeding risk for each patient.

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24. Ibanez B, James S, Agewall S, et al. 2017 ESC guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: the Task Force for the management of acute myocardial infarction in patients presenting with ST-segment elevation of the European Society of Cardiology (ESC). Eur Heart J 2018;39:119–77. https://doi.org/10.1093/eurheartj/ehx393; PMID: 28886621. 25. Berwanger O, Nicolau JC, Carvalho AC, et al. Ticagrelor vs clopidogrel after fibrinolytic therapy in patients with ST-elevation myocardial infarction: a randomized clinical trial. JAMA Cardiol 2018;3:391–9. https://doi.org/10.1001/ jamacardio.2018.0612; PMID: 29525822. 26. Berwanger O, Lopes RD, Moia DDF, et al. Ticagrelor versus clopidogrel in patients with STEMI treated with fibrinolysis: TREAT Trial. J Am Coll Cardiol 2019;73:2819–28. https://doi. org/10.1016/j.jacc.2019.03.011; PMID: 30898608. 27. Collet JP, Thiele H, Barbato E, et al. 2020 ESC guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation. Eur Heart J 2020. https://doi.org/10.1093/eurheartj/ehaa575; PMID: 32860058; epub ahead of press. 28. Lindholm D, Varenhorst C, Cannon CP, et al. Ticagrelor vs. clopidogrel in patients with non-ST-elevation acute coronary syndrome with or without revascularization: results from the PLATO trial. Eur Heart J 2014;35:2083–93. https://doi. org/10.1093/eurheartj/ehu160; PMID: 24727884. 29. Liu HL, Wei YJ, Ding P, et al. Antiplatelet effect of different loading doses of ticagrelor in patients with non-ST-elevation acute coronary syndrome undergoing percutaneous coronary intervention: the APELOT Trial. Can J Cardiol 2017;33:1675–82. https://doi.org/10.1016/j.cjca.2017.09.002; PMID: 29173606. 30. Valgimigli M. Pretreatment with P2Y12 inhibitors in non-STsegment-elevation acute coronary syndrome is clinically justified. Circulation 2014;130:1891–903. https://doi. org/10.1161/CIRCULATIONAHA.114.011319; PMID: 25403595. 31. Montalescot G, Bolognese L, Dudek D, et al. Pretreatment with prasugrel in non-ST-segment elevation acute coronary syndromes. N Engl J Med 2013;369:999–1010. https://doi. org/10.1056/NEJMoa1308075; PMID: 23991622. 32. Wilson SJ, Newby DE, Dawson D, et al. Duration of dual antiplatelet therapy in acute coronary syndrome. Heart 2017;103:573. https://doi.org/10.1136/heartjnl-2016-309871; PMID: 29713989. 33. Liu R, Lyu SZ, Zhao GQ, et al. Comparison of the performance of the CRUSADE, ACUITY-HORIZONS, and ACTION bleeding scores in ACS patients undergoing PCI: insights from a cohort of 4939 patients in China. J Geriatr Cardiol 2017;14:93-9. https://doi.org/10.11909/j.issn.16715411.2017.02.011; PMID: 28491083. 34. Held C, Asenblad N, Bassand JP, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes undergoing coronary artery bypass surgery: results from the PLATO (Platelet Inhibition and Patient Outcomes) trial. J Am Coll Cardiol 2011;57:672–84. https://doi.org/10.1016/j. jacc.2010.10.029; PMID: 21194870. 35. Cannon CP, Harrington RA, James S, et al. Comparison of

2020 APSC Consensus Recommendations on P2Y12 Inhibitor Use ticagrelor with clopidogrel in patients with a planned invasive strategy for acute coronary syndromes (PLATO): a randomised double-blind study. Lancet 2010;375:283–93. https://doi.org/10.1016/S0140-6736(09)62191-7; PMID: 20079528. 36. Chen IC, Lee CH, Fang CC, et al. Efficacy and safety of ticagrelor versus clopidogrel in acute coronary syndrome in Taiwan: a multicenter retrospective pilot study. J Chin Med Assoc 2016;79:521–30. https://doi.org/10.1016/j. jcma.2016.02.010; PMID: 27339180. 37. Lee CH, Cheng CL, Kao Yang YH, et al. Cardiovascular and bleeding risks in acute myocardial infarction newly treated with ticagrelor vs. clopidogrel in Taiwan. Circ J 2018;82:747– 56. https://doi.org/10.1253/circj.CJ-17-0632; PMID: 29081474. 38. Kim C, Shin DH, Hong SJ, et al. One-year clinical outcomes of ticagrelor compared with clopidogrel after percutaneous coronary intervention in patients with acute myocardial infarction: from Korean health insurance review and assessment data. J Cardiol 2019;73:191–7. https://doi. org/10.1016/j.jjcc.2018.08.005; PMID: 30770037. 39. Park KH, Jeong MH, Ahn Y, et al. Comparison of short-term clinical outcomes between ticagrelor versus clopidogrel in patients with acute myocardial infarction undergoing successful revascularization; from Korea Acute Myocardial Infarction Registry – National Institute of Health. Int J Cardiol 2016;215:193–200. https://doi.org/10.1016/j. ijcard.2016.04.044; PMID: 27128530. 40. Wang HY, Li Y, Xu XM, et al. impact of baseline bleeding risk on efficacy and safety of ticagrelor versus clopidogrel in chinese patients with acute coronary syndrome undergoing percutaneous coronary intervention. Chin Med J (Engl) 2018;131:2017–24. https://doi.org/10.4103/03666999.239306; PMID: 30127210. 41. Wu B, Lin H, Tobe RG, et al. Ticagrelor versus clopidogrel in East-Asian patients with acute coronary syndromes: a metaanalysis of randomized trials. J Comp Eff Res 2018;7:281–91. https://doi.org/10.2217/cer-2017-0074; PMID: 29094604. 42. Misumida N, Aoi S, Kim SM, et al. Ticagrelor versus clopidogrel in East Asian patients with acute coronary syndrome: systematic review and meta-analysis. Cardiovasc Revasc Med 2018;19:689–94. https://doi.org/10.1016/j. carrev.2018.01.009; PMID: 29452843. 43. Yun JE, Kim YJ, Park JJ, et al. Safety and effectiveness of contemporary P2Y12 inhibitors in an East Asian population with acute coronary syndrome: a nationwide populationbased cohort study. J Am Heart Assoc 2019;8:e012078. https://doi.org/10.1161/jaha.119.012078; PMID: 31310570. 44. Kang J, Han JK, Ahn Y, et al. Third-generation P2Y12 inhibitors in East Asian acute myocardial infarction patients: a nationwide prospective multicentre study. Thromb Haemost 2018;118:591–600. https://doi.org/10.1055/s-0038-1626697; PMID: 29534250. 45. Goodman SG, Clare R, Pieper KS, et al. Association of proton pump inhibitor use on cardiovascular outcomes with clopidogrel and ticagrelor: insights from the platelet inhibition and patient outcomes trial. Circulation 2012;125:978–86. https://doi.org/10.1161/ circulationaha.111.032912; PMID: 22261200. 46. Jackson LR, 2nd, Peterson ED, McCoy LA, et al. impact of proton pump inhibitor use on the comparative effectiveness and safety of prasugrel versus clopidogrel: insights from the treatment with adenosine diphosphate receptor inhibitors: longitudinal assessment of treatment patterns and events after acute coronary syndrome (TRANSLATE-ACS) Study. J

Am Heart Assoc 2016;5. https://doi.org/10.1161/ jaha.116.003824; PMID: 27792656. 47. Yan Y, Wang X, Fan JY, et al. Impact of concomitant use of proton pump inhibitors and clopidogrel or ticagrelor on clinical outcomes in patients with acute coronary syndrome. J Geriatr Cardiol 2016;13:209–17. https://doi.org/10.11909/j. issn.1671-5411.2016.03.007; PMID: 27103915. 48. Scott SA, Owusu Obeng A, Hulot JS. Antiplatelet drug interactions with proton pump inhibitors. Expert Opin Drug Metab Toxicol 2014;10:175–89. https://doi.org/10.1517/1742525 5.2014.856883; PMID: 24205916. 49. Shah R, Khan S, Rashid A, et al. An updated meta-analysis of radial versus femoral access for percutaneous coronary intervention in the context of aggressive bleeding avoidance strategies. Cardiovasc Revasc Med 2020;21:242–4. https://doi.org/10.1016/j.carrev.2019.08.079; PMID: 31492625. 50. Gurbel PA, Bliden KP, Butler K, et al. Randomized doubleblind assessment of the ONSET and OFFSET of the antiplatelet effects of ticagrelor versus clopidogrel in patients with stable coronary artery disease: the ONSET/ OFFSET study. Circulation 2009;120:2577–85. https://doi. org/10.1161/circulationaha.109.912550; PMID: 19923168. 51. Han YL. De-escalation of anti-platelet therapy in patients with acute coronary syndromes undergoing percutaneous coronary intervention: a narrative review. Chin Med J (Engl) 2019;132:197–210. https://doi.org/10.1097/ cm9.0000000000000047; PMID: 30614864. 52. Kupka D, Sibbing D. De-escalation of P2Y12 receptor inhibitor therapy after acute coronary syndromes in patients undergoing percutaneous coronary intervention. Korean Circ J 2018;48:863–72. https://doi.org/10.4070/kcj.2018.0255; PMID: 30238704. 53. Li XY, Su GH, Wang GX, et al. Switching from ticagrelor to clopidogrel in patients with ST-segment elevation myocardial infarction undergoing successful percutaneous coronary intervention in real-world China: occurrences, reasons, and long-term clinical outcomes. Clin Cardiol 2018;41:1446–54. https://doi.org/10.1002/clc.23074; PMID: 30225843. 54. Cuisset T, Deharo P, Quilici J, et al. Benefit of switching dual antiplatelet therapy after acute coronary syndrome: the TOPIC (Timing Of Platelet Inhibition after acute Coronary syndrome) randomized study. Eur Heart J 2017;38:3070–8. https://doi.org/10.1093/eurheartj/ehx175; PMID: 28510646. 55. Liu L, Liao H, Zhong S, et al. Effects of switching ticagrelor to clopidogrel on cardiovascular outcomes in patients with acute coronary syndrome. Medicine (Baltimore) 2018;97:e13381. https://doi.org/10.1097/ md.0000000000013381; PMID: 30508934. 56. Kim HS, Kang J, Hwang D, et al. Prasugrel-based de-escalation of dual antiplatelet therapy after percutaneous coronary intervention in patients with acute coronary syndrome (HOST-REDUCE-POLYTECH-ACS): an open-label, multicentre, non-inferiority randomised trial. Lancet 2020;396:1079–89. https://doi.org/10.1016/S01406736(20)31791-8; PMID: 32882163. 57. Angiolillo DJ, Rollini F, Storey RF, et al. international expert consensus on switching platelet P2Y12 receptor-inhibiting therapies. Circulation 2017;136:1955–75. https://doi. org/10.1161/circulationaha.117.031164; PMID: 29084738. 58. Udell JA, Bonaca MP, Collet JP, et al. Long-term dual antiplatelet therapy for secondary prevention of cardiovascular events in the subgroup of patients with

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previous myocardial infarction: a collaborative meta-analysis of randomized trials. Eur Heart J 2016;37:390–9. https://doi. org/10.1093/eurheartj/ehv443; PMID: 26324537. 59. Bansilal S, Bonaca MP, Cornel JH, et al. ticagrelor for secondary prevention of atherothrombotic events in patients with multivessel coronary disease. J Am Coll Cardiol 2018;71:489–96. https://doi.org/10.1016/j.jacc.2017.11.050; PMID: 29406853. 60. Bhatt DL, Bonaca MP, Bansilal S, et al. reduction in ischemic events with ticagrelor in diabetic patients with prior myocardial infarction in PEGASUS-TIMI 54. J Am Coll Cardiol 2016;67:2732–40. https://doi.org/10.1016/j.jacc.2016.03.529; PMID: 27046160. 61. Wallentin L, James S, Storey RF, et al. Effect of CYP2C19 and ABCB1 single nucleotide polymorphisms on outcomes of treatment with ticagrelor versus clopidogrel for acute coronary syndromes: a genetic substudy of the PLATO trial. Lancet 2010;376:1320–8. https://doi.org/10.1016/s01406736(10)61274-3; PMID: 20801498. 62. Zheng L, Yang C, Xiang L, Hao Z. Genotype-guided antiplatelet therapy compared with conventional therapy for patients with acute coronary syndromes: a systematic review and meta-analysis. Biomarkers 2019;24:517–23. https://doi.org/10.1080/1354750x.2019.1634764; PMID: 31215825. 63. Jiang M, You JH. CYP2C19 LOF and GOF-guided antiplatelet therapy in patients with acute coronary syndrome: a costeffectiveness analysis. Cardiovasc Drugs Ther 2017;31:39–49. https://doi.org/10.1007/s10557-016-6705-y; PMID: 27924429. 64. Lee JH, Ahn SG, Lee JW, et al. Switching from prasugrel to clopidogrel based on cytochrome P450 2C19 genotyping in East Asian patients stabilized after acute myocardial infarction. Platelets 2016;27:301–7. https://doi.org/10.3109/09 537104.2015.1095875; PMID: 26556524. 65. Su-Yin DT. Using pharmacogenetic testing or platelet reactivity testing to tailor antiplatelet therapy: are Asians different from Caucasians? Eur Cardiol 2018;13:112–4. https:// doi.org/10.15420/ecr.2018.13.2.EO2; PMID: 30697355. 66. Sibbing D, Aradi D, Alexopoulos D, et al. Updated expert consensus statement on platelet function and genetic testing for guiding P2Y12 receptor inhibitor treatment in percutaneous coronary intervention. JACC Cardiovasc Interv 2019;12:1521–37. https://doi.org/10.1016/j.jcin.2019.03.034; PMID: 31202949. 67. James S, Budaj A, Aylward P, et al. Ticagrelor versus clopidogrel in acute coronary syndromes in relation to renal function: results from the Platelet Inhibition and Patient Outcomes (PLATO) trial. Circulation 2010;122:1056–67. https:// doi.org/10.1161/circulationaha.109.933796; PMID: 20805430. 68. James S, Angiolillo DJ, Cornel JH, et al. Ticagrelor vs. clopidogrel in patients with acute coronary syndromes and diabetes: a substudy from the PLATelet inhibition and patient Outcomes (PLATO) trial. Eur Heart J 2010;31:3006–16. https://doi.org/10.1093/eurheartj/ehq325; PMID: 20802246. 69. Husted S, James S, Becker RC, et al. Ticagrelor versus clopidogrel in elderly patients with acute coronary syndromes: a substudy from the prospective randomized PLATelet inhibition and patient Outcomes (PLATO) trial. Circ Cardiovasc Qual Outcomes 2012;5:680–8. https://doi. org/10.1161/circoutcomes.111.964395; PMID: 22991347. 70. Bhatt DL, Pollack CV, Weitz JI, et al. Antibody-based ticagrelor reversal agent in healthy volunteers. N Engl J Med 2019;380:1825–33. https://doi.org/10.1056/NEJMoa1901778; PMID: 30883047.

COVID-19

Coronavirus Disease 2019: Cardiac Complications and Considerations for Returning to Sports Participation Daniel X Augustine ,1,2 Tracey Keteepe-Arachi3 and Aneil Malhotra

4,5

1. Royal United Hospitals Bath NHS Foundation Trust, Bath, UK; 2. Department for Health, University of Bath, Bath, UK; 3. Poole Hospital NHS Foundation Trust, Poole, UK; 4. Division of Cardiovascular Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK; 5. Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK

Abstract

Coronavirus disease 2019 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus 2. While the majority of symptoms and morbidity relate to the lung, cardiac complications have been well reported and confer increased mortality. Many countries in Europe have passed the peak of the pandemic and adaptations are being made as we progress towards a ‘new normal’. As part of this, governments have been planning strategies for the return of elite sports. This article summarises the potential implications of COVID-19 for athletes returning to sport, including common cardiac complications of the disease; consensus recommendations for the return to sport after having COVID-19; and international recommendations for the management of cardiac pathology that may occur as a result of COVID-19. The authors also examine the potential overlap of pathology with physiological change seen in athletes’ hearts.

Keywords

COVID-19, sport, myocarditis, echo, cardiac MRI Disclosure: The authors have no conflicts of interest to declare. Received: 7 September 2020 Accepted: 3 December 2020 Citation: European Cardiology Review 2021;16:e03. DOI: https://doi.org/10.15420/ecr.2020.36 Correspondence: Aneil Malhotra, Division of Cardiovascular Sciences, Core Technology Facility, University of Manchester, 46 Grafton St, Manchester M13 9WU, UK. E: aneil.malhotra@manchester.ac.uk Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

In December 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was identified as the pathogen responsible for a series of cases of pneumonia in the Chinese province of Hubei, Wuhan.1 This became known as coronavirus disease 2019 (COVID-19). On 11 March 2020, the WHO declared COVID-19 a pandemic after numerous cases and deaths in more than 100 different countries.2 Globally, as of 7 February 2021, confirmed cases reached 105,394,301 (35,481,004 in Europe) with 2,302,302 deaths.3 The activation of the surface spike protein of SARS-CoV-2 allows it to bind to the human angiotensin-converting enzyme 2 (ACE2) receptor. ACE2 is expressed in the lung and appears the main site of entry for the virus.4 ACE2 is also expressed in the heart, vascular endothelium, kidneys and intestinal epithelium, thus providing a potential mechanism for the multiorgan effects of COVID-19.5,6 The main symptoms of COVID-19 are fever, a new persistent cough and a loss or change to sense of smell or taste.7 There is a long list of other reported symptoms, including myalgia and diarrhoea.8 Cardiovascular manifestations of COVID-19 include MI, heart failure and myocarditis (Figure 1).9–15 Baseline blood tests and common cardiac investigations will help to diagnose these pathologies. Under initial lockdown measures, elite sports were halted but as the pandemic has progressed and plans are made for a ‘new normal’, consensus

recommendations for cardiac assessment of athletes who may be affected by COVID-19 have been proposed.16–22 The consensus recommendations and preparticipation screening commonly involve an ECG and some also recommend an echocardiogram. Athletic training regimens can often exceed ‘normal’ physical limits and if continued, cardiovascular adaptation to exercise can occur. These cardiac changes, known as athlete’s heart (AH) may manifest on investigations such as the ECG or echocardiogram and can mimic mild phenotypes of cardiac pathology. As preparticipation sports screening in the COVID-19 era becomes more routine, an understanding of how to differentiate physiological adaptation from pathological change in athletes will aid clinical decision-making. The objectives of this review are to:

• Describe the main cardiovascular manifestations of COVID-19. • To discuss the potential overlap – or the ‘grey zone’ – where

physiological adaptation due to AH may overlap with mild pathological change. • Summarise recent consensus algorithms for the cardiac assessment of athletes who may have been affected by COVID-19. • Highlight international recommendations for the management of athletes with cardiac pathology related to COVID-19.

COVID-19: Cardiac Considerations for Athletes Figure 1: The Epidemiology, Symptoms, Risk Factors and Cardiovascular Complications of COVID-19 Epidemiology ● ● ●

>105 million confirmed cases >2.3 million deaths >200 countries

Heart failure

Symptoms ● ● ●

Cough, fever, dyspnoea, loss of smell or taste Myalgia, headache, sore throat Abdominal pain, diarrhoea, vomiting

● ● ● ● ● ●

Older age Cardiovascular disease Diabetes Hypertension Chronic kidney disease Obesity Ethnicity: Black, Asian, minority ethnic

The presence of myocardial injury is an important finding in those with COVID-19 and is associated with increased severity of illness as well as worse prognosis.12,28,29 Myocardial injury is defined as the elevation of high sensitivity cardiac troponin (hs-cTn) above the 99th percentile of normal or new echocardiographic/ECG abnormality.12 Ischaemic and nonischaemic aetiology of increased troponin levels are described below.

MI COVID-19

Cardiac complications

Myocarditis

Risk factors ●

Cardiac Manifestations of COVID-19

Thromboembolism

Arrhythmia

Severity and General Clinical Manifestations of COVID-19

When assessing athletes with a current or past history of COVID-19, it is important to consider individual demographics and comorbidities which have been shown to confer worse outcomes. It is less likely that younger athletes will have the same risk profile associated with COVID-19 as masters athletes (aged >35 years). While severe illness due to COVID-19 can occur in healthy people irrespective of age, it predominantly occurs with advancing age and in those with multiple comorbidities. Adults of middle and older age are most commonly affected. Studies with hospitalised cohorts have shown that 74–86% are at least 50 years old.1 Advanced age is also associated with increased mortality from COVID-19.23 Ethnicity also plays an important role in prognosis. Death rates in the UK from COVID-19 among people from black, Asian and minority ethnic (BAME) backgrounds have been shown to be higher than their white counterparts.24 In addition, a systematic review has shown that BAME people are at higher risk of acquiring the virus.25 Comorbidities associated with severe COVID-19 illness and mortality include pre-existing cardiovascular disease, diabetes, hypertension, malignancy, chronic lung disease, smoking, obesity and chronic kidney disease.11 General clinical manifestations of COVID-19 from large registry data include: cough (50%), fever (43%), myalgia (36%), headache (34%), dyspnoea (29%), sore throat (20%), diarrhoea (19%) and nausea/vomiting (12%). Loss of smell or taste, abdominal pain and rhinorrhoea were reported in fewer than 10% of cases each.26 With specific reference to athletes, symptoms of breathlessness disproportionate to the level of exercise should prompt a cardiovascular assessment. There is a wide spectrum of illness as reported by the Chinese Center for Disease Control and Prevention.27 This ranges from mild disease, with no symptoms or mild pneumonia, in 81% of the cohort; severe disease – such as dyspnoea, hypoxia and significant lung changes on imaging – in 14% of the cohort; critical disease – such as shock, respiratory failure, multiorgan failure – in 5% of the cohort. Overall, the case fatality rate was 2.3% with no deaths reported in non-critical cases.

MI can occur as a result of systemic inflammatory response syndrome caused by severe viral infections. In COVID-19, severe inflammatory stress leads to a release of circulating cytokines. This may lead to plaque instability with higher risk of rupture and thrombus formation leading to acute coronary syndrome (type 1 acute MI).30 A type 2 MI due to a myocardial mismatch in oxygen demand and supply may also be a complication of viral infections. Hypoxaemia, vasoconstriction and the haemodynamic consequences of sepsis cause this mismatch which leads to myocardial ischaemia. The medical management of MI in the era of COVID-19 is through established pathways.31

Heart Failure

Acute illness caused by COVID-19 may precipitate heart failure in those with pre-existing or undiagnosed heart disease or due to acute myocardial injury, such as coronary artery disease, stress cardiomyopathy and cytokine storm.11,15

Cardiac Arrhythmias

Cardiac dysrhythmias can occur as a sequelae of a primary cardiac pathology, such as MI or a fibrotic substrate due to myocarditis and have also been reported in the setting of viral illness due to hypoxia, inflammatory stress and fever.11

Thromboembolism

Increased risk of thromboembolism in patients with COVID-19 has been reported with a variety of mechanisms postulated including immobility, hypercoagulable status, a propensity for disseminated intravascular coagulopathy and active inflammation.11,12

Myocarditis

Many viruses are able to bind directly to molecular targets in the myocardium to inflict damage via a range of mechanisms.30 Myocarditis is characterised by inflammatory infiltrates and myocardial injury in the absence of an ischaemic cause. Cases of COVID-19-related myocarditis have been reported, with some reviews suggesting that up to 7% of COVID-19 deaths were attributable to myocarditis.14,32 This may be an overestimate, as the clinical diagnosis in most cases is assumed rather than confirmed by myocardial biopsy. COVID-19 myocarditis may present with a variety of symptoms, including fatigue, chest discomfort or breathlessness. In athletes, symptoms such as fatigue may be more difficult to establish at an earlier stage due to confounding factors such as the return to full participation in sports after a reduced workload. Typical baseline investigations for those with suspected myocarditis include blood tests and ECG. Imaging investigations which may be undertaken include echocardiography and cardiac MRI (CMR). These main investigations are discussed below:33

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COVID-19: Cardiac Considerations for Athletes Figure 2: Factors that Can Help Differentiate Physiological Adaptation from Pathological Change in Athletes Physiology

Pathology

Asymptomatic

Breathless, chest pain palpitations, syncope

History

• Usually normal size but can have ventricular dilatation, particularly endurance athletes (grey zone 60–65 mm) • Usually normal but can have mildly reduced EF, usually endurance athletes. Grey zone EF 45–50%. • Usually normal LVWT but can be increased: • Black men ≤15 mm • Black women ≤12 mm • White men ≤13 mm • White women ≤11 mm

Echo

• White athletes TWI V1–V2 • Black athletes TWI V1–V4, often accompanied by J point ST elevation

ECG

LGE may be a feature in healthy athletes: patchy fibrosis in basal inferior lateral wall has been seen in masters athletes

CMR

• Regional wall motion abnormality • Ventricular dilatation or mildly reduced EF not in keeping with sports participation type and amount • LVWT exceeding that for ethnicity/sex • Inability to augment EF >11% or achieve peak exercise EF of >63% is more in keeping with DCM rather than athletic adaptation

• • • •

Lateral TWI ST depression Q waves Arrhythmia at rest or on exertion LGE in pathological distribution with other clinical investigations/history suspicious of pathology

CMR = cardiac MRI; DCM = dilated cardiomyopathy; EF = ejection fraction; LGE = late gadolinium enhancement; LVWT = left ventricular wall thickness; TWI = T wave inversion.

• Blood tests: myocarditis often results in elevated levels of

inflammatory markers, such as C-reactive protein. Baseline cardiac enzymes such as troponin and N-terminal pro-B-type natriuretic peptide (BNP) can also be elevated.11 • ECG: changes include ST elevation/depression, PR depression and T wave inversion (TWI). • Echocardiography: echocardiographic features which may be in keeping with myocarditis include the findings of pericardial effusion; ventricular dysfunction (global or regional wall motion abnormality and reduction in ejection fraction. Left ventricular (LV) hypertrophy has been reported in cases of acute myocarditis as a consequence of myocardial oedema.34 • CMR: an important imaging tool in the diagnosis and risk stratification of myocarditis. Late gadolinium enhancement allows detection of fibrosis and has been shown in studies to be an adverse predictor of mortality when present.35

Diagnostic Conundrum in Asymptomatic Athletes: The Grey Zone

An understanding of the ‘grey-zone’ overlap between physiological adaptation and pathology in certain cardiac investigations is important when assessing athletes regarding potential cardiovascular complications of COVID-19. This is particularly relevant during cardiac screening of athletes who have not had COVID-19 symptoms to try to reduce the misdiagnosis of cardiac pathology. Differentiating physiology from pathology with regards to the main investigations used in preparticipation screening is described below and summarised in Figure 2.

Troponin Levels

A considerable proportion of patients hospitalised with COVID-19 have been found to have elevated troponin levels, with some reports finding this in up to 28% of affected cases.30 Care should be taken when interpreting troponin levels in asymptomatic athletes if they have recently participated in sport or training. Several studies have reported transient troponin elevation after marathons, triathlon events, cycling and other forms of physical activity.

Exercise intensity and duration cannot reliably predict the magnitude of troponin release. Cardiac biomarker alterations have been described following table tennis games and prolonged walking.36 There are reports of troponin release beginning as early as 30 minutes into sustained endurance exercise which may represent a normal response to exercise.37–39

ECG

Repolarisation changes such as TWI may be associated with COVID-19related cardiovascular complications, such as myocarditis. However, athletic adaptation to exercise is associated with a number of ECG changes, which are also dependant on age, sex, ethnicity and sporting discipline.40–44 As a general rule men, black athletes and athletes participating in high endurance sport tend to exhibit more profound ECG changes. Studies assessing physiological ECG changes have shown that TWI can be normal in white athletes when seen in leads V1–V2.42,44 This is more commonly seen in women (4.3% versus 1.4% in men) and more prevalent in athletes when compared to healthy sedentary controls in women (6.5% versus 3.8%) and men (2.1% versus 1.1%). Black athletes are recognised to have greater prevalence of TWI than white athletes. In leads V1–V4 this may be interpreted as an ethnically determined normal physiological response to exercise.42 Papadakis et al. described ECG findings in 904 black athletes and compared them with 1,819 white athletes, 119 black controls and 52 black patients with hypertrophic cardiomyopathy.45 TWI was seen in 22.8% of black athletes, predominantly confined to leads V1–V4, often with preceding J-point elevation and convex ST elevation (12.7%). Sheikh et al. compared ECGs of black and white adolescent athletes and showed a higher prevalence of TWI in the black athletes (V1–V4, 14.3%).40 More recently, Mango et al. raised awareness that premature ventricular beats occurred more frequently in low QRS voltage among Olympic athletes.46 Such anomalies may be suggestive of underlying pathology particularly in subtle cases of myocarditis.

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COVID-19: Cardiac Considerations for Athletes Table 1. Summary of Recent Return to Training Consensus Statements in Athletes with Confirmed or Suspected COVID-19 COVID-19 Symptoms Exercise in the SARS-CoV-2 Positive era22

COVID-19 Test Result

Recommendations

Positive

• Self-isolate 7–14 days • No exercise until symptom-free for 7 days • Consider troponin and CRP • If troponin positive, consider ECG; CMR; TTE; ECG monitoring • If no cardiac involvement, graduated return to play after symptom-free for 7 days

• Consider repeat COVID-19 testing to ensure negative status prior to return to training

Negative

• No exercise for 7 days from test result • If symptom-free at day 7 then graduated return to training • Consider repeat COVID-19 testing to ensure negative status

Positive

prior to return to training

Positive

• Manage as coryzal symptoms • If high index of suspicion for COVID-19 then re-test or treat as

Negative

though COVID-19 positive

A game plan for the resumption of sport and exercise after COVID-19 Infection17

Negative

Positive

Mild – not hospitalised

Positive

• No limitations • No exercise for 14 days then slow monitored resumption • Following symptoms, no exercise for 14 days • Before resumption of activity 12-lead ECG, TTE, high sensitivity troponin and additional tests as guided by symptoms

Significant symptoms – hospitalised

• Troponin and cardiac investigations in hospital as needed • If troponin/cardiac study abnormal then investigate for

Positive

myocarditis

• If normal hospital cardiac investigations: no exercise for first 14 days while asymptomatic; consider cardiac testing if not done in hospital; slow resumption of activity

Return to sports after COVID-19 infection20

Positive

Negative

Positive

• Consider following pathway as if COVID-19 positive • No intense or competitive exercise for 14 days • If symptom-free and normal ECG then return to full competitive sports

Positive

• Clinical investigations according to severity • If no evidence of myocarditis then sports restriction for at

Positive

least 2–4 weeks. Subsequent cardiology follow-up: if normal then return to full competitive sports. If abnormal and not in keeping with myocarditis then consider differential diagnosis • If evidence of myocarditis then treat as per recognised guidelines

The resurgence of sport in the wake of COVID-19: cardiac considerations in competitive athletes21

Graduated return to play guidance following COVID-19 infection19

• Treat as COVID-19 positive • Repeat COVID-19 testing

Positive

Negative

Asymptomatic/ Antibody Positive

Mild Symptoms (NonModerate to Severe Symptoms (Hospitalised) hospitalised) with Confirmed/ with Confirmed/Suspected COVID-19 Suspected COVID-19

• Focused medical history and physical • Focused medical history and physical • Comprehensive evaluation to include blood biomarker, ECG, examination

examination

TTE, exercise testing, ECG monitoring

(or ECG shows new changes compared with previous)

TTE, exercise testing, ECG monitoring and CMR

• Consider 12-lead ECG • 12-lead ECG • In athletes with documented myocardial injury then • Further evaluation if above abnormal • Further evaluation if above abnormal comprehensive evaluation to include blood biomarker, ECG,

Mild to Moderate Infection

Complicated or Prolonged Infection

• 10 rest days and at least 7 days symptom-free • 7 days of graduated increase in exercise incrementing type of

• Specialty review with advanced tests, such as cardiac biomarker blood tests, ECG, echocardiogram, exercise tolerance test, CMR

exercise, duration, heart rate max %

CMR = cardiac MRI; COVID-19 = coronavirus disease 2019; CRP = C-reactive protein; TTE = transthoracic echocardiography.

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COVID-19: Cardiac Considerations for Athletes Table 2. Risk Stratification of Those with Coronary Disease Prior to Sports Participation Probability for Exercise-Induced Adverse Cardiac Events Low Probability

High Probability

• <70% stenosis of major coronary artery or <50% left main stem disease • Ejection fraction ≥50% and no wall motion abnormality • Normal age-adjusted exercise capacity • Absence of inducible ischaemia on maximal exercise testing • Absence of major ventricular tachyarrhythmias (non-sustained VT, frequent ventricular

• >70% stenosis of at least one major coronary artery or >50% left main stem disease • Ejection fraction <50% • Dyspnoea at low exercise intensity • Exercise-induced ischaemia on maximal exercise testing • Major ventricular tachyarrhythmias (non-sustained VT, frequent ventricular ectopic

ectopic beats) at rest or during maximal stress testing.

beats) at any time

• Dizziness or syncope on exertion • High degree of myocardial scarring on CMR imaging

CMR = cardiac MRI; VT = ventricular tachycardia.

Echocardiogram

Left Ventricular Dilatation

LV dilatation and dysfunction may be a feature of cardiac pathology, such as heart failure or myocarditis, due to COVID-19. Overlap between physiological change and a pathological process may exist in a subset of athletes, particularly endurance athletes. This assessment of LV cavity size has been shown to be increased in athletes when compared to healthy controls.47 While athletes may demonstrate increased cavity dimensions, it is unusual for proportions to reach the pathological threshold, for example with dilated cardiomyopathy (DCM). However, studies have reported that cavity dilatation >60 mm can be seen in up to 14% of male participants. This level of dilatation is more commonly seen in high capacity endurance sports, such as cycling.47,48

compared to white female athletes. Studies have demonstrated LVWT >11 mm in 3% of black female athletes versus none in white female athletes (with no female athlete exceeding an LVWT of 13 mm).56–58

Cardiac MRI

As with male athletes, it is unusual for LV cavity dimensions in female athletes to exceed normal limits. Pelliccia et al. studied 600 elite female athletes and found that an LV end diastolic dimension >54 mm was seen in 8% and >60 mm seen in 1%.49 Again, those with greater LV cavity diameter were more likely to be endurance athletes.

CMR allows advanced assessment of tissue characterisation in addition to ventricular volume and function assessment. The presence of late gadolinium enhancement (LGE), indicating myocardial fibrosis, has been shown to be a predictor of mortality in those with myocarditis irrespective of ejection fraction.59,60 Normal CMR in those with suspected myocarditis correspond to a low annual major adverse event rate of 0.8% and a death rate of 0.3%.61 LGE distribution in acute myocarditis has been documented to predominantly have a subepicardial or mid-myocardial distribution.62 Several studies have also reported myocardial fibrosis detected by LGE on CMR in athletes, with cohorts of master athletes showing patterns of non-ischaemic fibrosis.63–65 Further studies are needed to assess whether this finding in athletes represents a pathological manifestation of cardiac disease or a reflection of physiological stresses due to prolonged bouts of sports participation.

Left Ventricular Ejection Fraction

Returning to Sport Post COVID-19: Guidance

Physiological adaptation may cause some athletes to exhibit a reduced ejection fraction that overlaps with pathological LV systolic dysfunction (ejection fraction 45–49%). This occurs in a minority of athletes, particularly from endurance sports. Abergel et al. showed that in a group of 286 elite cyclists, 147 (51.4%) demonstrated LV end diastolic dilatation (>60 mm) and of these 17 (11.6%) demonstrated reduced LVEF (<52%).50 More recently, Millar et al. reported that an improvement of 11% in ejection fraction from baseline using exercise stress echocardiography has the greatest discriminatory value in differentiating between grey-zone athletes and asymptomatic patients with DCM.51

Left Ventricular Wall Thickness

LV hypertrophy is a rare complication of acute myocarditis.52 Knowledge of physiological hypertrophy in athletes will be of use in differentiating physiological from pathological hypertrophy. Studies have shown that black male athletes have a greater mean maximal wall thickness than white athletes (11.3 mm versus 10 mm). It is uncommon for athletes to exceed the upper limit of normal wall thickness (12 mm in men and 11 mm in women).53 It is more common to see increased wall thickness in black athletes when compared to white athletes: LV wall thickness (LVWT) >12 mm (18% black male athletes versus 4% white male athletes) and >15 mm (3% black male athletes versus 0% white male athletes). Physiological adaptation rarely causes LVWT >16 mm, irrespective of ethnicity.45,54,55A similar finding of increased LVWT is seen in black female athletes when

Current recommendations for a return to sport following COVID-19 infection are based on consensus. Some have advocated no participation in intense exercise or competitive sports for 14 days in those who are asymptomatic with a positive COVID-19 test and a normal ECG.20 The use of biomarkers, such as high sensitivity troponin, in asymptomatic people has also been recommended by some before a return to full training.18 A recent graduated return to play consensus statement describes implementation of a protocol following a 10-day rest period (with at least a 7-day symptom-free period).19 Here, activity duration, heart rate percentage and type of exercise is described with a goal of returning to normal training by day 7. It is widely agreed that athletes who have a complicated COVID-19 illness with cardiac symptoms or who have abnormal cardiac biomarker results require a more detailed cardiac assessment including ambulatory ECG monitoring, echocardiography and CMR.16–20 A summary of recent consensus guidelines on return to sports following confirmed or suspected COVID-19 is shown in Table 1.

Cardiac Complications of COVID-19 in Athletes: Returning to Sport

Myocarditis:66 • Consensus guidelines from the European Association of Preventative Cardiology (EAPC) were published in 2019, followed most recently by the European Society of Cardiology’s updated guidelines.67 • Exercise programmes should be restricted for 3–6 months. • Resumption of training can be considered when LV systolic function

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COVID-19: Cardiac Considerations for Athletes has returned to normal range, serum biomarkers of myocardial injury have normalised and clinically relevant arrhythmias are absent on 24-hour ECG monitoring and exercise test. • Asymptomatic athletes with LGE should remain under annual clinical surveillance. Pericarditis:66 • Athletes with pericarditis should not participate in competitive sports during the acute phase and can return following complete resolution of the active disease. Three months is considered an appropriate time period to ensure complete clinical and biochemical resolution but shorter periods of at least 1 month may be considered in selected mild cases that have prompt resolution. • Return to play is reasonable if serum biomarkers, LV function and rhythm monitoring (either 24-hour ECG or exercise ECG) are normal. • Athletes with myocardial involvement should be treated with recommendations for myocarditis. • Asymptomatic athletes with small pericardial effusion detected incidentally by imaging but without myopericarditis should not be restricted from sports participation. Periodic surveillance is advisable. Left ventricular dysfunction:66 • Athletes with DCM and mild LV dysfunction (EF ≥ 40%) who are asymptomatic or do not have a history of syncope or complex rhythm disturbance may compete in sports, with the exception of those 1. Wiersinga WJ, Rhodes A, Cheng AC, et al. Pathophysiology, transmission, diagnosis, and treatment of coronavirus disease 2019 (COVID-19): a review. JAMA 2020;324:782–93. https://doi.org/10.1001/jama.2020.12839; PMID: 32648899. 2. WHO. WHO Director-General’s opening remarks at the media briefing on COVID-19 – 11 March 2020. WHO, 11 March 2020. https://www.who.int/director-general/ speeches/detail/who-director-general-s-opening-remarks-atthe-media-briefing-on-covid-19---11-march-2020 (accessed 16 December 2020). 3. WHO. WHO Coronavirus Disease (COVID-19) Dashboard. Geneva: WHO, 2020. https://covid19.who.int (accessed 7 February 2021). 4. Clerkin KJ, Fried JA, Raikhelkar J, et al. Coronavirus disease 2019 (COVID-19) and cardiovascular disease. Circulation 2020;141:1648–55. https://doi.org/10.1161/ CIRCULATIONAHA.120.046941; PMID: 32200663. 5. Zhang H, Penninger JM, Li Y, et al. Angiotensin-converting enzyme 2 (ACE2) as a SARS-CoV-2 receptor: molecular mechanisms and potential therapeutic target. Intensive Care Med 2020;46:586–90. https://doi.org/10.1007/s00134-02005985-9; PMID: 32125455. 6. Tikellis C, Thomas MC. Angiotensin-converting enzyme 2 (ACE2) is a key modulator of the renin angiotensin system in health and disease. Int J Pept 2012;2012:256294. https://doi. org/10.1155/2012/256294; PMID: 22536270. 7. NHS. Coronavirus (COVID-19). NHS, 2020. https://www.nhs. uk/conditions/coronavirus-covid-19 (accessed 16 December 2020). 8. Rodriguez-Morales AJ, Cardona-Ospina JA, GutiérrezOcampo E, et al. Clinical, laboratory and imaging features of COVID-19: A systematic review and meta-analysis. Travel Med Infect Dis 2020;34:101623. https://doi.org/10.1016/j. tmaid.2020.101623; PMID: 32179124. 9. Kochi AN, Tagliari AP, Forleo GB, et al. Cardiac and arrhythmic complications in patients with COVID-19. J Cardiovasc Electrophysiol 31:1003–8. https://doi.org/10.1111/ jce.14479; PMID: 32270559. 10. Sala S, Peretto G, Gramegna M, et al. Acute myocarditis presenting as a reverse Tako-Tsubo syndrome in a patient with SARS-CoV-2 respiratory infection. Eur Heart J 2020;41:1861–2. https://doi.org/10.1093/eurheartj/ehaa286; PMID: 32267502. 11. Long B, Brady WJ, Koyfman A, Gottlieb M. Cardiovascular complications in COVID-19. Am J Emerg Med 2020;38:1504–7. https://doi.org/10.1016/j.ajem.2020.04.048; PMID: 32317203. 12. Kang Y, Chen T, Mui D, et al. Cardiovascular manifestations and treatment considerations in COVID-19. Heart

where syncope may be associated with serious harm or death, such as motor racing, scuba diving and rock climbing. • Athletes with DCM should be advised not to engage in competitive sports if they are symptomatic or have one of the following: LV ejection fraction <40%; extensive LGE on CMR; frequent complex ventricular tachyarrhythmias on monitoring or a history of unexplained syncope. MI:68 • Athletes with proven coronary artery disease as documented by an earlier clinical event, CT scan or coronary angiography should be assessed on an individual basis. The aim is to risk stratify the likelihood of an exercise-induced cardiac event (Table 2). Athletes considered as having a low probability for cardiac events are eligible for most sports although restrictions may apply on an individual basis for certain sports with the highest cardiovascular demand, such as extreme power and endurance disciplines.

Conclusion

This review has highlighted recent consensus statements for the return to sports participation following confirmed or suspected COVID-19. An understanding of the cardiovascular complications of COVID-19 together with an overview of investigation findings that can help differentiate physiology from pathology in athletes will benefit clinical decision-making.

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ISCHEMIA Trial

Pharmacotherapy in Stable Coronary Artery Disease: Historical Perspectives and New Insights from the ISCHEMIA Trial Jonathan Yap,1,2 Derek P Chew,3 Gregg W Stone4,5 and Jack Wei Chieh Tan1,2 1. National Heart Centre Singapore, Singapore; 2. Duke-NUS Graduate Medical School, Singapore; 3. College of Medicine and Public Health, Flinders University, Adelaide, Australia; 4. The Zena and Michael A Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, NY, US; 5. Cardiovascular Research Foundation, New York, NY, US

Disclosure: JY reports honoraria from Johnson & Johnson and Terumo. GWS has received speaker or other honoraria from Cook, Terumo, QOOL Therapeutics and Orchestra Biomed; has served as a consultant to Valfix, TherOx, Vascular Dynamics, Robocath, HeartFlow, Gore, Ablative Solutions, Miracor, Neovasc, V-Wave, Abiomed, Ancora, MAIA Pharmaceuticals, Vectorious, Reva, Matrizyme and Cardiomech; and has equity/options from Ancora, Qool Therapeutics, Cagent, Applied Therapeutics, Biostar family of funds, SpectraWave, Orchestra Biomed, Aria, Cardiac Success, MedFocus family of funds and Valfix. JWCT reports honoraria from Astra Zeneca, Bayer, Amgen, Medtronic, Abbott Vascular, Biosensors, Alvimedica, Boehringer Ingelheim and Pfizer; research and educational grants from Medtronic, Biosensors, Biotronik, Philips, Amgen, AZ, Roche, Otsuka, Terumo and Abbott Vascular; and consulting fees from Elixir and CSL Behring. DPC has no conflicts of interest to declare. Received: 8 December 2020 Accepted: 8 December 2020 Citation: European Cardiology Review 2021;16:e04. DOI: https://doi.org/10.15420/ecr.2020.48 Correspondence: Jack Tan Wei Chieh, National Heart Centre Singapore, 5 Hospital Drive, Singapore 169609. E: jack.tan.w.c@singhealth.com.sg Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

The recently published International Study of Comparative Health Effectiveness with Medical and Invasive Approaches (ISCHEMIA) trial has shed further light on the importance of pharmacotherapy in the management of stable coronary artery disease (CAD).1 In brief, the ISCHEMIA trial was designed to study the impact of an initial invasive strategy (cardiac catheterisation and revascularisation with percutaneous coronary intervention [PCI] or coronary artery bypass grafting [CABG] where feasible) compared with initial medical therapy in patients with stable CAD and moderate or severe ischaemia. Patients with frequent angina (all class IV and most class III), left main (LM) stenosis ≥50% or left ventricular ejection fraction (LVEF) <35% or heart failure were excluded. A total of 5,179 randomised patients were followed up for a median of 3.2 years. Approximately 80% of patients in the invasive strategy arm underwent revascularisation (with about three-quarters of these having PCI and onequarter having CABG) and approximately 15% in the medical therapy arm underwent revascularisation before the occurrence of a primary outcome event. At 4 years, the cumulative rate of major adverse cardiovascular event (MACE) – the composite of cardiovascular death, MI or hospitalisation for unstable angina, heart failure or resuscitated cardiac arrest – was similar, at 13.3% in the invasive group and 15.5% in the medical therapy group. Although the mortality rate was low in both randomised groups (6.5% versus 6.4% at 4 years), the invasive group had fewer late nonprocedural MIs at the cost of an increase in procedural MIs. Of note, the relative outcomes of the primary endpoint were similar between the two treatment arms in patients with and without high-risk characteristics, such as multivessel disease, severe ischaemia, diabetes or proximal left anterior descending artery (LAD) stenosis. To appreciate the gap that the ISCHEMIA trial addresses in the treatment of stable CAD, it is important to briefly contextualise the evolution of the

impact of medical therapy (Table 1). The therapeutic importance of medical therapy in stable CAD has been well-established since the mid-20th century. One of the first major randomised controlled trials (RCTs), CASS, performed in the 1970s, compared CABG versus medical therapy in patients with CAD. Patients with LM stenosis ≥70% or LVEF <35% were excluded, similar to the ISCHEMIA trial.2 At 5-year follow-up, there was no significant difference in the annualised mortality rate between the CABG and the medical therapy group (1.1% versus 1.6%), regardless of single, double or triple vessel disease. The annual rate of CABG in the medical therapy group was 4.7%. With longer follow-up to 10 years, a survival advantage with CABG was observed in patients with LVEF <50% and either proximal LAD disease or triple vessel disease.3 In that era, medical therapy was suboptimal compared with contemporary standards, with relatively low use of antiplatelet agents (56–69%), lipid-lowering drugs (31–36%), beta-blockers (43–44%), nitrates (45–47%), and other antihypertensives (17–21%).2,3 With advances in both medical therapy and PCI techniques at the turn of the 21st century, the pivotal COURAGE trial was conducted to determine if routine PCI in addition to optimal medical therapy provided additional benefit compared with optimal medical therapy alone in patients with stable symptomatic CAD (again, patients with LM stenosis ≥50% or LVEF <30% were excluded).4 In that RCT, a total of 2,287 patients were followed for a median of 4.6 years (up to 7 years). The event rate of all-cause death or non-fatal MI at the end of the follow-up period was similar between study arms, at 19.0% in the PCI group and 18.5% in the medical therapy group (p=0.62). Although there were no significant differences in the individual components of mortality, MI and stroke, the medical therapy group had a greater incidence of unplanned revascularisation during follow up. However, bare metal stents were used in most patients, and the optimisation of pharmacotherapy in that trial was notable. At 1 year in the

Pharmacotherapy in Stable CAD: The ISCHEMIA Trial Table 1: Selected Randomised Controlled Trials on the Role of Medical Therapy and Revascularisation in Stable Coronary Artery Disease Trial

CASS2,3

COURAGE4,5

FAME 26,7

ISCHEMIA1

Years of recruitment 1975–1979

1999–2004

2010–2012

2012–2018

Sample size

780

2,287

888 (randomised)

5,179

Comparison

Medical therapy versus CABG

Medical therapy versus PCI

Medical therapy versus FFR-guided PCI

Medical versus revascularisation (CABG/PCI)

Duration of follow up 10 years

Median 6.2 years

5 years

Median 3.2 years

Details of medical therapy

Antiplatelet 56–69% Anticoagulation 59–67% Lipid-lowering drugs 31–36% β-blockers 43–44% Nitrates 45–47% Other antihypertensive 17–21% Oral hypoglycaemic agents 26–28%

Aspirin 95% Statin (mainly simvastatin) 95% ACEI/ARB 72% β-blockers 89%

Aspirin 92% Clopidogrel/prasugrel 35% Statins (atorvastatin recommended) 100% ACEI/ARB 87% β-blockers 84%

Antiplatelet/anticoagulation 100% Statin 95% (66% high intensity) Ezetimibe 24% ACEI/ARB 69%

Clinical outcomes

At 5 years Mortality: 8% medical therapy versus 5.5% CABG (NS) At 10 years Mortality: 21% medical therapy versus 18% CABG (NS)

At median 4.6 years At 5 years At 5 years Mortality: 8.3% medical therapy Mortality: 5.2% medical therapy Mortality: 8.3% medical therapy versus versus 7.6% PCI (NS) versus 5.1% PCI (NS) 9% invasive strategy (NS) MI: 12.3% medical therapy versus MI: 12% medical therapy versus MI: 11.9% medical therapy versus 13.2% PCI (NS) 8.1% PCI (NS) 10.3% invasive strategy (NS) Mortality, MI, stroke: 19.5% medical Mortality, MI, urgent revascularisation: CV mortality, MI, resuscitated cardiac therapy versus 20% PCI (NS) 27% medical therapy versus arrest, hospitalisation for UAP/HF: Revascularisation: 32.6% medical 13.9% PCI (significant at p<0.001) 18.2% medical therapy versus 16.4% therapy versus 21.1% PCI Urgent revascularisation: 21.1% invasive strategy (NS) (p<0.001) medical therapy versus 6.3% PCI At median 6.2 years (n=1,211), (95% CI [0.18–0.41]) Mortality: 24% medical therapy versus Any revascularisation: 51% medical 25% PCI (NS) therapy versus 13.4% PCI (95% CI [0.14–0.26])

ACEI = angiotensin-converting enzyme inhibitor; ARB = angiotensin II receptor blocker; CABG = coronary artery bypass grafting; CV = cardiovascular; FFR = fractional flow reserve; HF = heart failure; PCI = percutaneous coronary intervention; UAP = unstable angina pectoris.

medical therapy group (similar rates in the PCI group), aspirin was used in 95% of patients, statins (predominantly simvastatin) in 95%, angiotensinconverting enzyme inhibitors (ACEIs) or angiotensin II receptor blocker (ARB) in 72% and β-blockers in 89%. This was reflected in the average systolic blood pressure (SBP) of 124 mmHg, diastolic blood pressure of 70 mmHg and LDL of 2.1 mmol/l achieved at the end of 1 year. In a subset of 1,211 patients (53% of original population) followed for up to 15 years (median 6.2 years), survival remained similar in both groups.5 Nearly a decade later, the randomised (FAME 2 study was conducted to compare medical therapy versus PCI in patients with stable CAD with a functionally significant stenosis, defined as fractional flow reserve (FFR) ≤0.80.6 FFR is a pressure wire-based index obtained during coronary angiography that examines the haemodynamic significance of an anatomic coronary stenosis. Of the 888 patients, PCI resulted in a lower primary event rate of death, MI, or urgent revascularisation at 2 years (12.7% versus 4.3%, p<0.001), driven predominantly by a lower rate of urgent revascularisation. There were no differences in the individual components of death or MI. Results were similar at 5 years, although PCI was associated with fewer non-procedural MIs at the cost of greater procedural MIs (as seen in ISCHEMIA).7 Of note, drug-eluting stents were utilised in 97% of cases. At 1 year, the optimisation of medical therapy in the medical therapy group was similar to the COURAGE trial with aspirin used in 92% of patients, clopidogrel or prasugrel in 35%, statins (atorvastatin recommended) in 100%, ACEI/ARB in 87% and β-blockers in 84%. In the ISCHEMIA trial, the goals of optimal medical therapy are summarised in Figure 1.1 These objectives were selected based on guidelines and a wealth of evidence; these include SBP <130 mmHg, LDL <1.8 mmol/l and

HbA1c <8% (<7% if possible). This was achieved through a holistic approach involving both pharmacotherapy and behavioural modifications, including smoking cessation, physical activity and diet. In the setting of this largescale, international RCT, these goals were achieved in many, but not all, patients, with a median SBP of 129 mmHg, LDL of 1.7 mmol/l and HbA1c of 6.3% for the overall cohort (similar for both invasive and medical therapy groups). The prescription of recommended medications was similarly high, with 100% of patients on antiplatelet or anticoagulation therapy, 95% on statins (66% on high-intensity statins), 24% on ezetimibe and 69% on an ACEI/ARB. These observations demonstrate that the leaderships of most contemporary randomised trials of revascularisation versus medical therapy in CAD have strongly focused on foundational medical therapies to prevent long-term ischaemic events, as opposed to merely managing angina symptoms. In the management of stable CAD, a multi-pronged pharmacotherapy approach is favoured (coupled with risk factor control and lifestyle modifications, which are beyond the scope of the current review). Long-term anti-thrombotic therapy with a single antiplatelet therapy remains the backbone of treatment of stable CAD without PCI. The utility of more potent antiplatelet or anti-thrombin agents for the treatment of stable CAD without PCI remains controversial. The addition of low-dose rivaroxaban to aspirin in patients with stable CAD in the largescale randomised COMPASS trial showed a reduction in MACE but at the expense of increased bleeding.8 The benefits were particularly evident in those with peripheral vascular disease. The THEMIS study randomised patients with diabetes and stable CAD to aspirin with ticagrelor versus aspirin alone. In that study, aspirin with

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Pharmacotherapy in Stable CAD: The ISCHEMIA Trial ticagrelor resulted in a lower incidence of ischaemic events at the expense of increased bleeding.9 A net clinical benefit was noted primarily in the subset of patients with prior PCI and not in those without prior stenting.10 The role of ticagrelor monotherapy in stable CAD without PCI is not well-studied. As regards lipid-lowering therapy, the introduction of high-intensity statins at the turn of the 21st century, followed by other LDL-lowering adjuncts, such as ezetimibe and the proprotein convertase subtilisin/kexin type 9 (PCSK-9) inhibitors, have improved outcomes in the treatment of patients with CAD. Backed by strong evidence from numerous RCTs, the 2018 American Heart Association/American College of Cardiology lipid guidelines recommend a high-intensity statin (atorvastatin or rosuvastatin). If LDL remains ≥1.8 mmol/l despite maximally tolerated statins, the addition of newer therapies such as ezetimibe or PCSK-9 inhibitors to achieve target is endorsed.11 These therapies were all utilised in the ISCHEMIA trial (although few patients received PCSK-9 inhibitors). The evidence for non-LDL reduction therapies remains limited. However, the REDUCE-IT using high-dose icosapent ethyl showed a significant reduction in MACE outcomes in patients with cardiovascular disease (CVD) and raised triglyceride levels despite statin therapy.12 Achieving optimal blood pressure is also crucial. The SPRINT trial showed that targeting SBP <120 mmHg (target achieved 121 mmHg) versus SBP <140 mmHg (target achieved 136 mmHg) in patients without diabetes at high risk for cardiovascular events reduced mortality and MACE (although with greater complications such as hypotension, syncope, electrolyte abnormalities and acute renal failure, mandating close follow-up).13 After the publication of SPRINT the target SBP in the ISCHEMIA trial was lowered from 140 mmHg to 130 mmHg during the trial, with a median SBP of 129 mmHg achieved.1 In the higher risk subset of patients with diabetes and stable CAD, the advent of newer oral hypoglycaemic agents has ushered in a new era in glucose control. Numerous RCTs on sodium-glucose cotransporter-2 inhibitors have shown significant reductions in MACE rates in people with diabates and known CVD.14,15 While debate may exist on the role of routine revascularisation in the treatment of stable CAD without heart failure or LM disease, PCI and CABG provide symptom control and improved quality of life for patients in whom anti-angina agents either fail to control symptoms or result in unacceptable side-effects. Nevertheless, the importance of intensive 1. Maron DJ, Hochman JS, Reynolds HR, et al. Initial invasive or conservative strategy for stable coronary disease. N Engl J Med 2020;382:1395–1407. https://doi.org/10.1056/ NEJMoa1915922; PMID: 32227755. 2. Coronary Artery Surgery Study (CASS): a randomized trial of coronary artery bypass surgery. Survival data. Circulation 1983;68:939–50. https://doi.org/10.1161/01.cir.68.5.939; PMID: 6137292. 3. Chaitman BR, Ryan TJ, Kronmal RA, et al. Coronary Artery Surgery Study (CASS): comparability of 10 year survival in randomized and randomizable patients. J Am Coll Cardiol 1990;16:1071–8. https://doi.org/10.1016/07351097(90)90534-v; PMID: 2229750. 4. Boden WE, O’Rourke RA, Teo KK, et al. Optimal medical therapy with or without PCI for stable coronary disease. N Engl J Med 2007;356:1503–16. https://doi.org/10.1056/ NEJMoa070829; PMID: 17387127. 5. Sedlis SP, Hartigan PM, Teo KK, et al. Effect of PCI on longterm survival in patients with stable ischemic heart disease. N Engl J Med 2015;373:1937–46. https://doi.org/10.1056/ NEJMoa1505532; PMID: 26559572. 6. De Bruyne B, Pijls NH, Kalesan B, et al. Fractional flow

10.

11.

Figure 1: Goals of Medical Therapy in the ISCHEMIA Trial1 Physiological • SBP <130 mmHg • LDL <1.8 mmol/l • BMI <25 kg/m2 (or 10% weight loss) • HbA1c <8% (<7% in selected patients)

Behavioural • Smoking cessation • Exercise: moderate (30 min, 5 times/week) • Diet: <7% saturated fats

Goals of medical therapy in stable CAD

Pharmacotherapy • Aspirin (low dose) • High-intensity statin (atorvastatin, rosuvastatin) • ACEI/ARB (hypertension, diabetes, CKD, LVEF <40%) • β-blocker (prior MI, LVEF <40%) • P2Y12 receptor antagonist (contraindication to aspirin/post-PCI status/ACS) • Ezetimibe (unable to reach LDL goal on statin) • Evolocumab (unable to reach LDL goal on statin) ACEI = angiotensin-converting enzyme inhibitor; ACS = acute coronary syndrome; ARB = angiotensin II receptor blocker; CAD = coronary artery disease; CKD = chronic kidney disease; LVEF = left ventricular ejection fraction; PCI = percutaneous coronary intervention; SBP = systolic blood pressure.

(non-anginal) medical therapy as the foundation for treatment of these patients is undisputed, regardless of initial strategy chosen, given the persistent need to prevent atherosclerosis progression and recurrent acute coronary events. Practically, limitations exist in real life. The prescription of goal-directed medical therapy by medical practitioners in a busy clinic setting and patient adherence to multiple medications in a non-trial setting are often suboptimal. Even within the confines of an RCT, the ISCHEMIA trial had an adherence to medication of only approximately 82%, and only approximately 40% of patients achieved the four established goals of LDL <1.8 mmol/l and on statin, SBP <140 mmHg, aspirin use and smoking cessation.1 Ongoing efforts to improve education and modify clinical protocols targeted towards both physicians and patients are essential to improve clinical outcomes through the optimisation of foundational medication prescription and adherence.

reserve-guided PCI versus medical therapy in stable coronary disease. N Engl J Med 2012;367:991–1001. https:// doi.org/10.1056/NEJMoa1205361; PMID: 22924638. Xaplanteris P, Fournier S, Pijls NHJ, et al. Five-year outcomes with PCI guided by fractional flow reserve. N Engl J Med 2018;379:250–59. https://doi.org/10.1056/ NEJMoa1803538; PMID: 29785878. Eikelboom JW, Connolly SJ, Bosch J, et al. Rivaroxaban with or without aspirin in stable cardiovascular disease. N Engl J Med 2017;377:1319–30. https://doi.org/10.1056/ NEJMoa1709118; PMID: 28844192. Steg PG, Bhatt DL, Simon T, et al. Ticagrelor in patients with stable coronary disease and diabetes. N Engl J Med 2019;381:1309–20. https://doi.org/10.1056/NEJMoa1908077; PMID: 31475798. Bhatt DL, Steg PG, Mehta SR, et al. Ticagrelor in patients with diabetes and stable coronary artery disease with a history of previous percutaneous coronary intervention (THEMIS-PCI): a phase 3, placebo-controlled, randomised trial. Lancet 2019;394:1169–80. https://doi.org/10.1016/S01406736(19)31887-2; PMID: 31484629. Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/

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12.

13.

14.

15.

AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation 2019;139:e1082–143. https://doi.org/10.1161/ CIR.0000000000000625; PMID: 30586774. Bhatt DL, Steg PG, Miller M, et al. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med 2019;380:11–22. https://doi.org/10.1056/ NEJMoa1812792; PMID: 30415628. SPRINT Research Group. A randomized trial of intensive versus standard blood-pressure control. N Engl J Med 2015;373:2103–16. https://doi.org/10.1056/NEJMoa1511939; PMID: 26551272. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015;373:2117–28. https://doi.org/10.1056/ NEJMoa1504720; PMID: 26378978. Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2019;380:347–57. https://doi.org/10.1056/NEJMoa1812389; PMID: 30415602.

Management and Comorbidities

Bridging the Gap in a Rare Cause of Angina Sumanth Khadke ,1 Jovana Vidovic

and Vinod Patel3

1. Our Lady of Fatima University, Fatima College of Medicine, Manila, Philippines; 2. Semmelweis University, Budapest, Hungary; 3. Division of Cardiology, Mount Sinai Hospitals, New York, NY, US

Abstract

Myocardial bridging occurs when coronary arteries run intramurally. Episodes of tachycardia can cause a dynamic obstruction that extends into diastole, compromising coronary filling time, and subsequently leading to ischaemia. Myocardial ischaemia, acute coronary syndrome, coronary spasm, myocardial stunning, arrhythmia, takotsubo cardiomyopathy, and sudden cardiac death have all been reported with bridging. Atherosclerotic plaques develop proximally in the bridge due to low shear stress and high oscillatory wall-flow. Factors affecting atherosclerotic build-up include disrupted flow patterns (particularly flow recirculation, which exacerbates LDL internalisation), cell adhesion and monocyte adhesion to the endothelium. Endothelial health depends on arterial flow patterns, given that the vessel reacts differently to various flow types, as confirmed in 3D simulations. Medication is the first-line therapy, while surgical de-roofing and coronary bypass are reserved for severe stenosis. Distinguishing physiological arterial compression from pathological stenosis is essential. Deeper bridges correlating with recurrent angina with an instantaneous wave-free ratio ≤0.89 or fractional flow reserve ≤0.80 are treated.

Keywords

Coronary bridging, intramural, instantaneous wave-free ratio, fractional flow reserve, atherosclerosis, chest pain, milking effect Disclosure: The authors have no conflicts of interest to declare. Received: 17 August 2020 Accepted: 26 October 2020 Citation: European Cardiology Review 2021;16:e05. DOI: https://doi.org/10.15420/ecr.2020.33 Correspondence: Jovana Vidovic, Semmelweis University, Üllői út 26, 1085, Budapest, Hungary. E: jovanavidoviczim@gmail.com Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Coronary arteries typically run a subepicardial course; however, they sometimes tunnel intramurally through the myocardium in an anatomic variant known as myocardial bridging (MB). The exact prevalence of MB is unknown. It is seen in 5–58% of autopsies and on average it is present in one-third of all adults.1 The MB rate on coronary CT is similar to the rate in autopsies, whereas the rate on angiography is 0.5–16%.2 The discrepancy between these numbers suggests a possible underreporting of MB when angiography is used as the imaging tool of choice. In angiography, many factors play a role in the visualisation of the dynamic and phasic narrowing of the artery, namely, the length of the affected segment, the thickness of the myocardium, the orientation of the segment with respect to its surrounding myocardium and the observer’s experience.3 This congenital anomaly typically affects, but is not exclusive to, the midsegment of the left anterior descending artery (LAD). Less frequently, the diagonal and marginal arteries are affected, in 18% and 40% of cases, respectively.1 The length of the MB segment is typically 10–30 mm and it usually runs at a depth of 1–10 mm.4,5 MB deeper than 5 mm is typically not managed with a myotomy.6 According to a retrospective study in Turkey, the prevalence of MB was higher in men than in women, but the influence of or association with hormones was not explored in that study.7 A similar finding is reported by many prior studies without a correlation between hormone effects and MB.5 Prevalence is also increased in patients with hypertrophic cardiomyopathy (HCM) and in heart transplant recipients.8,9

Myocardial Bridging and Heart Transplantation

Between 33% and 63% of heart transplant recipients have been found to have MB.9,10 Most commonly, the bridges have been found to occur in the LAD. Wymore et al. believe that the stiffness and hypertrophy of the transplanted heart allow for better MB detection on angiography, due to the restrictive haemodynamic pattern that forms after the transplant.9 The theory that a decrease in compliance and an increase in fibrosis is associated with the discovery of a higher incidence of MB, is supported by other studies in which there was a higher incidence of MB in patients with left ventricular hypertrophy (LVH), the hallmark of which is the development of myocardial fibrosis.11,12 Wymore et al. also found that the bridge length and degree of stenosis changed over time. This could have occurred due to the differences in the imaging used over time, but they also proposed that it could be due to the changing status of the myocardium secondary to transplant, wherein fibrosis occurs secondary to therapy with drugs such as cyclosporine, and the stiffness of the transplanted heart increases due to chronic rejection.9 Tanaka et al. conducted a study on MB after heart transplantation and found that heart transplant patients with MB had significant acute proximal atherosclerotic plaque build-up when compared with non-MB heart transplant patients, who had diffuse atherosclerotic build-up in the LAD. On Kaplan–Meier analysis, the presence of MB was associated with low event-free survival after heart transplant.13 Hence, it has been proposed that preoperative screening should be done on all donors before

Bridging the Gap in a Rare Cause of Angina Figure 1: Diagnostic Algorithm and Modalities Used to Diagnose Myocardial Bridging Symptomatic MB

Invasive testing

Non-invasive testing

CAG*

FFR

iFR

IVUS

Intracoronary Doppler

<0.75–0.80

<0.89

‘Half-moon’: a persistent echolucent area between the bridge and epicardium

‘Fingertip’ phenomenon

MSCT

SPECT

Stress TOE

FFRCT

At least 1 mm of myocardium covering coronary artery

Segmental perfusion defect

Focal septal buckling with apical sparing

FFR <0.75–0.80

*Shows milking effect due to dynamic systolic compression extending into diastole. CAG = coronary angiography; FFR = fractional flow reserve; FFRCT = CT-derived flow fractional reserve; iFR = instantaneous wave-free ratio; IVUS = intravascular ultrasound; MB = myocardial bridging; MSCT = multi-slice CT; SPECT = single-photon emission CT; TOE = trans-oesophageal echocardiogram.

harvesting and implantation, especially in young donors with an unexplained or suspicious cause of death.10,14 Clinically, MB is usually not associated with adverse events. However, the haemodynamics in an individual with MB can be affected, leading to cardiac events. Whether a patient is symptomatic or not will depend on the length and thickness of the segment, the orientation of the MB in respect to the surrounding myocardium and the presence of any adipose or connective tissue.6 Patients with MB have presented with myocardial ischaemia, acute coronary syndrome (ACS) and coronary spasms.15–17 It has also been associated with myocardial stunning, ventricular arrhythmias, takotsubo cardiomyopathy (TCM) and sudden death.2,18–21 MB should always be considered as a differential diagnosis in young patients without any coronary risk factors who present with exertional chest pain or who have anteroseptal perfusion defects.1

Pathophysiological Alterations in Haemodynamics Due to Myocardial Bridging

In autopsies, as well as on intravascular ultrasound (IVUS), the intramural, as well as the distal portion of the MB, have a lower burden of atherosclerotic plaque compared with the proximal portion. It is the proximal segment that is predisposed to plaque formation due to the low wall shear stress and high oscillatory wall-flow. In vessels with these types of shear stress patterns, as in the proximal MB segment, there is an increased expression of vascular cell adhesion molecule 1, intercellular adhesion molecule-1, C-reactive protein, interleukin-6 and reactive oxygen species, leading to a highly pro-atherogenic environment for the development of plaque.22,23 Furthermore, the increased wall tension and stretch may lead to endothelial injury and plaque rupture, which will consequently lead to thrombus formation in the proximal segment.1 Within the bridged segment, it is thought that the high shear stress is protective against the formation of large clinically significant plaque. Masuda et al. showed that tunnelled segments expressed a lower concentration of endothelial nitric oxide synthase (e-NOS), angiotensin-

converting enzyme and endothelin-1.24 Additionally, in MB there is a lower tendency to branch off than in other segments, which leads to different haemodynamics.25 The study that showed this, however, did not look further into whether this had a protective role in the vessel.25 A few studies suggest that MB has a pivotal role in causing coronary spasms.26 In studies on the effect of MB on the coronary flow reserve, not only was the systolic component of the artery compressed, but this obstruction also continued into diastole for an average time of 136 ms. There is a continuous delay in early diastolic gain with a reduction in mid-diastolic diameter of >30%.27 Taking this into consideration, it implies that situations with tachycardia will lead to decreased diastolic filling time, which then leads to the amplification of any abnormalities that are occurring during systole.6,27 Using intracoronary Doppler, diastolic flow disturbances were seen to predominate in rapid atrial pacing and there were instances of drops in the systemic arterial pressure or coronary perfusion pressure.27 Individuals with MB are also more likely to present with clinical symptoms if they have concomitant hypertrophy of the left ventricle (LV), increased platelet aggregation, or abnormal vasomotion of the coronaries.27

3D Reconstruction of Myocardial Bridging Using Computational Flow Dynamics

One of the recent advances in the field of biomedical engineering is computational flow dynamics (CFD), which enables reconstruction of a 3D model of the coronary artery using a real-time simulation with a more magnified explanation of haemodynamic variation in the stenosed part of the arterial segments.28 The CFD models show that there is high shear stress in the tunnelled artery without any recirculation zones. The proximal segment of the tunnelled artery has different dynamics wherein there is low shear stress but multiple recirculation zones, which, along with an oscillatory flow pattern, cause blood particles to stay in the vessel longer than usual, thus contributing to vessel remodelling and plaque formation.28 Factors

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Bridging the Gap in a Rare Cause of Angina Figure 2: Manifestation of Myocardial Bridging on Coronary Angiogram

Severe stenosis in the middle left anterior descending artery with mild squeezing distal to the stenosis.

affecting atherosclerotic build-up include disrupted flow patterns (especially flow recirculation, which exacerbates LDL internalisation), cell adhesion and monocyte adhesion to the endothelium.29 The range of recirculatory flow governs the appearance of prothrombotic and atherogenic biomarkers at the bifurcation of arteries. Oxidised LDL uptake, monocyte adhesion and tissue factor expression are increased by up to threefold, while phosphorylated e-NOS and Krüppel-like factor 2 have been shown to decrease by up to twofold in recirculation areas. The endothelial health depends highly on arterial flow patterns, and vessels react differently to various flow types, as seen on 3D flow simulations using CFD. The carotid and coronary artery bifurcations behave similarly in multiple aspects.29

Diagnosis of Myocardial Bridging

There is no gold standard test for the diagnosis of MB. It can be visualised using both invasive and non-invasive techniques (Figure 1). It is important that if such a diagnosis is made, the haemodynamic effects should also be assessed, using Doppler flow catheters or intracoronary pressure wires.1 On conventional coronary angiography, the first impression of MB is as an intramural course of epicardial arteries (Figure 2).

Tools to Diagnose Ischaemia in a Stenosed Segment

Instantaneous Wave-free Ratio versus Fractional Flow Reserve

Traditionally, fractional flow reserve (FFR) has been considered the gold standard for the measurement of differences of pressure across coronary artery stenosis. However, it has limitations with regards to deciding the need for intervention when the value lies between 0.75 and 0.80. This is known as the FFR grey zone. According to the principle of physiologic autoregulation, for a stenosis to be significantly noticeable, it should affect the diastolic phase. The probability of the decision to revascularise will change by nearly 50% in this grey zone area. The specificity of FFR falls to 80% when compared with non-invasive methods in this grey zone, which calls for attention. Clinicians should personalise the treatment strategy if FFR is in the grey zone.30,31

FFR assumes a directly proportional relationship between pressure and flows in the intracoronary stenosed segment. The measurement of FFR requires a constant flow of blood across the distal stenosis, hence, adenosine (intracoronary vasodilator) is administered to measure FFR throughout the cardiac cycle. FFR is a pressure-based gauging modality to estimate a loss of blood flow based on pressure loss: for example, a 20% pressure loss across the stenosis is equivalent to an FFR value of 0.80.30 During systole, there is high intracoronary resistance and high compression in myocardial vessels and vice versa in diastole. This shows that the nature of resistance is not constant; instead, it is dynamic and varies periodically. The dilating effect of adenosine is an unwelcome experience for many patients because it causes chest heaviness and tightness, can aggravate atrioventricular blockade and in some cases can lead to dyspnoea with hypotensive episodes. All the aforementioned factors limit the usage of FFR for the diagnostic quantification of stenosis. This makes the instantaneous wave-free ratio (iFR) a better option over FFR.31,32 iFR measures the physiological impact of the stenosis on the distal coronary bed using wave intensity analysis. It can separate six kinds of waves that originate in the myocardium at specific points and which are directional in nature. These waves can be categorised, based on their origin, as distal or proximal; and, based on their effect on blood flow, as compressive or expansive. The ideal phase for quantification of stenosis is in diastole, given that it is the wave-free period.30 Two noteworthy clinical trials, iFR-SWEDEHEART (NCT02166736) and DEFINE-FLAIR (NCT02053038) have proven that iFR is non-inferior to FFR in deciding the need for intervention.32 iFR-deferred intervention outcomes were similar to FFR-deferred intervention outcomes. It was found that ACS patients had worse outcomes than stable coronary artery disease patients when FFR was used and had similar outcomes when iFR was used.33 iFR is also the best modality to diagnose a diffuse atherosclerotic disease, to enable clinicians to opt for coronary artery bypass graft (CABG) instead of stent placement.30 FFR values are unreliable due to the dynamic nature of coronary obstruction due to MB. The systolic overshooting and negative systolic pressure gradient (i.e. the

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Bridging the Gap in a Rare Cause of Angina Myocardial Bridging in Hypertrophic Cardiomyopathy and Systolic Dyssynchrony

Figure 3: Diagnostic Sign of Myocardial Bridging on Intravascular Ultrasound

HCM is one of the causes of sudden cardiac death (SCD) due to its capricious course and heterogeneity. There is an ongoing dilemma about whether MB is associated with ischaemic mortality in HCM. The presence of wall motion abnormalities and abnormal thallium-201 scans points towards faulty perfusion associated with the MB phenomenon. Angiographic evidence of MB over LAD is found in 30–50% of HCM cases and such stenosis should be alarming in documented HCM due to possible SCD.12 Myocardial ischaemia is a well-documented cause of SCD in HCM, although it is not clear whether MB is a primary factor or a confounder in the extensive ischaemia that leads to SCD in these patients.37

A half-moon-shaped echo-lucent area (arrowheads) is seen between the bridged segment and the epicardial tissue. This persists throughout the cardiac cycle (Supplementary Video 2).

average coronary pressure distal to the MB is higher than the aortic pressure during systoler) compromise FFR readings.33 FFR is validated for a fixed stenotic lesion that is not affected by systolic compression at rest or by inotropic challenge.33 In contrast, iFR allows us to anatomically localise and highlight coronary arteries that run intramurally and to locate points of pressure drops (tunnelled segments) during the cycle.33

Non-invasive Myocardial Bridging Assessment

Non-invasive techniques to assess MB include multi-slice CT (MSCT), single-photon emission CT (SPECT) and stress echocardiography (Figure 1). MSCT allows us to visualise the segment of coronary that is enveloped by myocardium and to assess the haemodynamic effect that MB may have. Stress SPECT can correlate the amount of systolic luminal narrowing to the amount of ischaemia.6 A study was carried out in patients with MB in the LAD (confirmed on IVUS), in which the team sought to identify any unique findings on exercise echocardiogram in patients with symptomatic MB. They found that there was transient focal buckling at the end-systolic–early diastolic motion of the septum with apical sparing.34 Using invasive imaging, MB can be visualised on angiography (Figure 2) and on IVUS (Figures 3 and 4). With conventional angiography, a change known as the ‘milking effect’ (Supplementary Material Video 1) can be observed when there is a reduction of the minimum luminal diameter (MLD) by at least 70% during systole and there is a persistent MLD >35% by the mid-end phase of diastole. This milking effect can be further exaggerated by positive chronotropic effects (which decrease the diastolic filling time) such as those due to dobutamine infusion or if the patient is on nitroglycerin, which can cause reflex tachycardia.6,27 It is this characteristic dynamic and phasic narrowing of the affected segment that distinguishes it from a fixed plaque.1 On angiography, MB is graded according to the severity of systolic compression of LAD as grade 1, <50%; grade 2, 50–75%; and grade 3, >75%.35 In a 5-year follow up of a retrospective study, it was found that patients with symptomatic MB who had objective signs of ischaemia (classified as type B as per Shwartz classification [Figure 5]), responded well to treatment with β-blockers or calcium channel blockers.36 IVUS is an essential modality to diagnose MB (Supplementary Material Video 2). It is characterised by a half-moon-shaped echo-lucent area found between the bridged segment and the epicardial tissue that persists throughout the cardiac cycle (Figure 3).6

According to clinical studies to date, there is no significant mortality in patients with HCM and MB as compared with HCM without MB.8 This does not necessarily rule out the role of MB in a pathological accentuation of clinical symptoms. In a study by Basso et al. in which they morphologically analysed 250 hearts, there was no systemic association between MB in HCM patients and HCM-related sudden death, although MB was commonly found in phenotypically expressed HCM patients.11 Hence, the most acceptable treatment strategy is to identify additional risk factors and to quantify the severity of MB in HCM patients. It has long been questioned as to what percent of stenosis and length of MB are critical to affect LV functioning. Cai et al. noted a prevalence of LV systolic dyssynchrony in 25.7% (9/35) in patients with isolated symptomatic LAD MB.38 The presence of hypertension was an independent causative factor for dyssynchrony, and the combination of MB with critical stenosis and hypertension contributed significantly to systolic dyssynchrony.38 The study emphasised that stenosis >50% causes critical systolic compression and that the stenosis and length of MB have a synergistic effect on the development of dyssynchrony.38 At a critical stenosis of 50% and above, the length of the MB segment starts to have a significantly deleterious effect on LV systolic and diastolic function, which affects stroke volume. The study also emphasised that hypertension leads to diastolic dysfunction, which again contributes to dyssynchrony.38 Yetman et al. also noted that the presence of MB in HCM in children is associated with a poor prognosis.12

Myocardial Bridging Causing Arrhythmia and Role of QT Dispersion

It is believed that arrhythmias arise in patients with MB due to the limited coronary flow that occurs during periods of increased oxygen demand. Under these circumstances, the ischaemia induced by the decreased diastolic filling time leads to myocardial electrical heterogeneity.39 Increased electrical heterogeneity increases the propensity towards the development of cardiac arrhythmias. Ventricular repolarisation indices such as Tpeak–Tend interval, their dispersions and ratios, as well as QT dispersion (QTd) have all been found to be significantly increased in patients with MB, particularly during exercise.39,40 QTd is defined as the difference between the minimum and the maximum QT intervals; it is an effective marker for electrical myocardial heterogeneity and higher values are associated with an increased risk of cardiac arrhythmia.41 QTd is also a measure of the regional variability between myocardial excitability and recovery in the ECG leads used in the measurement of corrected QT interval.12 One plausible explanation for MB-associated arrhythmias is the chronic myocardial ischaemia that develops, which causes diffuse fibrosis and an increased disarray of myocardial fibres, creating an arrhythmogenic focus.12

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Bridging the Gap in a Rare Cause of Angina Figure 4: Intravascular Ultrasound Findings of Myocardial Bridging Along the Left Anterior Descending Artery Pre-intervention IVUS findings Longitudinal image

Proximal reference

Minimum lumen area

Distal reference

Lumen area: 8.2 mm2

Lumen area: 1.8 mm2 Vessel area: 15.4 mm2

Lumen area: 6.0 mm2 Vessel area: 8.6 mm2

Vessel area: 18.8 mm2

A: Proximal reference segment; lumen (yellow circle) and vessel (red circle) areas measure 8.2 mm2 and 18.8 mm2, respectively. The proximal reference vessel diameter measures 5.0 mm × 4.9 mm with an average vessel diameter of 4.9 mm. B: Slice with both first septal (S1) and first diagonal (D1) branches. C: Slice with superficial calcium. D: Minimum lumen area site with positively remodelled non-calcified plaque. The lumen (yellow circle) and vessel (red circle) areas measure 1.8 mm2 and 15.4 mm2, respectively. E: Distal reference segment, and lumen (yellow circle) and vessel (red circle) areas measure 6.0 mm2 and 8.6 mm2, respectively. E: Distal reference site, and muscle bridge on the top of the left anterior descending artery (LAD). The distal reference vessel diameter measured 3.7 mm × 3.0 mm with an average vessel diameter of 3.4 mm. The total length of myocardial bridge measured 17 mm.

Heart rate (HR) and HR recovery (HRR) can also be investigated in patients with MB to provide prognostic information. Under a graded exercise scheme, HRR can be used to indicate the autonomic activity of the heart, which can predict adverse cardiovascular events. This is done by subtracting the first-, second- and third-minute HR from the maximum HR achieved during exercise. In patients with MB, the HRR was blunted compared with normal patients, particularly when the LAD was involved.42 This is related to the fact that there is an imbalance in the autonomic nervous system in patients with MB.42 One may therefore propose that not only does the ischaemia-induced myocardial heterogeneity increase the propensity toward arrhythmias, but so does the increased sympathetic overactivation during exercise in patients with MB. A study by Nishikii-Tachibana et al. found that during exercise, patients with MB developed premature ventricular contractions and non-sustained ventricular tachycardia more frequently than the general population.19 Hence, patients with MB benefit from β-blockers because they reduce systolic compression and have a negative inotropic effect.42 Although, theoretically, a multivessel bridge can cause significant ischaemia to trigger atrial dysrhythmia (fibrillation), we did not find sufficient existing research correlating MB with AF.

MI Due to Myocardial Bridging

There are two hypotheses for the incidence of MI in MB patients. One involves the dynamic compression of myocardial fibres forming the tunnel, and the other, the accelerated formation of atherosclerosis in the proximal segments of the MB. The former appears to be a prime mechanism of coronary insufficiency in psychophysical exertion in young patients, while the latter mechanism is seen in elderly patients.43 Hostiuc et al. conducted a meta-analysis and meta-regression study and found that MB increased the likelihood of major adverse cardiac events and ischaemia in the presence of hypertension, smoking and diabetes.41 Intracoronary Doppler showed a fingertip-like anterograde blood flow, with a sharp increase in flow velocity during early diastole, followed by a steep decrease in speed, ultimately plateauing in mid-late diastole. During systole there is a decreased, absent or reversed forward flow.41 The myocardium dilates at the end of diastole, causing negative pressure in the bridge segment, which results in a ‘sucking phenomenon’.41,44 This compression is commonly eccentric rather than concentric, leading to half-moon-shaped echo-lucency as mentioned before.41,44 If the systolic compression of MB is elliptical, it is associated with 50% stenosis; and if the compression is concentric, then it translates to 75% stenosis of the luminal area.41,45

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Bridging the Gap in a Rare Cause of Angina The extent and duration of compression of bridged segments of coronary arteries are of clinical importance because the compression can trigger exertional chest pain, which may mimic MI in young people. The mechanisms leading to MI are the extension of systolic compression of the bridged segment into diastole, causing diastolic lag in the filling, which reduces the coronary reserve; endothelial dysfunction in the intramural course of the artery; and haemodynamic changes proximal to a bridged segment of the artery.46

is an increase in sympathetic drive from the surge in catecholamines that leads to an increased heart rate, aggravating the compression of the bridge, especially if LVH is present. The result is clinically symptomatic MB and the development of TCM.53

The plaque formation in the proximal artery segment could be explained by a change in the properties of the endothelium due to the chronic coronary pressure gradient that exists between the tunnelled and nontunnelled segments, which creates a coronary pressure overload.47 Intracoronary acetylcholine normally causes vasodilation by releasing endothelium-dependent relaxing factor if the endothelium is healthy and intact. However, it causes a paradoxical vasoconstriction if atherosclerotic lesions have affected the endothelium. Bilen et al. showed that patients with MB had an increased mean platelet volume, which causes increased reactivity and induces more production of prothrombotic factors.48 A confluence of decreased prostacyclin and nitric oxide, impaired endothelin-dependent vasodilation and increased proximal atherosclerosis causes chronic ischaemic milieu and possible MI.

In terms of acute therapy in the setting of TCM with MB, it is logical to think that the contractility induced by the surge of catecholamines may be suppressed with the use of a negative inotrope such as a β-blocker. Kato et al. found that this may be an option.20

Coronary Artery Spasms Caused by Myocardial Bridging

Coronary spasms occur more often in MB compared with non-MB patients. Chronic endothelial and smooth muscle cell dysfunction may be involved in the genesis of spasms. Ultrastructural studies conducted by Ishii et al. showed loss of smooth muscle cells both proximally and distally to the bridge.49 Turbulent flow causes tumour necrosis factoralpha-induced endothelial activation. The endothelial dysfunction and activation, and the turbulent flow of the blood in the tunnel can cause spasms due to ischaemia.26

Broken Heart Syndrome due to Coronary Anomalies

Takotsubo cardiomyopathy, also known as broken heart syndrome or stress-induced cardiomyopathy, is thought to be associated with the aetiology of anomalous coronary circulation. MB with a long, recurrent wraparound LAD (wrap-LAD) has been postulated to cause worsening of TCM.51 To understand this association, we need to understand coronary artery tortuosity (CAT). CAT is identified using two criteria: ≥3 consecutive curvatures ≥90°; or ≥2 consecutive turns ≥180°.50–52 Wrap-LAD was defined as any part of the vessel outreaching the apex of the LV. It is the most common anatomical anomaly associated with TCM.50 The combination of a catecholamine surge bringing a hypersympathetic response with a pre-existing coronary wrap-LAD along with MB can cause TCM.50 It was also hypothesised that plaque rupture in wrap-LAD with transient coronary artery occlusion and spontaneous thrombolysis can cause regional wall motion abnormalities in the middle and apical anterior and inferior segments, as observed by Arcari et al.50 Symptomatic MB can contribute to the worsening of TCM outcomes. Kato et al. found that TCM patients with MB had a higher in-hospital death rate than patients with TCM and no MB.20 The majority of deaths in that study, however, were from a non-cardiac origin, possibly due to the differing degree of systolic compression in each case.20 Migliore et al. suggest that MB acts as a substrate for the development of TCM. During the emotional distress that occurs at the onset of TCM, there

Most commonly, typical apical ballooning is found in TCM when MB is present.20 This may be explained by the fact that it is predominantly the LAD that is enveloped in myocardium.53–55

Coronary Artery Dissection in Myocardial Bridging

Although rare, MB is associated with dissection in some cases. The separation of intima and media requires high shear stress and severe vasoconstriction. Acetylcholine is known to cause vasoconstriction in dysregulated endothelium burdened with atherosclerosis.47 The tunnelled artery has high shear stress along with coronary spasms, which could be linked to the occurrence of coronary artery dissection. Some studies report an association of SCD with coronary artery dissection in patients with MB.56,57

Treatment of Myocardial Bridging

There is an ongoing dilemma of whether to surgically de-roof MB or perform CABG, or to treat it with medication or to place a stent. According to the literature, MB is to be treated only when the patients have symptoms.27 A treatment algorithm for MB is given in Figure 5. Medication therapy consists of β-blockers, calcium channel blockers and antiplatelet therapy. However, with refractory symptoms, surgery may be warranted. Unless there is a significant co-existing coronary vasospasm, nitrates should be avoided in patients with MB because the rebound tachycardia that they induce can exacerbate the stenosis. β-blockers decrease the HR, decrease the contractility and compression of the coronary arteries and reduce coronary filling time, thus they have been used as first-line treatment.6,33 Certain studies suggest that iFR ≤0.89 or FFR ≤0.80 with signs of chest pain and heaviness should be managed with medical or surgical intervention.31 MB that runs deep (>5 mm deep) should be treated with CABG because it has been shown to be better than surgical myotomy.58 MB that is short or intermediate in depth and severity should be treated with medication alone.58,59 Surgical de-roofing of MB poses a risk of ventricular injury leading to bleeding and the formation of aneurysm. However, in a small series of patients who have solitary, haemodynamically significant and symptomatic MB that was resistant to the maximally tolerated dosage of medication, their symptoms improved dramatically after surgical intervention.60 Percutaneous coronary intervention has been selectively used on affected vessels given that the rates of stent restenosis, fracture and stent failure are high.59,60 Atherosclerotic plaque formation in association with MB raises concern regarding a significant reduction in blood supply. It is challenging to treat such cases given that many physicians hold different opinions as to when to treat patients with significant comorbidities. Significant groups of patients have mild MB with several chest pain episodes, decreasing their quality of life, whereas other patients may have rare events with the significant deep bridging of the LAD. Such patients should always be

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Bridging the Gap in a Rare Cause of Angina Figure 5: Treatment Algorithm for Myocardial Bridging According to Severity Myocardial bridging

Schwarz classification

iFR ≤0.89 or FFR ≤0.80 with chest pain

Morphology of bridge

Class A: no therapy indicated

Treat with BBs/CCBs

Short or intermediate depth and severity: treat with BBs/CCBs

Class B: BBs/CCBs

If resistant to medication, perform surgery >5 mm in depth: treat with CABG

Class C: BBs/CCBs, or if resistant to medical therapy, consider revascularisation

If solitary, haemodynamically significant, symptomatic and resistant to the maximally tolerated dosage of medication, perform surgical de-roofing

BB = β-blocker; CABG = coronary artery bypass graft; CCB = calcium channel blocker; FFR = fractional flow reserve; iFR = instantaneous wave-free ratio.

advised to return to hospital if the pain presents for prolonged periods, with atypical manifestations of MI explained well-beforehand by cardiologists. Patient education can play an important role in the management of MB.

haemodynamic effects not only affect the systole but also continue into diastole, affecting coronary perfusion. Clinical suspicion should remain high for MB in all cases of typical and atypical chest pain, especially in young patients without any coronary risk factors.

Conclusion

Treatment of patients with MB is based on risk factors and symptomatology. It is not yet known how MB contributes to cardiac morbidity and prognostic outcomes in cardiac patients. The treatment depends on the depth of MB and on the severity of haemodynamic disturbance compromising cardiac function. Currently, medication is the accepted first-line therapy, while surgical de-roofing and CABG are reserved for severe stenosis.

MB is a congenital condition that is commonly found on autopsy, coronary CT and angiography. It is typically a benign condition but is often under- or over-treated. MB can run a clinically dangerous course given that it has been associated with myocardial ischaemia, ACS, coronary spasm, coronary artery dissection, myocardial stunning and arrhythmia. Plaque burden slowly builds in the proximal segment and the obstructive 1. Mohlenkamp S, Hort W, Ge J, Erbel R. Update on myocardial bridging. Circulation 2002;106:2616–22. https://doi. org/10.1161/01.CIR.0000038420.14867.7A; PMID: 12427660. 2. Alegria JR, Herrmann J, Holmes Jr DR, et al. Myocardial bridging. Eur Heart J 2005;26:1159–68. https://doi. org/10.1093/eurheartj/ehi203; PMID: 15764618. 3. Sorajja P, Iskandrian AE, Tarantini G. Myocardial bridging of the coronary arteries. UpToDate 22 April 2019. 4. Penther P, Blanc JJ, Boschat J, et al. Intramural anterior interventricular artery. Anatomical study. Arch Mal Coeur Vaiss 1977;70:1075–9 [in French]. PMID: 413516. 5. Angelini P, Trivellato M, Donis J, Leachman RD. Myocardial bridges: a review. Prog Cardiovasc Dis 1983;26:75–88. https://doi.org/10.1016/0033-0620(83)90019-1; PMID: 6346395. 6. Corban MT, Hung OY, Eshtehardi P, et al. Myocardial bridging: contemporary understanding of pathophysiology with implications for diagnostic and therapeutic strategies. J Am Coll Cardiol 2014;63:2346–55. https://doi.org/10.1016/j. jacc.2014.01.049; PMID: 24583304. 7. Aydar Y, Yazici HU, Birdane A, et al. Gender differences in the types and frequency of coronary artery anomalies. Tohoku J Exp Med 2011;225:239–47. https://doi.org/10.1620/ tjem.225.239; PMID: 22056781. 8. Sorajja P, Ommen SR, Nishimura RA, et al. Myocardial bridging in adult patients with hypertrophic cardiomyopathy. J Am Coll Cardiol 2003;42:889–94. https://doi.org/10.1016/ S0735-1097(03)00854-4; PMID: 12957438. 9. Wymore P, Yedlicka JW, Garcia-Medina V, et al. The incidence of myocardial bridges in heart transplants. Cardiovasc Intervent Radiol 1989;12:202–6. https://doi. org/10.1007/BF02577154; PMID: 2513117. 10. Brewer ZE, Strehl C, Khush KK, Schnittger I. Myocardial bridging is associated with worsened survival in heart

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17. Ural E, Bildirici U, Celikyurt U, et al. Long-term prognosis of non-interventionally followed patients with isolated myocardial bridge and severe systolic compression of the left anterior descending coronary artery. Clin Cardiol 2009;32:454–7. https://doi.org/10.1002/clc.20570; PMID: 19685519. 18. Morales AR, Romanelli R, Boucek RJ. The mural left anterior descending coronary artery, strenuous exercise and sudden death. Circulation 1980;62:230–7. https://doi.org/10.1161/01. CIR.62.2.230; PMID: 7397963. 19. Nishikii-Tachibana M, Pargaonkar VS, Schnittger I, et al. Myocardial bridging is associated with exercise-induced ventricular arrhythmia and increases in QT dispersion. Ann Noninvasive Electrocardiol 2018;23(2):e12492. https://doi. org/10.1111/anec.12492; PMID: 28921787. 20. Kato K, Kitahara H, Saito Y, et al. Impact of myocardial bridging on in-hospital outcome in patients with takotsubo syndrome. J Cardiol 2017;70:615–9. https://doi.org/10.1016/j. jjcc.2017.04.004; PMID: 28522138. 21. Marchionni N, Chechi T, Falai M, et al. Myocardial stunning associated with a myocardial bridge. Int J Cardiol 2002;82:65–7. https://doi.org/10.1016/S0167-5273(01)005800; PMID: 11786161. 22. Caroline C, Dennie T, Rien vH, et al. Atherosclerotic lesion size and vulnerability are determined by patterns of fluid shear stress. Circulation 2006;113:2744–53. https://doi. org/10.1161/circulationaha.105.590018; PMID: 16754802. 23. McNally JS, Davis ME, Giddens DP, et al. Role of xanthine oxidoreductase and NAD(P)H oxidase in endothelial superoxide production in response to oscillatory shear stress. Am J Physiol Heart Circ Physiol 2003;285:H2290–7. https://doi.org/10.1152/ajpheart.00515.2003; PMID: 12958034. 24. Masuda T, Ishikawa Y, Akasaka Y, et al. The effect of

Bridging the Gap in a Rare Cause of Angina myocardial bridging of the coronary artery on vasoactive agents and atherosclerosis localization. J Pathol 2001;193:408–14. https://doi.org/10.1002/10969896(2000)9999:9999<::AID-PATH792>3.0.CO;2-R; PMID: 11241423. 25. Loukas M, Bhatnagar A, Arumugam S, et al. Histologic and immunohistochemical analysis of the antiatherogenic effects of myocardial bridging in the adult human heart. Cardiovasc Pathol 2014;23:198–203. https://doi.org/10.1016/j. carpath.2014.03.002; PMID: 24768417. 26. Teragawa H, Fukuda Y, Matsuda K, et al. Myocardial bridging increases the risk of coronary spasm. Clin Cardiol 2003;26:377–83. https://doi.org/10.1002/clc.4950260806; PMID: 12918640. 27. Bourassa MG, Butnaru A, Lespérance J, Tardif J-C. Symptomatic myocardial bridges: overview of ischemic mechanisms and current diagnostic and treatment strategies. J Am Coll Cardiol 2003;41:351–9. https://doi. org/10.1016/S0735-1097(02)02768-7; PMID: 12575960. 28. Javadzadegan A, Moshfegh A, Fulker D, et al. Development of a computational fluid dynamics model for myocardial bridging. J Biomech Eng 2018;140:091010. https://doi. org/10.1115/1.4040127. PMID: 29801175. 29. Martorell J, Santomá P, Kolandaivelu K, et al. Extent of flow recirculation governs expression of atherosclerotic and thrombotic biomarkers in arterial bifurcations. Cardiovasc Res 2014;103:37–46. https://doi.org/10.1093/cvr/cvu124; PMID: 24841070. 30. Götberg M, Cook CM, Sen S, et al. the evolving future of instantaneous wave-free ratio and fractional flow reserve. J Am Coll Cardiol 2017;70:1379–402. https://doi.org/10.1016/j. jacc.2017.07.770; PMID: 28882237. 31. Baumann S, Chandra L, Skarga E, et al. Instantaneous wave-free ratio (iFR®) to determine hemodynamically significant coronary stenosis: a comprehensive review. World J Cardiol 2018;10:267–77. https://doi.org/10.4330/wjc.v10. i12.267; PMID: 30622685. 32. Stegehuis VE, Wijntjens GW, Murai T, et al. Assessing the haemodynamic impact of coronary artery stenoses: intracoronary flow versus pressure measurements. Eur Cardiol 2018;13:46–53. https://doi.org/10.15420/ecr.2018:7:2; PMID: 30310471. 33. Waterbury TM, Tarantini G, Vogel B, et al. Nonatherosclerotic causes of acute coronary syndromes. Nat Rev Cardiol 2020;17:229–41. https://doi.org/10.1038/s41569019-0273-3; PMID: 31582839. 34. Lin S, Tremmel JA, Yamada R, et al. A novel stress echocardiography pattern for myocardial bridge with invasive structural and hemodynamic correlation. J Am Heart Assoc 2013;2:e000097. https://doi.org/10.1161/ JAHA.113.000097; PMID: 23591827. 35. Noble J, Bourassa MG, Petitclerc R, et al. Myocardial bridging and milking effect of the left anterior descending coronary artery: normal variant or obstruction? Am J Cardiol 1976;37:993–9. https://doi.org/10.1016/0002-9149(76)90414-

8; PMID: 1274883. 36. Schwarz ER, Gupta R, Haager PK, et al. Myocardial bridging in absence of coronary artery disease: proposal of a new classification based on clinical-angiographic data and longterm follow-up. Cardiology 2009;112:13–21. https://doi. org/10.1159/000137693; PMID: 18577881. 37. Olivotto I, Cecchi F, Yacoub MH. Myocardial bridging and sudden death in hypertrophic cardiomyopathy: Salome drops another veil. Eur Heart J 2009;30:1549–50. https://doi. org/10.1093/eurheartj/ehp216; PMID: 19491131. 38. Cai W, Dong Y, Zhou X, et al. Left ventricular systolic dyssynchrony in patients with isolated symptomatic myocardial bridge. Scand Cardiovasc J Suppl 2013;47:11–9. https://doi.org/10.3109/14017431.2012.736635; PMID: 23036109. 39. Aparci M, Yalcin M, Isilak Z, et al. Increased propensity to arrhythmia in patients with myocardial bridging. J Am Coll Cardiol 2013;62(18 Suppl 2):C204. https://doi.org/10.1016/j. jacc.2013.08.579. 40. Aksan G, Nar G, İnci S, et al. Exercise-induced repolarization changes in patients with isolated myocardial bridging. Med Sci Monit 2015;21:2116–24. https://doi.org/10.12659/ MSM.893632; PMID: 26198682. 41. Hostiuc S, Rusu MC, Hostiuc M, et al. Cardiovascular consequences of myocardial bridging: a meta-analysis and meta-regression. Sci Rep 2017;7:14644. https://doi. org/10.1038/s41598-017-13958-0; PMID: 29116137. 42. Okutucu S, Aparci M, Sabanoglu C, et al. Assessment of cardiac autonomic functions by heart rate recovery indices in patients with myocardial bridge. Cardiol J 2016;23:524– 31. https://doi.org/10.5603/cj.a2016.0046; PMID: 27387063. 43. Lujinovic A, Kulenovic A, Kapur E, Gojak R. Morphological aspects of myocardial bridges. Bosn J Basic Med Sci 2013;13:212–7. https://doi.org/10.17305/bjbms.2013.2304; PMID: 24289755. 44. Ge J, Jeremias A, Rupp A, et al. New signs characteristic of myocardial bridging demonstrated by intracoronary ultrasound and Doppler. Eur Heart J 1999;20:1707–16. https:// doi.org/10.1053/euhj.1999.1661; PMID: 10562478. 45. Angelini P, Trivellato M, Donis J, et al. Myocardial bridges: a review. Prog Cardiovasc Dis 1983;26:75–88. https://doi. org/10.1016/0033-0620(83)90019-1; PMID: 6346395. 46. Javadzadegan A, Moshfegh A, Hassanzadeh Afrouzi H. Relationship between myocardial bridge compression severity and haemodynamic perturbations. Comput Methods Biomech Biomed Eng 2019;22:752–63. https://doi.org/10.1080/ 10255842.2019.1589458; PMID: 30880461. 47. Tajrishi FZ, Ahmad A, Jamil A, et al. Spontaneous coronary artery dissection and associated myocardial bridging: current evidence from cohort study and case reports. Med Hypotheses 2019;128:50–3. https://doi.org/10.1016/j. mehy.2019.05.012; PMID: 31203908. 48. Bilen E, Tanboga IH, Kurt M, et al. Increase in mean platelet volume in patients with myocardial bridge. Clin Appl Thromb

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Hemost 2013;19:437–40. https://doi.org/10.1177/ 1076029612439342; PMID: 22387585. 49. Ishii T, Asuwa N, Masuda S, et al. Atherosclerosis suppression in the left anterior descending coronary artery by the presence of a myocardial bridge: an ultrastructural study. Mod Pathol 1991;4:424–31. PMID: 1924274. 50. Arcari L, Limite LR, Cacciotti L, et al. Tortuosity, recurrent segments, and bridging of the epicardial coronary arteries in patients with the takotsubo syndrome. Am J Cardiol 2017;119:243–8. https://doi.org/10.1016/j. amjcard.2016.09.055; PMID: 27866652. 51. Gaibazzi N, Rigo F, Reverberi C. Severe coronary tortuosity or myocardial bridging in patients with chest pain, normal coronary arteries, and reversible myocardial perfusion defects. Am J Cardiol 2011;108:973–8. https://doi. org/10.1016/j.amjcard.2011.05.030; PMID: 21784382. 52. Groves SS, Jain AC, Warden BE, et al. Severe coronary tortuosity and the relationship to significant coronary artery disease. W V Med J 2009;105:14–7. PMID: 19585899. 53. Migliore F, Maffei E, Perazzolo Marra M, et al. LAD coronary artery myocardial bridging and apical ballooning syndrome. JACC Cardiovasc Imaging 2013;6:32–41. https://doi. org/10.1016/j.jcmg.2012.08.013; PMID: 23328559. 54. Ibáñez B, Navarro F, Farré J, et al. Tako-tsubo syndrome associated with a long course of the left anterior descending coronary artery along the apical diaphragmatic surface of the left ventricle. Rev Esp Cardiol 2004;57:209–16 [in Spanish]. https://doi.org/10.1016/s0300-8932(04)77092-x; PMID: 15056424. 55. Lemaitre F, Close L, Yarol N, et al. Role of myocardial bridging in the apical localization of stress cardiomyopathy. Acta Cardiol 2006;61:545–50. https://doi.org/10.2143/ AC.61.5.2017770; PMID: 17117755. 56. Wu S, Liu W, Zhou Y. Spontaneous coronary artery dissection in the presence of myocardial bridge causing myocardial infarction: an insight into mechanism. Int J Cardiol 2016;206:77–8. https://doi.org/10.1016/j.ijcard.2016.01.085; PMID: 26780679. 57. Ge JB, Huang Z-Y, Liu X-B, et al. Spontaneous coronary dissection associated with myocardial bridge causing acute myocardial infarction. Chin Med J (Engl) 2008;121:2450–3. PMID: 19102967. 58. Attaran S, Moscarelli M, Athanasiou T, Anderson J. Is coronary artery bypass grafting an acceptable alternative to myotomy for the treatment of myocardial bridging? Interact Cardiovasc Thorac Surg 2013;16:347–9. https://doi.org/10.1093/ icvts/ivs459; PMID: 23171516. 59. Alsoufi B. Do not miss the bridge. J Thorac Cardiovasc Surg 2018;156:1627–8. https://doi.org/10.1016/j.jtcvs.2018.02.082; PMID: 29602419. 60. Boyd JH, Pargaonkar VS, Scoville DH, et al. Surgical unroofing of hemodynamically significant left anterior descending myocardial bridges. Ann Thorac Surg 2017;103:1443–50. https://doi.org/10.1016/j. athoracsur.2016.08.035; PMID: 27745841.

Atrial Fibrillation

Atrial Fibrillation in Congenital Heart Disease Irene Martín de Miguel

1,2,3

and Pablo Ávila

1,2,3

1. Cardiology Department, Hospital General Universitario Gregorio Marañón, Madrid, Spain; 2. Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain; 3. Faculty of Medicine, Universidad Complutense and CIBERCV, Madrid, Spain

Abstract

The increasing prevalence of AF in a growing population of adults with congenital heart disease (CHD) poses new challenges to clinicians involved in the management of these patients. Distinctive underlying anatomies, unique physiological aspects, a high diversity of corrective surgeries and associated comorbidities can complicate clinical decision-making. In this review, the authors provide an overview of the current knowledge on epidemiology and pathophysiology, with a special focus on the differences to the non-CHD population and the clinical impact of AF in adults with CHD. Acute and long-term management strategies are summarised, including the use of antiarrhythmic drugs, catheter or surgical ablation and prophylaxis of thromboembolism. Finally, gaps of knowledge and potential areas of future research are highlighted.

Keywords

Atrial fibrillation, atrial arrhythmias, adult congenital heart disease, anticoagulation, antiarrhythmic drugs, catheter ablation Disclosure: The authors have no conflicts of interests to declare. Received: 20 October 2020 Accepted: 8 December 2020 Citation: European Cardiology Review 2021;16:e06. DOI: https://doi.org/10.15420/ecr.2020.41 Correspondence: Pablo Ávila, Cardiac Arrhythmias Unit, Adult Congenital Heart Disease Program, Cardiology Department, Hospital General Universitario Gregorio Marañón, 46 Doctor Esquerdo St, 28007, Madrid, Spain. E: pablo.avila@salud.madrid.org Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Epidemiology

The survival of patients with congenital heart disease (CHD) has improved dramatically over the past decades, due to continuous advances in medical care and surgical techniques. More than 85% of these individuals reach adulthood and there has been an estimated 63% rise in this population since 2000.1–3 Therefore, physicians must now deal with potential consequences derived from the natural progression of the disease, late sequelae from previous interventions or acquired conditions.4

with CHD, including paediatric and adult cardiologists and electrophysiologists with expertise in CHD, collaborate to ensure appropriate patient management.3,10,11

Pathophysiology

Although the specific mechanisms of AF in the non-CHD population remain to be elucidated, ectopic activity (mainly rapid firing from the pulmonary veins) and reentry play important roles in its initiation and perpetuation.12,13

Atrial arrhythmias are the most common complication in adults with CHD and they are the leading cause of morbidity and hospital admissions. Although intra-atrial reentrant tachycardias (IART) are the most frequent presenting type of arrhythmia, the incidence of AF is increasing as patients age, surpassing IART in people over the age of 50 years.5 Furthermore, AF in CHD patients tends to develop at a younger age, with a markedly increased risk when compared to their non-CHD peers.6 Globally, IART accounts for the majority of presenting arrhythmias in patients with complex cases of CHD. In simpler lesions, both IART and AF have a similar prevalence.5

In CHD patients, both conditions can be favoured by numerous reasons. First, triggers outside the pulmonary veins, including the right atrium or the superior vena cava (right or left persistent), seem to be relevant in this population.14–17 Second, structural remodelling through atrial fibrosis from previous corrective or palliative surgeries, added to atrial enlargement caused by residual septal defects, valvular disease, ventricular dysfunction or acquired conditions, promote conduction delay and alter ion channel function, facilitating reentry.13,18,19 Finally, chronic atrial pressure and/or volume overload favour triggered activity, causing premature beats or focal atrial tachycardia (AT) that, in turn, can also trigger AF.12,20

Patients with certain conditions, such as atrial or atrioventricular septal defects, Ebstein anomaly, tetralogy of Fallot, univentricular hearts, leftsided obstructive lesions and pre-existing pulmonary hypertension, are particularly prone to developing AF.7–9

Although the risk factors related to AF in CHD patients are common to the general population, including age, hypertension and acquired cardiovascular conditions, the described predisposing factors may contribute to AF development at a younger age (Figure 1).5 Nevertheless, research into AF pathophysiology in this population is still scarce and further studies are warranted to better understand the underlying mechanisms and determinants of AF in CHD patients that could potentially lead to improved management.

As the CHD population continues to age, it is likely that AF prevalence and other arrhythmic issues will continue to increase in the next decades. It is of utmost importance that all physicians involved in the care of patients

AF in Congenital Heart Disease Figure 1. Atrial Arrhythmias in the Ageing Population with Congenital Heart Disease: Changing Types and Patterns Permanent

Increased CHD complexity

Higher BMI Focal atrial tachycardia

AF Hypertension

Bradyarrhythmia/ pacemaker

Number of cardiac surgeries

Older age

Intra-atrial reentrant tachycardia

Dyslipidaemia

Paroxysmal

Cigarette smoking

Coronary artery disease CHD = congenital heart disease. Source: Labombarda et al. 2017.5 Reproduced with permission from Elsevier.

Clinical Impact of AF

Three main potential consequences may result from AF development in CHD patients: heart failure (HF), stroke and mortality. HF is the most frequent complication, with an estimated prevalence of about 11% in young CHD patients; its risk sharply increases (up to 11 times) compared to patients with CHD and no AF and in turn HF increases the risk of atrial arrhythmia recurrence.6,21 HF has also been consistently the strongest independent predictor of ischaemic stroke in this population, especially in young patients and in the first 3 years after onset.22,23 Ischaemic stroke is a dramatic and disabling complication of AF, as neurological sequelae may be permanent in up to 25% of all cases.24 Previous data have shown that young patients with CHD have a 10-fold increased risk of stroke compared to the general population. AF, HF and traditional cardiovascular risk factors independently contribute to increase this risk. The highest cumulative incidence corresponds to the more complex conditions, such as Fontan circulation and cyanotic CHD, but patients with left-sided lesions and uncorrected pre-tricuspid left-to-right shunts are also particularly at risk.23,24 Mortality rates are also greater in this patient group and this derives from AF complications. Data from more than 38,000 patients with CHD from Quebec, Canada, have shown an almost 50% increase in the risk of overall mortality in patients with atrial arrhythmias.25 Some may be related to thromboembolic events, but AF, as other atrial arrhythmias, may also contribute to sudden death.26 Fast ventricular rates may provoke ischaemia because of a mismatch in oxygen demand and supply, which can induce ischaemia-related ventricular arrhythmias, mostly in patients with impaired systolic function or single or systemic right ventricle.27–29 Most patients present with paroxysmal AF, although evolution to persistent or permanent forms is common.5 Teuwen et al. observed a rapid progression in 26% of subjects after only 3 years from the first episode. These patients, usually with more complex CHD, developed AF at younger ages. Moreover, approximately one-third had coexistence of other regular atrial arrhythmias, which generally preceded AF.30 Finally, AF may appear in the long term even after successful ablation of IART. In a cohort of

repaired atrial septal defect (ASD) patients, 30% developed AF during the follow-up, 25% of them requiring AF management.31 Some CHD, such as ASD, tetralogy of Fallot, Ebstein anomaly, heterotaxy syndromes and Fontan palliation, carry a higher likelihood of the patient developing AF.32 Reasons for this are speculative and are likely to be based on many factors. First, patients with simpler forms are more likely to live longer and are more commonly exposed to classical risk factors and develop acquired cardiovascular conditions. Second, it is likely that specific haemodynamics have a different effect on atrial remodelling. In ASDs, significant structural remodelling in the left atrium, such as reduced voltage, delayed and heterogenous conduction, has been described.33 It seems reasonable to believe that similar remodelling may be observed in other CHD, such as Ebstein anomaly or left-sided lesions, that may be associated with atrial enlargement. Third, other predisposing factors, such as sinus node dysfunction, are more common in some CHD, such as heterotaxy syndromes, as opposed to others. AF risk in patients with ASD, despite defect closure, remains higher than in a non-CHD matched population. Early closure, either surgical or percutaneous, reduces this risk compared to late repair.34–37 Patients with tetralogy of Fallot are susceptible to developing atrial arrhythmias in the long term, with AF increasing in prevalence, predominantly in those with concomitant left-sided lesions.38 In subjects with Ebstein anomaly, although supraventricular tachycardias mediated by accessory pathways are the cornerstone arrhythmia, atrial tachycardias (including AF) can be encountered in 25–65% of the patients.39,40 Finally, subjects with Fontan physiology, depending on the type of surgery they have had, 10–50% may suffer atrial arrhythmias as a late complication, presenting initially with IART or focal AT that can evolve to AF. It is also a high-risk condition for thrombotic complications.41–43

Acute Management

AF has a negative haemodynamic effect in CHD patients because of the loss of atrioventricular synchrony and, if present, the fast ventricular rate. The restoration of sinus rhythm should be considered the first option in the majority of cases. Haemodynamically unstable patients must undergo urgent electrical cardioversion (CV), regardless of the duration of the

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AF in Congenital Heart Disease arrhythmia and their anticoagulation status.44 In a non-urgent setting, a strategy of 4 weeks of anticoagulation with direct CV has proven to be safe in low-risk patients with CHD.45 Although classically no anticoagulation was recommended for acute CV if AF began in the previous 48 hours, recent data suggest that patients with predisposing factors (CHA2DS2VASc ≥2) have an increased risk of thromboembolic events, especially if delaying CV more than 12 hours after onset. Periprocedural anticoagulation in this context reduced this risk by 82%.46,47 Therefore, irrespective of AF duration, in subjects with high-risk conditions, such as patients with mechanical prosthesis, moderate to severe atrioventricular stenosis, a prior history of thromboembolism, moderate to severe CHD, or if it is more than 12 hours since AF began and CHA2DS2-VASc ≥2, transoesophageal echocardiogram (TOE) or 3 weeks of anticoagulation before CV is recommended. A combination of both may be considered in this context as a Class IIbC suggestion in the recent European AF guidelines (Figure 2).11,48,49

Figure 2: Acute Management of AF in Adults with Congenital Heart Disease

Choosing between electrical or pharmacological CV should be done on an individual basis. Although pharmacological CV avoids sedation, evidence of antiarrhythmic drugs in CHD is limited and proarrhythmic effects may be of particular concern.50 Literature about efficacy or safety of acute CV for atrial arrhythmias in this population is scarce. Most experience has been reported with ibutilide or dofetilide, which are not available in Europe.51–54 The procedure should be monitored with resuscitation equipment available, as the risk of torsades de pointes is estimated at about 4.3%.32,55 Amiodarone may also be a reasonable option.56 A summary of the available evidence is presented in Table 1.

CHD = congenital heart disease; CV = cardioversion; TOE = transoesophageal echocardiography.

Long-term Management

Similar to the non-CHD population, Class I antiarrhythmic agents are not recommended in patients with coronary artery disease or moderate to severely impaired systolic function of a systemic or subpulmonary ventricle because of potential increased mortality, so they are reserved for simple or moderate CHD without any of these factors.11,60–63

The mainstream long-term therapy for AF includes anticoagulation, if indicated, in addition to pharmacological and interventional strategies to prevent arrhythmia recurrence. CHD patients are not represented in rate versus rhythm control randomised trials and no direct comparison between the two strategies has been performed in this population. Considering the deleterious effects of losing sinus rhythm, both the American and European consensus documents for arrhythmia management in adults with CHD advocate a rhythm control strategy as the initial approach (IIaC and IC recommendations, respectively).32,44 Maintenance of atrioventricular synchrony is especially relevant in complex conditions such as univentricular physiology or dysfunctional systemic right ventricles.14 Nevertheless, before a definitive management strategy is established, reversible causes of AF should be sought and corrected if possible – such as residual shunts, obstructive or regurgitant lesions, reduced left ventricular function and myocardial ischaemia – as part of AF management to avoid recurrences. If the patient develops bradycardia-tachycardia syndrome, pacemaker implantation may be considered to prevent tachyarrhythmia if successful ablation fails or is not feasible (Class IIaC recommendation).10 Achieving this goal poses several challenges. First, evidence about antiarrhythmic drugs in CHD is limited and comes mainly from retrospective studies. Second, despite its use, the recurrence rate is high so ablation emerges as an appealing alternative and is being increasingly performed; however, its experience in the CHD setting is still limited, and the underlying lesion or prior interventions may make it difficult to access the ablation targets. Finally, little is known regarding pre-emptive measures that could reduce the risk of AF, particularly in complex patients with cyanotic conditions, restrictive physiologies, univentricular hearts or systemic right ventricles.30,57–59

Acute management of AF in adults with CHD Is the patient haemodynamically unstable? Yes

Direct electrical CV

<48 hours duration No

Yes

Moderate/complex CHD Prosthetic valves Mitral valve stenosis

Simple CHD CV

Anticoagulation ≥3 weeks or/and TOE before CV

Rhythm Control

Antiarrhythmic Drugs

Several aspects must be considered when choosing an antiarrhythmic drug in adults with CHD, including ventricular function, conduction disturbances, such as sinus node dysfunction, impaired AV nodal conduction, pregnancy plans, comorbidities such as kidney or hepatic failure that may affect pharmacokinetics, and concomitant therapies with potential significant interactions.

Class III agents seem to be more effective than any other class in preventing atrial arrhythmia recurrences. Nevertheless, adverse events, mostly described with amiodarone, are common and lead to discontinuation of therapy in a high proportion of patients, especially if required in the long term.56,64 Thyroid dysfunction, mostly amiodaroneinduced thyrotoxicosis, is the most frequent complication, potentially causing exacerbation of tachyarrhythmias. Patients with Fontan circulation are particularly vulnerable because of their altered hepatic metabolism. Additional high-risk subgroups are women, people with cyanotic conditions, other univentricular physiologies and a BMI <21 kg/m2.65–67 The incidence of induced bradyarrhythmia seems to be low.64 Complete or partial control of refractory tachyarrhythmias can be achieved with sotalol, especially if combined with non-pharmacological approaches.68 However, because of its proarrhythmic effects, it should not be used in patients with significant ventricular systolic dysfunction. Extrapolating data from the general population, dronedarone is not recommended in people with moderate or complex CHD, HF or at least moderate ventricular dysfunction because of the concerns of augmented mortality, worsening of heart failure and stroke.69,70 In summary, Class I agents may be considered as the first-line therapy for the simple/moderate forms of CHD without significant ventricular hypertrophy or dysfunction or myocardial scarring. Otherwise, amiodarone with a IIaC recommendation or dofetilide with a IIaB recommendation can

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AF in Congenital Heart Disease Table 1: Evidence of Acute Pharmacological Cardioversion in Adult Congenital Heart Disease Study

Design

Hoyer et al. 200751

Age

Type of CHD

Type of AT

Drug

Dosage

CV Achieved

Adverse Events§

Retrospective 19

16 (6 months– 34 years)

Simple 11% Moderate 33% Complex 56%

AFL 95% AF 5%

Ibutilide

1 mg IV in 10 min (<60 kg; 0.01 mg/kg) 2nd dose: the same

One dose 47% 1% TdP Overall 71% 1% NSVT

Wells et al. 200954

Retrospective 20

30 (19–53) years Simple 5% Moderate 15% Complex 80%

AF 35% IART 65%

Dofetilide

125 μg twice daily* 85%† 125 μg three times a day* 250 μg twice daily* 500 μg twice daily*

Koyak et al. 201356

Retrospective 92

51 ± 16 years

Simple 50% Moderate 17% Complex 14% Unclassified 19%

AF 68% AFL 14% IART 8% Focal AT 7% Unclassified 3%

Adenosine Not reported for acute Flecainide management Procainamide Metoprolol Sotalol Amiodarone Verapamil

90%‡

Not reported for acute management

Banchs et al. 201452

Retrospective 13

40 ± 11 years

Simple 15% Moderate 31% Complex 54%

AF 15% AFL 31% Focal AT 54%

Dofetilide

250 μg twice daily* 500 μg twice daily*

70%

10% TdP

El-Assaad et al. 201653 Retrospective 64

42 ± 14 years

Simple 14% AF 55% Moderate 31% IART 45% Complex 52% Unclassified 3%

Dofetilide

125 μg twice daily* 250 μg twice daily* 500 μg twice daily*

68%

1.5%TdP 1.5% VT 1.5% QTc prolongation 1.5% SND

10%TdP 55% QTc prolongation

*Based on creatinine clearance. †Includes maintenance of sinus rhythm in patients with sinus rhythm at dofetilide administration. ‡Includes electrical cardioversion. §Resulting in drug discontinuation. AFL = atrial flutter; AT = atrial tachycardia; CHD = congenital heart disease; CV = cardioversion; IART = intra-atrial reentrant tachycardia; NSVT = non-sustained ventricular tachycardia; QTc = corrected QT interval; SND = sinus node dysfunction; TdP = torsades de pointes; VT = ventricular tachycardia.

be used. Long-term therapy with amiodarone should be avoided in young adults because of common side-effects. Attention should be paid to dofetilide contraindications (creatinine clearance <20 ml/min, hypokalaemia, QTc >440 ms) and cardiac monitoring for 72 hours after initiation is advised (Figure 3).32,44

Catheter and Surgical Ablation

The disappointing results and the aforementioned limitations of antiarrhythmic drugs, together with the significant improvements in technical aspects of ablation procedures and the growing evidence for its use in the general population, has resulted in an expanding use in CHD patients.71,72 Thorough preprocedural planning is mandatory to minimise complications and maximise success. Documenting arrhythmia to rule out other atrial arrhythmias, review of individual anatomical features with multimodality imaging and careful evaluation of vascular accesses are of utmost importance.73–75 Transseptal puncture may pose additional challenges in CHD patients because of distorted anatomy or the presence of atrial surgical patches or closure devices.76 Puncture through surgically or percutaneously repaired ASDs can be difficult but it’s feasible in most cases. Access can be obtained through the native septum or, if not possible, through the device.77 Occasionally, residual shunts may facilitate access to the left atrium. Intracardiac echocardiography may be helpful to guide the transseptal puncture and detect residual shunts. Most of the reported experience with catheter ablation is related to radiofrequency. Procedures should be performed using 3D mapping technology (Class Ib recommendation) and irrigated-tip catheters for ablation (Class IIaB recommendation).32,44,78 The role of novel mapping tools like high-density or rotor mapping remain to be elucidated. Additional ablation targets beyond the pulmonary veins may be considered, especially in redo procedures, including additional lines, such as atrial roof, mitral or cavotricuspid to pulmonary vein isolation

isthmus, or non-pulmonary vein triggers.79,80 Success rates at 1 year with or without antiarrhythmic drugs range from 33–84%. Difficulties accessing the left atrium with reduced catheter contact, the inability to deliver transmural lesions because of excessive wall thickness or the less relevant role of the pulmonary veins may account for some of the reasons of high recurrence rates in this population.14,81,82 Initial experience with cryoablation has proven safe, with high acute success but also modest long-term outcomes.83 Evidence for catheter ablation in CHD is summarised in Table 2. Despite being considered a first-line treatment for other atrial arrhythmias, the increased complexity of the procedure and the modest results, the limited experience and the peculiarities of these patients have translated to a IIbC recommendation for catheter-based pulmonary vein ablation in patients with drugrefractory AF.10 It should only be performed in centres with experience in both AF ablation and CHD management.11 The role of AF ablation in this specific setting needs to be further explored. Research to shed light on predictors of success or failure in order to detect appropriate candidates for AF ablation, or targeting AF precursors to prevent AF, such as focal atrial tachycardias or IART is warranted. Finally, surgical ablation (the Cox-Maze procedure) at the time of congenital heart defects repair – surgical ASD closure, Ebstein anomaly and Fontan conversion – in presence of symptomatic AF is recommended (Class IIaC), and even prophylactic surgical ablation in patients at high risk of AF, can be considered (Class IIbC).11,32 Extensive Maze procedures are recommended to avoid the potential proarrhythmic effects of limited atrial Maze techniques.84 Surgical management of atrial arrhythmias at the time of CHD surgery does not seem to increase complications and has reasonable outcomes, with arrhythmia-free survival of 75% at 6 year follow-up.85,86 This has made some groups advocate for systematic surgical management of preoperatively diagnosed atrial arrhythmias at

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AF in Congenital Heart Disease Figure 3: Long-term Management of AF in Adults with Congenital Heart Disease 2. Rhythm control

3. Rate control

Systemic ventricular hypertrophy or ventricular dysfunction

β-blockers¶ or nondihydropyridine calcium channel antagonists**††

1. Anticoagulation indication Simple CHD +CHA2DS2VASc ≥2* Moderate/ complex CHD

NOAC, VKA

Fontan surgery Cyanotic disease Prosthetic valves Mitral valve stenosis

VKA

Yes

Amiodarone† or dofetilide‡

Insufficient control

Simple/moderate CHD

Complex CHD

First choice: flecainide/ propafenone§ Second choice: sotalol,|| amiodarone† or dofetilide‡

First choice: amiodarone† or dofetilide‡ Second line: sotalol||

Add digoxin††

4. Nonpharmacological approaches for refractory AF First choice: Catheter ablation. Surgical ablation as alternative in selected patients Second choice: Atrioventricular node ablation and pacemaker implantation‡‡ Second choice: Pacemaker implantation if sinus node dysfunction§§

*If 1 point other than for sex, anticoagulation is decided on an individual basis. †Caution if thyroid dysfunction, hepatic or pulmonary disease, cyanotic heart disease, univentricular physiology, BMI <21 kg/m2 and corrected QT interval prolongation. Avoid prolonged treatment in young adults. ‡Contraindicated if creatinine clearance <20 ml/min, hypokalaemia or QT interval prolongation. § Contraindicated in coronary artery disease. ||Caution if QT interval prolongation, conduction disease, renal insufficiency or hypokalaemia. ¶Of choice in D-transposition of the great arteries and ventricular preexcitation. **Contraindicated if moderate or severe ventricular dysfunction. ††Avoid in ventricular preexcitation. ‡‡If successful ablation fails. §§To prevent tachyarrhythmia if successful ablation fails. CHD = congenital heart disease, NOAC = non-vitamin K antagonist oral anticoagulant; VKA = vitamin K antagonist.

time of surgery, because defect correction alone will not significantly diminish arrhythmic risk. Nevertheless, it is important to note that surgical access in patients with prior sternotomies may be difficult and limited. AF surgical ablation without other concomitant surgery can be considered on an individual basis after repeated catheter ablation failures, absence of percutaneous access to ablation targets or if alternative approaches such as rate control or atrioventricular node ablation and pacemaker stimulation are not desirable.

Rate Control

Whenever rhythm control strategy is abandoned, rate control is essential to avoid secondary development of tachycardiomyopathy or worsening heart failure.26 For this purpose, both β-blockers and nondihydropyridine calcium channel blockers can be used. Some data support the preference of β-blockers due to a protective effect against ventricular tachycardia in specific situations such as transposition of the great arteries corrected with atrial switch.27,29 Digoxin is usually left as a second choice, mostly in combination with one of the other drugs (Figure 3).87 There is no specific data in CHD patients regarding the optimal target heart rate, so following a similar strategy to the general population seems reasonable.88,89 Atrioventricular node ablation and pacemaker implantation might be considered in case of uncontrolled ventricular rates despite the association of multiple rate control drugs and should be reserved as the last resort.11,90 Adequate transvenous access for pacing and ablation should be confirmed. The atrioventricular node may be difficult to locate in CHD related to anatomical variations or after reparative surgeries.

Anticoagulation

Standard scores used to guide oral anticoagulation do not consider CHD and have not been validated in this specific population.91 Besides, stroke risk is much higher in CHD patients. A recent multicentre retrospective

study found that CHD complexity was an independent risk factor for thromboembolic events. In this cohort, the CHADS2 and CHA2DS2-VASc score did not correctly identify patients at risk as they were young and did not have other conventional risk factors.58 Current recommendations advocate taking into account disease complexity in addition to traditional scores. Thus, patients with moderate (Class IIaC recommendation) or complex (Class IC) CHD and sustained or recurrent AF should be on longterm oral anticoagulation. For patients with simple forms of CHD and without valvular prosthesis the decision on anticoagulation should be based on the CHA2DS2-VASc and HAS-BLED scores (Class IIbB).92,93 Since their appearance, non-vitamin K antagonist oral anticoagulants (NOACs) seem an appealing option for CHD patients. Recent evidence suggests that they are safe even in moderate and complex forms of CHD, including those with significant valvular lesions and bioprosthetic valves.94,95 Subjects with Fontan palliation are still a challenge, as thromboembolic episodes and significant bleeding have been described in this group of patients despite NOAC therapy in the multicentre prospective NOTE registry but further research is warranted to expand their use in this subgroup of patients.96 The European guidelines on the management of adult CHD recommend NOACs as the first treatment option for CHD patients, excluding those with Fontan physiology, chronic cyanosis, mechanical prosthetic valves or significant mitral stenosis.10 Left atrial appendage occlusion (LAAO) is an option for AF with high bleeding risk or relative/absolute contraindication for long-term anticoagulation (Class IIbB) or for those with AF undergoing cardiac surgery (Class IIbC).11 Evidence of the LAAO role in CHD is centred on ASDs, where it has proven to be safe and feasible when implanted before or at the time of ASD closure.97 In other conditions with very high thromboembolic risk, such as patients with mechanical prostheses, anticoagulation cannot be stopped despite LAAO, although it could be considered as a means to reduce embolic risk.98

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AF in Congenital Heart Disease Table 2: Evidence of Catheter Ablation for AF in Adults With Congenital Heart Disease Study

Design

Followup

Age

Type of CHD

Type of AF

Procedure

Success Rate

Comments

pAF 72% CHD 53% NSHD perAF* 27% CHD 40% NSHD

RF (8 mm): ICE guided, PVI ± LL

Without AADs: No differences between 1st procedure 42% CHD and NSHD (300days) 27% (4 years) With or without AADs: 1st procedure 84% (300 days) 61% (4 years)

Philip et al. Retrospective 36 CHD 7 months 201272 355 NSHD

53 ± 2 years Simple 71% CHD Moderate 21% 57 ± 2 years Complex 8% NSHD

Sohns et al. Retrospective 57 201880

41 ± 36 months

51.1 ± 14.8 years

Simple 61.4% pAF 36.8% Irrigated tip RF: Moderate 17.5% perAF 63.2% Systematic EA mapping, Complex 21.1% sequential approach: PVI+LL, CFAE

Abadir et al. Retrospective 10 201983

2.8 (1.4–4.5) years

57.9 years (48.2–61.7)

Simple 80% Moderate/ complex 20%

Liang et al. Retrospective 84 201979

709 ± 808 51.5 ± 12.1 days years

Simple 60.7% pAF 45.2% RF:† Moderate 26.2% perAF 54.8% EA mapping, Complex 13.1% PVI alone 35.7%, PVI ± CTI, LL, CFAE 64.3%

53.1% (1 year) without Trend to less success in AADs complex CHD (not 71.6% (1 year) with or significant) without AADs

Guarguagli Retrospective 58 et al. 201959

24 (11–69) 51 years months (44–63)

Simple 43% pAF 45% Moderate 34% perAF 55% Complex 23%

1st procedure 32.8% 2nd procedure 40.9% 3rd procedure 36.5% pAF, normal left atrium and simple/moderate CHD: 60% at 1 year

pAF 80% perAF 20%

1st procedure 63% (1 year), 22% (5 years) 2nd procedure 99% (1 year), 83% (5 years)

Cryoablation: 1st procedure 60% Fluoroscopy, at least one (1 year): 40% without 240 s application, additional AADs LL: not systematic

Irrigated tip RF: EA, HD sequential or SNI mapping, PVI ± FAA, CTI, GP, LL, CFAE 60% multiple procedures

Success independent from CHD complexity and AF type FAA improved outcome 1 transient phrenic nerve palsy

Predictors of recurrence: CHD complexity AF type Left atrium size Better outcome if CTI ablation

*1% in the congenital heart disease cohort and 7% in the non-congenital structural heart disease cohort were permanent forms of AF. †Type of ablation catheter not specified. AAD = antiarrhythmic drug; CFAE = complex fractionated atrial electrogram; CHD = congenital heart disease; CTI = cavotricuspid isthmus; EA = electroanatomical; FAA = focal activity ablation; GP = ganglionated plexus; HD = high density; ICE = intracardiac echocardiography; LL = linear lesions; SNI = simultaneous non-invasive; NSHD = non-congenital structural heart disease; pAF = paroxysmal AF; perAF = persistent AF; PVI = pulmonary vein isolation; RF = radiofrequency.

Future Directions

The high and increasing prevalence of AF in the expanding CHD population requires rapid advances in knowledge. Research in the underlying mechanisms that differ from the general population should be pursued, as a better understanding has the potential to translate into improved therapies and better outcomes for patients. Strategies for diagnosis and correction of risk factors and identification of particularly vulnerable patients are necessary. The use of prophylactic surgical or percutaneous ablation concomitant to defect correction 1. Gurvitz M, Dunn JE, Bhatt A, et al. Characteristics of adults with congenital heart defects in the United States. J Am Coll Cardiol 2020;76:175–82. https://doi.org/10.1016/j.jacc.2020. 05.025; PMID: 32646567. 2. Warnes CA, Liberthson R, Danielson GK, et al. Task force 1: the changing profile of congenital heart disease in adult life. J Am Coll Cardiol 2001;37:1170–5. https://doi.org/10.1016/ S0735-1097(01)01272-4; PMID: 11300418. 3. Gilboa SM, Devine OJ, Kucik JE, et al. Congenital heart defects in the United States: estimating the magnitude of the affected population in 2010. Circulation 2016;134:101–9. https://doi.org/10.1161/CIRCULATIONAHA.115.019307; PMID: 27382105. 4. Oliver JM, Gallego P, Gonzalez AE, et al. Risk factors for excess mortality in adults with congenital heart diseases. Eur Heart J 2017;38:1233–41. https://doi.org/10.1093/ eurheartj/ehw590; PMID: 28077469. 5. Labombarda F, Hamilton R, Shohoudi A, et al. Increasing prevalence of atrial fibrillation and permanent atrial arrhythmias in congenital heart disease. J Am Coll Cardiol 2017;70:857–65. https://doi.org/10.1016/j.jacc.2017.06.034; PMID: 28797355. 6. Mandalenakis Z, Rosengren A, Lappas G, et al. Atrial fibrillation burden in young patients with congenital heart disease. Circulation 2018;137:928–37. https://doi.org/10.1161/

needs to be explored. Also, appropriate timing, techniques and targets for catheter and surgical ablation need to be defined. Studies comparing anticoagulation strategies in the CHD population are warranted. The role of NOACs for patients with Fontan circulation and cyanotic conditions needs to be further explored to establish evidencebased recommendations. Overcoming these and future challenges will require multicentre or network collaboration so large cohorts of CHD patients can be studied.

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amjcard.2013.07.029; PMID: 23993125. 57. Bokma JP, Zegstroo I, Kuijpers JM, et al. Factors associated with coronary artery disease and stroke in adults with congenital heart disease. Heart 2018;104:574. https://doi. org/10.1136/heartjnl-2017-311620; PMID: 28847851. 58. Khairy P, Aboulhosn J, Broberg CS, et al. Thromboprophylaxis for atrial arrhythmias in congenital heart disease: a multicenter study. Int J Cardiol 2016;223:729–35. https://doi.org/10.1016/j. ijcard.2016.08.223; PMID: 27573597. 59. Guarguagli S, Kempny A, Cazzoli I, et al. Efficacy of catheter ablation for atrial fibrillation in patients with congenital heart disease. Europace 2019;21:1334–44. https://doi.org/10.1093/ europace/euz157; PMID: 31168581. 60. Anderson JL, Halperin JL, Albert NM, et al. Management of patients with atrial fibrillation (compilation of 2006 ACCF/ AHA/ESC and 2011 ACCF/AHA/HRS recommendations): a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2013;61:1935–44. https://doi.org/10.1016/j. jacc.2013.02.001; PMID: 23558044. 61. Fish FA, Gillette PC, Benson DW. Proarrhythmia, cardiac arrest and death in young patients receiving encainide and flecainide. J Am Coll Cardiol 1991;18:356–65. https://doi. org/10.1016/0735-1097(91)90586-X; PMID: 1906902. 62. Echt DS, Liebson PR, Mitchell LB, et al. Mortality and morbidity in patients receiving encainide, flecainide, or placebo. The Cardiac Arrhythmia Suppression Trial. N Engl J Med 1991;324:781–8. https://doi.org/10.1056/ NEJM199103213241201; PMID: 1900101. 63. Duff HJ, Stemler M, Thannhauser T, et al. Proarrhythmia of a class Ic drug: suppression by combination with a drug prolonging repolarization in the dog late after infarction. J Pharmacol Exp Ther 1995;274:508–15. PMID: 7616438. 64. Moore BM, Cordina RL, McGuire MA, et al. Adverse effects of amiodarone therapy in adults with congenital heart disease. Congenit Heart Dis 2018;13:944–51. https://doi. org/10.1111/chd.12657; PMID: 30239160. 65. Stan MN, Ammash NM, Warnes CA, et al. Body mass index and the development of amiodarone-induced thyrotoxicosis in adults with congenital heart disease – a cohort study. Int J Cardiol 2013;167:821–6. https://doi.org/10.1016/j. ijcard.2012.02.015; PMID: 22386642. 66. Thorne SA, Barnes I, Cullinan P, et al. Amiodaroneassociated thyroid dysfunction: risk factors in adults with congenital heart disease. Circulation 1999;100:149–54. https://doi.org/10.1161/01.CIR.100.2.149; PMID: 10402444. 67. Stan MN, Hess EP, Bahn RS, et al. A risk prediction index for amiodarone-induced thyrotoxicosis in adults with congenital heart disease. J Thyroid Res 2012;2012:210529. https://doi. org/10.1155/2012/210529; PMID: 22518347. 68. Miyazaki A, Ohuchi H, Kurosaki K, et al. Efficacy and safety of sotalol for refractory tachyarrhythmias in congenital heart disease. Circ J 2008;72:1998–2003. https://doi.org/10.1253/ circj.CJ-08-0194; PMID: 18931451. 69. Køber L, Torp-Pedersen C, McMurray JJ, et al. Increased mortality after dronedarone therapy for severe heart failure. N Engl J Med 2008;358:2678–87. https://doi.org/10.1056/ NEJMoa0800456; PMID: 18565860. 70. Connolly SJ, Camm AJ, Halperin JL, et al. Dronedarone in high-risk permanent atrial fibrillation. N Engl J Med 2011;365:2268–76. https://doi.org/10.1056/NEJMoa1109867; PMID: 22082198. 71. Sherwin ED, Triedman JK, Walsh EP. Update on interventional electrophysiology in congenital heart disease: evolving solutions for complex hearts. Circ Arrhythm Electrophysiol 2013;6:1032–40. https://doi.org/10.1161/ CIRCEP.113.000313; PMID: 24129205. 72. Philip F, Muhammad KI, Agarwal S, et al. Pulmonary vein isolation for the treatment of drug-refractory atrial fibrillation in adults with congenital heart disease. Congenit Heart Dis 2012;7:392–9. https://doi.org/10.1111/j.1747-0803. 2012.00649.x; PMID: 22469422. 73. Tops LF, de Groot NM, Bax JJ, et al. Fusion of electroanatomical activation maps and multislice computed tomography to guide ablation of a focal atrial tachycardia in a Fontan patient. J Cardiovasc Electrophysiol 2006;17:431–4. https://doi.org/10.1111/j.1540-8167.2005.00305.x; PMID: 16643369. 74. Windram JD, Siu SC, Wald RM, et al. New directives in cardiac imaging: imaging the adult with congenital heart disease. Can J Cardiol 2013;29:830–40. https://doi. org/10.1016/j.cjca.2013.04.020; PMID: 23725862. 75. Di Salvo G, Miller O, Babu Narayan S, et al. Imaging the adult with congenital heart disease: a multimodality imaging approach-position paper from the EACVI. Eur Heart J Cardiovasc Imaging 2018;19:1077–98. https://doi.org/10.1093/ ehjci/jey102; PMID: 30084968. 76. Acena M, Anguera I, Dallaglio PD, et al. Atrial fibrillation

AF in Congenital Heart Disease ablation in adults with repaired congenital heart disease. J Atr Fibrillation 2016;8:1363. https://doi.org/10.4022/jafib.1363; PMID: 27909479. 77. Santangeli P, Di Biase L, Burkhardt JD, et al. Transseptal access and atrial fibrillation ablation guided by intracardiac echocardiography in patients with atrial septal closure devices. Heart Rhythm 2011;8:1669–75. https://doi. org/10.1016/j.hrthm.2011.06.023; PMID: 21703215. 78. Lukac P, Pedersen AK, Mortensen PT, et al. Ablation of atrial tachycardia after surgery for congenital and acquired heart disease using an electroanatomic mapping system: which circuits to expect in which substrate? Heart Rhythm 2005;2:64–72. https://doi.org/10.1016/j.hrthm.2004.10.034; PMID: 15851267. 79. Liang JJ, Frankel DS, Parikh V, et al. Safety and outcomes of catheter ablation for atrial fibrillation in adults with congenital heart disease: a multicenter registry study. Heart Rhythm 2019;16:846–52. https://doi.org/10.1016/j. hrthm.2018.12.024; PMID: 30593868. 80. Sohns C, Nürnberg JH, Hebe J, et al. Catheter ablation for atrial fibrillation in adults with congenital heart disease: lessons learned from more than 10 years following a sequential ablation approach. JACC Clin Electrophysiol 2018;4:733–43. https://doi.org/10.1016/j.jacep.2018.01.015; PMID: 29929666. 81. Wolf CM, Seslar SP, den Boer K, et al. Atrial remodeling after the Fontan operation. Am J Cardiol 2009;104:1737–42. https:// doi.org/10.1016/j.amjcard.2009.07.061; PMID: 19962486. 82. Fürnkranz A, Julian JK, Schmidt B, et al. Ipsilateral pulmonary vein isolation performed by a single continuous circular lesion: role of pulmonary vein mapping during ablation. Europace 2011;13:935–41. https://doi.org/10.1093/ europace/eur067; PMID: 21454334. 83. Abadir S, Waldmann V, Dyrda K, et al. Feasibility and safety of cryoballoon ablation for atrial fibrillation in patients with congenital heart disease. World J Cardiol 2019;11:149–58.

https://doi.org/10.4330/wjc.v11.i5.149; PMID: 31171960. 84. Zeng Y, Cui Y, Li Y, et al. Recurrent atrial arrhythmia after minimally invasive pulmonary vein isolation for atrial fibrillation. Ann Thorac Surg 2010;90:510–5. https://doi. org/10.1016/j.athoracsur.2010.04.063; PMID: 20667341. 85. Giamberti A, Pluchinotta FR, Chessa M, et al. Surgery for supraventricular tachycardia and congenital heart defects: long-term efficacy of the combined approach in adult patients. Europace 2017;19:1542–8. https://doi.org/10.1093/ europace/euw278; PMID: 27738072. 86. Khositseth A, Danielson GK, Dearani JA, et al. Supraventricular tachyarrhythmias in Ebstein anomaly: management and outcome. J Thorac Cardiovasc Surg 2004;128:826–33. https://doi.org/10.1016/j. jtcvs.2004.02.012; PMID: 15573066. 87. Whitbeck MG, Charnigo RJ, Khairy P, et al. Increased mortality among patients taking digoxin – analysis from the AFFIRM study. Eur Heart J 2013;34:1481–8. https://doi. org/10.1093/eurheartj/ehs348; PMID: 23186806. 88. Van Gelder IC, Groenveld HF, Crijns HJ, et al. Lenient versus strict rate control in patients with atrial fibrillation. N Engl J Med 2010;362:1363–73. https://doi.org/10.1056/ NEJMoa1001337; PMID: 20231232. 89. Mulder BA, Van Veldhuisen DJ, Crijns HJ, et al. Lenient vs. strict rate control in patients with atrial fibrillation and heart failure: a post-hoc analysis of the RACE II study. Eur J Heart Fail 2013;15:1311–8. https://doi.org/10.1093/eurjhf/hft093; PMID: 23759284. 90. Friedman RA, Will JC, Fenrich AL, et al. Atrioventricular junction ablation and pacemaker therapy in patients with drug-resistant atrial tachyarrhythmias after the Fontan operation. J Cardiovasc Electrophysiol 2005;16:24–9. https:// doi.org/10.1046/j.1540-8167.2005.03272.x; PMID: 15673382. 91. Mongeon FP, Macle L, Beauchesne LM, et al. Non-vitamin K antagonist oral anticoagulants in adult congenital heart disease. Can J Cardiol 2019;35:1686–97. https://doi.

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org/10.1016/j.cjca.2019.06.022; PMID: 31635950. 92. Olesen JB, Torp-Pedersen C, Hansen ML, et al. The value of the CHA2DS2-VASc score for refining stroke risk stratification in patients with atrial fibrillation with a CHADS2 score 0–1: a nationwide cohort study. Thromb Haemost 2012;107:1172–9. https://doi.org/10.1160/TH12-03-0175; PMID: 22473219. 93. Roldán V, Marín F, Manzano-Fernández S, et al. The HASBLED score has better prediction accuracy for major bleeding than CHADS2 or CHA2DS2-VASc scores in anticoagulated patients with atrial fibrillation. J Am Coll Cardiol 2013;62:2199–204. https://doi.org/10.1016/j. jacc.2013.08.1623; PMID: 24055744. 94. Arslani K, Notz L, Zurek M, et al. Anticoagulation practices in adults with congenital heart disease and atrial arrhythmias in Switzerland. Congenit Heart Dis 2018;13:678–84. https:// doi.org/10.1111/chd.12627; PMID: 30033686. 95. Pujol C, Niesert AC, Engelhardt A, et al. Usefulness of direct oral anticoagulants in adult congenital heart disease. Am J Cardiol 2016;117:450–5. https://doi.org/10.1016/j. amjcard.2015.10.062; PMID: 26725103. 96. Yang H, Bouma BJ, Dimopoulos K, et al. Non-vitamin K antagonist oral anticoagulants (NOACs) for thromboembolic prevention, are they safe in congenital heart disease? Results of a worldwide study. Int J Cardiol 2020;299:123–30. https://doi.org/10.1016/j.ijcard.2019.06.014; PMID: 31307847. 97. Gafoor S, Franke J, Boehm P, et al. Leaving no hole unclosed: left atrial appendage occlusion in patients having closure of patent foramen ovale or atrial septal defect. J Interv Cardiol 2014;27:414–22. https://doi.org/10.1111/ joic.12138; PMID: 25059287. 98. Cruz-González I, Rama-Merchan JC, Rodríguez-Collado J, et al. Simultaneous percutaneous closure of left atrial appendage and atrial septal defect after mitral valve replacement. JACC Cardiovasc Interv 2016;9:e129–30. https:// doi.org/10.1016/j.jcin.2016.04.025; PMID: 27318843.

COVID-19

The Renin–Angiotensin–Aldosterone System and Coronavirus Disease 2019 Eliecer Coto ,1,3,4,5 Pablo Avanzas

2,3,4

and Juan Gómez

1,3

1. Genética Molecular, Hospital Universitario Central Asturias, Oviedo, Spain; 2. Cardiología, Hospital Universitario Central Asturias, Oviedo, Spain; 3. Instituto de Investigación Sanitaria del Principado de Asturias, ISPA, Oviedo, Spain; 4. Universidad de Oviedo, Oviedo, Spain; 5. Red de Investigación Renal (REDINREN), Madrid, Spain

Abstract

The renin–aldosterone–angiotensin system (RAAS) plays an important role in the pathogenesis of coronavirus disease 2019 (COVID-19), which is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Angiotensin-converting enzyme 2 (ACE2) is the cellular receptor for SARS-CoV-2 and the host’s expression of this membrane-bound protein could affect susceptibility to infection. The RAAS is an important regulator of cardiovascular physiology and ACE2 has an essential role. People with hypertension and other traits have shown to have an imbalance in ACE/ ACE2 levels and reduced levels of ACE2 could enhance the risk of adverse outcome in patients with COVID-19. It has been hypothesised that the RAAS may mediate the interplay between cardiovascular disease and COVID-19 severity. Evidence shows that antihypertensive drugs that target the RAAS have no significant effect on the risk of infection and disease outcome. Variations in RAAS genes have been associated with the risk of developing hypertension and cardiovascular disease and could partly explain the heterogenous response to SARS-CoV-2 infection. This article explores the interplay between the RAAS and COVID-19, with emphasis on the possible relationship between genetic variations and disease severity.

Keywords

SARS-CoV-2, COVID-19, coronavirus, renin–angiotensin–aldosterone system, angiotensin-converting enzyme polymorphisms, cardiovascular comorbidities, angiotensin-converting enzyme inhibitors, angiotensin II receptor inhibitors Disclosure: This work was supported by a grant from the Spanish Plan Nacional de Investigación Científica, Desarrollo e Innovación Tecnológica, Ministerio de Economía y Competitividad and a grant from the European Regional Development Fund (ISCIII-Red de Investigación Renal-REDINREN RD16/9/5 [EC]). The authors have no other conflicts of interest to disclose. Received: 4 June 2020 Accepted: 10 October 2020 Citation: European Cardiology Review 2021;16:e07. DOI: https://doi.org/10.15420/ecr.2020.30 Correspondence: Eliecer Coto, Genetica Molecular, Hospital Universitario Central Asturias, 33011, Oviedo, Spain. E: eliecer.coto@sespa.es Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

In this article, we discuss severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the role of the renin–angiotensin–aldosterone system (RAAS) in the pathogenesis of coronavirus disease 2019 (COVID-19), with special emphasis on the association between gene variants and the risk of infection and disease severity. SARS-CoV-2 was first identified in Wuhan, China in December 2019. Due to the similarity of its genetic sequence and pathophysiological mechanisms when compared with the coronavirus that caused severe acquired respiratory syndrome (SARS-CoV-), this novel coronavirus was designated SARS-CoV-2. The virus has rapidly spread worldwide with millions of people affected and a significant number of deaths. The main manifestation of COVID-19 is a respiratory disease that varies from almost no symptoms to a pneumonia that requires hospitalisation. Some patients will have severe pneumonia that needs to be treated with mechanical respiratory support in an intensive care unit (ICU). The rate of mortality was not clear because of the heterogeneous values between countries. It was only clear that the mortality was higher among older patients. Figure 1 shows the age distribution of people with COVID-19 who required hospitalisation (either non-severe or severe ICU cases during the first

wave of the pandemic from March to July 2020) in Asturias in northern Spain, which has a total population of about 1 million. On 28 July 2020, there were a total of 2,433 confirmed cases in Asturias, of whom 42% were men. Of these 2,433 cases, 1,117 were hospitalised and 421 needed respiratory support in the ICU. More men had severe cases and needed to be treated in an ICU. There was a total of 334 COVID-19 deaths in the first wave of the pandemic (March–July 2020). COVID-19 is suspected by its clinical symptoms and is confirmed by a positive genetic test based on the amplification of the viral genome from nasopharyngeal swabs or bronchoalveolar lavage. Despite COVID-19 presenting a challenge to health systems because of the large number of patients who require hospitalisation, most people who test positive for the virus show none or very mild flu-like symptoms.

RAAS and COVID-19 Infection

Many of the disease-causing mechanisms of SARS-CoV-2 have been elucidated. Its genome has been well characterised, and this facilitates the viral detection and the identification of protein epitopes that can be used in vaccine design. Similar to SARS-CoV-1, this coronavirus binds to the human angiotensin-converting enzyme 2 (ACE2) protein in cell surfaces. ACE2 is a high-affinity receptor for the viral spike (S) protein.

Renin–Angiotensin–Aldosterone System and COVID-19 Figure 1: COVID-19 Patients Who Required Hospitalisation During the First Wave of the Pandemic Between March and July 2020 in Asturias, Showing Severity and Deaths per Age Range Cases (n) 450 400 350 300 250 200 150 100 50 0

0–9

10–19

20–29

30–39

40–49

50–59

60–69

70–79

80–89

≥90

Age range (years) Total

Mild

Severe (ICU)

Death

*Most of the deaths among patients over the age of 80 years were not hospitalised and received medical attention at nursing homes. Source: https://obsaludasturias.com, 28 July 2020.

Figure 2: The Renin–Angiotensin–Aldosterone System Angiotensinogen SARS-COV-2

Renin Ang I Ang 1–9

ACE 1

ACE 1 Ang II Ang II ACE2

Ang I

COVID-19, RAAS and Cardiovascular Disease

Ang 1–7

Ang II

ACE2 Membrane AT1R

Viral infection

cytoplasm

Inflammation Hypertrophy Fibrosis Hypertension

AT2R

ACE2 in SARS-CoV-2 infection raised some initial concerns about the effect of ACE inhibitors (ACEIs) and angiotensin-2 (Ang II) receptor blockers (ARBs) on this disease.

MasR

Protective signal Inflammation Fibrosis Hypertrophy Hypertension

Angiotensinogen is cleaved by renin to render Ang I, which in turn is hydrolysed by ACE to Ang II. Ang II binds to the AT1R to trigger the cellular response. ACE2 catalyses a reaction that transforms Ang II to Ang 1–7 that is the endogenous ligand for the AT2R and MAS-related GPR family member G (MasR). SARS-Cov-2 binds to ACE2 through its viral spike protein and this could reduce the number of receptors accessible to Ang 1–7. The binding of the virus would also lead to the downregulation of ACE2, and this would impair the activation of the AT2R axis. A reduction of the AT2R/AT1R balance could result in lung damage and the progression toward severe symptoms. Gene variants that increase the expression of ACE or reduce the ACE2 levels, which could reduce the ACE2/ACE balance and increase the risk of developing severe COVID-19. Ang = Angiotensin; ACE: Angiotensin-converting enzyme; ATR = Angiotensin receptor; MasR = Mas receptor.

After binding to ACE2, a membrane protease (TMPRSS2) modifies the S-protein facilitating the fusion of the cell membrane with the viral membrane. Once in the cytoplasm, the viral genome dictates the synthesis of proteins necessary for the replication and spread of SARS-CoV-2. The cellular levels of ACE2 depend on several factors, including the activity of other RAAS components, gene polymorphisms and clinical conditions, such as hypertension (Figure 2). All these factors could contribute to a person’s risk of infection and disease severity. The role of

Initial data showed that cardiac injury may be present in up to 30% of patients who had been hospitalised with COVID-19.1–3 Evidence clearly shows that in addition to older age, hypertension, diabetes and cardiovascular disease (CVD) were risk factors for developing severe COVID-19, and patients with cardiovascular comorbidities were at a higher risk of death from COVID-19 (Figure 3). The putative mechanisms of myocardial injury in COVID-19 include ischaemia due to circulatory and respiratory failure, epicardial or intramyocardial small coronary artery thrombotic obstruction due to increased coagulability, and myocarditis secondary to systemic inflammation or direct binding of the virus to ACE2 in cardiomyocytes. Persistent immune activation upon SARS-CoV-2 infection would also increase the risk of developing dilated cardiomyopathy.4 ACE2 is a membrane-bound carboxy-dipeptidase expressed in many cell types and tissues, including the upper airway, lung, heart, kidney and small intestine.5 The wide distribution of ACE2 would make these organs accessible for viral infection and could explain some of the extrapulmonary manifestations of COVID-19 and the SARS-CoV-2 genome has been amplified from samples obtained from several tissues. Being male or older are the main predictors of severe COVID-19. Age and sex differences for disease progression between people with COVID-19 could be explained in part by the fact that the rate of ACE2 expression varies with age and seems to differ between men than women.6 The physiological effects of ACE and ACE2 are mediated by two angiotensin II receptors, type 1 (AT1R) and type 2 (AT2R). Each display opposite responses, with ATR1 mediating vasoconstriction, proliferation,

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Renin–Angiotensin–Aldosterone System and COVID-19 fibrosis and inflammation, and AT2R mediating vasodilation, antifibrosis and anti-inflammation responses (Figure 2). The two converting enzymes are thus seen as positive and negative regulators of the RAAS response and the deregulation of the ACE/ACE2 balance could result in cardiovascular disease, hypertension, cardiac hypertrophy and heart failure, among other conditions. ACE2 has been shown to be an essential regulator of cardiac function in a study that showed ACE2 knockout mice developing severe left ventricular dysfunction, and the reduction in cardiac contractility being restored by a reversion of the knockout phenotype. In addition, a DNA variant in the human ACE2 gene has been associated with the risk of cardiovascular death.7,8 This could have implications for COVID-19 in terms of a genetic susceptibility to infection or the risk of developing a severe form of the disease.

Figure 3: Rate of Comorbidities Among COVID-19 Patients Hospitalised in the Region of Asturias

The fact that pulmonary lesions induced by the SARS coronavirus were more aggressive in ACE2 knockout mice compared with wild-type mice (an effect that was attenuated by blocking the RAAS) suggests that ACE2 expression levels could also influence the severity of respiratory disease found in patients with COVID-19.9

Renal = impaired renal function. Source: https://obsaludasturias.com, 28 July 2020.

SARS-CoV-2 Infection and Cardiac Injury

Cardiac cells express ACE2 which means that myocardial infection by SARS-CoV-2 could be possible. The viral genome has been amplified in post-mortem myocardial tissue from patients who died from SARS, but the notion that there is a direct effect of SARS-CoV-2 on myocarditis is controversial. The systemic inflammation and metabolic imbalance could also explain the cardiac arrhythmias seen in some patients. COVID-19 patients also showed significantly elevated levels of D-dimer, a fibrin degradation product of thrombosis.10 The elevation of this marker seems to be a strong predictor of mortality from COVID-19, although the prevalence of acute coronary syndromes due to increased thrombotic activity is unknown. Since COVID-19 has arisen from a novel virus, we do not have data about its long-term manifestations. It could be, for example, that the inflammatory exacerbation could enhance the development of atherosclerotic plaques and increase the risk for future ischaemic episodes. Several studies have shown that ACE2 is implicated in atherosclerosis pathophysiology. Among others, ACE2-deficient mice showed increased levels of proatherogenic mediators with an impaired endothelium-dependent relaxation that was attenuated by the blockade of angiotensin 1–7; while the overexpression of ACE2 in human endothelial cells stimulated endothelial cell migration and limited the expression of monocyte and cellular adhesion molecules.11,12 Moreover, the inhibition of ACE2 in atherosclerosis-prone apolipoprotein E-deficient mice increased the proatherogenic effect of a high-fat diet.13 Some authors have speculated that the binding of the virus to the receptor could reduce the amount of ACE2 accessible for Ang II, with a downregulation of the AT2R-mediated response (Figure 2). This hypothesis is plausible considering the reported downregulation of ACE2 among mice that had been infected with SARS-CoV-2.9 Moreover, injecting the spike protein into mice downregulated ACE2 in the lung and worsened acute lung failure, which was attenuated by blocking the renin-angiotensin pathway.9 Another study has shown significantly higher levels of ACE2 in the lungs of patients with comorbidities associated with severe COVID-19 compared with controls.14 This finding might explain the higher risk of developing severe COVID-19 in people with such comorbidities, but there is no evidence that SARS-CoV-2 has a significant effect on ACE2 expression and activity.

Women Men

60 50

40 30 20 10 0

Hypertension Stroke

Renal

Diabetes

Cancer

Lung disease

Heart disease

The involvement of ACE2 and its deregulation in COVID-19 patients could increase the risk of future acute coronary events, particularly in people who are already predisposed to these events, such as those with diabetes, hypercholesterolaemia or hypertension. Although this hypothesis is plausible based on current evidence, it requires experimental validation. Due to the large number of COVID-19 cases, a new line of research to define the long-term cardiovascular effects is recommended.

RAAS Drugs and COVID-19: A Cause for Concern?

During the early weeks of the pandemic there were concerns about the effect that antihypertensive drugs that target the RAAS may have on the risk of COVID-19 infection and disease outcomes.15–18 ACE inhibitors and AT1R blockers have a protective cardiovascular effect by limiting the AT1R-mediated response, but also increase the ACE2 expression enhancing the vasoprotective axis of the RAAS. Higher levels of ACE2 would also reduce the risk of developing atherosclerosis. It is not so surprising that the identification of ACE2 as the receptor for SARS-CoV-2 raised speculations about the detrimental effect of RAAS-drugs in relation to COVID-19. ACEIs and ARBs promote the expression of ACE2 perhaps making the patients treated with these drugs more susceptible to infection, which is important when we consider the relationship between COVID-19, hypertension and mortality. At least one study has addressed the association between ACEIs and ARBs and testing positive for COVID-19. In this retrospective cohort of 18,472 patients, the authors found no association between these drugs and a positive COVID-19 test.15 The most recent large, well-conducted observational studies also suggest no harm from these drugs. Among others, a study including 1,128 adult patients with hypertension diagnosed with COVID-19 found a lower mortality rate among patients treated with ACEI/ARB after adjustment for age, sex, comorbidities and in-hospital medications. Mortality was also lower in the ACEI/ARB group.16 A large population-based study performed in Italy examined 6,272 COVID-19 patients and population controls. The use of ACEIs and ARBs was more common among those with COVID-19 because there was a higher prevalence of the disease among people with CVD.17 The use of these drugs did not show any association with disease outcomes, severity or death. There was also no association between sex and the clinical variables observed. A simple picture of the effect of ACEIs and ARBs would show the net balance between the enhancement of ACE2 levels that might be detrimental due to the increased amount of receptor accessible for viral infection, but also beneficial by promoting the AT2R-mediated response

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Renin–Angiotensin–Aldosterone System and COVID-19 (Figure 2). Although SARS-CoV-2 might downregulate ACE2, reducing its protective effects and exacerbating injurious Ang II effects, retrospective observational studies do not show that ACEI or ARB users are at increased risk of infection or severe symptoms, and medication changes should be considered based on the individual patient’s clinical condition.18,19

Genetics of RAAS in Cardiovascular Disease and COVID-19

One of the most intriguing issues that the COVID-19 pandemic has raised is the heterogeneous manifestations between individuals exposed to SARS-CoV-2. Many people who test positive for the virus show very mild or even no symptoms and would not require medical attention. The identification of these asymptomatic carriers is a major challenge because they can transmit the virus to others and spread the disease. In other cases, the new coronavirus triggers a deleterious response that could require hospitalisation and admission to ICU. As indicated above there are several well-recognised risk factors for COVID-19 severity and mortality, such as sex, that could be associated with either biological differences between men and women or a higher frequency of smoking and other acquired respiratory risk factors among men.20,21 It has been proposed that the levels of several cellular components required for the viral infection depends on the patient’s sex. For instance, ACE2 expression seems to be higher in women than men and it decreases with age. A study that measured plasma ACE2 concentrations in older people with heart failure found higher levels in men than in women and use of neither an ACEI nor ARB was associated with higher plasma ACE2 concentrations.6 A complete vision of the pathogenesis of the effects of SARS-CoV-2 must consider non-modifiable factors, such as age and sex, but also genetic variability in each individual.22 In this context we can use our extensive knowledge of the genetics of the RAAS and how the variation of the genes that encode proteins in this pathway modulate the risk of developing hypertensive and cardiovascular traits. A common insertion/deletion polymorphism in the ACE gene (ACE-I/D) is one of the best characterised human variants and has been extensively studied in several traits. The deletion allele is associated with higher expression of ACE and deletion homozygotes have significantly higher ACE blood levels compared to insertion carriers. ACE-D has thus been associated with diseases in which the RAAS could be overactive with increased circulation levels of Ang II, such as hypertension, cardiac hypertrophy, heart failure or nephropathies.23,24 This polymorphism has also been associated with the response to physical training because the insertion seems to be more prevalent among elite athletes. There are several mechanisms by which ACE activity could regulate the progression of COVID-19, including the modulation of the ACE2 expression that would make some individuals more susceptible to COVID-19 than others. Some authors have speculated that ethnic differences in ACE-I/D frequency could explain the apparently heterogeneous inter-population rate of infection. The expression of the two ACEs seems to correlate and might 1. Guo T, Fan Y, Chen M, et al. Cardiovascular implications of fatal outcomes of patients with coronavirus disease 2019 (COVID-19). JAMA Cardiol 2020;5:811–8. https://doi. org/10.1001/jamacardio.2020.1017; PMID: 32219356. 2. Shi S, Qin M, Shen B, et al. Association of cardiac injury with mortality in hospitalized patients with COVID-19 in Wuhan, China. JAMA Cardiol 2020;5:802–10. https://doi.org/10.1093/ eurheartj/ehaa408; PMID: 32211816. 3. Bonow RO, Fonarow GC, O’Gara PT, et al. Association of coronavirus disease 2019 (COVID-19) with myocardial injury and mortality. JAMA Cardiol 2020;5:751–3. https://doi. org/10.1001/jamacardio.2020.1105; PMID: 32219362.

be influenced by hypertension status.25 An interesting hypothesis is that functional variants in the two ACEs (and other RAAS genes) could modify the ACE/ACE2 balance and disease susceptibility and severity. The association between ACE polymorphisms and acute respiratory failure is controversial.26–28 Whether these variants define COVID-19 severity and mortality should be investigated.

The ACE2 Gene: A Putative Player in COVID-19

The ACE2 gene is on the X chromosome, so men carry only one copy, a fact that could help explain why the disease seems to be more severe among men. Because women carry two gene copies, a functional variant that confers disease risk when homozygosis would be less frequent among women. The role of ACE2 in cardiovascular and lung disease could explain not only any genetic association with COVID-19 outcomes, but also the susceptibility to SARS-CoV-2 infection. The lack of the C-C chemokine receptor type 5 (CCR5) due to a common mutation confers resistance to HIV infection, and individuals with a complete lack of CCR5 do not develop AIDS in spite of exposure to HIV. A similar mechanism could happen for ACE2 in cases resistant to infection by SARS-CoV-2, but this is unlikely because contrary to the viability of individuals with a complete deletion of CCR5, no mutation that abrogates the ACE2 has been reported. In fact, the data from human genome sequences reveals that the ACE2 gene shows a very low polymorphic rate in the coding sequence, suggesting a constraint against mutations. Our group has sequenced the ACE2 coding sequence in 50 patients with COVID-19, including 25 severe cases, and no variant affecting the protein sequence was identified.29 Of course, ACE2 variants related with reduced protein expression could make the cells less prone to infection and could result in partial resistance among carriers, but at the same time, this would reduce the beneficial effect of ACE2 expression making the individuals more susceptible to adverse COVID-19 outcomes.

Conclusion

The RAAS is implicated in the COVID-19 pandemic through the pivotal role of ACE2 in viral infection. Sex- and age-dependent ACE2 expression could partly explain the higher risk of severe COVID-19 and mortality among older men. In addition, the imbalance of the components of the RAAS could explain the frequency of hypertension and other cardiovascular traits among severe cases. The current evidence suggests that ACEIs or ARBs do not increase the risk of infection or the development of severe COVID-19. A genetic predisposition due to ACE2 gene variants could contribute to define the susceptibility and outcomes of COVID-19. However, this is mere speculation in most COVID-19 literature and although it is based on a plausible hypothesis there is a lack of experimental validation. We are currently viewing the immediate acute effects of COVID-19 in people with cardiovascular comorbidities, but the long-term effects on the cardiovascular system requires the follow-up of patients who have recovered from COVID-19.

4. Komiyama M, Hasegawa K, Matsumori A. Dilated cardiomyopathy risk in patients with coronavirus disease 2019: how to identify and characterise it early? Eur Cardiol 2020;15:e49. https://doi.org/10.15420/ecr.2020.17; PMID: 32536978. 5. Zou X, Chen K, Zou J, et al. Single-cell RNA-seq data analysis on the receptor ACE2 expression reveals the potential risk of different human organs vulnerable to 2019nCoV infection. Front Med 2020;14:185–92. https://doi. org/10.1007/s11684-020-0754-0; PMID: 32170560. 6. Sama IE, Ravera A, Santema BT, et al. Circulating plasma concentrations of angiotensin-converting enzyme 2 in men

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and women with heart failure and effects of reninangiotensin-aldosterone inhibitors. Eur Heart J 2020;41:1810– 7. https://doi.org/10.1093/eurheartj/ehaa373; PMID: 32388565. 7. Crackower MA, Sarao R, Oudit GY, et al. Angiotensinconverting-enzyme 2 is an essential regulator of heart function. Nature 2002;417:822–8. https://doi.org/10.1038/ nature00786; PMID: 12075344. 8. Vangjeli C, Dicker P, Tregouet DA, et al. A polymorphism in ACE2 is associated with a lower risk for fatal cardiovascular events in females: the MORGAM project. J Renin Angiotensin Aldosterone Syst 2011;12:504–9. https://doi.org/10.1177/

Renin–Angiotensin–Aldosterone System and COVID-19 1470320311405557; PMID: 21490025. 9. Kuba K, Imai Y, Rao S, et al. A crucial role of angiotensinconverting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury. Nat Med 2005;11:875–9. https://doi.org/10.1038/ nm1267; PMID: 16007097. 10. Bansal A, Singh AD, Jain V, et al. The association of D-dimers with mortality, intensive care unit admission or acute respiratory distress syndrome in patients hospitalized with coronavirus disease 2019 (COVID-19): A systematic review and meta-analysis. Heart Lung 2021;50:9–12. https:// doi.org/10.1016/j.hrtlng.2020.08.024; PMID: 33041057. 11. Lovren F, Pan Y, Quan A, et al. Angiotensin converting enzyme-2 confers endothelial protection and attenuates atherosclerosis. Am J Physiol Heart Circ Physiol 2008;295:H1377–84. https://doi.org/10.1152/ ajpheart.00331.2008; PMID: 18660448. 12. Sahara M, Ikutomi M, Morita T, et al. Deletion of angiotensin-converting enzyme 2 promotes the development of atherosclerosis and arterial neointima formation. Cardiovasc Res 2014;101:236–46. https://doi. org/10.1093/cvr/cvt245; PMID: 24193738. 13. Thatcher SE, Zhang X, Howatt DA, et al. Angiotensinconverting enzyme 2 deficiency in whole body or bone marrow-derived cells increases atherosclerosis in lowdensity lipoprotein receptor-/- mice. Arterioscler Thromb Vasc Biol 2011;31:758–65. https://doi.org/10.1161/ ATVBAHA.110.221614; PMID: 21252069. 14. Pinto BGG, Oliveira AER, Singh Y, et al. ACE2 expression is increased in the lungs of patients with comorbidities associated with severe COVID-19. J Infect Dis 2020;222:556–63. https://doi.org/10.1093/infdis/jiaa332; PMID: 32526012. 15. Mehta N, Kalra A, Nowacki AS, et al. Association of use of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers with testing positive for coronavirus

disease 2019 (COVID-19). JAMA Cardiol 2020;5:1020–6. https://doi.org/10.1001/jamacardio.2020.1855; PMID: 32936273. 16. Zhang P, Zhu L, Cai J, et al. Association of inpatient use of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers with mortality among patients with hypertension hospitalized with COVID-19. Circ Res 2020;126:1671–81. https://doi.org/10.1161/ CIRCRESAHA.120.317134; PMID: 32302265. 17. Mancia G, Rea F, Ludergnani M, et al. Renin-angiotensinaldosterone system blockers and the risk of Covid-19. N Engl J Med 2020;382:2431–40. https://doi.org/10.1056/ NEJMoa2006923; PMID: 32356627. 18. Chung MK, Karnik S, Saef J, et al. SARS-CoV-2 and ACE2: the biology and clinical data settling the ARB and ACEI controversy. EBioMedicine 2020;58:102907. https://doi. org/10.1016/j.ebiom.2020.102907; PMID: 32771682. 19. Sanchis-Gomar F, Lavie CJ, Perez-Quilis C, et al. Angiotensin-converting enzyme 2 and antihypertensives (angiotensin receptor blockers and angiotensin-converting enzyme inhibitors) in coronavirus disease 2019. Mayo Clin Proc 2020;95:1222–30. https://doi.org/10.1016/j. mayocp.2020.03.026; PMID: 32376099. 20. Komiyama M, Hasegawa K. Smoking cessation as a public health measure to limit the coronavirus disease 2019 pandemic. Eur Cardiol 2020;15:e16. https://doi.org/10.15420/ ecr.2020.11; PMID: 32373189. 21. Zhang H, Rostami MR, Leopold PL, et al. Expression of the SARS-CoV-2 ACE2 receptor in the human airway epithelium. Am J Respir Crit Care Med 2020;202:219–29. https://doi. org/10.1164/rccm.202003-0541OC; PMID: 32432483. 22. Ellinghaus D, Degenhardt F, Bujanda L, et al. Genomewide association study of severe Covid-19 with respiratory failure. N Engl J Med 2020;383:1522–34. https://doi.org/10.1056/ NEJMoa2020283; PMID: 32558485.

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23. Li Y. Angiotensin-converting enzyme gene insertion/deletion polymorphism and essential hypertension in the Chinese population: a meta-analysis including 21,058 participants. Intern Med J 2012;42:439–44. https://doi. org/10.1111/j.1445-5994.2011.02584.x; PMID: 21883781. 24. Bleumink GS, Schut AF, Sturkenboom MC, et al. Genetic polymorphisms and heart failure. Genet Med 2004;6:465–74. https://doi.org/10.1097/01.GIM.0000144061.70494.95; PMID: 15545741. 25. Wakahara S, Konoshita T, Mizuno S, et al. Synergistic expression of angiotensin-converting enzyme (ACE) and ACE2 in human renal tissue and confounding effects of hypertension on the ACE to ACE2 ratio. Endocrinology 2007;148:2453–57. https://doi.org/10.1210/en.2006-1287; PMID: 17303661. 26. Imai Y, Kuba K, Rao S, et al. Angiotensin-converting enzyme 2 protects from severe acute lung failure. Nature 2005;436:112–6. https://doi.org/10.1038/nature03712; PMID: 16001071. 27. Marshall RP, Webb S, Bellingan GJ, et al. Angiotensin converting enzyme insertion/deletion polymorphism is associated with susceptibility and outcome in acute respiratory distress syndrome. Am J Respir Crit Care Med 2002;166:646–50. https://doi.org/10.1164/rccm.2108086; PMID: 12204859. 28. Villar J, Flores C, Pérez-Méndez L, et al. Angiotensinconverting enzyme insertion/deletion polymorphism is not associated with susceptibility and outcome in sepsis and acute respiratory distress syndrome. Intensive Care Med 2008;34:488–95. https://doi.org/10.1007/s00134-0070937-z; PMID: 18060663. 29. Gomez J, Albaiceta G, García-Clemente M, et al. Angiotensin-converting enzymes (ACE, ACE2) gene variants and COVID-19 outcome. Gene 2020;762:145102. https://doi. org/10.1016/j.gene.2020.145102; PMID: 32882331.

Intervention

Abstract

Patients with ST-elevation MI (STEMI) usually have a huge thrombus burden in the infarct-related artery. Stenting may lead to high chances of the slow-flow/no-reflow phenomenon that leads to periprocedural MI and adverse cardiovascular events. Deferred stenting may be beneficial in this situation as the thrombus burden will reduce, mitigating the slow-flow/no-reflow phenomenon. However, routine deferral of stenting in patients with STEMI has not been found to be beneficial, but when the patient is properly selected, deferred stenting has the potential for reducing the final infarct size. The authors report the safety and feasibility of deferred stenting after 5 days of prolonged anticoagulation in a 45-year-old smoker with STEMI who had a large thrombus load shown on an angiogram. They review the registries, trials and meta-analyses on deferred stenting in the literature and analyse the benefits and harms of the strategy. They also propose an algorithm for applying a strategy for deferred stenting in clinical practice based on the available data.

Keywords

Slow flow, no reflow, periprocedural MI, deferred stenting, heparin, ST-elevation MI, anticoagulant Disclosure: The authors have no conflicts of interest to declare. Received: 17 June 2020 Accepted: 14 November 2020 Citation: European Cardiology Review 2021;16:e08. DOI: https://doi.org/10.15420/ecr.2020.31 Correspondence: Rishi Sethi, Department of Cardiology, King George’s Medical University, Lucknow, India. E: drrishisethi1@gmail.com Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Primary percutaneous coronary intervention (PCI) is the standard of care for the treatment for acute ST-elevation MI (STEMI) because it improves the prognosis by salvaging the jeopardised myocardium.1,2 However, in acute situations there is a high load of thrombus in the infarct-related artery and the coronary vascular resistance is also high. Stent placement in such a case enhances the chances of the thrombus shifting both proximally and distally in the microvasculature. The occlusion of microvasculature by thrombus leads to the no-reflow phenomenon.3 The pathophysiology of no reflow revolves around distal embolisation of clot, microvascular spasm and thrombosis.3 No reflow is seen in about 10% of cases of primary PCI and the predisposing factors include advanced age and delayed presentation and a completely occluded culprit artery with heavy thrombus burden.3–7 Table 1 lists the various clinical factors that predispose to the slow-flow/no-reflow phenomena.8,9 The no-reflow phenomenon leads to increased morbidity and mortality thus negating some of the benefits of PCI.4,7 Thrombus aspiration is an important adjunctive treatment but failure in randomised controlled trials (RCTs) led to guidelines advising against its routine use.10,11 Deferred stenting is a novel strategy that aims to postpone stent placement for a fixed time window after stable distal flow has been achieved. The period of deferment allows gradual resorption of thrombus, improvement in thrombolysis in MI (TIMI) flow, decrease in vasospasm and decreased periprocedural complications of slow flow. Further, not infrequently the stent placement may be deferred altogether. The need for two procedures leads to prolonged hospitalisation and may add to the

cost of the treatment, but the improvement of periprocedural outcomes and obviation of the need for a coronary stent can justify the financial burden. Hence, further studies are needed to elucidate whether the short-term increase in medical expenses by using the deferred PCI strategy is cost effective by improving long-term prognosis and reducing social expenses. We report the case of successful deferred stenting in a 45-year-old man with STEMI and high thrombus burden. The deferred angiogram revealed significant attenuation of thrombus burden and improved TIMI flow. We further discuss the various trials, registries and meta-analyses reporting on the strategy.

Case Report

A 45-year-old man presented to the emergency department with acute anterior-wall MI of 8 hours duration. The patient had a history of hypertension and was a smoker. His echocardiogram showed hypokinesis in the left anterior descending (LAD) artery with an ejection fraction of 38%. The patient was thrombolysed and taken up for pharmaco-invasive PCI. His coronary angiogram showed a significant stenosis with grade IV thrombus in proximal LAD with TIMI 2 flow (Figure 1A). Due to high thrombus burden, stenting was deferred and the patient was put on IV eptifibatide (a glycoprotein IIb IIIa inhibitor) infusion for 18 hours followed by subcutaneous low molecular weight heparin twice daily. Rescue PCI was planned in case the patient developed chest pain. After 5 days, his angiogram showed moderate stenosis and the thrombus in

Deferred Stenting for Heavy Thrombus Burden During PCI for STEMI Table 1: Factors Associated with Increased Incidence of No Reflow Phenomenon Favourable (OR for Developing Slow Flow/No Reflow) Hypertension (0.65) Prior use of statins (0.41) History of previous MI (0.38)

Unfavourable (OR for Developing Slow Flow/No Reflow) Age (per year increase: 1.032) Number of Q waves (per wave increase: 1.122) Lesion length (per mm increase: 1.025) Thrombus grade (per grade increase: 1.881) SYNTAX score in infarct-related artery (1.042 per single unit increase) Baseline TIMI flow <1 (1.1) Intra-aortic balloon bump use before percutaneous coronary intervention (1.94) Reperfusion time >6 h (1.27) Systolic blood pressure on admission <100 mmHg (1.91) TIMI = thrombolysis in MI. Source: Alidoosti et al. 20188 and Zhou et al. 2014.9

Figure 1: Comparison of Thrombus Burden in the First and Deferred Coronary Angiograms of the Patient A Thrombus in LAD with stenosis

Thrombus in proximal LAD with stenosis

Deferred Stenting Strategy: A Primer

The strategy of deferred stenting represents a radical change in the management of patients with STEMI during PCI especially if they have a high thrombus burden. The stent placement is delayed by a finite interval after the index procedure when stable distal flow has been restored by PCI or thrombolysis. This time of deferment has multiple benefits – gradual clearing of the thrombus, improvement of microvascular flow, reduction of vasospasm, prevention of distal embolisation, avoidance of slow flow/no reflow and attenuated periprocedural MIs. Indeed, data suggests the coexistence of thrombus and spasm and hence a deferred strategy can lead to better stent selection (large and short stents).20,21 In some cases, it can lead to deferment of stent placement altogether. Moreover, placing a stent in an artery with high thrombus burden can lead to malapposition and increased stent thrombosis as documented in imaging studies, probably due to selection of smaller size stents and longer devices.22,23 On the other hand, there is a possible risk of reocclusion during the waiting period which can be mitigated by parenteral anticoagulants and glycoprotein (GP) IIb/IIIa inhibitors. A rescue PCI should be considered if necessary. A prolonged systemic anticoagulation can increase the risk of bleeding which can be detrimental. However, the use of the CRUSADE bleeding risk score can help to assess the baseline bleeding risk of the patient. It has been validated in a cohort of nearly 18,000 patients and scores <20 indicate a very low risk of in-hospital bleeding.24 The use of GPIIb/IIIa inhibitor infusion should be avoided in patients who have a high CRUSADE score (>20) to mitigate the bleeding risk from prolonged anticoagulation (intracoronary bolus may be considered in high-risk patients). Patients with a score >50 are at a very high risk of bleeding and the duration of low-molecular-weight duration should be reduced to 72 hours instead of the standard proposed duration of 5–7 days.

A: Coronary angiogram showing heavy thrombus burden in proximal LAD with stenosis at index procedure. B: Check angiogram after 5 days of antithrombotic therapy showing complete resolution of thrombus. LAD = left anterior descending artery.

LAD was almost absent with improved TIMI 3 flow (Figure 1B). Since there was a significant obstruction in LAD, a direct stenting procedure with a 3 × 24 mm everolimus-eluting stent was performed and the results were optimised by post-dilation with a non-compliant balloon. The end result obtained was a TIMI 3 flow without any residual stenosis or complications.

Discussion and Literature Review

debris are important contributors to interventional slow flow/no reflow. Thrombus removal with thrombectomy devices has been found to be useful, but RCTs of mechanical and manual thrombectomy and distal protection have not shown consistent benefits and, an association with stroke was observed in some trials.13–16 Presence of residual thrombus even after manual aspiration is one of the pitfalls and it predicts poor outcomes.17,18 Thrombus grading on angiography is done by the Gibson’s angiographic score/TIMI criteria.19 A thrombus grade higher than 3 is usually considered as high thrombus burden.

Primary PCI within the window period of 12 hours of symptom onset is the standard of care for patients with STEMI.1,2 However, in a fraction of these patients reduced coronary blood flow (slow flow or no reflow) is seen despite epicardial vessel patency with PCI, and this is associated with a worse prognosis.3,12 Distal migration of thrombus and atherosclerotic

Another pitfall with deferred PCI is the need for two procedures that will lead to prolonged hospitalisation, as well as adding to the cost of the treatment. However, the improvement of periprocedural outcomes and obviation of the need for a coronary stent can justify the financial burden. This calls for further studies to evaluate the short-term increase in medical expenses versus the improved long-term prognosis and whether this will translate into reduced care costs during follow-up. Figure 2 summarises the key advantages and pitfalls of a deferred strategy versus an immediate stenting approach. Other terminology used in the literature for a procrastinated stenting approach include delayed PCI and secondary PCI.25 Minimally invasive mechanical intervention (MIMI) is an adjuvant technique during primary PCI before deferring stent placement in arteries with TIMI 0–1 flow.26 The strategy entails the use of a guidewire, an undersized balloon catheter and thrombus aspiration to establish distal coronary flow.27 The aim is to restore the flow with minimal forward propagation of thrombus. In the following sections, we discuss the available data regarding this approach.

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Deferred Stenting for Heavy Thrombus Burden During PCI for STEMI Single Centre and Non-randomised Studies

Initial registries and non-randomised data (before 2010) suggested that a strategy of delayed or deferred stenting, when stable coronary blood flow has been achieved in the infarct-related artery reduces the risk of embolisation and thereby potentially improves the clinical outcome.28–30 Data accumulated in the past decade has reaffirmed that deferred stenting reduces thrombus burden, improves microvascular flow, increases myocardial salvage, improves left ventricular ejection fraction (LVEF) and attenuates major adverse cardiac events (MACE) in patients with STEMI.31–34 Male sex, younger age, larger size of culprit artery and higher thrombus burden at baseline were predictors of greater benefit from deferred stenting.33 It is also interesting to note that association between stent implantation and improved outcomes has not been very consistent.35,36

Figure 2. Potential Advantage and Pitfalls of a Deferred Stenting Strategy Compared to Immediate Stenting in Patients with High Thrombus Burden

Disadvantages

Deferred stenting

In a Danish pilot study, the need for subsequent stenting was reduced by 38% without any risk of reocclusion at 3 months with a deferred strategy.37 In a previous study by Ke et al., subsequent stents were avoided in 23% of patients.32 In a French study, Souteyrand et al. used optic coherence tomography (OCT) to guide deferred stenting.38 The study tested the safety of three different strategies – acute (<2 days), early (up to 7 days) and late deferral (up to 1 month) in the setting of STEMI with large thrombus burden on angiogram. There were no MACE recorded between initial and final procedure at a mean of 9 days. The thrombus presence as assessed by OCT continued to diminish from acute phase (94.1%) to early phase (78%) to late phase (32%). Not only presence of thrombus but also the length, score and area of thrombus continued to decline on OCT from acute to late groups. This study demonstrated that OCT-guided postponement of stent implantation led to good procedural outcomes with 100% success and alleviation of no-reflow events. This is the first imaging-guided evidence for the continuum of resorption of thrombus on prolonged deferral until a week and beyond up to 30 days. Building upon the results of previous studies, the SUPER-MIMI study tested a longer deferral time of 7 days in 155 patients with STEMI.39 There was an improvement in TIMI flow, decrease in thrombus burden and stenosis severity diminished. More importantly, stenting was also avoided in 38% cases with a minimal chance of reocclusion (1.3%). Studies have not only used metallic drug-eluting stents (DES), but also bioresorbable stent (BRS), with Combaret et al. demonstrating successful deferred implantation of BRS in 45 patients with STEMI under OCT guidance between 2 and 7 days. 40 TIMI flow improved and thrombus burden declined on subsequent angiograms. BRS implantation was altogether avoided in 25% cases and MACE rate was low at 6 months.40

Randomised Controlled Trials DEFER STEMI

In the DEFER-STEMI study, patients were randomised to either conventional stenting or deferred stenting with an intent to implant stent after prolonged antithrombotic therapy after an initial achievement of TIMI 2–3 flow.41 Patients with STEMI along with angiographic or clinical features for risk of slow flow/no reflow were enrolled for the study. There was significant reduction in incidence of the primary endpoint of slow flow/no reflow in the deferred group (5.9% versus 28.6%, OR -0.16; p=0.005). There were also fewer thrombotic events during PCI while the final TIMI flow was higher. The amount of myocardium salvaged on cardiac MRI was higher in the deferred stenting group on long-term follow-up and the percentage of salvaged myocardium is one of the prognostic indicators in

• Reocclusion • Unplanned revascularisation • Increase bleeding from extended parenteral anticoagulation • Increased medical expenses

Problems with immediate stenting

Advantages

• Increased slow flow/no reflow • Increased stent thrombosis • Late stent malapposition • Smaller stent sizes due to vasospasm

• • • • • •

Low thrombus burden Decreased periprocedural MI Improved thrombolysis in MI flow Slow flow/no reflow prevented Larger stent size Lesser number of stents implantation • Smaller infarct size

STEMI PCI. Also, a larger percentage of patients achieved greater stent diameter in the deferred strategy group.

DANAMI 3-DEFER

On the contrary, the DANAMI 3-DEFER trial failed to show any benefit of deferred stenting on clinical outcomes.42 About 1,200 patients were randomised to a deferred stent strategy versus an immediate stenting technique. There was no significant difference in the primary outcome (composite of all-cause death, hospitalisation for heart failure, repeat MI and unplanned revascularisation; 7% versus 18%; p=0.92). In addition, there was a slightly higher, although not significant, chance of reocclusion rates (2%) in the deferred stenting group. However, there was an insignificant improvement in LVEF in the deferred stenting group, but whether that translates into better clinical outcomes is not known. An MRI sub-study also failed to find any benefit on myocardial infarct size, microvascular obstruction and myocardial salvage index.43 However, in patients with lesion length/stent >24 mm, the deferred strategy significantly reduced infarct size. This finding has been corroborated in other studies.21

Comparing Randomised Controlled Trials

Why are there contrasting results from two large RCTs on deferred PCI? First, the DEFER STEMI enrolled patients at high risk of slow flow based on clinical angiographic features, whereas DANAMI 3-DEFER was an allcomer primary PCI study (Supplementary Material Table 1). A deferral strategy should only be applied after careful angiographic selection. Second, DEFER STEMI was an angiographic and MRI endpoint study whereas DANAMI 3-DEFER looked at clinical outcomes. We know that clinical outcomes are affected by many variables and imaging features are only one of the facets. We can conclude that the benefits of reducing slow flow in some high-risk patients could have been counterbalanced by reocclusions due to unnecessary deferral in low-risk patients. Third, DANAMI 3-DEFER was a larger, multicentre, randomised study, in contrast to DEFER, which was a small, single-centre, proof of concept study. The analogy is similar to renal denervation studies where data from the small SYMPLICTY 1 and 2 studies failed to translate into benefit in the large SYMPLICTY 3 study.44

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Deferred Stenting for Heavy Thrombus Burden During PCI for STEMI Figure 3. Non-uniform Time Intervals Between Index and Deferred Angiograms Across Various Randomised and Non-randomised Studies Ke et al.32 (7 days) Tang et al.31 (7 days)

Deferred angiogram

SUPER-MIMI39 (7 days) Pascal et al.34 (4.3 days) 7 days

INNOVATION47 (3–7 days)* Echavarría-Pinto et al.33 (60 h) 96 h

Danish pilot study37 (48–72 h) DANAMI 3-DEFER42 (48 h)*

72 h

MIMI46 (24–48 h)* 48 h

DEFER STEMI41 (4–16 h)* 24 h

Index angiogram *Randomised trials

Fourth, the use of GPIIb/IIIa inhibitors in DANAMI 3-DEFER was significantly lower compared to DEFER STEMI (35% versus 98%). The duration of infusion was also lower (at least 4 hours versus 12 hours). Robust parenteral anticoagulant and antithrombotic agents are integral components of a defer strategy, as discussed earlier. In fact, the majority of patients in the DANAMI 3-DEFER study received bivalirudin which is no longer recommended during PCI because of high rates of stent thrombosis.45 These factors could be the major contributors to high reocclusion rates seen and attenuation of clinical benefits in the deferred arm. Finally, there was high crossover to immediate stenting (22%) in the defer arm of the DANAMI trial which further weakened the results.

Recent Trials

In the MIMI trial, deferred stenting at a median 36 hours was studied in 140 patients with STEMI.46 Microvascular obstruction on cardiac MRI at 5 days was non-significantly lower in the immediate stenting group. The INNOVATION study did not find any merit in a routine defer strategy during primary PCI at two centres in South Korea.47 In the subset of anterior infarction, the primary endpoint – infarct size and microvascular obstruction – was significantly attenuated. PRIMACY is the latest RCT in the series, with results presented at the European Society of Cardiology congress in 2019. The study randomised 305 STEMI patients to immediate versus delayed stenting. Only demographic and angiographic characteristics were reported separately and the outcomes of the study were reported as pooled data of 1,873 subjects after combining data from the four RCTs discussed above (DEFER STEMI, DANAMI 3-DEFER, MIMI and INNOVATION).48 The data from PRIMACY was treated as exchangeable with the four other RCTs and a patient-level data metaanalysis was used with hierarchical predefined distribution of the risk ratio.49 There was adequate use of GPIIb/IIIa inhibitors (80–90%) and the mean delay in stenting was 42 hours. The slow-flow/no-reflow rates were reduced in the deferred arm (24% versus 27%). Distal embolisation was also lower in

the deferred arm as was the composite of adverse angiographic events. The combined endpoint of cardiovascular death, MI, heart failure and urgent target vessel revascularisation (TVR) in the pooled analysis was not different in either of the arms. However, a deferred strategy led to reduction in cardiovascular death and heart failure in the long term, which was counterbalanced with increased rates of unplanned TVR. Full data from the meta-analysis is yet to be published.

Meta-analysis Data

A meta-analysis by Freixa et al., which encompasses six studies (five nonrandomised) demonstrated that deferred stenting was safe with only three coronary reocclusions occurring among 283 patients and beneficial as it improved left ventricular function with a lower MACE rate.50 The main criticism of the meta-analysis is the exclusion of all the RCTs discussed above. The only RCT included enrolled patients with non-STEMI and assessed the role of early versus delayed invasive PCI unrelated to thrombus or slow flow. Subsequently, Qiao et al. in their meta-analyses of nine studies (three RCTs and six observation studies) found no difference in incidence of slow flow/no reflow overall.51 But observational studies showed a significant decline in its incidence (OR 0.12; p=0.002). Deferred stenting conferred an advantage in terms of improvement in LVEF in the long term but no difference in MACE. Most recently, Cassese et al. in a collaborative meta-analysis of all four RCTs of deferred stenting with MRI data, concluded that baseline thrombus burden (>grade 3) and longer stent length correlated with slow flow and microvascular obstruction.52 Deferred stenting potentially improved angiographic outcomes however, this did not translate into clinical and imaging outcomes.

What Should Be the Ideal Deferral Time?

The studies discussed have used variable time intervals between the index angiogram and the deferred angiogram (Figure 3). The usual time

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Deferred Stenting for Heavy Thrombus Burden During PCI for STEMI Figure 4. A Suggested Algorithm Regarding Optimal Use of a Deferred Strategy During Percutaneous Coronary Intervention of STEMI Primary PCI/ pharmacoinvasive PCI

TIMI 0–1 flow

TIMI 2–3 flow High thrombus burden or

MIMI*

Lesion length >24 mm or High-risk features for slow flow†

TIMI 0–1 flow

TIMI 2–3 flow No

Yes * Aggressive balloon dilatation Plaque modification/intracoronary pharmacotherapy

Defer PCI 5–7 days

Standard PCI

LMWH+ GPIIb/IIIa

Check angiogram

Medical Rx

Residual stenosis and vessel >2 mm

Yes

Standard PCI

*Patients excluded from RCTs; †Minimal invasive mechanical intervention; ‡Refer to Table 1 for high-risk features of slow/no reflow. GP = glycoprotein; LMWH = low-molecular-weight heparin; PCI = percutaneous coronary intervention; Rx = prescription; TIMI = thrombolysis in MI.

elapsed is between 24–72 hours in the RCTs except INNOVATION, which used a time lag of 3–7 days. Similarly, the majority of the 10 nonrandomised studies also used a time delay between 24–72 hours. Only four studies have used a longer 6–7-day window period for deferral.28,32,33,40 Many researchers, including our group, consider the 24–48-hour window period too short for meaningful thrombus resorption and to register effective action of antithrombotic agents.53 The French study clearly demonstrated persistent thrombus resolution with time delay up to 30 days. There was also increase in arterial diameter, decrease in stenosis diameter and improved TIMI flow with time too. Although appealing, a 1-month deferral is not practical as it leads to a prolonged hospital stay, challenges in parenteral anticoagulation and a financial burden on the health system. A 7-day deferral is plausible with additional thrombus attenuation and improved periprocedural advantages though only a minority of RCTs enrolled such patients. Moreover, to achieve the optimum benefits of the defer strategy, we believe a deferral time of 5–7 days is needed in patients with a high thrombus burden. At our institution, we administer IV GPIIb/IIIa inhibitor for 12–16 hours after the procedure followed by low molecular weight heparin for 5–7 days or until the next angiogram depending upon the baseline CRUSADE score. In patients with a CRUSADE score >20, the GP IIb/IIIa infusion is avoided and only intracoronary bolus is provided. For those at very high risk of bleeding (score >50), the duration of heparin is also reduced. This protocol minimises the chances of reocclusion and bleeding events are also reduced. A rescue PCI should be performed whenever needed.

How to Select Patients for Deferred Treatment

A uniform approach was missing among the RCTs and non-randomised studies (Supplementary Material Table 2). While the DEFER STEMI trial

selected patients based on one or more angiographic feature of slow flow/no flow, the other four RCTs were all-comer primary PCI studies with TIMI 2–3 flow achieved after a MIMI strategy. On the contrary, most singlecentre observational and non-randomised registry studies recruited patients with high thrombus burden.27,30–32,37–38 Moreover, two different definitions of high thrombus burden were used.19,54 Selection of such a high-risk group poised for adverse events with immediate PCI could have resulted in success in the majority of non-randomised studies while the majority of RCTs enrolling an all-comer population failed to demonstrate benefits. Indeed, large thrombus burden is an ardent precursor for stent thrombosis and MACE with DES implantation in acute MI.55 The failure of DANAMI DEFER and other RCTs precludes a defer strategy for all STEMI patients. However, the success of the randomised and nonrandomised studies that chose high-risk subjects favours such a strategy in routine practice. First, the presence of large thrombus burden on angiogram during PCI for STEMI or acute coronary syndrome (ACS) is the most widely accepted criteria for a defer strategy. In the setting of primary PCI, a MIMI strategy is highly recommended and was used in most RCTs. In case of a pharmacoinvasive PCI, the use of MIMI is optional and will depend upon the clinical scenario as well as operator preference. Second, presence of long lesion/stent length >24 mm is an additional indication for a defer strategy. When neither of these are present, the presence of two or more clinical and non-clinical criteria predisposing to a high risk of slow flow could be the third criterion used to guide a defer strategy (Table 1). Younger age, male sex and large diameter of culprit vessel are other candidates who will do well with a defer strategy. Last, anterior infarction is another subset which purportedly attains benefit from a defer strategy, probably owing to the large area of myocardium at risk, warranting a low threshold to adopt a defer strategy in anterior wall MIs.

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Deferred Stenting for Heavy Thrombus Burden During PCI for STEMI A suggested algorithm for optimal use of a defer strategy during PCI for STEMI/ACS is presented in Figure 4. We would like to emphasise that the prerequisite for implementing defer PCI is securing a TIMI 3 flow. In some situations, optimal TIMI flow may not be secured even after MIMI. Extensive microvasculature damage and inadequate treatment of culprit lesion are common mechanisms for failure to achieve adequate TIMI flow in such a scenario. Therefore, both of these situations require more intensive intervention than MIMI, rather than defer PCI. Uncommonly, even after aggressive lesion preparation and intracoronary pharmacotherapy, a TIMI 3 flow might not be feasible. Deferred PCI in such a scenario has not been tested in randomised trials but nevertheless the use of a coronary stent would also be questionable. Such patients represent a grey area and an individualised approach is needed.

Future Directions

Two future studies of defer stenting are underway to provide more answers – INNOVATIONCORE (NCT03744000) and OPTIMAL 1. Keeley EC, Boura JA, Grines CL. Primary angioplasty versus intravenous thrombolytic therapy for acute myocardial infarction: a quantitative review of 23 randomized trials. Lancet 2003;361:13–20. https://doi.org/10.1016/S01406736(03)12113-7; PMID: 12517460. 2. O’Gara PT, Kushner FG, Ascheim DD, et al. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2013;61:485–510. https://doi.org/10.1016/j.jacc.2012.11.019; PMID: 23256914. 3. Jaffe R, Charron T, Puley G, et al. Microvascular obstruction and the no-reflow phenomenon after percutaneous coronary intervention. Circulation 2008;117:3152–6. https://doi.org/10.1161/ CIRCULATIONAHA.107.742312; PMID: 18559715. 4. Morishima I, Sone T, Okumura K, et al. Angiographic no-reflow phenomenon as a predictor of adverse long-term outcome in patients treated with percutaneous transluminal coronary angioplasty for first acute myocardial infarction. J Am Coll Cardiol 2000;36:1202–9. https://doi.org/10.1016/ s0735-1097(00)00865-2; PMID: 11028471. 5. Antoniucci D, Valenti R, Migliorini A, et al. Direct infarct artery stenting without predilation and no-reflow in patients with acute myocardial infarction. Am Heart J 2001;142:684– 90. https://doi.org/10.1067/mhj.2001.117778; PMID: 11579360. 6. Ndrepepa G, Tiroch K, Keta D, et al. Predictive factors and impact of no reflow after primary percutaneous coronary intervention in patients with acute myocardial infarction. Circ Cardiovasc Interv 2010;3:27–33. https://doi.org/10.1161/ CIRCINTERVENTIONS.109.896225; PMID: 20118156. 7. Harrison RW, Aggarwal A, Ou FS, et al. Incidence and outcomes of no-reflow phenomenon during percutaneous coronary intervention among patients with acute myocardial infarction. Am J Cardiol 2013;111:178–84. https://doi. org/10.1016/j.amjcard.2012.09.015; PMID: 23111142. 8. Alidoosti M, Lotfi R, Lotfi-Tokaldany M, et al. Correlates of the “no-reflow” or “slow-flow” phenomenon in patients undergoing primary percutaneous coronary intervention. J Tehran Heart Cent 2018;13:108–14. https://doi.org/10.18502/ jthc.v13i3.130; PMID: 30745923. 9. Zhou H, He XY, Zhuang SW, et al. Clinical and procedural predictors of no-reflow in patients with acute myocardial infarction after primary percutaneous coronary intervention. World J Emerg Med 2014;5:96–102. https://doi.org/10.5847/ wjem.j.issn.1920-8642.2014.02.003; PMID: 25215156. 10. Levine GN, Bates ER, Blankenship JC, et al. 2011 ACCF/AHA/ SCAI guideline for percutaneous coronary intervention. J Am Coll Cardiol 2011;58:e44–122. https://doi.org/10.1016/j. jacc.2011.08.007; PMID: 22070834. 11. Windecker S, Kolh P, Alfonso F, et al. 2014 ESC/EACTS guidelines on myocardial revascularization. Eur Heart J 2014;35:2541–619. https://doi.org/10.1093/eurheartj/ehu278; PMID: 25173339. 12. Henriques JP, Zijlstra F, Ottervanger JP, et al. Incidence and clinical significance of distal embolization during primary angioplasty for acute myocardial infarction. Eur Heart J 2002;23:1112–7. https://doi.org/10.1053/euhj.2001.3035. PMID: 12090749. 13. Kelbaek H, Terkelsen CJ, Helqvist S, et al. Randomized comparison of distal protection versus conventional treatment in primary percutaneous coronary intervention:

(NCT03282773). The publication of an updated meta-analysis of five RCTs including PRIMACY will also shed further light.

Conclusion

Heavy thrombus burden is not uncommon during PCI for STEMI and is an important contributor to the slow-flow /no-reflow phenomenon. Deferred stenting aims to lower thrombus burden and improve TIMI flow during the deferment time with the help of anticoagulants. Multiple studies and meta-analyses have shown benefits in terms of reduced slow flow/no reflow, improvement in ejection fraction and decreased MACE in some. A routine deferred strategy has not been shown to be beneficial and is definitely not advisable. But cases with high thrombus burden, longer lesions, high-risk features for slow flow and those with suboptimal TIMI flow (0–1) after thrombus aspiration can be candidates for deferred stenting. The ideal window for deferral is a matter of debate but longer deferral periods up to 5–7 days have proven to be safe and are advocated. Adjuvant parenteral anticoagulation is essential.

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EXCEL Trial

Editorial: The EXCEL Trial Pablo Avanzas

1,2,3

and Juan Carlos Kaski

1. Heart Area, Hospital Universitario Central de Asturias, Oviedo, Spain; 2. Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Spain; 3. University of Oviedo, Oviedo, Spain; 4. St George’s, University of London, London, UK

Received: 18 January 2021 Accepted: 25 January 2021 Citation: European Cardiology Review 2021;16:e09. DOI: https://doi.org/10.15420/ecr.2021.02 Correspondence: Pablo Avanzas, Heart Area, Hospital Universitario Central de Asturias, Av Roma, s/n 33011 Oviedo, Asturias, Spain. E: avanzas@secardiologia.es Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Left main coronary artery disease (LMCAD) is identified in about 5% of patients undergoing coronary arteriography for the assessment of obstructive coronary artery disease (CAD) and is associated with increased morbidity and mortality.1 For decades, coronary artery bypass grafting (CABG) has been the gold standard treatment for LMCAD. However, with continuing advances in interventional cardiology, percutaneous coronary intervention (PCI) has become a safe and effective management option in selected patients with LMCAD.2 The XIENCE versus Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization (EXCEL) trial assessed the safety and efficacy of CABG versus PCI for the management of LMCAD. The authors reported their 3-year follow-up data in December 2016 and 5-year follow-up data in September 2019.3,4 In this contemporary, non-inferiority trial, 1,905 patients with low or intermediate anatomical complexity LMCAD were randomly assigned to undergo either PCI with fluoropolymer-based cobalt-chromium everolimus-eluting stents (PCI group, n=948) or CABG (CABG group, n=957). Results at 30-day, 3- and 5-year follow-up are shown in Table 1. The authors concluded that treatment with PCI and CABG did not differ significantly regarding the composite outcome of death, stroke or MI in patients with LMCAD of low or intermediate anatomical complexity. Although the EXCEL trial has many strengths including its recruitment and successful follow-up of a large number of patients, the interpretation of its findings has generated controversy and the lead surgical investigator withdrew his name from its final publication. Moreover, in December 2019, the European Association for Cardio-thoracic Surgery council withdrew its support for the treatment recommendations on LMCAD published in the 2018 European Society of Cardiology/European Association for Cardiothoracic Surgery myocardial revascularisation guidelines that were largely based on the EXCEL trial findings.5 A number of issues in the trial have been extremely controversial and debated by the scientific community worldwide. Two main issues have captured the attention of clinicians, researchers and patients alike:

• The reporting of the overall results as ‘neutral’ at 5-years follow-up with similar outcomes for CABG and PCI treatments.

• Discrepancies that emerged after the publication of the study regarding the definition of periprocedural MI used in the trial.

‘Neutral’ Overall Results

The authors reported that in patients with LMCAD and a low and intermediate SYNTAX score, the study’s composite primary endpoint – death, stroke or MI – at 5 years was 22% in the PCI group and 19.2% in the CABG group (p=0.13) and concluded that there were no significant differences between revascularisation with PCI or CABG. Moreover, allcause mortality was reported as being essentially equal between the PCI and CABG groups at 1 and 2 years but it began to diverge in a sustained fashion such that endpoint rates became 13.0% versus 9.9% (OR 1.38; 95% CI [1.03– 1.85]) by 5 years. The mortality rate at 5 years was 38% higher in the PCI arm compared to the CABG arm. To provide additional insights into the interpretation of data reported by EXCEL, Bayesian methods were proposed, which give probability estimates of clinical interest and allow the consideration of pre-existing evidence and how it can influence test results and aid medical decisionmaking.6 These methods have been recommended to assist in the interpretation of clinical trials for more than 20 years.7 Reanalysis of the EXCEL trial data with the use of Bayesian methods resulted in the opposite conclusions to what was initially reported by the EXCEL investigators: the mean difference regarding incidence of the primary composite outcome was 3% lower in the CABG group compared to the PCI, whereas mortality was 1% lower with CABG than with PCI at 5 years. Similar results were reported in a systematic review of all previous CABG versus PCI studies. This analysis suggests that long-term results with the use of PCI are inferior to CABG in patients with LMCAD.8

Discrepancies in the Different Definition of MI in the EXCEL Trial

In the EXCEL protocol, the universal definition of MI from the joint European Society of Cardiology/American College of Cardiology/American Heart Association/World Heart Federation Task Force for the Redefinition of MI was a pre-specified secondary endpoint. However, the EXCEL investigators used the Society for Cardiovascular Angiography and Interventions (SCAI) definition of MI when the results were reported. This is problematic, as the universal definition was a pre-specified secondary endpoint in the original EXCEL protocol and this definition was not used in the 3-year or 5-year publications. Post-revascularisation myonecrosis was assessed after PCI and CABG by serial measurements of creatine kinase-MB (CK-MB) and defined using an identical threshold for PCI and CABG (CK-MB elevation >10 × the upper

The EXCEL Trial – Editorial Table 1: EXCEL Trial Outcomes at 30 Days, 3 Years and 5 Years 30 days

3 years

5 years

PCI (n=948)

CABG (n=957)

HR [95% CI]

p-value PCI (n=948)

CABG (n=957)

HR [95% CI]

p-value PCI (n=948)

CABG (n=957)

HR [95% CI]

Death, stroke or MI

4.9%

7.9%

0.61 [0.42–0.88]

0.008

15.4%

14.7%

1.00 [0.79–1.26]

0.98

22.0%

19.2%

1.19 [0.95–1.50]

Death

1.0%

1.1%

0.90 [0.37–2.22]

0.82

8.2%

5.9%

1.34 [0.94–1.91]

0.11

13.0%

9.9%

1.38 [1.03–1.85]

Stroke

0.6%

1.3%

0.50 [0.19–1.33]

0.15

2.3%

2.9%

0.77 [0.43–1.37]

0.37

2.9%

3.7%

0.78 [0.46–1.31]

3.9%

6.2%

0.63 [0.42–0.95]

0.02

8.0%

8.3%

0.93 [0.67–1.28]

0.64

10.6%

9.1%

1.14 [0.84–1.55]

Values are presented as event rate (%). CABG = coronary artery bypass grafting; PCI = percutaneous coronary intervention

reference limit (URL) within 72 hours post-procedure, or >5× URL with new Q waves, angiographic vessel occlusion or loss of myocardium on imaging). Troponin assessments were optional and, according to the authors, were collected in a minority of patients, which seriously compromises the diagnosis of procedural MI using alternative definitions. In a letter to the editor published in the New England Journal of Medicine in July 2020, the authors provided evidence on the cumulative incidence of MI at the 5-year follow-up using the third universal definition of MI and a large discrepancy has become apparent in the number of CABG-related 1. Ragosta M. Left main coronary artery disease: importance, diagnosis, assessment, and management. Curr Probl Cardiol 2015;40:93–126. https://doi.org/10.1016/j.cpcardiol. 2014.11.003; PMID: 25765453. 2. Alasnag M, Yaqoub L, Saati A, Al-Shaibi K. Left main coronary artery interventions. Interv Cardiol 2019;14:124–30. https://doi.org/10.15420/icr.2019.10.R2; PMID: 31871488. 3. Stone GW, Sabik JF, Serruys PW, et al. Everolimus-eluting stents or bypass surgery for left main coronary artery disease. N Engl J Med 2016;375:2223–5. https://doi. org/10.1056/NEJMoa1610227; PMID: 27797291. 4. Stone GW, Kappetein AP, Sabik JF, et al. Five-year outcomes after PCI or CABG for left main coronary disease. N Engl J

procedural MIs when data using these two different definitions are compared.9,10 Unfortunately, the letter did not include a calculation of the primary composite outcome using the universal definition of MI.

Conclusion

The evidence indicates that the jury is still out as to whether CABG or PCI is a better treatment option for patients with LMCAD and the issue continues to be debated. A review process initiated by the NEJM is under way and it is hoped that its conclusions will help gain insight into the true findings of the EXCEL trial.

Med 2019;381:1820–30. https://doi.org/10.1056/ NEJMoa1909406; PMID: 31562798. 5. Neumann FJ, Sousa-Uva M, Ahlsson A. 2018 ESC/EACTS guidelines on myocardial revascularization. Eur Heart J 2019;40:87–165. https://doi.org/10.1093/eurheartj/ehy394; PMID: 30165437. 6. Spiegelhalter DJ, Myles JP, Jones DR, Abrams KR. Methods in health service research. An introduction to Bayesian methods in health technology assessment. BMJ 1999;319:508–12. https://doi.org/10.1136/bmj.319.7208.508; PMID: 10454409. 7. Brophy JM, Joseph L. Placing trials in context using Bayesian analysis: GUSTO revisited by Reverend Bayes.

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JAMA 1995;273:871–5. https://doi.org/10.1001/ jama.1995.03520350053028; PMID: 7869558. 8. Brophy JM. Bayesian Interpretation of the EXCEL trial and other randomized clinical trials of left main coronary artery revascularization. JAMA Intern Med 2020;180:986–92. https:// doi.org/10.1001/jamainternmed.2020.1647; PMID: 32478838. 9. Lozano I, Rondan J, Vegas JM. PCI or CABG for left main coronary artery disease. N Engl Med 2020;383:290–1. https://doi.org/10.1056/NEJMc2000645. PMID: 32668124. 10. Stone GW, Serruys PW, Sabik JF. PCI or CABG for left main coronary artery disease. Reply. N Engl J Med 2020;383:292– 4. https://doi.org/10.1056/NEJMc2000645; PMID: 32668128.

ISCHEMIA Trial

The ISCHEMIA Trial: And the Winner Is… the Patient Pablo Avanzas

1,2,3

and Juan Carlos Kaski

Received: 19 January 2021 Accepted: 25 January 2021 Citation: European Cardiology Review 2021;16:e10. DOI: https://doi.org/10.15420/ecr.2021.03 Correspondence: Pablo Avanzas, Heart Area, Hospital Universitario Central de Asturias, Av. Roma, s/n, 33011 Oviedo, Asturias, Spain. E: avanzas@secardiologia.es Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Mainly influenced by the results of the most recent large comparative studies of medical versus revascularisation treatment, the current European Society of Cardiology guidelines for the management of patients with chronic coronary syndrome (CCS) recommend optimal medical treatment (OMT) as a key therapy for reducing symptoms, halting the progression of atherosclerosis and preventing atherothrombotic events. Myocardial revascularisation is also strongly recommended, in addition to medical treatment, in the management of a specific CCS.1

was 5.3% in the invasive strategy group and 3.4% in the conservative strategy group (difference 1.9%; 95% CI [0.8–3.0]); at 5 years, the cumulative event rate was 16.4% and 18.2%, respectively (difference, −1.8%; 95% CI [−4.7, 1.0]). Results were similar with respect to the key secondary outcome. The incidence of the primary outcome was sensitive to the definition of MI, and a secondary analysis yielded more procedural MIs of uncertain clinical importance. There were 145 deaths in the invasive strategy group and 144 deaths in the conservative strategy group (HR 1.05; 95% CI [0.83–1.32]).

The CCS therapeutic scenario has evolved markedly over the past few years. Earlier trials suggested myocardial revascularisation to both alleviate symptoms and improve prognosis in patients with stable angina, but contemporary studies report similar rates of death and MI in stable angina patients receiving OMT only when compared with percutaneous coronary intervention (PCI) as in the COURAGE trial, or PCI or coronary artery bypass grafting, as in the BARI 2D trial.2–5 These two studies received criticism regarding potential limitations in the study design (i.e. selection bias), given that randomisation was performed after the coronary anatomy was known; there was a lack of a defined threshold for myocardial ischemia for inclusion; and drug-eluting stents were used in only a very small number of patients.

Undeniably, ISCHEMIA addressed a very important issue, namely the comparative effects of coronary revascularisation and OMT management in a contemporary cohort of patients with stable coronary disease, currently described as CCS, receiving the most up-to-date medical treatment, including therapies shown to beneficially modify the natural history of ischaemic heart disease.

The International Study of Comparative Health Effectiveness with Medical and Invasive Approaches (ISCHEMIA) trial, the latest of the larger contemporary studies comparing OMT with coronary revascularisation for the management of stable angina, attempted to overcome at least some of these limitations. The ISCHEMIA trial aimed to determine the best management strategy for higher risk patients with stable ischaemic heart disease and moderate or severe ischaemia. Eligible patients were randomly assigned, in a 1:1 ratio, to an initial invasive strategy of OMT, angiography, and revascularisation when feasible, or to an initial conservative strategy of OMT alone, with angiography reserved for failure of medical therapy. The primary outcome was a composite of death from cardiovascular causes, MI, hospitalisation for unstable angina or heart failure or resuscitated cardiac arrest. A key secondary outcome was death from cardiovascular causes or MI.

The original primary endpoint of ISCHEMIA was cardiovascular death or MI. Of importance, and representing at least a minor limitation of the study, in view of the low rate of events and slow patient recruitment, the independent advisory panel of the National Heart, Lung, and Blood Institute modified the double primary endpoint of the trial to incorporate a combination of five variables, that is, cardiovascular death, MI, resuscitated cardiac arrest, and hospitalisation for unstable angina or heart failure.8 Although understandable, given the unexpected difficulties regarding recruitment, this amendment of the study protocol is generally considered to represent an undesirable event in clinical studies of this sort.9

The results were presented in two main papers in the New England Journal of Medicine.6,7 In brief, over a median of 3.2 years, 318 primary outcome events occurred in the invasive strategy group and 352 occurred in the conservative strategy group. At 6 months, the cumulative event rate

The inclusion criteria were rigorous: for patients to be included in the study, coronary artery disease was defined as a >50% diameter reduction on non-invasive CT coronary angiography, and myocardial ischemia was required to be documented (with 50% of randomised patients undergoing nuclear medicine assessment).

Although the ISCHEMIA trial provides extremely useful information regarding the initial management of patients with CCS, the study is not strictly a PCI versus OMT trial, given that after follow-up, only 80% of patients in the invasive strategy group did indeed undergo revascularisation, and 23% of the subjects assigned to the conservative strategy group received revascularisation. Moreover, 74% of the patients underwent revascularisation with PCI, while coronary artery bypass grafting was performed in the remaining cases.

The ISCHEMIA Trial: Editorial What exactly did ISCHEMIA report regarding the relative roles of invasive or interventional strategies and OMT versus OMT alone? The main results of the study indicate that when the two treatment options were compared, there were no significant differences in the risk of the combined endpoint of cardiovascular death, MI, resuscitated cardiac arrest, and hospitalisation for unstable angina or heart failure, between the two options. ISCHEMIA showed that an initial conservative strategy entails a lower risk of developing a periprocedural MI, for obvious reasons, or hospitalisation for heart failure, while an initial invasive strategy carries a lower risk of MI and hospitalisation for unstable angina, and results in greater symptomatic benefit and improvement of quality of life in those patients with frequent angina symptoms. In relation to adverse events recorded in the study, intervention specialists often argue that it might be reasonable to assume that periprocedural MIs do not have the same prognostic implications as larger spontaneous MIs. Moreover, the curves of spontaneous MI and of the primary endpoint continued to diverge at the end of the follow-up, favouring the revascularisation strategy over time, despite the relatively large proportion of patients in the conservative group who underwent revascularisation. Therefore, further analysis of the implications of these 1. Knuuti J, Wijns W, Saraste A, et al. 2019 ESC guidelines for the diagnosis and management of chronic coronary syndromes. Eur Heart J 2020;41:407–77. https://doi. org/10.1093/eurheartj/ehz425; PMID: 31504439. 2. Fleg JL, Forman DE, Berra K, et al. Secondary prevention of atherosclerotic cardiovascular disease in older adults: a scientific statement from the American Heart Association. Circulation 2013;128:2422–46. https://doi.org/10.1161/01. cir.0000436752.99896.22; PMID: 24166575. 3. Hachamovitch R, Rozanski A, Shaw LJ, et al. Impact of ischaemia and scar on the therapeutic benefit derived from myocardial revascularization vs. medical therapy among patients undergoing stress-rest myocardial perfusion scintigraphy. Eur Heart J 2011;32:1012–24. https://doi.

findings in stable angina patients is necessary, and constructive conversations between the interventionists and clinical cardiologists managing these patients need to take place sooner rather than later. In summary, the ISCHEMIA trial is an extremely important study that has undoubtedly highlighted the importance of ‘aggressive’ OMT in patients with stable coronary disease, and shown that the managing clinician can afford to start OMT in patients with stable angina despite the presence of significant coronary artery stenosis (except for left main coronary artery disease and severe angina) without the need to rush patients to coronary revascularisation. ISCHEMIA, however, is not about the victory of OMT versus myocardial revascularisation, or vice versa, but about selecting the right intervention for the right patient and providing stable angina patients with all the relevant information regarding the true beneficial effects and problems associated with both treatment options. They should not expect revascularisation to improve survival and prevent heart attacks, and they should be made aware of the disease-modifying potential of OMT, particularly given the incorporation of the most recent pharmacological lipid-lowering agents, anti-diabetes drugs and non-anti-vitamin K anticoagulants into the current therapeutic armamentarium.

org/10.1093/eurheartj/ehq500; PMID: 21258084. 4. Boden WE, O’Rourke RA, Teo KK, et al. for the COURAGE Trial Research Group. Optimal medical therapy with or without PCI for stable coronary disease. N Engl J Med 2007;356:1503–16. https://doi.org/10.1056/NEJMoa070829; PMID: 17387127. 5. BARI 2D Study Group. A randomized trial of therapies for type 2 diabetes and coronary artery disease. N Engl J Med 2009;360:2503–15. https://doi.org/10.1056/ NEJMoa0805796; PMID: 19502645. 6. Maron DJ, Hochman JS, Reynolds HR, et al. Initial invasive or conservative strategy for stable coronary disease. N Engl J Med 2020;382:1395–1407. https://doi.org/10.1056/ NEJMoa1915922; PMID: 32227755.

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7. Spertus JA, Jones PG, Maron DJ, et al. Health-status outcomes with invasive or conservative care in coronary disease. N Engl J Med 2020;382:1408–19. https://doi. org/10.1056/NEJMoa1916370; PMID: 32227753. 8. ISCHEMIA Trial Research Group. International Study of Comparative Health Effectiveness with Medical and Invasive Approaches (ISCHEMIA) trial: rationale and design. Am Heart J 2018;201:124–35. https://doi.org/10.1016/j.ahj.2018.04.011; PMID: 29778671. 9. Maron DJ, Harrington RA, Hochman JS. Planning and conducting the ISCHEMIA trial. Circulation 2018;138:1384–6. https://doi.org/10.1161/CIRCULATIONAHA.118.036904; PMID: 3035434.

Pharmacotherapy

A Practical Guide for Cardiologists to the Pharmacological Treatment of Patients with Type 2 Diabetes and Cardiovascular Disease Tariq Ahmad ,1 Ralph J Riello1 and Silvio E Inzucchi

1. Section of Cardiovascular Medicine, Yale University School of Medicine, New Haven, CT, US; 2. Section of Endocrinology, Yale University School of Medicine, New Haven, CT, US

Abstract

Patients with type 2 diabetes are at increased cardiovascular risk. Until recently, reductions in HbA1c and the use of specific glucose-lowering agents have not had a clear, reproducible benefit in reducing the incidence of cardiovascular disease. However, over the past 5 years, members of two categories of diabetes medications, sodium–glucose cotransporter 2 inhibitors and glucagon-like peptide-1 receptor agonists, have been associated with improved rates of major adverse cardiovascular events when used in high-risk type 2 diabetes patients. Importantly, these effects are not necessarily linked to these agents’ effects on HbA1c. Sodium–glucose cotransporter 2 inhibitors have also been associated with reductions in heart failure hospitalization, a benefit that appears to extend to individuals without diabetes with established heart failure. Cardiovascular specialists should become familiar with these emerging data and be prepared to implement corresponding strategies in their practice to improve the cardiovascular outcomes of their patients. Recent clinical trial data and the changing landscape of corresponding professional guidelines are reviewed. Practical recommendations for safe prescribing of these anti-diabetes drugs are provided.

Keywords

Type 2 diabetes, glucose-lowering therapy, cardiovascular disease, heart failure Disclosure: RR is on the advisory board of AstraZeneca, Janssen and Johnson & Johnson, and has received honoraria/consultation fees from Janssen, Johnson & Johnson and Pfizer. SEI is a consultant/trial leader at Boehringer-Ingelheim, AstraZeneca, Novo Nordisk, Sanofi/Lexicon and Merck. TA has no conflicts of interest to declare. Received: 20 January 2020 Accepted: 16 September 2020 Citation: European Cardiology Review 2021;16:e11. DOI: https://doi.org/10.15420/ecr.2020.01.R1 Correspondence: Silvio E Inzucchi, Section of Endocrinology, Fitkin 1, Yale School of Medicine, 333 Cedar St, New Haven, CT 06520, US. E: silvio.inzucchi@yale.edu Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Patients with cardiovascular disease (CVD) and type 2 diabetes (T2D) suffer very high rates of cardiovascular (CV) morbidity and mortality.1 Traditional paradigms for their treatments focus on the management of blood pressure and hyperlipidaemia by primary care physicians and/or cardiologists, and glucose control by primary care physicians and/or endocrinologists. As the ultimate goal of caring for these patients is to improve clinical outcomes, there has been a recent focus on alignment of goals, especially after the realisation that improvements in glucose management alone do not necessarily translate into the avoidance of adverse CV events.2 One reason for these efforts was a mandate by the Food and Drug Administration (FDA) in 2008 to require an assessment of CV outcomes predominantly for the purpose of ensuring safety prior to approval of new glucose-lowering therapies for T2D. This requirement has resulted in the discovery of several novel agents to have significant benefits in the risk of major adverse CV events (MACE), a goal that had been previously largely elusive with older, traditional antihyperglycaemic medications.3 The greatly expanded therapeutic armamentarium for the treatment of patients with CVD and T2D has also stimulated a re-examination of the conventional roles of various medical specialties in their management. In a patient-centred model of care, all clinicians taking care of these highrisk patients should be comfortable prescribing therapies that improve outcomes – even if they have traditionally existed within disciplines. The goal of this review is to provide a brief history of the development of

therapies for T2D, in the context of attempting to improve CV outcomes. We then provide a practical guide to the management of these patients that integrates the best available contemporary understanding and results from clinical trials, allowing the reader to be comfortable with the use of diabetes therapies that can now be used to address CVD risk.

Drug Development for Type 2 Diabetes: Focus on CVD

There has been a long track record in cardiology of therapies that improve surrogate measures of disease, but do not necessarily translate to better patient outcomes.4 As a result, the threshold for therapeutic approval of cardiac medications by regulatory agencies has generally required a large, randomised controlled trial with clear, demonstrable benefits of actual clinical events. Until recently, however, this was not the case in drug development for diabetes medications. There was an assumption that tight glucose control, as reflected by improved HbA1c, would lead not only to reductions in microvascular outcomes, such as retinopathy and diabetic kidney disease, but would also reduce macrovascular complications – despite a lack of definitive support for the latter. In fact, the ACCORD trial revealed increased CV mortality for patients assigned to a more intensive glucose-lowering strategy.5 Other studies, such as ADVANCE and VADT, demonstrated no improvement in CV outcomes with more stringent glucose control.6,7 These and other data have called into question the utility of the surrogate measure of HbA1c for CV risk.8

Type 2 Diabetes Treatment in Patients with CVD Figure 1: The Most Common Glucose-lowering Drug Classes Used in Type 2 Diabetes and Their Sites of Action Multiple complex pathophysiological abnormalities in T2D Insulin

GLP-1R agonists

Pancreatic insulin secretion SUs

Incretin effect

DPP-4 inhibitors

Pancreatic glucagon secretion

Gut carbohydrate delivery & absorption

HYPERGLYCAEMIA TZDs Metformin

+ Renal glucose excretion Hepatic glucose production

SGLT-2 inhibitors

Peripheral glucose uptake

DPP-4 = dipeptidyl peptidase-4; T2D = type 2 diabetes; GLP-1R = glucagon-like peptide-1 receptor; SGLT-2 = sodium–glucose cotransporter 2; SUs = sulfonylureas; TZD = thiazolidinedione.

Despite long-standing controversies regarding the link between glucose control and CV disease, it had always been presumed that glucoselowering therapies would at least not increase adverse CV events. Indeed, prior to 2008, approval of T2D therapies was largely contingent on evidence of glycaemic efficacy based on HbA1c reductions alone. An inflection point came when two meta-analyses raised concerns about the potential for increased CV risk with the thiazolidinedione rosiglitazone and an investigational dual peroxisome proliferatoractivated receptor alpha/gamma agonist.9,10 Although the overall CV safety of rosiglitazone was later mostly proved by a randomised clinical trial, concerns about diabetes drug safety stemming from these retrospective data sets persisted. In response, the FDA issued a guidance statement to the pharmaceutical industry in 2008, outlining expectations for the development of new antihyperglycaemic agents for T2D. This document essentially required all such therapies to demonstrate, at the minimum, CV safety when compared with a placebo.3 Similar requirements were subsequently issued by the European Medicines Agency. Rather than suppress innovation, as was once feared, many new therapies have since been evaluated under this new guidance with one or more dedicated CV safety studies. The results from these trials have provided unprecedented information about the CV impact of therapies tailored to target one of the most important risk factors for coronary artery disease and heart failure (HF). In the decade since the FDA guidance was issued, there have been 25 longterm prospective clinical trials involving >200,000 participants. While some are yet to report, the available data have already transformed the management of patients with T2D and CVD. Trials showing reductions in MACE with two newer classes, sodium–glucose cotransporter 2 (SGLT-2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists, have in fact

prompted a paradigm shift beyond a focus on glucose control alone towards more comprehensive CV risk reduction.11 In accordance with these insights, there has been a call for cardiologists to play a more active role in prescribing medications for diabetes management, especially since their mechanism of benefit appears beyond merely lowering glucose.12 Furthermore, these findings have streamlined the recommendations for therapies, as improvement in such hard outcomes has surpassed lowering of glycaemia as a therapeutic goal.

Modes of Action of Commonly Used Glucose-lowering Medications

Pharmacological advances in recent years have led to several mechanistically distinct therapies for T2D. The most commonly used classes of antihyperglycaemic agents can be broadly subdivided into those that increase insulin supply, improve the body’s response to insulin (insulin sensitisers), enhance incretin levels or promote urinary excretion of glucose (Figure 1).13 Sulfonylureas work by stimulating insulin secretion and require residual beta cell function. The sulfonylurea receptor is a component of the adenosine triphosphate-sensitive potassium channel in the pancreatic beta cells. The triphosphate-sensitive potassium channel regulates insulin release from pancreatic beta cells. Sulfonylurea binding inhibits these channels, altering cell resting potential, leading to calcium influx, thereby stimulating insulin secretion. The net effect is increased beta cell responsiveness, promoting greater insulin release at any blood glucose concentration, with the consequent risk of hypoglycaemia. Metformin, a biguanide, works mainly in the liver to reduce hepatic glucose production, and may be considered a liver insulin sensitiser. The precise mode of action at a cellular level remains controversial, but most likely involves alterations in mitochondrial respiration. When renal function

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Type 2 Diabetes Treatment in Patients with CVD Table 1: Overview of Cardiovascular Outcome Trials with Glucose-lowering Therapies Agent

Trial

Population

Median MACE Outcome, Follow-up HR [95% CI] (Years)

Dipeptidyl Peptidase-4 Inhibitors Saxagliptin

SAVOR

Age ≥40 years with ASCVD; ≥55 years men or ≥60 years women with ≥1 CV risk factor

16,492 2.1

HR 1.00 [0.89–1.12]

Alogliptin

EXAMINE

Age ≥18 years with recent ACS

5,380

1.5

HR 0.96 [≤1.16]

Sitagliptin

TECOS

Age ≥50 years with ASCVD

14,671

3.0

HR 0.98 [0.88–1.09]

Linagliptin

CARMELINA

History of ASCVD and micro- or macro-albuminuria

6,979

2.2

HR 1.02 [0.89–1.17]

Linagliptin

CAROLINA*

ASCVD; ≥2 CV risk factors; age ≥70 years and microvascular complications

6,042

6.3

HR 0.98 [0.84–1.14]

Glucagon-like Peptide-1 Receptor Agonists Lixisenatide

ELIXA

Age ≥30 years with ASCVD

6,068

2.1

HR 1.02 [0.89–1.17]

Liraglutide

LEADER

Age ≥50 years with ASCVD; age ≥60 years with ≥1 CV risk factor

9,340

3.8

HR 0.87 [0.78–0.97]

Semaglutide

SUSTAIN-6

Age ≥50 years with ASCVD; CHF or stage 3–5 CKD; age ≥60 years with ≥1 CV risk factor 3,297

HR 0.74 [0.58–0.95]

Semaglutide (oral) PIONEER-6

Age ≥50 years with ASCVD or CKD; ≥60 years with ≥1 CV risk factor

3,183

1.3

HR 0.79 [0.57–1.11]

Exenatide XR

EXSCEL

73% had ASCVD

14,752 3.2

HR 0.91 [0.83–1.00]

Albiglutide†

Harmony Outcomes

Age ≥40 years with ASCVD

9,463

1.6

HR 0.78 [0.68–0.90]

Dulaglitide

REWIND

Age ≥50 years with ASCVD, age ≥55 years with ASCVD or 1 CV risk factor; age ≥60 years 9,901 with ≥2 CV risk factors

5.4

HR 0.88 [0.79–0.99]

Sodium–Glucose Cotransporter 2 Inhibitors Empagliflozin

EMPA-REG OUTCOME Age ≥18 years with ASCVD

7,020

3.1

HR 0.86 [0.744–0.99]

Canagliflozin

CANVAS

Age ≥30 years with ASCVD; age ≥50 years with ≥2 risk factors

10,142

3.6‡

HR 0.86 [0.75–0.97]

Canagliflozin

CREDENCE

eGFR 30–90 and albumin:creatinine ratio >300

4,401

2.6

HR 0.70 [0.59–0.82]

Dapagliflozin

DECLARE

Age ≥40 years with. ASCVD; age ≥55 years men with ≥2 CV risk factors; age ≥60 years women with ≥1 CV risk factor

17,160

4.2

HR 0.93 [0.84–1.03]

Dapagliflozin

DAPA-HF

NYHA class II–IV HF with LVEF ≤40%

4,744

1.5

HR 0.74 [0.65–0.85]

Ertugliflozin

VERTIS-CV

Age ≥40 years with ASCVD

9,463

1.6

HR 0.95 [0.85–1.11]

*Compared with glimepiride; all other trials are compared with placebo. †Removed from the market by the manufacturer due to poor penetration. ‡Data expressed as the mean. ACS = acute coronary syndrome; ASCVD = atherosclerotic cardiovascular disease; CHF = congestive heart failure; CKD = chronic kidney disease; CV = cardiovascular; eGFR = estimated glomerular filtration rate; HF = heart failure; LVEF = left ventricular ejection fraction; NYHA = New York Heart Association.

is severely reduced, metformin accumulates in the plasma, and may predispose to lactic acidosis. Thiazolidinediones reduce insulin resistance by binding to the peroxisome proliferator-activated receptor gamma nuclear receptor, which is found at the highest concentrations in adipocytes, promoting adipocyte differentiation, reducing hepatic fat accumulation and increasing fatty acid storage in peripheral, rather than central, locations. Glucose uptake into skeletal muscle increases and circulating insulin levels decrease with the use of thiazolidinediones, indicating a reduction in insulin resistance. Pioglitazone has been shown to reduce MACE in high-risk T2D patients, as a secondary outcome in the PROactive study, and in insulin-resistant stroke patients without diabetes in the IRIS trial.14,15 These drugs result in weight gain and oedema, and increase the risk of HF. The three newest glucose-lowering drug categories include dipeptidyl peptidase-4 (DPP-4) inhibitors, GLP-1 receptor agonists and SGLT2 inhibitors. DPP-4 inhibitors reduce the degradation of the incretins – GLP-1 and glucose-dependent insulinotropic peptide – thus increasing insulin release, especially in the postprandial state, and suppressing glucagon release as well.16 They are generally well tolerated. GLP-1 receptor agonists act directly on this pathway, and as more powerful agents, not only beneficially modulate pancreatic insulin and glucagon secretion, but also slow gastric emptying and decrease appetite, the latter probably through central

mechanisms.17 Major side-effects pertain to the gastrointestinal system. SGLT-2 inhibitors lower blood glucose by selectively inhibiting a cotransporter expressed in the proximal convoluted tubule of the nephron. This blocks glucose reabsorption, thereby reducing the renal threshold for glucose and leading to increased urinary glucose excretion.18 Their major side-effects are genitourinary in nature.

Results from Cardiovascular Outcomes Trials

As noted, since the FDA guidance statement for CV safety with glucoselowering therapies, several large, industry-sponsored, placebo-controlled trials have tested the safety and efficacy of these latter three groups of medications (Table 1). Most participants had established T2D and either overt CVD or were at high CVD risk owing to multiple concomitant risk factors.

Dipeptidyl Peptidase-4 Inhibitors

Several DPP-4 inhibitor trials have been completed, showing neither inferiority nor superiority compared with a placebo with respect to MACE risk. Of note, however, saxagliptin was associated with an increased incidence of hospitalisation for HF in the SAVOR–TIMI 53 trial.19 There was also a non-statistically significant increase in hospitalisations for HF with alogliptin in the EXAMINE trial.20 Such trends for HF were noted in neither the TECOS nor CARMELINA, large CV outcome trials involving two additional DPP-4 inhibitors versus a placebo, but also,

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Type 2 Diabetes Treatment in Patients with CVD neither was able to establish any CV superiority.21,22 Finally, the CAROLINA demonstrated no differences in CV risk for linagliptin versus glimepiride in the only active comparator CV outcome trial for a DPP-4 inhibitor.23 As a result of these studies, DPP-4 inhibitors are deemed to be generally safe for use in high-risk CV patients, perhaps with the exception of saxagliptin and potentially alogliptin with regard to possible HF risk. However, this class clearly does not prevent CV events in high-risk patients with T2D.

Glucagon-like Peptide-1 Receptor Agonists

Several GLP-1 receptor agonists have demonstrated benefits for the reduction of adverse CV events among patients with T2D. Seven CV outcomes studies evaluating GLP-1 receptor agonists have been reported to date, with several showing superior CV outcomes. The LEADER trial randomised 9,340 patients with T2D and high CV risk (the majority with established CVD) to liraglutide or a placebo in addition to standard of care.24 After a median follow-up duration of 3.8 years, participants in the liraglutide group experienced a significantly reduced risk versus placebo for the primary composite three-point MACE outcome (CV death, non-fatal myocardial infarction or non-fatal stroke). Although CV mortality was also reduced, no reduction in HF events were observed. The SUSTAIN-6 trial enrolled 3,297 patients using similar eligibility criteria and the same primary composite endpoint as LEADER. Although SUSTAIN-6 was not powered for superiority, semaglutide significantly reduced the risk of MACE in a consistent manner.25 A separate trial examining oral as opposed to injectable semaglutide, PIONEER 6, randomised 3,183 high-risk T2D patients; rates of CV outcomes were similar in either arm of the trial, although both the secondary outcomes of CV and all-cause mortality appeared to be significantly reduced.25 The EXSCEL trial enrolled 14,752 subjects, with most having overt CVD, and showed a directionally lower risk of outcomes for exenatide compared with a placebo, but this difference did not reach statistical significance.26 Lixisenatide, which was tested in 6,068 patients with acute coronary syndrome in the ELIXA trial, showed no signal for any reduction in MACE.27 The HARMONY Outcomes randomised 9,463 participants with CVD, finding albiglutide to be superior to a placebo with respect to MACE.28 Despite these findings, the drug’s manufacturer has withdrawn it from the worldwide market due to disappointing sales. Finally, the REWIND trial involving 9,901 patients, most of whom had CV risk factors, but not established CVD, showed that weekly injections of dulaglutide improved CV outcomes in patients with type 2 diabetes regardless of prior CV events, with an overall effect size similar to that observed in other GLP-1 receptor agonist CV outcomes trials.29 A recently published meta-analysis included 56,004 participants and pooled data from ELIXA (lixisenatide), LEADER (liraglutide), SUSTAIN-6 (semaglutide), EXSCEL (exenatide), Harmony Outcomes (albiglutide), REWIND (dulaglutide) and PIONEER 6 (oral semaglutide).30 Overall, GLP-1 receptor agonist treatment reduced MACE by 12% (HR 0.88; 95% CI [0.82–0.94]; p<0.0001), with no evidence of treatment heterogeneity across the subgroups examined. The drug class also appeared to broadly improve renal outcomes, reducing a composite of new-onset macroalbuminuria, decline in the glomerular filtration rate, progression to

end-stage kidney disease or death attributable to kidney causes by 17% (HR 0.83; 95% CI [0.78–0.89]; p<0·0001). It should be noted, however, that in contrast to SGLT-2 inhibitors (see below), this renal composite endpoint is driven mainly by a reduction in macroalbuminuria, with no clear effect to decrease the decline in glomerular filtration rates. The authors appropriately concluded that treatment with GLP-1 receptor agonists (as a class) have beneficial effects on CV and, potentially, kidney outcomes in patients with T2D.30

Sodium–Glucose Cotransporter 2 Inhibitors

SGLT-2 inhibitors were the first glucose-lowering drug category to show a reduction in MACE among T2D patients at high CV risk. The EMPA-REG OUTCOME trial randomised 7,020 patients with T2D and established CVD to empagliflozin versus a placebo; those receiving empagliflozin had a lower rate of the primary composite three-point MACE than did patients receiving placebo.31 Notably, the primary driver of this risk reduction was a striking 38% reduction in the risk of CV death. Moreover, the drug was associated with a 35% reduction in the risk of HF hospitalisation. In a prespecified secondary outcome, empaglifozin use was associated with a lower risk of progression of kidney disease, including both macroalbuminuria and ‘harder’ renal outcomes, such as a doubling of the serum creatinine level and initiation of renal replacement therapy.32 Following the EMPA-REG OUTCOME were results from the CANVAS program, which integrated findings from two placebo-controlled trials, and included 10,142 subjects with T2D and either known CVD or age >50 years, and at least two additional CV risk factors.33 The rate of the MACE primary outcome was significantly lower with canagliflozin than with a placebo, and there was also similar evidence of benefit in regard to both HF hospitalisations and in the progression of kidney disease. The MACE benefit appeared to be concentrated among patients with established CVD, although the HF and renal benefits appeared to be shared by even those with CV risk factors alone. Finally, the DECLARE–TIMI 58 trial randomised a lower-risk population – those with T2D who had or were at risk for atherosclerotic CVD – to receive either dapagliflozin or a placebo.34 While there were no significant differences in the MACE dual primary outcome, a significant decrease in the risk of the second dual primary outcome, CV death or hospitalisation for HF was observed. Furthermore, as with the prior trials, there was a signal of benefit for various renal outcomes. The final T2D-CV outcome trial involving an SGLT-2 inhibitor, ertugliflozin, was VERTIS CV, including 8,246 participants with T2D and established CVD. In contrast to the earlier studies, VERTIS CV did not meet its primary efficacy outcome.35 While ertugliflozin was non-inferior to a placebo for MACE, the HRs for the composite (HR 0.97; 95% CI [0.85–1.11]) and each of its components was statistically neutral. However, HF hospitalisations were less frequent in the active therapy arm (HR 0.70; 95% CI [0.54–0.90]). Findings from the first three CV outcome trials of SGLT-2 inhibitors were consolidated in a meta-analysis of 34,322 patients that summarised these drugs to have a moderate impact on MACE among patients with established CVD, but striking reductions in HF hospitalisations and progression of kidney disease regardless of the presence of overt CVD or HF at baseline.36 Moreover, observational data from large international studies of insurance claims, registries and electronic medical records from a broad T2D population observed in real-world practice have reinforced findings from

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Type 2 Diabetes Treatment in Patients with CVD Table 2: Prescribing Information for Glucagon-like Peptide-1 Receptor Agonists and Sodium–Glucose Cotransporter 2 Inhibitors (Based on US Labels) Generic Name

Brand Name

Doses

Schedule Additional Information

GLP-1R agonists (all injectables except Rybelsus) Exenatide

Byetta

5, 10 µg

Twice daily

32 G pen needles supplied separately; prefilled, single-use pen

Exenatide extended release Bydureon

2 mg

Weekly

23 G, hidden needles pre-attached; prefilled autoinjector device

Dulaglutide

Trulicity

0.75, 1.5 mg

Weekly

29 G hidden needles pre-attached; prefilled autoinjector device

Liraglutide

Victoza

0.6, 1.2, 1.8 mg

Daily

Indicated to reduce the risk of MACE in T2D with established CVD; 32-G pen needles supplied separately; prefilled, multi-dose pen

Lixisenatide

Adlyxin

10, 20 µg

Daily

≤8 mm pen needles supplied separately; prefilled, single-use pen

Semaglutide (injection)

Ozempic

0.25, 0.5 mg

Weekly

32 G 4 mm pen needles included; prefilled, single-use pen

Semaglutide (oral)

Rybelsus

3, 7, 14 mg

Daily

Only oral GLP-1RA available

SGLT-2 inhibitors (all oral tablets, most available in fixed-dose combinations with metformin) Canagliflozin

Invokana

100, 300 mg

Daily

Indicated to reduce risk of MACE in T2D and established CVD; also indicated to reduce risk of progression of kidney disease, CV death and HF hospitalisation in T2D and diabetic kidney disease with macroalbuminuria

Dapagliflozin

Farxiga

5, 10 mg

Daily

Indicated to reduce risk of HF hospitalisation in T2D with established CVD or multiple CV risk factors

Empagliflozin

Jardiance

10, 25 mg

Daily

Indicated to reduce risk of CV death in T2D with established CVD

Ertugliflozin

Steglatro

5, 15 mg

Daily

CV outcomes trial (VERTIS-CV; NCT01986881)

CV = cardiovascular; CVD = cardiovascular disease; GLP-1R = glucagon-like peptide-1 receptor; GLP-1RA = glucagon-like peptide-1 receptor agonist; HF = heart failure; MACE = major adverse cardiovascular events; SGLT-2 = sodium–glucose cotransporter 2; T2D = type 2 diabetes.

the clinical trials.37,38 For example, CVD-REAL compared a propensitymatched cohort of patients receiving other oral medications for T2D. Those receiving SGLT-2 inhibitors had a 51% lower associated risk of allcause mortality and a 39% lower associated risk of hospitalisation for HF. Comparable results were found in the even larger CVD-REAL 2 study, with a 49% lower risk of all-cause mortality, 36% lower risk of hospitalisation for HF, and lower risks of MI and stroke. Another real-world data set comes from the EMPRISE study in the US, in which the initiation of empagliflozin was associated with at 50% lower risk of HF hospitalisation compared with patients initiating therapy with sitagliptin (a DPP-4 inhibitor).39 These findings buttress the benefits of SGLT-2 inhibitors in patients with T2D, as demonstrated in randomised clinical trials. Finally, since a major benefit of SGLT-2 inhibitors was thought to be in patients with HF, several clinical trials are ongoing to test this hypothesis. The first of these, DAPA-HF, randomised 4,744 patients with left ventricular ejection fraction ≤40% and symptomatic HF to dapagliflozin versus a placebo. The primary outcome was a composite of worsening HF (hospitalisation or an urgent visit resulting in IV therapy for HF) or CV death, occurring significantly less in the dapagliflozin arm (HR 0.74; 95% CI [0.65–0.85]; p<0.001).40 Importantly, the benefit did not appear to be dependent on whether the patient had diabetes or not. It is anticipated that SGLT-2 inhibitors will play a major role in the treatment of HF in the near future.41 Other dedicated HF studies with SGLT-2 inhibitors are underway or soon to report. These include EMPEROR-Reduced, EMPEROR-Preserved and DELIVER.

Prescribing Glucose-lowering Therapies for CVD

Currently, we have robust data demonstrating the benefits of GLP-1 receptor agonists and SGLT-2 inhibitors for patients with T2D and

coexisting CV disease. According to the most current T2D treatment guidelines from the American Diabetes Association and the European Association for the Study of Diabetes, metformin is first-line therapy for these patients, mainly due to extensive clinical experience and comparably low cost.42 Then, additional therapies are added, dictated initially by coexisting CV and/or kidney disease. If atherosclerotic CVD predominates the clinical picture, either a GLP-1 receptor agonist or a SGLT-2 inhibitor shown to improve CV outcomes should be used. If, in contrast, HF or CKD predominate, then a SGLT-2 inhibitor would be favoured, with a GLP-1 receptor agonist used if an SGLT-2 inhibitor were contraindicated; for example, if kidney dysfunction is too advanced. In addition, because the effects on glycaemia are unlikely to be driving the outcomes benefits of these agents, adding either GLP-1 receptor agonists and SGLT-2 inhibitors are now to be considered irrespective of HbA1c – a radical departure from older glucocentric approaches. The latest guidelines from the European Society of Cardiology are similar, but go a step further, proposing that for appropriate patients with or at high risk for CVD, beginning with an SGLT-2 inhibitor or a GLP-1 receptor agonist in lieu of metformin may be more prudent.43 Both American Diabetes Association and the European Association for the Study of Diabetes and European Society of Cardiology guidelines now identify a broader group of patients eligible for CV risk reduction with these newer drug categories, no longer restricting them to those with overt CVD. Both sets of guidelines are reasonable, with the American Diabetes Association and the European Association for the Study of Diabetes consensus report still endorsing metformin as foundation therapy – a concept that is not necessarily any longer evidence-based. Dosing and clinical considerations for these therapies are shown in Table 2. In cases of equipoise, other distinguishing features of these agents should dictate which one is initiated first. SGLT-2 inhibitors, for example, would seem to be preferred in the setting of HF or mild-to-moderate diabetic kidney disease. The available routes of administration are

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Type 2 Diabetes Treatment in Patients with CVD Table 3: Practical Advice for the Safe Use of Glucagon-Like Peptide-1 Receptor Agonists and Sodium–Glucose Cotransporter 2 Inhibitors Class

Recommendations

GLP-1 receptor agonists

• Start with lowest dose and titrate slowly • Nausea, vomiting and diarrhoea are the most common side-effects; caution patients to eat smaller meals and to eat slowly, stopping when they feel full • If starting medication in a diabetes patient, confer with clinician managing the diabetes, so that efforts can be aligned. If already on a sulfonylurea or

• Lower doses appear as effective as higher doses, only advance if additional glucose lowering is needed • Patients should be cautioned about likelihood of increased urinary output and frequency, and the need to maintain adequate hydration at all times • If starting medication in a diabetes patient, confer with clinician managing the diabetes, so that efforts can be aligned. If already on a sulfonylurea or

insulin, consider modest dose reductions (e.g. 25% for sulfonylurea, 20% for insulin if the patient is already tightly controlled, e.g. HbA1c <7% or if patient is already experiencing frequent hypoglycaemic episodes • If starting medication in a non-diabetes patient or in a diabetes patient not using sulfonylurea or insulin, there is essentially no risk of hypoglycaemia • Consider dose reductions of other diuretics if any signs of volume contraction. Doses of other hypertension medications usually do not need to be reduced • Consider other agents in patients with urinary incontinence or men with advanced prostatic disease and troublesome obstructive voiding symptoms • Genital mycotic infections are the most common side-effect (especially in woman and uncircumcised men), easily treated with topical agents or systemic antifungals (watch drug–drug interactions if using fluconazole). If recurrent, may need to discontinue therapy • Urinary tract infections may occur, but not commonly. However, would not use in patients with history of severe UTIs (pyelonephritis, urosepsis) or those at increased risk (indwelling urinary catheters/stents/ significant stone burden, etc) • One SGLT-2 inhibitor (canagliflozin) doubled the risk of lower extremity amputations in one study. Although not reported with other members of this class, consider other therapies if a patient has severe PAD, active foot ulcers and/or prior amputations • Do not use in those with advanced kidney disease; eGFR limit depends on specific agent. Most can be used safely down to eGFR of 30 ml/min/1.73m2, but glucose lowering effect diminishes <45 ml/min/1.73m2, while other benefits appear to be maintained • Avoid in those with hypotension, orthostasis, unexplained syncope or dizziness • Not approved for patients with type 1 diabetes or other patients who may be ketosis-prone • Hold 3 days prior to major surgical procedures (to avoid ketosis) • Hold medication temporarily when ill or hospitalised* (to avoid ketosis) *Consider the risks/benefits during heart failure admission and may be continued, depending on the clinical circumstances. eGFR = estimated glomerular filtration rate GI = gastrointestinal; GLP-1R = glucagon-like peptide-1 receptor; PAD = peripheral artery disease; SGLT-2 = sodium–glucose cotransporter 2.

perhaps among the most evident differences – oral for SGLT-2 inhibitors and subcutaneous for most GLP-1 receptor agonists, although the first oral GLP-1 receptor agonist (semaglutide) recently became available. Cost may also vary substantially based on local market availability, health system or payer formularies and individual health insurance coverage.

Side-effects and Practical Considerations

Most GLP-1 receptor agonists appear to benefit patients in whom atherosclerotic heart disease predominates, but they may be associated with transient nausea and even vomiting, especially when initiating therapy or uptitrating the dose. The subcutaneous route of administration of most GLP-1 receptor agonists dictates that the individual characteristics of each injection pen should also be considered to match patient preferences. Multi-dose pens, for example, are available with liraglutide, semaglutide and exenatide extended release; these agents also use identical needles to insulin pen therapy, and therefore may already be more familiar to insulin users. However, for insulin-naïve patients, the manual dexterity required to attach and remove pen needles for GLP-1 receptor agonist injectable devices before and after use requires direct education.

For clinicians prescribing these therapies, extensive use of the teachback technique during an office visit, preferably by experienced nurses or diabetes educators, to confirm a patient or caregiver’s ability to safely inject the medication may be necessary. Additionally, separate prescriptions for pen needles must be sent to the outpatient pharmacy if using liraglutide, exenatide and lixisenatide. Only injectable semaglutide contains pen needles in its original packaging. Dulaglitide or exenatide extended release contain built-in needles supplied in an autoinjector pen, which may be favourable for ease of use or patients for whom visible needles may be problematic. Patients must be coached regarding low initial dosing and gradual uptitration to mitigate gastrointestinal side-effects. We avoid these drugs in patients with complex pancreato-biliary disease, prior history of pancreatitis (per label, although no risk has been demonstrated in clinical trials), gastroparesis, prior bariatric surgeries and multiple or significant baseline gastrointestinal symptoms. An oral formulation of semaglutide recently became available. Because it uses a unique gastric absorption enhancer, this formulation must be taken on an empty stomach with a certain volume of water and with the

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Type 2 Diabetes Treatment in Patients with CVD subsequent avoidance of food or other medications for at least 30 minutes. However, this agent has not yet been demonstrated to reduce CV events. SGLT-2 inhibitors are also preferred in the context of atherosclerotic CVD, but appear to be particularly beneficial in cases of HF and/or mild-tomoderate kidney disease. They are known to increase the risk of genital mycotic infections, although the latter are usually easily treatable with topical creams. Other considerations include polyuria (which may be specifically problematic in older men with prostatic disease) and the potential for reductions in volume, causing adverse events – those with HF taking loop diuretics may need their dose reduced, particularly if already volume contracted. Caution is required when prescribing these agents (particularly canagliflozin) to patients with a history of prior amputations, significant peripheral artery disease, or active lower extremity soft tissue ulcers or infections. Rarely, diabetic ketoacidosis may occur (often euglycaemic, which may mask the initial presentation), but more commonly when these agents are used off-label in those with type 1 diabetes and, possibly, in very insulin-deficient, lean and more fragile T2D patients. Practical advice for the safe prescribing of these agents is listed in Table 3. 1. Scherer PE, Hill JA. Obesity, diabetes, and cardiovascular diseases: a compendium. Circ Res 2016;118:1703–5. https:// doi.org/10.1161/CIRCRESAHA.116.308999; PMID: 27230636. 2. Patel RB, Al Rifai M, McEvoy JW, et al. Implications of specialist density for diabetes care in the United States. JAMA Cardiol 2019;1174–5. https://doi.org/10.1001/ jamacardio.2019.3796; PMID: 31642870. 3. McGuire DK, Marx N, Johansen OE, et al. FDA guidance on antihyperglyacemic therapies for type 2 diabetes: one decade later. Diabetes Obes Metab 2019;21:1073–8. https:// doi.org/10.1111/dom.13645; PMID: 30690856. 4. Weintraub WS, Luscher TF, Pocock S. The perils of surrogate endpoints. Eur Heart J 2015;36:2212–8. https://doi. org/10.1093/eurheartj/ehv164; PMID: 25975658. 5. Gerstein HC, Miller ME, Byington RP, et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008;358:2545–59. https://doi.org/10.1056/ NEJMoa0802743; PMID: 18539917. 6. Duckworth W, Abraira C, Moritz T, et al. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med 2009;360:129–39. https://doi.org/10.1056/ NEJMoa0808431; PMID: 19092145. 7. Group AC, Patel A, MacMahon S, et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 2008;358:2560–72. https://doi. org/10.1056/NEJMoa0802987; PMID: 18539916. 8. Lipska KJ, Krumholz HM. Is hemoglobin A1c the right outcome for studies of diabetes? JAMA 2017;317:1017–18. https://doi.org/10.1001/jama.2017.0029; PMID: 28125758. 9. Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med 2007;356:2457–71. https://doi.org/10.1056/ NEJMoa072761; PMID: 17517853. 10. Nissen SE, Tuzcu EM, Schoenhagen P, et al. Statin therapy, LDL cholesterol, C-reactive protein, and coronary artery disease. N Engl J Med 2005;352:29–38. https://doi. org/10.1056/NEJMoa042000; PMID: 15635110. 11. American Diabetes Association. 9. Cardiovascular disease and risk management: standards of medical care in diabetes – 2018. Diabetes Care 2018;41(Suppl 1):S86–104. https://doi.org/10.2337/dc18-S009; PMID: 29222380. 12. Das SR, Everett BM, Birtcher KK, et al. 2018 ACC expert consensus decision pathway on novel therapies for cardiovascular risk reduction in patients with type 2 diabetes and atherosclerotic cardiovascular disease: a report of the American College of Cardiology Task Force on Expert Consensus Decision Pathways. J Am Coll Cardiol 2018;72:3200–23. https://doi.org/10.1016/j.jacc.2018.09.020; PMID: 30497881. 13. Meneses MJ, Silva BM, Sousa M, et al. Antidiabetic drugs: mechanisms of action and potential outcomes on cellular metabolism. Curr Pharm Des 2015;21:3606–20. https://doi.org

Conclusion

The requirement for testing glucose-lowering therapies developed for T2D in large CV outcomes trials has led to the identification of two medication classes conferring CV outcomes benefit –SGLT-2 inhibitors GLP-1 receptor agonists. These findings have shifted our clinical focus from reduction of HbA1c levels to reducing the risk of MACE, CV death and HF hospitalisations. The new emphasis on clinical outcomes promotes more patient-centred care over traditional disease-based care, where physicians across several specialties may now collaborate with patients to reduce morbidity and mortality with therapies that were once considered only in the purview of endocrine specialists. Since most patients with CVD and diabetes are seen by cardiologists, this specialty should become engaged in this process – either by discussing evidence-based glucose-lowering therapies with patients and their referring physicians or, potentially, by even taking ownership and prescribing them themselves. With increasing communication between specialties and a focus on implementation science, such as embedding user-friendly disease treatment algorithms within the electronic health record, we anticipate that the impressive benefits of these therapies seen in clinical trials will translate to widespread clinical benefits for patients in real-world settings.

/10.2174/1381612821666150710145753; PMID: 26166608. 14. Dormandy JA, Charbonnel B, Eckland DJ, et al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet 2005;366:1279–89. https://doi. org/10.1016/S0140-6736(05)67528-9; PMID: 16214598. 15. Kernan WN, Viscoli CM, Furie KL, et al. Pioglitazone after ischemic stroke or transient ischemic attack. N Engl J Med 2016;374:1321–31. https://doi.org/10.1056/NEJMoa1506930; PMID: 26886418. 16. Thornberry NA, Gallwitz B. Mechanism of action of inhibitors of dipeptidyl-peptidase-4 (DPP-4). Best Pract Res Clin Endocrinol Metab 2009;23:479–86. https://doi.org/10.1016/j. beem.2009.03.004; PMID: 19748065. 17. Drucker DJ. Mechanisms of action and therapeutic application of glucagon-like peptide-1. Cell Metab 2018;27:740–56. https://doi.org/10.1016/j.cmet.2018.03.001; PMID: 29617641. 18. van Baar MJB, van Ruiten CC, Muskiet MHA, et al. SGLT2 inhibitors in combination therapy: from mechanisms to clinical considerations in type 2 diabetes management. Diabetes Care 2018;41:1543–56. https://doi.org/10.2337/dc180588; PMID: 30030256. 19. Scirica BM, Bhatt DL, Braunwald E, et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med 2013;369:1317–26. https://doi. org/10.1056/NEJMoa1307684; PMID: 23992601. 20. White WB, Cannon CP, Heller SR, et al. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med 2013;369:1327–35. https://doi.org/10.1056/ NEJMoa1305889; PMID: 23992602. 21. Green JB, Bethel MA, Armstrong PW, et al. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N Engl J Med 2015;373:232–42. https://doi.org/10.1056/ NEJMoa1501352; PMID: 26052984. 22. Rosenstock J, Perkovic V, Johansen OE, et al. Effect of linagliptin vs placebo on major cardiovascular events in adults with type 2 diabetes and high cardiovascular and renal risk: the CARMELINA randomized clinical trial. JAMA 2019;321:69–79. https://doi.org/10.1001/jama.2018.18269; PMID: 30418475. 23. Rosenstock J, Kahn SE, Johansen OE, et al. Effect of linagliptin vs glimepiride on major adverse cardiovascular outcomes in patients with type 2 diabetes: the CAROLINA randomized clinical trial. JAMA 2019;322:1155–66. https:// doi.org/10.1001/jama.2019.13772; PMID: 31536101. 24. Correia LC, Latado A, Porzsolt F. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2016;375:1798. https://doi.org/10.1056/NEJMc1611289; PMID: 27806227. 25. Husain M, Birkenfeld AL, Donsmark M, et al. Oral

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semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med 2019;381:841–51. https://doi. org/10.1056/NEJMoa1901118; PMID: 31185157. 26. Holman RR, Bethel MA, Mentz RJ, et al. Effects of onceweekly exenatide on cardiovascular outcomes in type 2 diabetes. N Engl J Med 2017;377:1228–39. https://doi. org/10.1056/NEJMoa1612917; PMID: 28910237. 27. Pfeffer MA, Claggett B, Diaz R, et al. Lixisenatide in patients with type 2 diabetes and acute coronary syndrome. N Engl J Med 2015;373:2247–57. https://doi.org/10.1056/ NEJMoa1509225; PMID: 26630143. 28. Hernandez AF, Green JB, Janmohamed S, et al. Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial. Lancet 2018;392:1519–29. https://doi.org/10.1016/S01406736(18)32261-X; PMID: 30291013. 29. Gerstein HC, Colhoun HM, Dagenais GR, et al. Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial. Lancet 2019;394:121–30. https://doi.org/10.1016/S01406736(19)31149-3; PMID: 31189511. 30. Kristensen SL, Rorth R, Jhund PS, et al. Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet Diabetes Endocrinol 2019;7:776–85. https://doi.org/10.1016/ S2213-8587(19)30249-9; PMID: 31422062. 31. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015;373:2117–28. https://doi.org/10.1056/ NEJMoa1504720; PMID: 26378978. 32. Wanner C, Inzucchi SE, Lachin JM, et al. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med 2016;375:323–34. https://doi.org/10.1056/ NEJMoa1515920; PMID: 27299675. 33. Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med 2017;377:644–57. https://doi.org/10.1056/ NEJMoa1611925; PMID: 28605608. 34. Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2019;380:347–57. https://doi.org/10.1056/NEJMoa1812389; PMID: 30415602. 35. Cannon CP, McGuire DK, Cherney D, et al. Results of the eValuation of ERTugliflozin EffIcacy and Safety CardioVascular Outcomes Trial (VERTIS CV). Presented at 80th American Diabetes Association Scientific Sessions, 16 June 2020. 36. Zelniker TA, Wiviott SD, Raz I, et al. SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and

Type 2 Diabetes Treatment in Patients with CVD meta-analysis of cardiovascular outcome trials. Lancet 2019;393:31–9. https://doi.org/10.1016/S01406736(18)32590-X; PMID: 30424892. 37. Kosiborod M, Cavender MA, Fu AZ, et al. Lower risk of heart failure and death in patients initiated on sodium-glucose cotransporter-2 inhibitors versus other glucose-lowering drugs: The CVD-REAL study (Comparative Effectiveness of Cardiovascular Outcomes in New Users of Sodium-Glucose Cotransporter-2 Inhibitors). Circulation. 2017;136:249–59. https://doi.org/10.1161/CIRCULATIONAHA.117.029190; PMID: 28522450. 38. Kosiborod M, Lam CSP, Kohsaka S, et al. Cardiovascular events associated with SGLT-2 inhibitors versus other

glucose-lowering drugs: the CVD-REAL 2 study. J Am Coll Cardiol 2018;71:2628–39. https://doi.org/10.1016/j. jacc.2018.03.009; PMID: 29540325. 39. Patorno E, Pawar A, Franklin JM, et al. Empagliflozin and the risk of heart failure hospitalization in routine clinical care. Circulation 2019;139:2822–30. https://doi.org/10.1161/ CIRCULATIONAHA.118.039177; PMID: 30955357. 40. McMurray JJV, Solomon SD, Inzucchi SE, et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med 2019;381:1995–2008. https://doi.org/10.1056/ NEJMoa1911303; PMID: 31535829. 41. Lam CSP, Chandramouli C, Ahooja V et al. SGLT-2 inhibitors in heart failure: current management, unmet needs, and

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therapeutic prospects. J Am Heart Assoc 2019;8:e013389. https://doi.org/10.1161/JAHA.119.013389; PMID: 31607208. 42. Buse JB, Wexler DJ, Tsapas A, et al. 2019 update to: Management of hyperglycemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetologia 2020;63:221–8. https://doi. org/10.1007/s00125-019-05039-w; PMID: 31853556. 43. Cosentino F, Grant PJ, Aboyans V, et al. 2019 ESC guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD. Eur Heart J 2020;41:255–323. https://doi.org/10.1093/eurheartj/ehz486; PMID: 31497854.

Heart Failure

Novel Pharmacological Treatment of Patients with Type 2 Diabetes and Cardiovascular Disease: What Cardiologists and Diabetologists Should Know Felipe Martínez Cordoba National University, Cordoba, Argentina

Disclosure: The author has no conflicts of interest to declare. Received: 25 September 2020 Accepted: 28 October 2020 Citation: European Cardiology Review 2021;16:e12. DOI: https://doi.org/10.15420/ecr.2020.38 Correspondence: Felipe Martinez, Cordoba National University, Av Colόn 2057. Cordoba X5003DSE, Argentina. E: dr.martinez@usa.net Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

People with diabetes have a higher than average risk of developing cardiovascular disease.1,2 The mechanisms underlying the relationship between diabetes and cardiovascular disease are not fully understood, but recent studies have explored this rapidly evolving research field.3 As a result, there is a clear need for cardiologists to improve and increase their involvement in the therapeutic management of diabetes. In this volume of European Cardiology Review, Ahmad et al. provide an update on the most recent pharmacological advances and mechanisms linking diabetes and cardiovascular disease, with a focus on clinical practice.4 A number of therapies in cardiology improve surrogate measures of disease, but do not necessarily translate to better patient outcomes.5 It was previously assumed that strict glucose control, reflected by improved HbA1c, would lead not only to reductions in microvascular outcomes but would also reduce cardiovascular complications.6 After some trials with hypoglycaemic drugs demonstrated an increase in major adverse cardiovascular events (MACE) and, in particular, heart failure-related outcomes, some of the main international regulatory agencies required that all antidiabetic therapies demonstrate cardiovascular safety when compared with placebo.7–9 Since that decision, a long list of compounds have been designed to evaluate not only the antidiabetic/metabolic effects, but also cardiovascular benefits and safety of diabetes drugs. The results of these trials showed surprising and important positive impacts in MACE, particularly in heart failure outcomes. Two groups of drugs are changing the management of diabetes and cardiovascular disease: glucagon-like peptide-1 (GLP-1) receptor agonists, also known as incretin mimetics, and sodium–glucose transporter 2 (SGLT2) inhibitors, also known as gliflozins.9 This editorial is focused on these two groups of drugs.

Glucagon-like Peptide-1 Receptor Agonists

GLP-1 receptor agonists differ in their structure and duration of action and have been studied in trials of varying sizes and with different patient populations; inconsistent effects on cardiovascular outcomes have been reported by Ahmad et al. after they analysed seven cardiovascular outcome studies evaluating GLP-1 receptor agonists, some demonstrating benefits in cardiovascular outcomes.4 These studies include large and well-known trials, such as LEADER (with liraglutide), SUSTAIN-6 (with semaglutide), EXSCEL (with exenatide), ELIXA (with lixisenatide) and HARMONY (with albiglutide).10–14 More than 50,000 diabetic patients were

randomised in those trials, and they generally demonstrated consistent results of reduced incidence of MACE.15 In a meta-analysis by Kristensen et al., GLP-1 receptor agonist treatment reduced MACE by 12% (HR 0.88, 95% CI [0.82–0.94], p<0.0001), with no evidence of treatment heterogeneity across the subgroups examined.16 The results also showed an improvement in renal outcomes. They observed a reduction in the composite of new-onset macroalbuminuria, estimated glomerular filtration rate, progression to end-stage kidney disease and death attributable to kidney causes by 17%. It has been demonstrated that these drugs reduce cardiovascular outcomes in people with diabetes, and there are ongoing trials investigating if the same benefits occur in people without diabetes.

SGLT2 Inhibitors: The New Star

Recent trials with SGLT2 inhibitors, have shown that this group of drugs is emerging as a new and viable option for preventing and treating cardiac and renal dysfunction.17 SGLT-2 inhibitors were the first glucose-lowering drugs to show a reduction in MACE in people with type 2 diabetes and at high cardiovascular risk, according to the results of the EMPA-REG OUTCOME trial.18,19 Another trial, CANVAS, showed similar results for people with diabetes.20 Both trials demonstrated a significant decrease in the rate of heart failure-associated hospitalisation and mortality. Other large studies, such as DECLARE–TIMI 58 (with dapaglifozine), were included in a meta-analysis by Zelniker et al. that demonstrated consistency of the results.21,22 More recently, the VERTIS trial of ertruglifozine demonstrated some similar findings.23 In all cases, the study populations only included subjects with diabetes and there was an observed decrease in MACE in patients receiving SGLT2 inhibitors, albeit with some differences. Registries of people with diabetes patients have also demonstrated that those treated with SGLT2 inhibitors show a lower morbidity and mortality compared with those treated with other antidiabetic drugs, indicating that the results of clinical trials are similar to those observed in real world clinical practice.24,25 SGLT2 inhibitors were initially thought to provide the most benefit to patients with heart failure and then clinical trials then began to test them in the general population. The first of these studies was DAPA-HF, which randomised 4,744 patients with left ventricular ejection fraction ≤40% and

Pharmacological Treatment of Type 2 Diabetes and CVD symptomatic heart failure to dapagliflozin versus placebo.26 The primary outcome was a composite of worsening heart failure (hospitalisation or an urgent hospital visit resulting in IV therapy for heart failure) or cardiovascular death. This endpoint was significantly less in the dapagliflozin arm (HR: 0.74, 95% CI [0.65–0.85]; p<0.001). Importantly, the benefits were almost identical in patients with and without diabetes. It was the first evidence of a benefit of a SGLT2 inhibitor in heart failure, and Ahmad et al. anticipate that SGLT-2 inhibitors will play a major role in the treatment of heart failure in the near future.4 Another study of DAPA-HF indicated that the beneficial effect of SGLT2 inhibitors was similar in subgroups of all ages, including elderly patients, in whom the incidence of heart failure is higher.27 The EMPEROR-Reduced study showed that patients in the empagliflozin group were found to have a lower risk of cardiovascular death or heartrelated hospitalisation compared with the control group, regardless of whether or not they had diabetes.28 The evidence of this trial added to the previous results of DAPA-HF, and was examined in a recent metaanalysis by Zannad et al.29 They found that the effects of both dapagliflozin and empagliflozin were consistent in lowering hospitalisation for heart failure with reduced ejection fraction patients. They suggested that these agents also improve renal outcomes and reduce all-cause and cardiovascular death. This study attracted media and medical attention, with many agreeing that the results of DAPA-HF and EMPEROR-Reduced substantially strengthened the rationale for the 1. Scherer PE, Hill JA. Obesity, diabetes, and cardiovascular diseases: a compendium. Circ Res 2016;118:1703–5. https:// doi.org/10.1161/CIRCRESAHA.116.308999; PMID: 27230636. 2. Patel RB, Al Rifai M, McEvoy JW, et al. Implications of specialist density for diabetes care in the United States. JAMA Cardiol 2019;4:1174–5. https://doi.org/10.1001/ jamacardio.2019.3796; PMID: 31642870. 3. McGuire DK, Marx N, Johansen OE, et al. FDA guidance on antihyperglycaemic therapies for type 2 diabetes: one decade later. Diabetes Obes Metab 2019;21:1073–78. https:// doi.org/10.1111/dom.13645; PMID: 30690856. 4. Ahmad T, Riello RJ, Inzucchi SE. A practical guide for cardiologists to the pharmacological treatment of patients with type 2 diabetes and cardiovascular disease. Eur Cardiol 2021;16:e11. https://doi.org/10.15420/ecr.2020.01.R1. 5. European Medicines Agency. Committee for Medicinal Products for Human Use (CHMP). Guideline on clinical investigation of medicinal products in the treatment or prevention of diabetes mellitus. 29 January 2018. CPMP/ EWP/1080/00 Rev. 2. 6. Lipska KJ, Krumholz HM. Is hemoglobin A1c the right outcome for studies of diabetes? JAMA 2017;317:1017–8. https://doi.org/10.1001/jama.2017.0029; PMID: 28125758. 7. Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med 2007;356:2457–71. https://doi.org/10.1056/ NEJMoa072761; PMID: 17517853. 8. Nissen SE, Tuzcu EM, Schoenhagen P, et al. Statin therapy, LDL cholesterol, C-reactive protein, and coronary artery disease. N Engl J Med 2005;352:29–38. https://doi. org/10.1056/NEJMoa042000; PMID: 15635110. 9. Zinman B, Wanner C, Lachin JM, et al. E-RO. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015;373:2117–28. https://doi.org/10.1056/ NEJMoa1504720; PMID: 26378978. 10. Correia LC, Latado A, Porzsolt F. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2016;375:1797–9. https://doi.org/10.1056/ NEJMc1611289; PMID: 27806227. 11. Husain M, Birkenfeld AL, Donsmark M, et al. Oral semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med 2019;381:841–51. https://doi. org/10.1056/NEJMoa1901118; PMID: 31185157. 12. Holman RR, Bethel MA, Mentz RJ, et al. Effects of onceweekly exenatide on cardiovascular outcomes in type 2 diabetes. N Engl J Med 2017;377:1228–39. https://doi. org/10.1056/NEJMoa1612917; PMID: 28910237.

use of SGLT2 inhibitors in patients with heart failure with reduced ejection fraction.30 There are currently two ongoing trials with gliflozins for heart failure with preserved ejection fraction: EMPEROR-Preserved and DELIVER. The results of both trials are expected to be presented in late 2021/early 2022.

Safety

Ahmad et al.’s review includes an in-depth analysis of the adverse effects of GLP-1 and SGLT2 drugs.4 GLP-1 receptor agonists are relatively safe, and most common side-effects are transient nausea and vomiting, especially when initiating therapy or up-titrating the dose. For SGLT2 inhibitors, an increase in the risk of genital mycotic infections has been reported, and more rarely, haemoconcentration.31

Conclusion

New drugs originally developed for the treatment of diabetes are showing consistent benefits in cardiovascular disease, including MACE and heart failure with reduced ejection fraction. Currently, the main evidence comes from trials using SGLT2 inhibitors in patients with and without diabetes and those investigating GLP-1s in people with diabetes. Ongoing trials will confirm if more GLP-1 and SGLT2 drugs have the same benefits, and if the results are similar for patients with heart failure with preserved ejection fraction. These findings will be important for cardiologists and diabetologists.

13. Pfeffer MA, Claggett B, Diaz R, et al. Lixisenatide in patients with type 2 diabetes and acute coronary syndrome. N Engl J Med 2015;373:2247–57. https://doi.org/10.1056/ NEJMoa1509225; PMID: 26630143. 14. Hernandez AF, Green JB, Janmohamed S, et al. Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial. Lancet 2018;392:1519–29. https://doi.org/10.1016/S01406736(18)32261-X; PMID: 30291013. 15. Li Y, Rosenblit P. Glucagon-like peptide-1 receptor agonists and cardiovascular risk reduction in type 2 diabetes mellitus: is it a class effect? Curr Cardiol Rep 2018;20:113. https://doi.org/10.1007/s11886-018-1051-2; PMID: 30259238. 16. Kristensen SL, Rorth R, Jhund PS, et al. Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet Diabetes Endocrinol 2019;7:776–85. https://doi.org/10.1016/ S2213-8587(19)30249-9; PMID: 31422062. 17. Arnott C, Li Q, Kang A, et al. Sodium-glucose cotransporter 2 inhibition for the prevention of cardiovascular events in patients with type 2 diabetes mellitus: a systematic review and meta-analysis. J Am Heart Assoc 2020;9:e014908. https://doi.org/10.1161/JAHA.119.014908; PMID: 31992158. 18. Zinman B, Wanner C, Lachin JM et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015;373:2117–28. https://doi.org/10.1056/ NEJMoa1504720; PMID: 26378978. 19. Wanner C, Inzucchi SE, Lachin JM, et al. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med 2016;375:323–34. https://doi.org/10.1056/ NEJMoa1515920; PMID: 27299675. 20. Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med 2017;377:644–57. https://doi.org/10.1056/ NEJMoa1611925; PMID: 28605608. 21. Wiviott SD, Raz I, Bonaca MP et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2019;380:347–57. https://doi.org/10.1056/NEJMoa1812389; PMID: 30415602. 22. Zelniker TA, Wiviott SD, Raz I, et al. SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet 2019;393:31–9. https://doi.org/10.1016/S01406736(18)32590-X; PMID: 30424892.

EUROPEAN CARDIOLOGY REVIEW Access at: www.ECRjournal.com

23. Cannon CP, McGuire DK, Cherney D, et al. Results of the eValuation of ERTugliflozin EffIcacy and Safety CardioVascular Outcomes Trial (VERTIS CV). Presented at: 80th American Diabetes Association Scientific Sessions, 16 June 2020. 24. Kosiborod M, Lam CSP, Kohsaka S, et al. Cardiovascular events associated with SGLT-2 inhibitors versus other glucose-lowering drugs: the CVD-REAL 2 study. J Am Coll Cardiol 2018;71:2628–39. https://doi.org/10.1016/j. jacc.2018.03.009; PMID: 29540325. 25. Kosiborod M, Cavender MA, Fu AZ, et al. Response by Kosiborod et al to Letters Regarding Article, “Lower risk of heart failure and death in patients initiated on sodiumglucose cotransporter-2 inhibitors versus other glucoselowering drugs: the CVD-REAL study (Comparative Effectiveness of Cardiovascular Outcomes in New Users of Sodium-Glucose Cotransporter-2 Inhibitors)”. Circulation 2018;137:989–91. https://doi.org/10.1161/ CIRCULATIONAHA.117.031847; PMID: 29483180. 26. McMurray JJV, Solomon SD, Inzucchi SE, et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med 2019;381:1995–2008. https://doi.org/10.1056/ BEJMoa1911303; PMID: 31535829. 27. Martinez FA, Serenelli M, Nicolau J, et al. Efficacy and safety of dapagliflozin in heart failure with reduced ejection fraction according to age. Circulation 2019;141:100–11. https://doi.org/10.1161/CIRCULATIONAHA.119.044133; PMID: 31736328. 28. Packer M, Anker S, Butler J, et al. Cardiovascular and renal outcomes with empagliflozin in heart failure. N Engl J Med 2020;383:1413–24. https://doi.org/10.1056/NEJMoa2022190; PMID: 32865377. 29. Zannad F, Ferreira J, Pocock S, et al. SGLT2 inhibitors in patients with heart failure with reduced ejection fraction: a meta-analysis of the EMPEROR-Reduced and DAPA-HF trials. Lancet 2020;396:819–29. https://doi.org/10.1016/S01406736(20)31824-9; PMID: 32877652. 30. Jarcho J. More evidence for SGLT2 inhibitors in heart failure. N Engl J Med 2020;383:1481–2. https://doi.org/10.1056/ NEJMe2027915; PMID: 32865378. 31. Donnan JR, Grandy CA, Chibrikov E, et al. Comparative safety of the sodium glucose co-transporter 2 (SGLT2) inhibitors: a systematic review and meta-analysis. BMJ Open 2019;9:e022577. https://doi.org/10.1136/ bmjopen-2018-022577; PMID: 30813108.

Inflammation

Role of Inflammation in Coronary Epicardial and Microvascular Dysfunction Shigeo Godo , Jun Takahashi, Satoshi Yasuda

and Hiroaki Shimokawa

Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan

Abstract

There is accumulating evidence highlighting a close relationship between inflammation and coronary microvascular dysfunction (CMD) in various experimental and clinical settings, with major clinical implications. Chronic low-grade vascular inflammation plays important roles in the underlying mechanisms behind CMD, especially in patients with coronary artery disease, obesity, heart failure with preserved ejection fraction and chronic inflammatory rheumatoid diseases. The central mechanisms of coronary vasomotion abnormalities comprise enhanced coronary vasoconstrictor reactivity, reduced endothelium-dependent and -independent coronary vasodilator capacity and increased coronary microvascular resistance, where inflammatory mediators and responses are substantially involved. How to modulate CMD to improve clinical outcomes of patients with the disorder and whether CMD management by targeting inflammatory responses can benefit patients remain challenging questions in need of further research. This review provides a concise overview of the current knowledge of the involvement of inflammation in the pathophysiology and molecular mechanisms of CMD from bench to bedside.

Keywords

Coronary artery disease, coronary microvascular dysfunction, endothelial function, endothelium, endothelium-dependent hyperpolarisation, inflammation, nitric oxide Disclosure: The authors have no conflicts of interest to declare. Acknowledgements: The authors appreciate the efforts of members of the Tohoku University Hospital Cardiac Catheterization Laboratory. The authors’ work reported in this article was supported in part by the Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology, Tokyo, Japan (16K19383 and 17K15983). Received: 3 December 2020 Accepted: 14 January 2021 Citation: European Cardiology Review 2021;16:e13. DOI: https://doi.org/10.15420/ecr.2020.47 Correspondence: Hiroaki Shimokawa, Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan. E: shimo@cardio.med.tohoku.ac.jp Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

In recent decades, structural and functional abnormalities of the coronary microvasculature, referred to as coronary microvascular dysfunction (CMD), have been implicated across the spectrum of cardiovascular diseases.1,2 The true prognostic impact of CMD in patients with angina but without obstructive coronary artery disease (CAD) is still debated, largely due to the heterogeneity of previous studies, depending on the presence or absence of concomitant non-significant CAD (<50% stenosis), in which acute coronary events (e.g. plaque rupture) often occur.2 Accordingly, a meta-analysis revealed that the long-term prognosis of this population was heterogeneous and depended on the presence of ischaemia, as verified by non-invasive imaging techniques (stress echocardiography or nuclear imaging), which was associated with a higher incidence of worse clinical outcomes.3 However, CMD has attracted much attention in view of its significant prognostic impacts in various cardiovascular diseases.4,5 The prevalence of CMD in cardiovascular disease is not negligible, and a large cohort study (n=1,439) reported that two-thirds of patients with chest pain but without obstructive CAD had endothelium-dependent or -independent CMD.6 Moreover, 42% of patients with chest pain who presented to an emergency department and in whom acute MI was ruled out, as well as approximately 10% of patients with acute MI, had CMD.7,8 A brief comparison of contemporary guidelines for the diagnosis and management of patients with microvascular angina and CMD is presented in Table 1.9–11

Chronic low-grade vascular inflammation plays an important role in the mechanisms underlying CMD, especially in patients with diabetes, obesity, chronic inflammatory rheumatoid diseases and heart failure with preserved ejection fraction (HFpEF).5,12 The endothelium plays a pivotal role in modulating vascular tone by synthesising and releasing endotheliumderived relaxing factors (EDRFs), including vasodilator prostaglandins, nitric oxide (NO) and endothelium-dependent hyperpolarisation (EDH) factors, in a distinct vessel size-dependent manner. NO predominantly mediates vasodilatation of relatively large, conduit vessels (e.g. the aorta and epicardial coronary arteries), whereas EDH factors mediate vasodilatation in small resistance vessels (e.g. arterioles and coronary microvessels; Figure 1).13,14 Inflammatory processes in the vascular wall can be accompanied by endothelial dysfunction, characterised by a reduction in the production and/or action of EDRFs, instigating the first step towards coronary atherosclerosis.14 A recent meta-analysis found a positive association between higher serum interleukin (IL)-1 receptor antagonist concentrations and an increased incidence of cardiovascular disease in the general population.15 Moreover, positive results of the recent randomised controlled trials targeting inflammatory mediators further support the inflammatory hypothesis of atherosclerotic cardiovascular diseases.16–18 In this review, we provide a concise overview of the current knowledge of the involvement of inflammation in the pathophysiology and molecular mechanisms of CMD from bench to bedside.

Inflammation in Coronary Epicardial and Microvascular Dysfunction Table 1: Comparison of Contemporary Guidelines for the Diagnosis and Management of Patients With Microvascular Angina and Coronary Microvascular Dysfunction 2013 JCS Guidelines for Diagnosis and Treatment of Patients with Vasospastic Angina9

2019 AHA Scientific Statement 2019 ESC Guidelines for the for Contemporary Diagnosis and Diagnosis and Management of Management of Patients with MINOCA10 Chronic Coronary Syndromes11

Country/region

Japan

Europe

Target

Microvascular angina

Coronary microvascular dysfunction

Microvascular angina

Diagnosis

• Measurement of CBF during a drug-induced

• Angiographic review (TIMI frame count) • Coronary microvascular function testing

• Guidewire-based CFR and/or microcirculatory

coronary spasm provocation testing (IIb) • Measurement of coronary sinus lactate levels during a drug-induced coronary spasm provocation testing (IIb)

• Calcium channel blocker • Fasudil (IIa) • ACEi • Nicorandil • Antioxidants

Treatment

resistance measurements (IIa, B)

• Intracoronary ACh provocation testing (IIa, B) • Non-invasive assessment of CFR by Doppler echocardiography, CMR and PET (IIb, B)

• Calcium channel blocker • β-blocker • L-arginine • Ranolazine • Dipyridamole • Aminophylline • Imipramine • α-blocker

• Calcium channel blocker • Long-acting nitrate • Control of risk factors • Lifestyle changes • β-blocker • ACEi • Statin

ACEi = angiotensin-converting enzyme inhibitor; ACh = acetylcholine; AHA = American Heart Association; CBF = coronary blood flow; CFR = coronary flow reserve; CMR = cardiac magnetic resonance; ESC = European Society of Cardiology; JCS = Japanese Circulation Society; MINOCA = MI with non-obstructive coronary arteries; TIMI = Thrombolysis in MI.

Figure 1: Vessel Size-dependent Contribution of Endothelium-derived Relaxing Factors and Rho-kinasemediated Vascular Smooth Muscle Hypercontraction Agonist

Shear stress

Receptor

Endothelium

Endothelium-derived relaxing factors Conduit artery

Resistance artery

Vasodilator prostaglandins NO EDH Agonist Receptor

Vascular smooth muscle

Rho-kinase Hyperpolarisation

cGMP Relaxation

Hypercontraction

Vasodilatation

Coronary vasospasm

EDH = endothelium-dependent hyperpolarisation; NO = nitric oxide.

Pathophysiology of Coronary Microvascular Dysfunction

There are three central mechanisms underlying coronary vasomotion abnormalities: enhanced coronary vasoconstrictive reactivity (e.g. coronary spasm) at the epicardial and microvascular levels, impaired endotheliumdependent and -independent coronary vasodilator capacity and increased coronary microvascular resistance induced by structural factors (e.g. luminal narrowing, vascular remodelling, vascular rarefaction and

extramural compression; Figure 2). The underlying mechanisms of CMD may be heterogeneous (including several structural and functional alterations) often coexist in various combinations and can cause myocardial ischaemia even in the absence of obstructive CAD.6,19 The major mechanism in the pathogenesis of coronary artery spasm is Rho-kinase-induced myosin light chain phosphorylation with resultant vascular smooth muscle cell (VSMC) hypercontraction (Figure 1).13,20,21 Intracoronary administration of the Rho-kinase inhibitor fasudil is effective in relieving not only refractory epicardial coronary spasm resistant to nitrates or calcium-channel blockers, but also coronary microvascular spasm and percutaneous coronary intervention (PCI)-related refractory myocardial ischaemia.22–24 However, fasudil has not been approved for clinical use by the European Medicines Agency or the US Food and Drug Administration. We recently demonstrated that fasudil-induced decreases in microvascular resistance (IMR) were greater in patients with vasospastic angina (VSA) who had higher IMR values.19 This evidence supports the role of Rhokinase activation in increased coronary microvascular resistance. In addition, enhanced epicardial and coronary microvascular spasms are associated with the increased production of mediators of vasoconstriction (e.g. serotonin), as well as inflammatory conditions (see below).25 Along with VSMC dysfunction, such as coronary artery spasm, endothelial dysfunction serves as another major mechanism involved in the pathogenesis of CMD. Inflammatory conditions and several key proinflammatory cytokines are also involved in the development of endothelial dysfunction.26 It is widely accepted that EDH factors, rather than NO, predominantly mediate the endothelium-dependent vasodilatation of resistance arteries.13,26 Thus, EDH factor-mediated vasodilatation is an important mechanism, especially in the microcirculation, where blood pressure and organ perfusion are finely tuned to meet fluctuating demand in the body (Figure 1). Comprehensive reviews of the detailed mechanisms of endothelial modulation of vascular tone are available elsewhere.13,14,26

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Inflammation in Coronary Epicardial and Microvascular Dysfunction Inflammation, Perivascular Adipose Tissue and Vasospastic Angina

Previous studies by us and others have revealed close relationships among inflammation, perivascular adipose tissue (PVAT) and vasa vasorum in the pathogenesis of coronary vasomotion abnormalities (Figure 2), as summarised in recent review articles in this Journal.27,28 For example, in vivo, the major inflammatory cytokine IL-1β induced intimal thickening and coronary vasospastic responses to intracoronary serotonin or histamine via ‘outside-to-inside’ signalling in pigs.29 In addition, in CAD patients who underwent elective coronary artery bypass grafting, the proinflammatory properties of the epicardial adipose tissue were significantly greater than those of subcutaneous adipose tissue, but this was not reflected by plasma concentrations of systemic inflammatory biomarkers or attenuated by chronic treatment with statins or angiotensinconverting enzyme inhibitors/angiotensin II receptor blockers.30 Using multimodality imaging techniques, including micro-CT and optical frequency domain imaging, we previously demonstrated that enhanced adventitial vasa vasorum formation was associated with coronary hyperconstriction via Rho-kinase activation, a predominant mechanism of coronary vasospasm, in patients with VSA.27,31 The vasa vasorum serves as a conduit for inflammatory cells and cytokines originating from the surrounding inflamed adipose tissue to the local coronary atherosclerotic lesions in the vascular wall (Figure 2). The novel link between inflammation and coronary vasomotion abnormalities is further supported by the findings that coronary vasoconstriction in response to acetylcholine (ACh) in patients with early CAD was greater in coronary artery segments with than without macrophage infiltration and vasa vasorum proliferation in an additive manner, indicating an important role of inflammation and vasa vasorum proliferation in the pathogenesis of CAD.32 It is conceivable that Rhokinase activation and inflammatory responses are the shared mechanisms underlying enhanced coronary vasoconstrictor reactivity (e.g. coronary spasm) at both the epicardial and microvascular levels, and thus similar phenomena will be seen in the coronary microvasculature as in the epicardial coronary arteries. There is growing evidence of a role for PVAT in the regulation of vascular tone in a wide variety of experimental and clinical settings, adding another layer of complexity to PVAT-mediated responses.33 PVAT has different pathophysiological roles depending on its location in the body and modulates vascular tone in a paracrine/autocrine manner by releasing an array of vasoactive mediators, including adiponectin, NO, hydrogen sulfide and others yet to be identified.33 For example, interscapular brown adipose tissue exerts an anticontractile effect through hydrogen peroxide (H2O2)induced cGMP-dependent protein kinase G (PKG) 1α activation and subsequent vasodilatation of small resistance arteries in mice.34 Considering that this oxidant-mediated PKG1α activation is a shared vasodilator mechanism of H2O2 as an EDH factor in coronary and mesenteric resistance arteries, targeting brown adipose tissue may be of therapeutic potential for the treatment of CMD.35–37 Perivascular inflammation has been shown to be associated with enhanced coronary vasoconstrictor reactivity in patients with VSA (Figure 2).28,38 Coronary PVAT volume measured by CT coronary angiography at the spastic coronary segment was significantly increased and positively correlated with the extent of coronary vasoconstriction provoked by intracoronary ACh in patients with VSA, although the total volume of epicardial adipose tissue was unchanged.28,38 In addition, coronary adventitial and PVAT inflammation evaluated by 18 F-fluorodeoxyglucose PET/CT was significantly increased in patients with

Figure 2: Novel Link Between Inflammation and Coronary Vasomotion Abnormalities Systemic low-grade inflammation

Inflamed perivascular adipose tissue

Inflammatory mediators

Epicardial coronary arteries

Coronary arterioles, capillaries and microcirculation

Enhanced coronary vasoconstrictor reactivity

Epicardial spasm

Impaired vasodilatation

Microvascular spasm

Endothelium dependent

Endothelium independent

CMD

CMD = coronary microvascular dysfunction.

VSA, along with enhanced adventitial vasa vasorum formation and Rhokinase activity of circulating leucocytes.38 Of note, the extent of coronary perivascular inflammation was markedly decreased in the spastic coronary artery after treatment with calcium channel blockers, which are the mainstay for the treatment of VSA.38,39

Sex Differences in Inflammation and Coronary Microvascular Dysfunction

Accumulating evidence indicates distinct sex differences in endothelial function and coronary vasomotion abnormalities, with major clinical implications.40,41 For example, the findings of the WISE study provide valuable insights into the aetiology of myocardial ischemia in female patients with chest pain in the absence of obstructive CAD, which is commonly attributed to CMD.42,43 Given the lower prevalence of obstructive CAD and higher prevalence of CMD in female patients in this population, the proper assessment and diagnosis of coronary functional rather than structural abnormalities should be considered.6 Many mechanisms have been proposed for the sex differences in the characteristics of CMD, including differences in sex hormone effects, autonomic regulation, genetic polymorphisms and susceptibility to proatherogenic mediators, such as inflammation, oxidative stress, endothelin-1 and angiotensin II.44,45 For example, oestrogens exert protective effects on endothelium-dependent vasodilatation through an anti-inflammatory effect on endothelium-derived mediators.26 In-depth reviews on this topic are available elsewhere.40,41

Inflammatory Modulators of Coronary Vascular Function: Beyond a Marker? High-Sensitivity C-reactive Protein

Low-grade inflammation, such as that associated with elevations in highsensitivity C-reactive protein (hs-CRP), significantly affects morbidity in atherosclerotic cardiovascular diseases and hs-CRP, among others, is an

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Inflammation in Coronary Epicardial and Microvascular Dysfunction easily obtainable practical marker to identify patients at risk of long-term mortality in many clinical settings. In a large-scale prospective cohort study of postmenopausal women with no history of cardiovascular disease or cancer, increased plasma markers of inflammation at baseline, such as hs-CRP, serum amyloid A, IL-6 and soluble intercellular adhesion molecule type 1 (sICAM-1), were significantly associated with the risk of future cardiovascular events.46 Of these markers, hs-CRP was the strongest predictor of the risk, and the addition of hs-CRP measurement to standard lipid screening better identified women at increased risk.46 In another study, sympathetic stimulation (cold pressor testing)-induced changes in epicardial luminal area and myocardial blood flow responses were significantly impaired in patients with elevated serum CRP concentrations (≥0.5 mg/dl) who had coronary risk factors but angiographically normal coronary arteries.47 Similarly, in patients with chest pain but angiographically normal coronary arteries, elevated CRP levels were associated with impaired coronary blood flow (CBF) responses to intracoronary ACh, but not with the change in coronary artery diameter (conduit vessels), suggesting a possible relationship between chronic vascular inflammation and CMD.48 In patients with typical angina and transient myocardial ischaemia despite angiographically normal coronary arteries, elevated hs-CRP concentrations (>0.3 mg/dl) were associated with CMD, as assessed by PET-derived myocardial blood flow and coronary flow reserve (CFR).49 This study provides the first direct evidence for a relationship between low-grade chronic inflammation and CMD.49 In patients with typical angina but without CAD, serum concentrations of soluble CD40 ligand and tumour necrosis factor (TNF)-α were significantly associated with a decrease in the myocardial perfusion reserve index (MPRI) during adenosine stress cardiac magnetic resonance (CMR), whereas serum concentrations of TNF-α and sICAM-1 were significantly associated with reductions in MPRI during ACh stress CMR.50 Reduced MPRI was significantly correlated with both endothelium-dependent and -independent changes in CBF in response to ACh and adenosine, respectively.50 Patients with acute chest pain who were found to have CMD, as assessed by reduced PET-derived CFR, but no evidence of CAD had elevated levels of serum renalase, an anti-inflammatory protein released from the heart and kidneys in response to acute ischaemic stress.51 Of note, these patients had similar concentrations of serum inflammatory markers (CRP, TNF-α, vascular endothelial growth factor, IL-1β, IL-6 and metalloproteinases) as control patients.51 These findings imply the dynamic nature of the inflammatory response to an acute ischaemic insult compared with chronic coronary syndrome.51 Another recent study using encompassing proteomic analysis of cardiovascular disease biomarkers also confirmed that the proinflammatory IL-1β/TNF-α/IL-6/CRP pathway was significantly associated with CMD in women with angina but no obstructive CAD.52 Together, these observations suggest that chronic subclinical inflammation contributes to the development of CMD.

Soluble Urokinase-Type Plasminogen Activator Receptor

Among several inflammatory mediators implicated in the pathogenesis of CMD and atherosclerotic cardiovascular diseases, soluble urokinase-type plasminogen activator receptor (suPAR) has emerged as an inflammatory marker with atherogenic properties and a potential contributor to endothelial dysfunction.53 Recent studies have unveiled an association

between suPAR and CMD in patients with non-obstructive CAD.54 The net production of suPAR across the coronary circulation can be calculated as follows: suPAR = (coronary sinus concentration − left coronary arterial concentration) × basal CBF Positive values indicate the production or release of suPAR, whereas negative values indicate the retention or metabolism of suPAR in the coronary circulation.54 Patients with endothelium-dependent CMD showed net transcoronary production of suPAR.54 There are three possible explanations for the link between endotheliumdependent CMD and epicardial coronary atherosclerosis based on the important role of suPAR in the pathogenesis of endothelium-dependent CMD and coronary atherosclerosis. First, the transcoronary production of suPAR in patients with endothelium-dependent CMD may reflect a local low-grade inflammatory state in the coronary circulation, a key process underlying atherosclerosis and endothelial dysfunction.26 This is in agreement with prior observations showing enhanced transcoronary production of inflammatory cytokines, such as lipoprotein-associated phospholipase A2 and IL-8, in patients with endothelium-dependent CMD.55 Second, suPAR may be an active promoter of endothelium-dependent CMD, based on early evidence showing suPAR-mediated cleavage and inactivation of vasodilator peptides such as calcitonin gene-related peptide, as well as the generation of vasoconstrictor endothelin-1.56 Third, suPAR may promote the development and progression of coronary atherosclerosis in a distinct milieu exposed to endothelium-dependent CMD. suPAR has been shown to be involved in the pathogenesis of atherosclerosis through macrophage foam cell formation, the migration and proliferation of VSMCs and the formation of vulnerable plaques.53 The polarised release of suPAR from the inflamed vascular wall in the basolateral direction acts locally within the plaque to accelerate atherosclerosis, whereas circulating suPAR reflects only a fraction of the receptor pool, which is shed from various sources in the body.57 These observations may provide insights into the mechanisms by which endothelium-dependent CMD, likely in association with altered patterns of endothelial shear stress or suPAR-mediated inflammatory processes, contributes to the development of epicardial coronary atherosclerosis, even though these focal lesions are located upstream to the microcirculation.58,59

Hallmarks of Disease Obesity

Reduced CFR in obese patients without obstructive CAD is associated with increased plasma IL-6 and TNF-α concentrations, independent of cardiovascular risk factors.60 These proinflammatory adipokines may contribute to the evolution and progression of CMD by virtue of their ability to induce vascular inflammation and disrupt microvascular systems. For example, aging and obesity induced a phenotype transition of PVAT into a proinflammatory state by increasing the activity of a disintegrin and metalloproteinase 17 (ADAM17) activity and soluble TNF release in adipose tissue, leading to impaired bradykinin-induced endothelium-dependent vasodilatation of human coronary arterioles and thereby the development of CMD.61 Moreover, coronary PVAT from obese pigs augmented the constriction of isolated coronary arteries in pigs, which occurred independent of coronary endothelial function.62 These observations

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Inflammation in Coronary Epicardial and Microvascular Dysfunction implicate potential roles of PVAT-derived factors in the pathogenesis of obesity-related CMD. Obesity also impairs PVAT-mediated vascular function through several mechanisms involving EDRFs. First, obesity has been shown to promote the recruitment of proinflammatory macrophages to PVAT and to impair the vasodilator properties of PVAT by reducing endothelial and VSMC production of hydrogen sulfide, a potent gaseous relaxing factor, leading to microvascular endothelial dysfunction.63 Second, in obesity, hypoxic conditions in expanding obese adipose tissue increased the expression of hypoxia-inducible factor-1α, which induced adipose tissue fibrosis and local inflammation, resulting in the overproduction of leptin, resistin, IL-6 and TNF-α.64 These proinflammatory adipokines and cytokines reach the coronary microcirculation via ‘inside-to-outside’ signalling to cause their remote effects by increasing oxidative stress in the coronary arteriolar wall, leading to reduced bioavailability of NO and impaired vasodilatation.64 Together, these lines of evidence indicate the therapeutic potential of targeting PVAT in the treatment of CMD. In addition, obesity has been acknowledged as a distinct phenotype of HFpEF, characterised by structural, functional and haemodynamic alterations in the heart in favour of impaired exercise capacity, higher biventricular filling pressure in response to exercise and reduced pulmonary vasodilator reserve.65 The emerging interactions among systemic inflammation, CMD and HFpEF are discussed below.

Heart Failure With Preserved Ejection Fraction

HFpEF is a common and globally recognised form of heart failure that accounts for approximately 50% of cases. A chain of events driven by systemic inflammation has been proposed as a new paradigm for the pathogenesis of HFpEF.66 Briefly, comorbidities that are common in patients with HFpEF (e.g. diabetes, hypertension and obesity) can elicit a systemic proinflammatory state. Elevated levels of inflammatory mediators, such as IL-6, TNF-α, soluble suppression of tumorigenicity 2 (ST2) and pentraxin 3, provoke coronary microvascular endothelial inflammation and promote the production of reactive oxygen species (ROS), leading to reductions in NO bioavailability, cGMP content and PKG activity in adjacent cardiomyocytes, which favours the development of hypertrophy and increases resting tension because of hypophosphorylation of titin.67,68 Consequently, stiff cardiomyocytes and interstitial fibrosis contribute to high diastolic left ventricular stiffness and the development of heart failure. Such paracrine endocardial–myocardial interactions may explain how an inflamed coronary microvasculature can modulate myocardial structure and function, and thereby affect the trajectory of the disorder. Accumulating evidence highlights the high prevalence and pathophysiological relevance of CMD in patients with HFpEF.1,69,70 A pioneering study showed that ACh-induced endothelium-dependent increases in CBF were impaired in heart failure patients with isolated left ventricular diastolic dysfunction, suggesting that coronary endothelial dysfunction may be an underlying mechanism of diastolic dysfunction.71 More recently, a relatively large cohort study of patients with HFpEF demonstrated a comparably high prevalence of both endotheliumdependent and -independent CMD, assessed by gold-standard invasive coronary reactivity testing.72 Intriguingly, endothelium-independent CMD was associated with worse diastolic dysfunction and increased mortality, although the measurements of diastolic function and haemodynamics were performed non-invasively only at rest and the effect of endotheliumdependent CMD may have been underestimated in that study.72 Indeed, a

subsequent study from the same group demonstrated that pulmonary artery wedge pressure in HFpEF patients with endothelium-dependent CMD was only significantly elevated during exercise, and not at rest.73 Moreover, significant associations among endothelium-independent CMD, many inflammatory biomarkers and cardiac diastolic dysfunction were noted in women with angina but no flow-limiting coronary artery stenosis, further supporting the role of systemic inflammation in both CMD and HFpEF, as well as providing insights into potential mechanisms underlying the pathophysiology of HFpEF.74 In this regard, a comprehensive invasive assessment of coronary endothelial function by ‘functional coronary angiography’ is safe, feasible and of diagnostic value to better differentiate between endothelium-dependent and -independent CMD. In light of the fact that H2O2 has potent vasodilator properties in coronary resistance vessels where EDH factor-mediated responses become relatively dominant to NO-mediated relaxations, it is conceivable that impaired H2O2/EDH factor-mediated vasodilatation may be involved in the pathogenesis of HFpEF driven by CMD. Indeed, we have recently demonstrated that CMD mediated by reduced H2O2/EDH factor-mediated vasodilatation is associated with cardiac diastolic dysfunction in mice lacking endothelial NO synthase.75 In line with these observations, a subanalysis of the PROMIS-HFpEF study showed that CMD was highly prevalent (75%) in patients with HFpEF and independently associated with increased risk of cardiovascular death and recurrent heart failure hospitalisation after adjusting for age, sex and confounding comorbidities.5 These studies suggest that CMD may be a promising therapeutic target for patients with HFpEF. Although no established treatment for CMD is available as yet in clinical practice, a recent animal study showed that treatment with a histone acetyltransferase p300 inhibitor in surtuin-3knockout mice improved CMD in association with reductions in the expression of proinflammatory mediators, such as nuclear factor (NF)-κ and vascular cell adhesion molecule 1, in the coronary artery.76 Of note, contrary to the expectation that augmenting NO-mediated vasodilatation could benefit patients with HFpEF, the results of randomised clinical trials of the systemic and long-term administration of inorganic nitrite, used as an NO donor, in HFpEF patients were discouraging, or even harmful.77 These lines of evidence indicate that it is important to avoid excessive NO supplementation.78 Nitrosative stress induced by an excessive amount of NO may explain this ‘paradox’ of NO-targeted therapy, implicating the importance of a physiological balance between NO and EDH factors in endothelium-dependent vasodilatation.79,80

Chronic Inflammatory Rheumatoid Diseases

In patients with chronic inflammatory rheumatoid diseases, such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and systemic sclerosis (SSc), coronary microvascular structure and function can be affected in a chronic inflammatory milieu, leading to the development of myocardial ischaemia and increased cardiovascular morbidity and mortality, even in the absence of obstructive epicardial CAD.12 Indeed, patients with such autoimmune rheumatic diseases are characterised by accelerated atherosclerosis and premature CAD, and are often found to have CMD in a subclinical, asymptomatic manner.12 A high prevalence of CMD defined by reduced CFR was unexpectedly found in patients with SSc in the absence of clinical evidence of ischaemic heart disease.81 Moreover, a marked reduction in CFR (<2.0) was noted in the diffuse form of SSc.81 Similarly, CFR calculated as PET-derived adenosine/

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Inflammation in Coronary Epicardial and Microvascular Dysfunction resting myocardial blood flow was reduced in patients with RA and SLE, even in the absence of both epicardial coronary stenoses and conventional coronary risk factors.12 Another study also noted that the presence of a chronic inflammatory disease, such as RA, SLE or SSc, was an independent predictor of CMD even in the absence of obstructive CAD.82 However, in that study, the CTderived coronary artery calcium score in the left anterior descending coronary artery was not associated with CMD.82 It is possible that prolonged systemic inflammation may precede and contribute to the development of premature CAD in patients with a chronic inflammatory disease. This is supported by the finding that high IL-6 levels in patients with RA are accompanied by elevated concentrations of circulating asymmetrical dimethylarginine and endothelial dysfunction, manifested as impaired flow-mediated dilatation, despite the absence of atherosclerosis.83 Psoriasis is another common chronic inflammatory skin disease. Psoriasis is characterised by systemic inflammation affecting multiple organs in the body, including the cardiovascular system, and is associated with an increased risk of cardiovascular disease.84 In patients with psoriasis without overt CAD, a high prevalence of CMD, defined as PET-derived myocardial flow reserve <2.0, has been found, regardless of conventional coronary risk factors or the burden of coronary atherosclerosis.84 Patients with psoriasis treated with TNF inhibitors showed marked improvement in CFR in parallel with reductions in serum hs-CRP and TNF-α concentrations, further supporting the role of systemic inflammation in the mechanisms underlying CMD in patients with psoriasis.85 Considering the high prevalence and prognostic significance of CMD in patients with psoriasis, early recognition of the underlying CMD is indispensable in optimising the therapeutic strategy for these patients. Inflammatory endothelial activation and oxidative stress may be a potential mechanistic link between chronic inflammatory rheumatoid diseases and CMD. For example, in a mouse model of RA, endotheliumdependent relaxation in response to ACh was impaired and inversely correlated with serum monocyte chemotactic protein-1 (MCP-1) concentrations, one of the major proinflammatory chemokines involved in the pathogenesis of RA and atherosclerosis.86 This endothelial dysfunction was ameliorated by statin therapy through inhibition of NF-κB binding to the MCP-1-induced protein gene enhancer.86

Therapeutic Potential of Anti-inflammatory Drugs Non-steroidal Anti-inflammatory Drugs

Although low-dose aspirin is the mainstay of secondary prevention of atherosclerotic cardiovascular diseases, a higher dose is needed to provide a systemic anti-inflammatory effect.87 In a small, randomised trial of high-dose salsalate for 4 weeks, endothelium-dependent vasodilatation was unexpectedly impaired by the treatment, suggesting possible unfavourable effects of anti-inflammatory doses of salsalate on endothelial function.87 This is explained, in part, by the fact that vasodilator prostaglandins play a small but constant role independent of vessel size in general, but their contribution is not negligible in the kidneys; prostaglandin E2 and prostacyclin play important roles in the regulation of glomerular filtration rate, renal blood flow and renovascular tone.26

Canakinumab

Based on the inflammatory hypothesis of atherosclerotic cardiovascular diseases, a large-scale randomised clinical trial, namely the CANTOS study, was performed to examine whether targeting IL-1β could reduce

the risk of recurrent cardiovascular events in patients with a history of myocardial infarction who had an hs-CRP level ≥0.2 mg/dl.16 Notably, the study population had a persistent proinflammatory response despite the use of aggressive secondary prevention strategies.16 Treatment with canakinumab, a selective anti-IL-1β monoclonal antibody, at a dose of 150 mg every 3 months significantly reduced the rate of the primary efficacy end point, which was a composite of non-fatal MI, non-fatal stroke or cardiovascular death, compared with placebo.16 Moreover, subanalysis of CANTOS showed that, independent of LDL levels, the magnitude of the reduction in hs-CRP was strongly associated with the reductions in cardiovascular events and all-cause mortality following canakinumab therapy; post-MI patients who achieved hs-CRP concentrations <0.2 mg/dl following a single dose of canakinumab had a 25% reduction in major adverse cardiac events and a 31% reduction in all-cause mortality compared with those who achieved hs-CRP concentrations ≥0.2 mg/dl.88 The results of CANTOS build on the inflammatory hypothesis of atherothrombosis, suggesting that targeting IL-1β (which drives the IL-6-mediated inflammatory pathways), rather than non-specific elimination of inflammatory mediators, may be beneficial in patients who have a residual proinflammatory response.

Colchicine

In recent years, the classical anti-inflammatory agent colchicine has attracted renewed attention for the treatment and secondary prevention of cardiovascular diseases. Two landmark clinical trials, namely the COLCOT and the LoDoCo2 trials, have demonstrated the efficacy and safety of low-dose colchicine at a dose of 0.5 mg/day in patients with stable CAD.17,18 A subanalysis of COLCOT revealed that a significant reduction in the primary endpoint was evident in patients who were initiated on colchicine within the first 3 days after MI, but not in those who were treated thereafter.89 In line with these results, the administration of low-dose colchicine at the same dose for 1 week significantly reduced the serum hs-CRP concentrations and improved endothelial function evaluated by flow-mediated dilatation in patients with CAD whose white blood cell count was ≥7,500 /µl.90 Although colchicine may have therapeutic potential in patients with CMD associated with inflammation, it should be noted that some studies reported a greater occurrence of non-cardiovascular deaths in the colchicine-treated groups.18,91

Conclusion

Patients with coronary vasomotion abnormalities are often complicated by inflammatory responses and peripheral endothelial dysfunction, in which CMD manifests as systemic vascular dysfunction beyond the heart.92 This further supports the concept of ‘primary coronary microcirculatory dysfunction’, and has important implications for practice and research.93 The results of two recent landmark clinical trials regarding the management of stable CAD, namely the ORBITA trial and the ISCHEMIA trial, have questioned the benefit of PCI and suggest the importance of coronary microvascular physiology.94,95 Although these trials did not focus directly on coronary microvascular function, an interesting speculation is that CMD may contribute to cardiac ischaemia even after successful revascularisation of significant epicardial coronary stenosis. Whether the management of CMD by targeting inflammatory mediators can improve the outcome of patients with the disease remains an open question. Further research and prospective trials are warranted to address this issue.

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83. Antoniades C, Demosthenous M, Tousoulis D, et al. Role of asymmetrical dimethylarginine in inflammation-induced endothelial dysfunction in human atherosclerosis. Hypertension 2011;58:93–8. https://doi.org/10.1161/ HYPERTENSIONAHA.110.168245; PMID: 21518967. 84. Weber B, Perez-Chada LM, Divakaran S, et al. Coronary microvascular dysfunction in patients with psoriasis. J Nucl Cardiol 2020. https://doi.org/10.1007/s12350-020-02166-5; PMID: 32419071; epub ahead of press. 85. Piaserico S, Osto E, Famoso G, et al. Treatment with tumor necrosis factor inhibitors restores coronary microvascular function in young patients with severe psoriasis. Atherosclerosis 2016;251:25–30. https://doi.org/10.1016/j. atherosclerosis.2016.05.036; PMID: 27236353. 86. He M, Liang X, He L, et al. Endothelial dysfunction in rheumatoid arthritis: the role of monocyte chemotactic protein-1-induced protein. Arterioscler Thromb Vasc Biol 2013;33:1384–91. https://doi.org/10.1161/ATVBAHA.113.301490; PMID: 23580143. 87. Nohria A, Kinlay S, Buck JS, et al. The effect of salsalate therapy on endothelial function in a broad range of subjects. J Am Heart Assoc 2014;3:e000609. https://doi. org/10.1161/JAHA.113.000609; PMID: 24390146. 88. Ridker PM, MacFadyen JG, Everett BM, et al. Relationship of C-reactive protein reduction to cardiovascular event reduction following treatment with canakinumab: a secondary analysis from the CANTOS randomised controlled trial. Lancet 2018;391:319–28. https://doi.org/10.1016/S01406736(17)32814-3; PMID: 29146124. 89. Bouabdallaoui N, Tardif JC, Waters DD, et al. Time-totreatment initiation of colchicine and cardiovascular outcomes after myocardial infarction in the Colchicine Cardiovascular Outcomes Trial (COLCOT). Eur Heart J 2020;41:4092–9. https://doi.org/10.1093/eurheartj/ehaa659; PMID: 32860034. 90. Kajikawa M, Higashi Y, Tomiyama H, et al. Effect of shortterm colchicine treatment on endothelial function in patients with coronary artery disease. Int J Cardiol 2019;281:35–9. https://doi.org/10.1016/j.ijcard.2019.01.054; PMID: 30683457. 91. Tong DC, Quinn S, Nasis A, et al. Colchicine in patients with acute coronary syndrome: the Australian COPS randomized clinical trial. Circulation 2020;142:1890–00. https://doi. org/10.1161/CIRCULATIONAHA.120.050771; PMID: 32862667. 92. Ohura-Kajitani S, Shiroto T, Godo S, et al. Marked impairment of endothelium-dependent digital vasodilatations in patients with microvascular angina: evidence for systemic small artery disease. Arterioscler Thromb Vasc Biol 2020;40:1400–12. https://doi.org/10.1161/ ATVBAHA.119.313704; PMID: 32237907. 93. Lerman A, Holmes DR, Herrmann J, Gersh BJ. Microcirculatory dysfunction in ST-elevation myocardial infarction: cause, consequence, or both? Eur Heart J 2007;28:788–97. https://doi.org/10.1093/eurheartj/ehl501; PMID: 17347176. 94. Al-Lamee R, Thompson D, Dehbi HM, et al. Percutaneous coronary intervention in stable angina (ORBITA): a doubleblind, randomised controlled trial. Lancet 2018;391:31–40. https://doi.org/10.1016/S0140-6736(17)32714-9; PMID: 29103656. 95. Maron DJ, Hochman JS, Reynolds HR, et al. Initial invasive or conservative strategy for stable coronary disease. N Engl J Med 2020;382:1395–407. https://doi.org/10.1056/ NEJMoa1915922; PMID: 32227755.

APSC Consensus Statements

Consensus Recommendations by the Asian Pacific Society of Cardiology: Optimising Cardiovascular Outcomes in Patients with Type 2 Diabetes Jack Wei Chieh Tan,1,2 David Sim,1 Junya Ako,3 Wael Almahmeed,4 Mark E Cooper,5 Jamshed J Dalal,6 Chaicharn Deerochanawong,7 David Wei Chun Huang,8,9,10 Sofian Johar,11 Upendra Kaul,12 Sin Gon Kim,13 Natalie Koh,1 Alice Pik-Shan Kong,14 Rungroj Krittayaphong,15 Bernard Kwok,16 Bien J Matawaran,17 Quang Ngoc Nguyen,18 Loke Meng Ong,19 Jin Joo Park,20 Yongde Peng,21 David KL Quek,22 Ketut Suastika,23 Norlela Sukor,24 Boon Wee Teo,25 Chee Kiang Teoh,26 Jian Zhang,27 Eugenio B Reyes28 and Su Yen Goh29 1. National Heart Centre, Singapore; 2. Sengkang General Hospital, Singapore; 3. Kitasato University and Hospital, Tokyo, Japan; 4. Cleveland Clinic Abu Dhabi, United Arab Emirates; 5. Monash University, Melbourne, Australia; 6. Cardiac Sciences, Kokilaben Hospital, Mumbai, India; 7. Rajavithi Hospital, Rangsit Medical School, Thailand; 8. Department of Critical Care Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan; 9. School of Medicine, National Yang-Ming University, Taipei, Taiwan; 10. Department of Physical Therapy, Fooyin University, Kaohsiung, Taiwan; 11. Ripas Hospital, Brunei; 12. Batra Hospital and Medical Research Centre, New Delhi, India; 13. Korea University College of Medicine, Seoul, South Korea; 14. The Chinese University of Hong Kong, Hong Kong, China; 15. Siriraj Hospital, Mahidol University, Bangkok, Thailand; 16. Farrer Park Medical Centre, Singapore; 17. University of Santo Tomas, Manila, the Philippines; 18. Department of Cardiology, Vietnam National Heart Institute, Hanoi Medical University, Hanoi, Vietnam; 19. Penang General Hospital, Penang, Malaysia; 20. Seoul National University Bundang Hospital, Seongnam, South Korea; 21. Shanghai Jiatong University, Shanghai, China; 22. Pantai Hospital Kuala Lumpur, Kuala Lumpur, Malaysia; 23. Udayana University, Bali, Indonesia; 24. Department of Medicine, Universiti Kebangsaan Malaysia Medical Centre, Kuala Lumpur, Malaysia; 25. Yong Loo Ling School of Medicine, National University of Singapore, Singapore; 26. Institut Jantung Negara, Kuala Lumpur, Malaysia; 27. Peking Union Medical College, Beijing, China; 28. Division of Cardiovascular Medicine, University of the Philippines, Philippine General Hospital, University of the Philippines Manila, Manila, the Philippines; 29. Singapore General Hospital, Singapore

Abstract

The Asian Pacific Society of Cardiology convened a consensus statement panel for optimising cardiovascular (CV) outcomes in type 2 diabetes, and reviewed the current literature. Relevant articles were appraised using the Grading of Recommendations, Assessment, Development and Evaluation system, and consensus statements were developed in two meetings and were confirmed through online voting. The consensus statements indicated that lifestyle interventions must be emphasised for patients with prediabetes, and optimal glucose control should be encouraged when possible. Sodium–glucose cotransporter 2 inhibitors (SGLT2i) are recommended for patients with chronic kidney disease with adequate renal function, and for patients with heart failure with reduced ejection fraction. In addition to SGLT2i, glucagon-like peptide-1 receptor agonists are recommended for patients at high risk of CV events. A blood pressure target below 140/90 mmHg is generally recommended for patients with type 2 diabetes. Antiplatelet therapy is recommended for secondary prevention in patients with atherosclerotic CV disease.

Keywords

Type 2 diabetes, cardiovascular, sodium-glucose cotransporter 2 inhibitor, glucagon-like protein 1 receptor agonist, consensus, Asia Pacific, prediabetes Disclosure: This work was funded through the Asian Pacific Society of Cardiology, with unrestricted educational grants from Abbott Vascular, Amgen, AstraZeneca, Bayer and Roche Diagnostics. JWCT reports honoraria from AstraZeneca, Bayer, Amgen, Medtronic, Abbott Vascular, Biosensors, Alvimedica, Boehringer Ingelheim and Pfizer; research and educational grants from Medtronic, Biosensors, Biotronik, Philips, Amgen, AZ, Roche, Otsuka, Terumo and Abbott Vascular; and consulting fees from Elixir and CSL Behring. DS reports honoraria from Abbott, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Medtronic, Menarini, Merck, Novartis, Otsuka, Pfizer, Roche and Servier. JA reports honoraria from AstraZeneca, Daiichi Sankyo, Bayer and Sanofi, and grants/grants pending from Daiichi Sankyo. MEC reports honoraria, speaking fees or grants from MSD/ Merck, Novo Nordisk, AstraZeneca, Boehringer-Ingelheim, Lilly, Bayer, Servier, Novartis and MundiPharma. JJD reports honoraria from Bayer and Pfizer. SJ reports honoraria from Biosense Webster and Medtronic. DKQ reports honoraria from AstraZeneca and Boehringer Ingelheim. BJM reports honoraria and CME grants from AstraZeneca, Boehringer Ingelheim, Lilly-Zuellig, MSD, Novartis, Novo Nordisk, Upjohn-Pfizer, Sanofi, and Servier. CKT reports honoraria from AstraZeneca, Boehringer Ingelheim, Novartis and Johnson & Johnson. SGK reports consulting/lecture fees or research grants from AstraZeneca, Boehringer Ingelheim, MSD, Pfizer, Takeda, Sanofi, Novo Nordisk, Novartis and Abbott. CD reports honoraria from AstraZeneca, Abbott, Bayor, Boehringer, Pfizer and Sanofi Aventis. BWT reports honoraria and consulting fees from Astellas, AstraZeneca, Boehringer Ingelheim and Otsuka. APSK reports honoraria from Abbott, AstraZeneca, Bayer, Eli Lilly and Company, Merck Serono, Nestle, Novo Nordisk, Pfizer and Sanofi. EBR reports consulting fees and speaker’s honoraria from Corbridge, Boehringer Ingelheim, E Merck, Torrent, Innogen and Servier, and research grants from MSD, Novartis and Pfizer. SYG reports advisory board honoraria from AstraZeneca, Boehringer Ingelheim, Bayer, Novo Nordisk and Sanofi. All other authors have no conflicts of interest to declare. Acknowledgement: Medical writing support was provided by Aizel Ebron and Ivan Olegario of MIMS Pte Ltd. Received: 23 December 2020 Accepted: 15 February 2021 Citation: European Cardiology Review 2021;16:e14. DOI: https://doi.org/10.15420/ecr.2020.52 Correspondence: Jack Wei Chieh Tan, National Heart Centre, 5 Hospital Dr, Singapore 169609. E: jack.tan.w.c@singhealth.com.sg Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

APSC Consensus on Optimising CV Outcomes in T2D In recent decades, there has been a significant increase in the number of people with type 2 diabetes (T2D), particularly in developing countries. Sixty per cent of the world’s diabetes cases are in Asia, largely due to its large population, posing significant social and economic burdens to most nations in the region.1 Systematic reviews have shown that the epidemiological data on the cardiovascular (CV) complications of T2D are substantially scarcer in the Asia Pacific region compared with western countries.2 However, the limited data suggest that the prevalence of CV disease (CVD) among T2D patients in the Asia Pacific (33.6–44.5%) is slightly higher compared with the West (27.5–46%). Furthermore, studies have also confirmed that T2D is associated with a twofold increased risk of CVD compared with non-T2D patients in the Asia-Pacific region.3 Poor glycaemic control and high variability of plasma glucose levels are the leading causes of CV mortality in patients with T2D. While glycaemic management is essential, specific organ protection is also important in the management of patients with T2D.

These consensus statements aim to provide guidance on specific organ protection in patients with T2D to optimise CV outcomes. Despite focusing on pharmacotherapy, these consensus statements cannot emphasise enough the central role of lifestyle modification on the comprehensive management of T2D. For example, several recent studies have confirmed the benefit of intensive dietary interventions (mostly low carbohydrate diets) in the control and overall course of disease among T2D patients.4–6 The panel endorses a tailored, multidisciplinary approach in prescribing dietary interventions for T2D patients, in accordance with clinical guidelines.7 Similarly, recent evidence also supports the inclusion of exercise in the management of T2D patients, preferably under the supervision of qualified professionals.8–10 These fundamental concepts should be kept in mind when applying these consensus statements in clinical practice.

Prediabetes

Methods

The Asian Pacific Society of Cardiology (APSC) convened a 28-member multidisciplinary expert panel of cardiologists, endocrinologists and nephrologists with clinical and research expertise in the diagnosis and treatment of T2D and CVD to develop consensus statements on optimising CV outcomes in patients with T2D. The aim of these consensus statements was to guide clinicians on specific organ protection in patients with T2D in the Asia Pacific setting. These experts represented 15 territories and countries in the Asia Pacific region. For these consensus statements, we adopted the criteria of the American Diabetes Association (ADA).2 Prediabetes was diagnosed by fasting plasma glucose (FPG) of 5.6–6.9 mmol/l, indicating impaired fasting glucose (IFG); or a 2-hour plasma glucose (PG) during a 75-g oral glucose tolerance test (OGTT) of 7.8–11 mmol/l, indicating impaired glucose tolerance (IGT); or HbA1c of 5.7–6.4% (39–47 mmol/mol). Diabetes was diagnosed by FPG ≥7 mmol/l, or 2-hour PG ≥11.1 mmol/l during OGTT, or a HbA1c level ≥6.5% (48 mmol/mol), or classic symptoms of hyperglycaemia and a random PG of ≥11.1 mmol/l.11 However, it should be kept in mind that countries in the Asia-Pacific region may use other cut-offs than the ADA criteria. For example, Singapore uses HbA1c ≥7% as the criterion for diabetes.12 In contrast, guidelines from India and the United Arab Emirates use the following: HbA1c ≥6.5%, FPG ≥7 mmol/l, or 2-hour PG ≥11.1 mmol/l during OGTT.13,14 After a comprehensive literature search, selected articles were reviewed and analysed using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system, as follows:

The available evidence was then discussed during two consensus meetings. Consensus statements were developed during the meetings, which were then put to an online vote. Each statement was voted on by each panel member using a three-point scale (agree, neutral or disagree). Consensus was reached when 80% of votes for a statement were agree or neutral. In cases of non-consensus, the statements were further discussed using email communication, and then revised accordingly until the criterion for consensus was reached.

Statement 1. Patients with prediabetes should be monitored closely and counselled regarding lifestyle interventions. Level of evidence: High. Level of agreement: 100% agree, 0% neutral, 0% disagree. Large randomised, controlled trials (RCTs) have shown that, compared with controls, lifestyle intervention and weight loss in patients with IGT leads to a significant reduction in the risk of diabetes, CV and all-cause mortality.16,17 The Diabetes Prevention Program Research Group also found that lifestyle interventions were significantly more effective than metformin in reducing the incidence of diabetes in individuals at high risk.18,19 Consistent with the findings of these large RCTs, the panel recommends the implementation of lifestyle interventions for patients with prediabetes.

Glycaemic Target Statement 2. Where possible, optimal glucose control should target HbA1c <7%. Level of evidence: High. Level of agreement: 96.4% agree, 3.6% neutral, 0% disagree. Statement 3. Hypoglycaemia increases the risk of mortality and CV events, and should be avoided. Level of evidence: Moderate. Level of agreement: 100% agree, 0% neutral, 0% disagree. Statement 4. A less stringent HbA1c target (<8%) may be appropriate in patients with advanced age, limited lifespan and comorbidities that predispose to hypoglycaemia. Level of evidence: Low. Level of agreement: 89.3% agree, 10.7% neutral, 0% disagree. Statement 5. Patients with complex glycaemic management may require referral to an endocrinologist. Level of evidence: Low. Level of agreement: 96.4% agree, 3.6% neutral, 0% disagree. A meta-analysis of five prospective RCTs in patients with T2D showed that, compared with standard treatment, intensive treatment that resulted

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APSC Consensus on Optimising CV Outcomes in T2D in a mean HbA1c of <7% at follow-up was associated with a significantly reduced risk of non-fatal MI and coronary heart disease, but not stroke or all-cause mortality.20 Currently, the concept of time-in-range from continuous glucose monitoring is not widely used in the Asia Pacific region; however, this may gain wider utilisation in the coming years. The DCCT/EDIC study in patients with type 1 diabetes (T1D) also showed that targeting an HbA1c of 7%, compared with 9%, resulted in a significant reduction in non-fatal MI, stroke or death from CVD through a mean follow-up of 17 years.21 Additionally, the UKPDS follow-up study found that patients on intensive therapy experienced a continued reduction in the risks of microvascular and emergent macrovascular complications, including MI and death from any cause, during the 10 years of post-trial follow-up.22 However, a review found that patients with type 1 diabetes and T2D were at increased risk of hypoglycaemia-induced CV events and mortality.23 The DIGAMI 2 prospective study (1,253 patients with T2D with hypoglycaemic episodes) also showed that severe hypoglycaemia is a pronounced risk factor of acute MI.24 Given these findings on the harms of hypoglycaemia, this complication should be avoided as much as possible. Older patients with diabetes are at greater risk for hypoglycaemia compared with younger patients, even with comparable glycaemic control. The presence of comorbidities, such as chronic renal or hepatic impairment, also contributes to an increased risk of hypoglycaemia.25 Hypoglycaemia is also associated with an increased risk of dementia and acute CV events in the elderly.26 Therefore, a less stringent HbA1c target is recommended in certain patients with increased risk of hypoglycaemia, such as the elderly and those with other comorbidities that predispose to hypoglycaemia.

Patients at High Risk of CV Events Statement 6. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) with proven CV benefits and sodium-glucose cotransporter-2 inhibitors (SGLT2i) are recommended in patients with T2D who have adequate renal function and are at high risk of CV events. Level of evidence: High. Level of agreement: 96.4% agree, 0% neutral, 3.6% disagree. As outlined in the 2020 APSC Chronic Coronary Syndrome consensus guide, patients with T2D who have any of the risk factors categorised according to the CVD system are considered at high risk of CV events.27 Results of the LEADER, SUSTAIN-6 and EXSCEL RCTs in patients with high CV risk (around 75% of patients had previous CVD and around 15% had pre-existing heart failure [HF]) demonstrated that, compared with placebo, GLP-1RA led to a reduction in major adverse CV events (MACE), but not in the risk of HF admission.28–30 The PIONEER-6 RCT demonstrated that, compared with placebo treatment, oral semaglutide led to reduced rates of MACE (HR 0.79, p<0.001 for non-inferiority) and significantly reduced the risk for CV death and all-cause death in patients with T2D and high CV risk.31 However, the REWIND trial found that dulaglutide was associated with a reduced rate of the primary composite outcome (non-fatal MI, non-fatal stroke or CV death; HR 0.88, p=0.026) compared with placebo, while all-cause mortality did not differ between the groups (p=0.067).32

Figure 1: Pharmacotherapeutic Options in Patients at High Risk of Cardiovascular Events Diabetes patients at high risk of CV events* X

Preferred drug: SGLT2 inhibitors or GLP-1RA with proven CV benefits

Other options: No preference

Avoid: None

*Based on the Asian Pacific Society of Cardiology cardiovascular disease scoring. CV = cardiovascular; GLP-1RA = glucagon-like protein 1 receptor agonist; SGLT2 = sodium–glucose cotransporter 2.

A meta-analysis of several CV outcome trials (CVOTs) showed that, compared with placebo, treatment with GLP-1RA was associated with a 10% relative risk reduction (RRR) in the three-point MACE, a 13% RRR in CV mortality and a 12% RRR in all-cause mortality.33 Regarding SGLT2i use, a meta-analysis was conducted on four studies: CANVAS, CREDENCE, DECLARE-TIMI 58 and EMPA-REG OUTCOME. The meta-analysis showed that MACE was reduced by 12% with this drug class (HR 0.88, 95% CI[0.82–0.94]). Importantly, when used for secondary prevention, SGLT2i therapy was associated with a 14% reduction in MACE (HR 0.86, 95% CI[0.80–0.93]), a 20% reduction in CV death (HR 0.80, 95% CI[0.71–0.90]) and a 17% reduction in all-cause death (HR 0.83, 95% CI[0.75–0.91]).34 Finally, a recent multicentre, double-blind trial (VERTIS-CV) found that patients with T2D and atherosclerotic CVD (ASCVD) who were treated with ertugliflozin had a lower risk of first hospitalisation for HF (hHF; HR 0.70, 95% CI[0.54–0.90]).35 While some studies, such as CANVAS, have demonstrated a small increase in the risk of amputation with canagliflozin (6.3 versus 3.4 per 1000 patient-years for placebo), SGLT2is are generally considered to have a favourable risk–benefit ratio.34,36 The recommended treatment options for patients with T2D at high risk of CV events are summarised in Figure 1.

Patients with Chronic Kidney Disease Statement 7. SGLT2i and GLP-1RA are recommended in patients with an estimated glomerular filtration rate (eGFR) >30 ml/min/1.73 m2 for their CV and renal benefits. Level of evidence: High. Level of agreement: 89.3% agree, 7.1% neutral, 3.6% disagree. Statement 8. Insulin, short-acting sulfonylureas and dipeptidylpeptidase 4 (DPP4) inhibitors are preferred in patients with end-stage renal disease (ESRD) on dialysis. Level of evidence: Low. Level of agreement: 92.9% agree, 7.1% neutral, 0% disagree. Statement 9. Metformin should be avoided in patients with an eGFR <30 ml/min/1.73 m2. Level of evidence: High. Level of agreement: 96.4% agree, 3.6% neutral, 0% disagree.

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APSC Consensus on Optimising CV Outcomes in T2D

Statement 10. Referral to a nephrologist should be considered in patients with T2D and an eGFR <30 ml/min/1.73 m2 or proteinuria >1 g/day, despite optimal blood pressure (BP) management and renin– angiotensin–aldosterone system blockade. Level of evidence: High. Level of agreement: 96.4% agree, 3.6% neutral, 0% disagree. The ADA 2020 guidelines and the 2020 Kidney Disease – Improving Global Outcomes (KDIGO) Diabetes Management in CKD guidelines both recommend the use of SGLT2i for patients with T2D and diabetic kidney disease when the eGFR ≥30 ml/min/1.73 m2 to reduce the risk of chronic kidney disease (CKD) progression and CV events.37,38 The DECLARE-TIMI 58 trial, which compared the SGLT2i dapagliflozin with placebo, demonstrated the CV safety of dapagliflozin, but not its benefits on MACE (HR 0.93, 95% CI[0.84–1.03]). Dapagliflozin was also associated with reduced risk for the composite efficacy endpoint of CV death or hHF (HR 0.83, 95% CI [0.73–0.95]) and a 24% reduction in risk of renal endpoints.39 A sub-analysis of the DAPA-HF study showed that the use of dapagliflozin was associated with a 28% RRR (absolute risk of 19.9% versus 26.3%, HR 0.72, 95% CI [0.59–0.86]) for the composite of CV death or worsening HF events in patients with CKD (eGFR <60 ml/min/1.73 m2 at baseline), and by a similar magnitude, in patients without CKD (13.8% versus 17.6%, HR 0.76, 95% CI [0.63–0.92]).40 The DAPA-CKD trial, which evaluated the efficacy of dapagliflozin compared with placebo in patients with eGFR ≥25 and ≤75 mL/min/1.73 m2 and elevated urinary albumin excretion, with and without T2D, was terminated early given the overwhelming efficacy demonstrated. The primary composite outcome (sustained decline in the eGFR of at least 50%, ESRD or death from renal or CV causes) was reduced by 39% in the dapagliflozin group (HR 0.61, 95% CI[0.51–0.72], p<0.001).41 Due to these results, some authors proposed to use a cut-off of 25 instead of 30 ml/ min/1.73 m2 for statement 7. However, for simplicity, when applying these statements in clinical practice, the current lower cut-off for CKD stage 3B (i.e. 30 ml/min/1.73 m2) is adapted. The CREDENCE trial in patients with T2D and CKD (eGFR 30–90 ml/ min/1.73 m2) demonstrated that, compared with placebo, canagliflozin led to a reduced risk of renal composite endpoints, including progression to ESRD, and on CV mortality, MACE and hHF. The efficacy of canagliflozin in reducing MACE, hHF, CV mortality and renal endpoints was similar regardless of the baseline status of CVD or CKD grades 2–3.42

reducing the risk of worsening eGFR, ESRD or renal death (HR 0.55, 95% CI [0.48–0.64], p<0.001).44 In addition to SGLT2Is, GLP-1RAs have been recommended by the 2020 KDIGO guidelines.38 This was based on a meta-analysis of CVOTs (including patients with eGFR >15 ml/min/1.73 m2), which showed a 15% reduction in the risk of MACE (HR 0.85, 95% CI [0.76–0.95]).45 However, data on GLP-1RA in those with more severe CKD are limited. For patients with CKD, including those with ESRD or those on dialysis, all currently available DPP4 inhibitors may be used.46 It has also been suggested that DPP4 inhibitors, may exert a kidney-protective effect by reducing the incidence of albuminuria.47,48 Three studies have also reported an improvement in albuminuria with DPP4 inhibitors.49–51 However, the panel did not find enough evidence to recommend DPP4 inhibitors as a preferred drug over other agents for patients on dialysis. For such patients, insulin or short-acting sulfonylureas are recommended, based on the extensive clinical experience with these drugs. As metformin is excreted renally, it is contraindicated in patients with eGFR <30 ml/min/1.73 m2. The ADA Standards of Medical Care in Diabetes––2020 state that referral to a nephrologist should take place when there is uncertainty about the aetiology of kidney disease, for difficult management issues (anaemia, secondary hyperparathyroidism, metabolic bone disease, resistant hypertension or electrolyte disturbances), or when there is advanced kidney disease (eGFR <30 ml/min/1.73 m2) requiring discussion of renal replacement therapy for ESRD.37 The recommended treatment options for improving CV and renal outcomes in patients with T2D and CKD are summarised in Figure 2.

Patients with Heart Failure Statement 11. SGLT2i are recommended in patients with HF with reduced ejection fraction (HFrEF; ≤40%) to reduce hospitalisation due to HF and CV death. Level of evidence: High. Level of agreement: 89.3% agree, 10.7% neutral, 0% disagree.

A subanalysis of patients of Asian ethnicity in the EMPA-REG OUTCOME trial demonstrated that empagliflozin reduced the risk, or the worsening, of nephropathy (HR 0.64, 95% CI[0.49–0.83]), progression to macroalbuminuria (HR 0.64, 95% CI[0.49–0.85]) and the composite of doubling of serum creatinine, initiation of renal replacement therapy or renal death (HR 0.48, 95% CI[0.25–0.92]). Furthermore, empagliflozintreated patients showed slower eGFR decline versus placebo-treated patient, and showed rapid urine albumin-to-creatinine ratio reduction at week 12, which was maintained through to week 164, with effects most pronounced in those with baseline microalbuminuria or macroalbuminuria.43

The DAPA-HF RCT in patients with HFrEF (≤40%) demonstrated that, compared with placebo, dapagliflozin led to a significant reduction in the risk of hospitalisation or urgent visit due to HF or CV death, as well as for HF events and total mortality due to hHF and CV death.52 It was also demonstrated in the DECLARE-TIMI 58 trials, CANVAS Program and EMPAREG OUTCOME that SGLT2i significantly reduced the risk CV death and hHF.36,39,53 A subanalysis of the DECLARE-TIMI 58 trial also showed that, compared with placebo, dapagliflozin led to around a 45% reduction in the risk of CV death and all-cause mortality in patients with HFrEF. These effects were not observed in patients without HFrEF.54 Finally, the EMPEROR-Reduced trial showed that, regardless of the presence or absence of diabetes, patients given empagliflozin had a lower risk of CV death or hospitalisation for worsening HF compared with those in the placebo group.55

A meta-analysis of the SGLT2i CVOT suggested a class effect in reducing the risk of CKD progression across high and lower CVD risk subgroups by

The recommended treatment options for improving CV outcomes in patients with T2D and HFrEF are summarised in Figure 3.

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APSC Consensus on Optimising CV Outcomes in T2D Figure 2: Pharmacotherapeutic Options for Type 2 Diabetes Patients Stratified by eGFR eGFR (ml/min/1.73 m2)

Preferred drugs

Other options

Avoid

1. SGLT2 inhibitors*† 2. GLP-1RA‡ 3. Dose-adjusted metformin for glucose management

1. DPP4 inhibitors 2. Sulfonylureas

None

30 Metformin 15 1. DPP4 inhibitors§

1. Short-acting sulfonylureas 2. Insulin

1. Metformin 2. TZD**

Dialysis 1. Insulin 2. Short-acting sulfonylureas 3. DPP4 inhibitors§

LEGEND

1. Metformin 2. TZD**

Evaluate options based on management goals and risk–benefit ratios *Avoid initiating if eGFR <30 ml/min/1.73 m2. †For renal and cardiovascular protection. ‡For cardiovascular benefits. §Linagliptin is recommended as no dose adjustment is required. **Due to fluid overload. DPP4 = dipeptidyl peptidase 4; eGFR = estimated glomerular filtration rate; GLP-1RA = glucagon-like protein 1 receptor agonist; SGLT2 = sodium–glucose cotransporter 2; TZD, thiazolidinedione.

Blood Pressure Target Statement 12. A BP target <140/90 mmHg is generally recommended in patients with T2D. Patients with T2D and hypertension at higher CV risk, or 10-year ASCVD ≥15% or other organ involvement should aim for a target BP <130/80 mmHg. Level of evidence: Moderate. Level of agreement: 96.4% agree, 3.6% neutral, 0% disagree. The UKPDS trial in 1,148 patients with T2D and hypertension demonstrated that systolic BP (SBP) control to a mean of 144 mmHg, compared with 154 mmHg, led to a significant reduction in the risks of diabetic endpoints, diabetes-related deaths, strokes and microvascular endpoints.56 Five years post-trial monitoring of 884 patients who were not made to maintain their previously assigned therapies showed that the benefits of previously improved BP control were not sustained when between-group differences in BP were lost.57 The ACCORD-BP RCT showed that in approximately 4,700 participants with diabetes, targeting an SBP of <120 mmHg, compared with a target of <140 mmHg, did not reduce the rate of composite outcome of fatal and non-fatal major CV events. Compared with the standard antihypertensive therapy group, targeting SBP <120 mmHg was associated with a 41% reduction in stroke rate, but significantly increased the rate of serious adverse events.58 A post-hoc analysis of the ACCORD-BP trial of patients who had additional CV risk factors (n=2592) showed that intensive BP control to 120 mmHg reduced the composite of CV death, non-fatal MI, non-fatal stroke, any revascularisation and HF.59 The SPRINT demonstrated CV benefits in patients with hypertension and without T2D randomised to SBP <120 versus <140 mmHg. Reasons proposed as to why this benefit was originally not observed in ACCORD-BP include statistical power and not

Figure 3: Pharmacotherapeutic Options for Type 2 Diabetes Patients with HFrEF HFrEF (≤40%)* X

Preferred drug: SGLT2 inhibitors to reduce hHF and CV death

Other options: No preference (caution with saxaglitin)

Avoid: TZD

*Based on evidence from DAPA-HF40 and EMPEROR-Reduced.55 CV = cardiovascular; HFrEF = heart failure with reduced ejection fraction; hHF = hospitalisation for heart failure; SGLT2 = sodium–glucose cotransporter 2; TZD = thiazolidinedione.

because of differences in CV profile for patients with diabetes.60 Additionally, a subgroup analysis showed that the risk of CV events was reduced in those on intensive BP treatment than in the standard BP treatment among those receiving standard glycaemic control (p=0.005), indicating a role of glycaemic control in determining net CV benefits.61 The American College of Cardiology/American Heart Association 2017 BP guidelines advocate a BP target of <130/80 mmHg for patients with T2D, on the basis that patients with diabetes are at a higher risk of CV events and improved CV; microvascular risk reduction is maintained at SBP <130 mmHg. Many joint guidelines advocate treating hypertension in people with diabetes to a blood pressure goal of <130/80 mmHg.62 While RCTs on BP targets directly relating to patients with diabetes are limited, there is an unequivocal call to treat hypertension in diabetes.63 The panel recommends a BP target of <140/90 mmHg for patients with T2D, and a target BP of <130/80 mmHg, but not beyond <120/70 mmHg, in the presence of other organ involvement, such as CKD or CVD.

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APSC Consensus on Optimising CV Outcomes in T2D These recommendations align with western guidelines. The 2012 KDIGO guidelines state that adults with diabetes and non-dialysis-dependent CKD, with urine albumin excretion <30 mg/24 hours with consistent SBP of >140 mmHg or diastolic BP (DBP) of >90 mmHg, be treated with BPlowering drugs to maintain a consistent SBP of ≤140 mmHg and DBP of ≤90 mmHg.64 However, adults with diabetes and non-dialysis-dependent CKD, with urine albumin excretion >30 mg/24 hours with consistent SBP of >130 mmHg or DBP of >80 mmHg, should be treated with BPlowering drugs to maintain a consistent SBP of ≤130 mmHg and DBP of ≤80 mmHg. The ADA Standards of Medical Care in Diabetes – 2019 state that, for patients with diabetes and hypertension at higher CV risk (existing atherosclerotic CVD or 10-year atherosclerotic CVD risk >15%), a BP target of <130/80 mmHg may be appropriate if it can be safely attained.65

Antiplatelet Therapy Statement 13. Antiplatelet therapy should be used for secondary prevention in patients with established CVD. Level of evidence: High. Level of agreement: 100% agree, 0% neutral, 0% disagree. A meta-analysis of secondary prevention trials showed that aspirin leads to a greater absolute reduction in serious vascular events, with a nonsignificant increase in haemorrhagic stroke, but 20% reduction in total stroke and coronary events.66 Consistent with previous recommendations, the panel recommends that antiplatelet therapy be used for secondary prevention in patients with T2D and established CVD.67 However, despite being able to reduce ischaemic risk, the use of more potent antiplatelet therapies and prolonged intensified therapy may also be associated with an increase in bleeding complications, which continues to be a major 1. Guariguata L, Whiting DR, Hambleton I, et al. Global estimates of diabetes prevalence for 2013 and projections for 2035. Diabetes Res Clin Pract 2014;103:137–49. https://doi. org/10.1016/j.diabres.2013.11.002; PMID: 24630390. 2. Einarson TR, Acs A, Ludwig C, Panton UH. Prevalence of cardiovascular disease in type 2 diabetes: a systematic literature review of scientific evidence from across the world in 2007–2017. Cardiovasc Diabetol 2018;17:83. https:// doi.org/10.1186/s12933-018-0728-6; PMID: 29884191. 3. Woodward M, Zhang X, Barzi F, et al. The effects of diabetes on the risks of major cardiovascular diseases and death in the Asia-Pacific region. Diabetes Care 2003;26:360– 6. https://doi.org/10.2337/diacare.26.2.360; PMID: 12547863. 4. Krentz AJ. DiRECT and indirect paths to reducing cardiovascular risk in diabetes: insights from Diabetes UK 2019. Cardiovasc Endocrinol Metab 2019;8:67–8. https://doi. org/10.1097/XCE.0000000000000174; PMID: 31588430. 5. Unwin D, Unwin J. Low carbohydrate diet to achieve weight loss and improve HbA1c in type 2 diabetes and prediabetes: experience from one general practice. Prac Diabetes 2014;31:76–9. https://doi.org/10.1002/pdi.1835. 6. Feinman RD, Pogozelski WK, Astrup A, et al. Dietary carbohydrate restriction as the first approach in diabetes management: critical review and evidence base. Nutrition 2015;31:1–13. https://doi.org/10.1016/j.nut.2014.06.011; PMID: 25287761. 7. Evert AB, Boucher JL, Cypress M, et al. Nutrition therapy recommendations for the management of adults with diabetes. Diabetes Care 2014;37(Suppl 1):S120–43. https:// doi.org/10.2337/dc14-S120; PMID: 24357208. 8. Taoli W, Yang L, Rongzhou Z, et al. Benefit effects of aerobic exercise and resistance training on the management of type 2 diabetes. Int J Clin Exp Med 2018;11:10433–45. 9. Yang Z, Scott CA, Mao C, et al. Resistance exercise versus aerobic exercise for type 2 diabetes: a systematic review and meta-analysis. Sports Med 2013;44:487–99. https://doi. org/10.1007/s40279-013-0128-8; PMID: 24297743. 10. Hordern MD, Dunstan DW, Prins JB, et al. Exercise

11.

12.

13.

14.

15.

16.

17.

18.

concern.68 Therefore, the use of P2Y12 inhibitors in patients with T2D needs to be individualised according to the overall ischaemic and bleeding risks of each patient. Low-dose aspirin might be considered for the primary prevention of ASCVD in select T2D patients with higher ASCVD risk (e.g. those with a >20% 10-year risk of CV events) who are not at increased risk of bleeding.69 However, low-dose aspirin should not be administered on a routine basis for the primary prevention of ASCVD among adults with T2D, especially in light of recent data suggesting an increased risk of bleeding that counterbalances its CV benefit with routine use.70–72 The decision to use aspirin for primary prevention should be done after careful consideration of the individual patient’s thrombotic and bleeding risks.

Limitations and Conclusion

These consensus statements aim to provide a comprehensive guide on the optimisation of CV outcomes among patients with T2D. However, the management of dyslipidaemia and the use of statins and other lipidlowering drugs among patients with prediabetes and T2D were not discussed, as this falls within the scope of separate work by the APSC. Importantly, the 13 statements presented in this paper aim to guide clinicians in providing optimum care to patients with T2D, but should not replace judicious clinical judgement. The optimisation of CV outcomes among patients with T2D should be managed on an individual basis, accounting for an individual’s baseline risk, clinical characteristics and comorbidities, as well as patient concerns and preferences. Clinicians should also be aware of the challenges that may limit the applicability of these consensus statements, such as the availability and affordability of specific drugs, interventions and other technologies, differences in each country’s healthcare resources and currently accepted standards of care, as well as cultural factors.

prescription for patients with type 2 diabetes and prediabetes: a position statement from Exercise and Sport Science Australia. J Sci Med Sport 2012/01 2012;15-:25–31. https://doi.org/10.1016/j.jsams.2011.04.005; PMID: 21621458. American Diabetes Association. 2. Classification and diagnosis of diabetes: standards of medical care in diabetes – 2020. Diabetes Care 2019;43(Suppl 1):S14–31. https://doi. org/10.2337/dc20-s002; PMID: 31862745. Goh SY, Ang SB, Bee YM, et al. Ministry of Health Clinical Practice Guidelines: diabetes mellitus. Singapore Med J 2014;55:334–47. https://doi.org/10.11622/smedj.2014079; PMID: 25017409. Chawla R, Madhu SV, Makkar BM, et al. RSSDI-ESI Clinical practice recommendations for the management of type 2 diabetes mellitus 2020. Indian J Endocrinol Metab 2020;24:1– 122. https://doi.org/10.4103/ijem.IJEM_225_20; PMID: 32699774. Alawadi F, Abusnana S, Afandi B, et al. Emirates Diabetes Society consensus guidelines for the management of type 2 diabetes mellitus – 2020. Dubai Diabetes Endocrinol J 2020;26:1–20. https://doi.org/10.1159/000506508. Balshem H, Helfand M, Schünemann HJ, et al. GRADE guidelines: 3. Rating the quality of evidence. J Clin Epidemiol 2011;64:401–6. https://doi.org/10.1016/j.jclinepi.2010.07.015; PMID: 21208779. Tuomilehto J, Lindström J, Eriksson JG, et al. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med 2001;344:1343–50. https://doi.org/10.1056/ nejm200105033441801; PMID: 11333990. Li G, Zhang P, Wang J, et al. Cardiovascular mortality, allcause mortality, and diabetes incidence after lifestyle intervention for people with impaired glucose tolerance in the Da Qing Diabetes Prevention Study: a 23-year follow-up study. Lancet Diabetes Endocrinol 2014;2:474–80. https://doi. org/10.1016/s2213-8587(14)70057-9; PMID: 24731674. Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention

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or metformin. N Engl J Med 2002;346:393–403. https://doi. org/10.1056/NEJMoa012512; PMID: 11832527. 19. Perreault L, Pan Q, Mather KJ, et al. Effect of regression from prediabetes to normal glucose regulation on long-term reduction in diabetes risk: results from the Diabetes Prevention Program Outcomes Study. Lancet 2012;379:2243–51. https://doi.org/10.1016/S01406736(12)60525-X; PMID: 22683134. 20. Ray KK, Seshasai SRK, Wijesuriya S, et al. Effect of intensive control of glucose on cardiovascular outcomes and death in patients with diabetes mellitus: a meta-analysis of randomised controlled trials. Lancet 2009;373:1765–72. https://doi.org/10.1016/s0140-6736(09)60697-8; PMID: 19465231. 21. Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study Research Group. Intensive diabetes treatment and cardiovascular outcomes in type 1 diabetes: the DCCT/EDIC study 30-year follow-up. Diabetes Care 2016;39:686–93. https://doi. org/10.2337/dc15-1990; PMID: 26861924. 22. Holman RR, Paul SK, Bethel MA, et al. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med 2008;359:1577–89. https://doi.org/10.1056/NEJMoa0806470; PMID: 18784090. 23. International Hypoglycaemia Study Group. Hypoglycaemia, cardiovascular disease, and mortality in diabetes: epidemiology, pathogenesis, and management. Lancet Diabetes Endocrinol 2019;7:385–96. https://doi.org/10.1016/ S2213-8587(18)30315-2; PMID: 30926258. 24. Mellbin LG, Malmberg K, Waldenstrom A, et al. Prognostic implications of hypoglycaemic episodes during hospitalisation for myocardial infarction in patients with type 2 diabetes: a report from the DIGAMI 2 trial. Heart 2009;95:721–7. https://doi.org/10.1136/hrt.2008.152835; PMID: 19029171. 25. Bramlage P, Gitt AK, Binz C, et al. Oral antidiabetic treatment in type-2 diabetes in the elderly: balancing the need for glucose control and the risk of hypoglycemia.

APSC Consensus on Optimising CV Outcomes in T2D Cardiovasc Diabetol 2012;11:122. https://doi.org/10.1186/14752840-11-122; PMID: 23039216. 26. Johnston SS, Conner C, Aagren M, et al. Evidence linking hypoglycemic events to an increased risk of acute cardiovascular events in patients with type 2 diabetes. Diabetes Care 2011;34:1164–70. https://doi.org/10.2337/dc101915; PMID: 21421802. 27. Asian Pacific Society of Cardiology Consensus Statements. Presented at: Advances in Medicine 2020, 26 September 2020. 28. Marso SP, Bain SC, Consoli A, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med 2016;375:1834–44. https://doi.org/10.1056/ nejmoa1607141; PMID: 28249135. 29. Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2016;375:311–22. https://doi.org/10.1056/ NEJMoa1603827; PMID: 27295427. 30. Holman RR, Bethel MA, Mentz RJ, et al. Effects of onceweekly exenatide on cardiovascular outcomes in type 2 diabetes. N Engl J Med 2017;377:1228–39. https://doi. org/10.1056/nejmoa1612917; PMID: 28910237. 31. Husain M, Birkenfeld AL, Donsmark M, et al. Oral semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med 2019;381:841–51. https://doi. org/10.1056/NEJMoa1901118; PMID: 31185157. 32. Gerstein HC, Colhoun HM, Dagenais GR, et al. Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial. Lancet 2019;394:121–30. https://doi.org/10.1016/S01406736(19)31149-3; PMID: 31189511. 33. Bethel MA, Patel RA, Merrill P, et al. Cardiovascular outcomes with glucagon-like peptide-1 receptor agonists in patients with type 2 diabetes: a meta-analysis. Lancet Diabetes Endocrinol 2018;6:105–13. https://doi.org/10.1016/ s2213-8587(17)30412-6; PMID: 29221659. 34. Arnott C, Li Q, Kang A, et al. Sodium-glucose cotransporter 2 inhibition for the prevention of cardiovascular events in patients with type 2 diabetes mellitus: a systematic review and meta-analysis. J Am Heart Assoc 2020;9:e014908. https://doi.org/10.1161/JAHA.119.014908; PMID: 31992158. 35. Cosentino F, Cannon CP, Cherney DZI, et al. Efficacy of ertugliflozin on heart failure-related events in patients with type 2 diabetes mellitus and established atherosclerotic cardiovascular disease: results of the VERTIS CV trial. Circulation 2020;142:2205–15. https://doi.org/10.1161/ CIRCULATIONAHA.120.050255; PMID: 33026243. 36. Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med 2017;377:644–57. https://doi.org/10.1056/ nejmoa1611925; PMID: 28605608. 37. American Diabetes Association. 11. Microvascular Complications and Foot Care: Standards of Medical Care in Diabetes−2020. Diabetes Care 2019;43(Suppl 1):S135–51. https://doi.org/10.2337/dc20-s011; PMID: 31862754. 38. de Boer IH, Caramori ML, Chan JCN, et al. Executive summary of the 2020 KDIGO Diabetes Management in CKD Guideline: evidence-based advances in monitoring and treatment. Kidney Int 2020;98:839–48. https://doi. org/10.1016/j.kint.2020.06.024; PMID: 32653403. 39. Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2019;380:347–57. https://doi.org/10.1056/NEJMoa1812389; PMID: 30415602. 40. Solomon SD, Jhund P, Kosiborod M et al. The Dapagliflozin in Heart Failure with Reduced Ejection Fraction Trial (DAPAHF): outcomes in patients with CKD and effects on renal function. Presented at: American Society of Nephrology Kidney Week, 8 November 2019. 41. Heerspink HJL, Stefánsson BV, Correa-Rotter R, et al. Dapagliflozin in patients with chronic kidney disease. N Engl J Med 2020;383:1436–46. https://doi.org/10.1056/ nejmoa2024816; PMID: 32970396.

42. Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med 2019;380:2295–306. https://doi.org/10.1056/nejmoa1811744; PMID: 30990260. 43. Kadowaki T, Nangaku M, Hantel S, et al. Empagliflozin and kidney outcomes in Asian patients with type 2 diabetes and established cardiovascular disease: Results from the EMPAREG OUTCOME® trial. J Diabetes Invest 2019;10:760–70. https://doi.org/10.1111/jdi.12971; PMID: 30412655. 44. Zelniker TA, Wiviott SD, Raz I, et al. Comparison of the effects of glucagon-like peptide receptor agonists and sodium-glucose cotransporter 2 inhibitors for prevention of major adverse cardiovascular and renal outcomes in type 2 diabetes mellitus. Circulation 2019;139:2022–31. https://doi. org/10.1161/circulationaha.118.038868; PMID: 30786725. 45. Kristensen SL, Rørth R, Jhund PS, et al. Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet Diabetes Endocrinol 2019;7:776–85. https://doi.org/10.1016/ S2213-8587(19)30249-9; PMID: 31422062. 46. Nakamura Y, Hasegawa H, Tsuji M, et al. Diabetes therapies in hemodialysis patients: Dipeptidase-4 inhibitors. World J Diabetes 2015;6:840–9. https://doi.org/10.4239/wjd.v6. i6.840; PMID: 26131325. 47. Abe M, Okada K. DPP-4 inhibitors in diabetic patients with chronic kidney disease and end-stage kidney disease on dialysis in clinical practice. Contrib Nephrol 2015;185:98–115. https://doi.org/10.1159/000380974; PMID: 26023019. 48. Bae JH, Kim S, Park EG, et al. Effects of dipeptidyl peptidase-4 inhibitors on renal outcomes in patients with type 2 diabetes: a systematic review and meta-analysis. Endocrinol Metab (Seoul) 2019;34:80–92. https://doi. org/10.3803/EnM.2019.34.1.80; PMID: 30912341. 49. Chan JCN, Scott R, Arjona Ferreira JC, et al. Safety and efficacy of sitagliptin in patients with type 2 diabetes and chronic renal insufficiency. Diabetes Obes Metab 2008;10:545–55. https://doi. org/10.1111/j.1463-1326.2008.00914.x; PMID: 18518892. 50. Yoon SA, Han BG, Kim SG, et al. Efficacy, safety and albuminuria-reducing effect of gemigliptin in Korean type 2 diabetes patients with moderate to severe renal impairment: A 12-week, double-blind randomized study (the GUARD Study). Diabetes Obes Metab 2017;19:590–8. https://doi.org/10.1111/dom.12863; PMID: 28019072. 51. Mosenzon O, Leibowitz G, Bhatt DL, et al. Effect of saxagliptin on renal outcomes in the SAVOR-TIMI 53 trial. Diabetes Care 2016;40:69–76. https://doi.org/10.2337/dc160621; PMID: 27797925. 52. McMurray JJV, Solomon SD, Inzucchi SE, et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med 2019;381:1995–2008. https://doi.org/10.1056/ NEJMoa1911303; PMID: 31535829. 53. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015;373:2117–28. https://doi.org/10.1056/ nejmoa1504720; PMID: 26378978. 54. Kato ET, Silverman MG, Mosenzon O, et al. Effect of dapagliflozin on heart failure and mortality in type 2 diabetes mellitus. Circulation 2019;139:2528–36. https://doi. org/10.1161/CIRCULATIONAHA.119.040130; PMID: 30882238. 55. Packer M, Anker SD, Butler J, et al. Cardiovascular and renal outcomes with empagliflozin in heart failure. N Engl J Med 2020;383:1413–24. https://doi.org/10.1056/NEJMoa2022190; PMID: 32865377. 56. UK Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ 1998;317:703–13. https://doi.org/10.1136/bmj.317.7160.703; PMID: 9732337. 57. Holman RR, Paul SK, Bethel MA, et al. Long-term follow-up after tight control of blood pressure in type 2 diabetes. N Engl J Med 2008;359:1565–76. https://doi.org/10.1056/

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Inflammation

Anti-inflammatory Treatment and Cardiovascular Outcomes: Results of Clinical Trials Alberto J Lorenzatti DAMIC Medical Institute, Rusculleda Foundation for Research, Cordoba, Argentina

Abstract

Atherosclerosis is a chronic inflammatory disorder of the vasculature where cholesterol accumulates in the arterial wall stimulating infiltration of immune cells. This plays an important role in plaque formation, as well as complications caused by its build up. Pro-inflammatory cytokines and chemokines are implicated throughout the progression of the disease and different therapies that aim to resolve this chronic inflammation, reduce cardiovascular (CV) events and improve clinical outcomes have been tested. The results from the pivotal CANTOS trial show that targeting the pro-inflammatory cytokine IL-1β successfully reduces the incidence of secondary CV events. This review briefly assesses the role of inflammation in atherosclerosis, providing a picture of the multiple players involved in the process and offering a perspective on targeting inflammation to prevent atherosclerotic CV events, as well as focusing on the results of the latest Phase III clinical trials.

Keywords

Inflammation, cardiovascular, C-reactive protein , cytokines, canakinumab, colchicine, methotrexate Disclosure: The author has no conflicts of interest to declare. Received: 23 December 2020 Accepted: 20 February 2021 Citation: European Cardiology Review 2021;16:e15. DOI: https://doi.org/10.15420/ecr.2020.51 Correspondence: Alberto J Lorenzatti, DAMIC Medical Institute, Rusculleda Foundation for Research, Av Colon 2057, X5003DCE, Cordoba, Argentina. E: alorenzatti@damic.com.ar Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

In the early 1990s, the concept that the inflammatory process is causally involved in plaque formation began to be recognised and referred to as ‘the inflammatory hypothesis of atherosclerosis’.1,2 Different investigations found evidence that inflammatory biomarkers are associated with the prognosis and severity of acute coronary syndrome (ACS) and other clinical manifestations of atherosclerosis.3,4 The contributions of Maseri, Libby, Ridker and Crea – among many others – have led to a better understanding of the importance of the inflammatory component in the pathogenesis of this condition.5,6 In fact, the idea that atherosclerosis carries characteristics of an inflammatory disease has been suspected since the 19th century, based on pathological observations made by Rudolf Virchow and others. However, it is only in recent years that chronic inflammation has been recognised as a contributing factor in the development, progression and complications of atherosclerosis, with new evidence supporting the inflammatory nature of the disease.7,8 While the purpose of an inflammatory process is the resolution of injuries, pathogens or infections by initiating an appropriate response, chronic inflammation represents a deviation from this natural biological response. In contrast to acute inflammatory events, which are usually self-limiting, atherosclerosis has been shown to be an unresolved chronic inflammatory condition that lacks the typical resolution phase.9 Greater attention has been focused on the relationship between inflammation and vascular calcification.10 Coronary artery calcification (CAC), which is concomitant with the development of advanced atherosclerosis, shows a close association with the total atherosclerotic

plaque burden and an increased risk of cardiovascular (CV) events and mortality.11 CAC pathologically begins as microcalcifications (0.5–15.0 μm) and grows into larger calcium fragments that are observed to occur concurrently with the progression of plaques. Recent studies suggest that massive dense calcifications are usually associated with stable plaques, whereas, microcalcifications are related to vulnerability.12 Increasing evidence now supports the concept that arterial calcification is an inflammatory disease, an active process associated with macrophage burden, which is stimulated by inflammatory pathways and exacerbated in certain clinical conditions, including diabetes.13,14

Cholesterol and Inflammation

In atherosclerosis, inflammation begins and evolves in response to the accumulation of cholesterol in the intima of large and medium-sized arteries. New discoveries about innate immunity have improved the understanding of the events that initiate and drive inflammation, changing several concepts about the pathogenesis of inflammatory disorders and showing that innate and adaptive immune responses play a key role throughout the initiation, progression and clinical consequences of atherosclerotic disease. In the initial stages, the endothelial cells are activated and inflammatory cells are recruited in the vascular wall in response to the accumulation of cholesterol-rich lipoproteins in the innermost part of the arteries, giving rise to a wide variety of macrophages derived from monocytes, T lymphocytes, mast cells and dendritic cells among others.15–17 The role of T-cell-mediated adaptive immunity in the pathogenesis of atherosclerosis is an increasing focus of study. Activated T lymphocytes, primarily T helper 1 cells (Th1) accumulate early and

Anti-inflammatory Treatment and Cardiovascular Outcomes Figure 1: The Complex Process Involving Multiple Players in the Development and Progression of the Atherosclerotic Lesion Lumen

Progression of the atherosclerotic lesion Activated platelets

Cell adhesion, chemotaxis and cell infiltration T cell

Monocyte

CCL5–CXCL4 CCL20

CXCR7 CXCR3

Release of chemokines

CXCL4–CCL5

CXCR3

CXCR3 CXCL11

Platelet activation

CXCL9

CXCL10 CXCL11

CXCL9

CXCL10

Thrombus formation

LDL

CXCL4, CCL5, CXCL7, CXCL1, CXCL5 Endothelium

OXLDL Plaque destabilisation and rupture proinflammatory cytokines

CXCL10 CXCL11

IL-8

Lipid loading

IL-8 IL-12

Intima

TNF IFN-

CXCR3 TNF IFN-

Oxidative stress and apoptosis

Foam cell

T cell Macrophage

CXCL9 Foam cell formation uptake of OXLDL CXCL10 through scavenger receptors CXCL11 Chronic inflammation

Smooth muscle cell Source: Szentes et al. 2018.20 Reproduced from Frontiers under a Creative Commons (CC BY 4.0) licence.

abundantly in atherosclerotic lesions. The Th1 cells recruited to the lesion recognise oxidised low-density lipoprotein (ox-LDL) as an antigen and produce pro-inflammatory mediators such as interferon-gamma (IFN-γ) and tumour necrosis factor (TNF).18,19 IFN-γ is the main pro-atherogenic cytokine and it promotes local expression of adhesion molecules, cytokines and chemokines such as CXCL9, CXCL10 and CXCL11 and their main receptor CXCR3 by macrophages and endothelial cells. Chemokine signalling via CXCR3 facilitates the recruitment of active Th1 cells (Figure 1).20 The Th1 subset of CD4+ T cells is the most abundant T cell population in human atherosclerotic plaques with CXCR3 being required for the generation of Th1 cells.21. Strong evidence supports that CXCR3 and its ligands play a key role in atherosclerosis. Although this has not yet been fully established, it would seem they have both beneficial and deleterious actions depending upon their timing and level of activation. CXCL10, which is involved in sustaining inflammation through Th1 recruitment, appears to have a role in preventing excessive fibrosis.21 While all of the above can contribute to some extent to the formation and progression of atherosclerosis, macrophage retention within the arterial wall is fundamental in atherosclerosis, with macrophages being the major

inflammatory cells involved in its progression. Structural alterations, in particular the exposure of proteoglycans, facilitate the retention of LDL particles in the intima, where they undergo oxidative modifications promoted by reactive oxygen species (ROS) and inflammatory cells.22,23 As a result, these lipoproteins become more pro-inflammatory and contribute to endothelial activation. Facilitated by adhesion molecules, the different types of leukocytes adhere to the activated endothelium covering the retained lipids and produce pro-inflammatory cytokines. Macrophages derived from monocytes take up the ox-LDL through scavenger receptors, transforming from the permanent accumulation of lipids into cells known as foams that secrete pro-inflammatory molecules and play an important role in collagen and matrix breakdown leading to plaque rupture.24,25 It has been reported that macrophages themselves can proliferate within atherosclerotic lesions. Related to this, both resident and recruited macrophages are thought to be mediated through the action of interleukin 4 (IL-4) which was sufficient to drive the accumulation of macrophages through self-renewal.26 Two different subtypes of macrophages – M1 and M2 – have been described, with M1 being induced (activated) by Th1 and cytokines such as

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Anti-inflammatory Treatment and Cardiovascular Outcomes IFN-γ and involved with pro-inflammatory activities. In contrast, M2 macrophages are stimulated by Th2 and cytokines including IL-4 or IL-13 and produce anti-inflammatory cytokines such as IL-10 and are able to counterbalance inflammatory responses to M1 macrophages by promoting the resolution of inflammation.27 Regulatory T cells that express transforming growth factor-beta (TGF-b) also tend to mitigate inflammation.8 Humoural immunity and B cells also participate in atherosclerosis with B1 lymphocytes appearing to be protective against atherosclerosis, whereas B2 lymphocytes can aggravate this process.28 Scavenger receptors class B type 1 (SR-B1) in endothelial cells have been postulated to mediate LDL delivery into arteries and its accumulation by macrophages, thereby promoting atherosclerosis.29 The ox-LDL exerts its action through several receptors, with the most important being the innate immune scavenger receptor lectin-like ox-LDL receptor 1 (LOX-1).30 An exacerbation of endothelial dysfunction has also been reported due to increased production of vasoconstrictors, an increase in ROS and a decrease in endothelial nitric oxide.31 Ox-LDL plays a key role in atherogenesis through LOX-1.32 This influences multiple cell types such as endothelial cells, smooth muscle cells (SMCs), fibroblasts, macrophages and platelets contributing to endothelial dysfunction, apoptosis, migration and the differentiation of monocytes and macrophages, proliferation and migration of SMCs and plaque instability, some of the mentioned critical factors in atherosclerosis.33 In synthesis, cholesterol and inflammation are interconnected, because the accumulation of cellular cholesterol promotes inflammatory responses. In addition, the activation of immune cells promotes cholesterol deposition by affecting the flow of cellular cholesterol.33 Therefore, atherosclerosis is characterised by quantitative and qualitative abnormalities of lipoproteins and an inadequate inflammatory response.15 The involvement of the inflammatory process is notably evident in acute coronary disease in which unstable plaques prone to rupture are characterised by significant infiltration of different inflammatory cells, a large and friable lipid core and a thin fibrous layer.16,34 Crystalline cholesterol, which is present and abundant in atherosclerotic lesions, has been identified as being the predominant endogenous danger signal that initiates an inflammatory response through the stimulation of the nucleotide-binding oligomerisation domain, NLR family pyrin domain containing 3 (NLRP3) and known as the inflammasome.35–37 As a result of the retention and oxidation of lipoproteins within the vessel wall, the accumulation of cholesterol can lead to the formation of cholesterol crystals, which are then absorbed by macrophages, causing an inflammatory reaction through the activation of the NLRP3 inflammasome and triggering a cascade of amplification of the immune responses.38 Therefore, cholesterol crystals can be an initiating or exacerbating factor in the atherosclerotic process, contributing to the rupture of foam cells and the expansion of the lipid-rich necrotic core in vulnerable plaques.39 In summary, the NLRP3 inflammasome is a fundamental component of the innate immune system which mediates the activation of caspase-1 and the secretion of pro-inflammatory cytokines IL-1β and IL-18 in response to microbial infection and cell damage, as well as being associated with several inflammatory disorders, including but not limited to diabetes and atherosclerosis.40 Imaging technologies, including CT, intravascular ultrasound (IVUS) and MRI, are critical for confirming the presence and extent of atherosclerosis,

with MRI permitting the characterisation of plaque composition, such as lipid core, fibrosis, calcification and intraplaque haemorrhage.41 When MRI is combined with positron emission tomography (PET), some functional and molecular insights are provided into the underlying biological processes. For quantifying vascular inflammation, 18-fludeoxyglucose PET (18-F-FDG PET) has been validated for determining macrophage infiltration to plaques, the relationship with disease activity, response to treatment and it can be predictive of future events.42 In addition, 18 F-fluoride PET (18-F-NaF PET) can identify culprit and ruptured plaques in patients with MI and symptomatic carotid disease. Moreover, histological characterisation has demonstrated that 18 F-fluoride activity localises to regions of plaque rupture with evidence observed of increased inflammation, calcification activity, necrosis and cell death.43 The latter method, capable of detecting microcalcifications can be very useful in patients with early atherosclerosis.44

Inflammation as a Treatment Target

The pharmacological modulation of inflammation aimed at reducing CV events is difficult, since many agents that can modulate the inflammatory response have been shown to be ineffective or have had off-target negative effects. We will now focus more extensively on the results of Phase III clinical trials for different treatment options.

Statins

The idea of addressing inflammation as a way of reducing mortality and morbidity from coronary artery disease (CAD) has received strong support based on the JUPITER study, where treatment with rosuvastatin reduced LDL-C levels by 50% and high-sensitivity C-reactive protein (hs-CRP) by 37% after a median follow-up of 1.9 years. A concurrent and significant reduction in the combined primary endpoint of MI, stroke, arterial revascularisation, hospitalisation for unstable angina or death from CV causes, was verified in favour of rosuvastatin (HR 0.56; 95% CI [0.46– 0.69]; p<0.00001).45 Likewise, it was observed that in those individuals who attained low levels of both LDL-C (<70 mg/dl) and hs-CRP (<1 mg/l), the relative risk reduction for CV events was 79%, (95% CI [0.09–0.52]; p<0.0001).46 Similarly, the IMPROVE-IT study analysed the relationship between the achievement of this dual target – LDL-C and hs-CRP – and the primary endpoint – CV death, major coronary event or stroke – for patients randomly assigned to simvastatin monotherapy or a combination of simvastatin and ezetimibe. In the 15,179 patients studied, simvastatin plus ezetimibe significantly increased the likelihood of achieving the predefined targets of LDL-C <70 mg/dl and hs-CRP <2 mg/l with those who achieved this dual target (39%) had lower primary event rates than those who did not (38.9% versus 28.0%, adjusted HR 0.73; 95% CI [0.660.81]; p<0.001).47 Nevertheless, a fundamental question remains as to whether or not inflammation still plays a role in patients who reach very low LDL-C levels, for example when they are treated with proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, which unlike statins have been shown not to modify hs-CRP values.48 In the FOURIER study, Bohula et al. explored whether the association of inflammation and risk of CV events persists even at very low levels of LDL-C. In patients with an LDL-C <20 mg/dl 1 month after randomisation, there was still a risk gradient under basal hs-CRP of <1, 1–3 and >3 mg/l with an event rate of 9.0%, 10.8% and 13.1%, respectively. This supports the concept of an inflammatory risk that is independent of LDL-C levels.49 Imaging-based studies support an association between statin and calcification progression, which is one of the ways by which statins prevent CV events, although the mechanism responsible for this effect is

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Anti-inflammatory Treatment and Cardiovascular Outcomes not completely understood.10 In a pooled analysis of eight randomised trials of serial IVUS, statins were shown to promote coronary calcium independent of plaque volume regression.50 Related to this, plaques with microcalcification (spotty calcium) found in the active stage of atherosclerosis inflammation have been shown to respond favourably to statin therapy confirming that the ability of statins to affect atheroma burden depends in part on the type of calcification.14 Yet, their modest effect on the absolute burden of atherosclerotic disease suggests that any protective effects on the arterial wall may result, in part, from compositional changes rather than a pure reduction in lesion size or the degree of stenosis. In the REVERSAL study, patients were randomly assigned to receive a moderate lipid-lowering regimen (pravastatin 40 mg) or an intensive one (atorvastatin 80 mg), and the primary efficacy parameter was calculated as the percentage change in atheroma volume assessed by IVUS. A progression of coronary atherosclerosis occurred in the pravastatin group (2.7%; 95% CI [0.2–4.7]; p=0.001) compared with baseline whereas progression in the atorvastatin group did not occur (−0.4%; 95% CI [−2.4– 1.5]; p=0.98). The baseline LDL-C level (mean = 150.2 mg/dl in both treatment groups) was reduced to 110 mg/dl in the pravastatin group and 79 mg/dl in the atorvastatin group (p<0.001). Interestingly, hs-CRP decreased by 5.2% with pravastatin and 36.4% with atorvastatin (p<0.001).51 Similarly, in the SATURN study, a significant lowering of the atherogenic lipoprotein levels (LDL-C), inflammatory status (hs-CRP) and elevations of anti-atherogenic lipoproteins (HDL-C) were associated with overall atheroma regression, mediated largely by a reduction in the fibro-fatty tissue component.52 In addition to reducing LDL-C, statins have also been shown to diminish inflammation independently of cholesterol, but this does not provide the proof of the principle of inflammatory causation in atherosclerosis. Therefore, the only way to corroborate this hypothesis was to attack inflammation without modifying the lipid levels and testing pure antiinflammatory therapies.

Canakinumab: the First Proof of Concept

CRP is an excellent marker of systemic inflammation and it is a useful parameter for evaluating the effectiveness of anti-inflammatory treatments. However, since it does not cause atherothrombosis, it does not qualify as a primary target for therapeutic intervention.53 On the other hand, IL-1β is critically involved in atherosclerosis and induces the production of IL-6 and subsequently CRP. Therefore, the IL-1 signalling pathway is a valuable treatment target.54 This background and several studies have supported the rationale for targeting IL-β specifically without affecting IL-1α, which may be involved in host defense. The CANTOS trial was designed to test whether reducing inflammation by neutralising IL-1β with canakinumab (a fully human monoclonal antibody) in patients with previous MI and elevated plasma hs-CRP levels (≥2 mg/l) would reduce the risk of recurrent CV events beyond standard secondary prevention therapies. This trial compared three doses of canakinumab – 50 mg, 150 mg and 300 mg administered subcutaneously every 3 months – with placebo. A total of 10,061 subjects were included, with a mean age of 61 years and with a median follow-up of 3.7 years. Although no changes in LDL-C were observed, the use of canakinumab resulted in large, dosedependent reductions in CRP and IL-6. The primary endpoint, a combination of non-fatal MI, non-fatal stroke or CV death was reduced by

15% in the 150 mg group (HR 0.85; 95% CI [0.74–0.98]; p=0.021); and by 14% in the 300 mg group, (HR 0.86; 95% CI [0.75–0.99]; p=0.031). However, there was no significant difference in all-cause mortality for all doses of canakinumab versus placebo (HR 0.94, 95% CI [0.83–1.06]; p=0.31). A potentially limiting fact for the use of this drug in coronary heart disease is that canakinumab was associated with a higher incidence of fatal infection which, although small in proportion, was statistically significant.55 It is important to note that the reduction in CV events was stronger in those who were identified as cytokine responders as they achieved lower levels of hs-CRP after initiation of the drug. Patients treated with canakinumab who reached hs-CRP concentrations on treatment of <2 mg/l showed a 25% reduction in major adverse CV events (MACE; p=0.0001) and a 31% decrease in both CV mortality (adjusted HR 0.69, 95% CI [0.56–0.85]; p=0.0004) and all-cause mortality (adjusted HR 0.69, CI [0.58–0.81]; p<0·0001) with the latter being partially explained by concomitant reductions in deaths from lung cancer. However, no significant reduction in these endpoints was observed among those treated with canakinumab who had hs-CRP concentrations of ≥2 mg/l.56 The calculated number needed to treat (NNT) of patients to avoid one MI, stroke, coronary revascularisation or death from any cause in the entire CANTOS cohort was calculated to be 24. However, among patients who reached hsCRP <2 mg/l with canakinumab, the estimated 5-year NNT figure dropped to 16. In contrast, the NNT increased to 57 for patients who reached hsCRP >2 mg/l on treatment.56 Compared with those allocated to placebo, patients treated with canakinumab who reached lower levels of IL-6 after the first dose (below the study median value of 1.65 ng/l), experienced a 32% reduction in MACE, (adjusted HR 0.68, 95% CI [0.56–0.82]; p<0.0001), a 52% reduction in CV mortality (adjusted HR 0.48, 95% CI [0.34–0.68]; p<0.0001) and a 48% reduction in all-cause mortality (adjusted HR 0.52, 95% CI [0.40– 0.68]; p<0.0001) thereby providing evidence that modulation of the IL-6 signalling pathway is associated with reduced CV event rates, independent of lipid lowering.57 Interestingly, canakinumab was shown to reduce MACE in chronic kidney disease (CKD) patients and was particularly effective in those who achieved a level of hsCRP <2 mg/l after the first dose with CV and all-cause mortality being reduced.58 Finally, subclinical inflammation-mediated in part by IL-1β participates in peripheral insulin resistance and impaired pancreatic insulin secretion. Although IL-1β inhibition with canakinumab had similar effects on major CV events in patients with or without diabetes in the CANTOS study, treatment over a median period of 3.7 years did not reduce incident diabetes.59

Methotrexate

The commonly used methotrexate (MTX) has shown favourable results in attenuating systemic inflammation and decreasing CV events.60–62 At low doses, it is also an effective, safe and well-tolerated anti-inflammatory agent used in patients with rheumatoid arthritis or psoriasis.63 The CIRT trial was designed to evaluate the results of low dose MTX (LD-MTX) on CV events in patients with chronic atherosclerosis and with diabetes or metabolic syndrome.64 It included 4,786 participants, most of whom had previous coronary revascularisation and were treated with standard preventive therapy prior to randomisation. These patients had a mean basal LDL-C of 68 mg/dl and a mean basal hs-CRP of 1.6 mg/l. However, the study was stopped early due to a lack of benefit of LD-MTX in preventing MACE in patients with

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Anti-inflammatory Treatment and Cardiovascular Outcomes Table 1: Selected Clinical Trials Targeting Inflammatory Modulation in Atherosclerotic Cardiovascular Disease Target/Pathway

Agent

Study

Results

Patient Group

Oxidised LDL

Succinobucol

ARISE79

6,144

No effect

Post ACS

sPLA2

Varespladib

VISTA-16

5,145

No effect

Post ACS

LpPLA2

Darapladib

STABILITY81

15,828

No effect

Stable CAD

LpPLA2

Darapladib

SOLID-TIMI 52

13,026

No effect

Post ACS

P-selectin

Inclacumab

SELECT-ACS

544

No effect

ACS/PCI

IL-1 receptor

Anakinra

VCU-ART284

No effect

ACS

P38 MAP kinase

Losmapimod

LATITUDE-TIMI 60

3,503

No effect

ACS

Neutrophil chemotaxis/NLRP3 inflammasome

Colchicine

LoDoCo71

532

Positive

Stable CAD

IL-1β

Canakinumab

CANTOS57

10,061

Positive

Stable CAD

Tumour necrosis factor/IL-6

Etanercept versus tocilizumab

ENTRACTE

3,080

No differences

Rheumatoid arthritis

Neutrophil chemotaxis/NLRP3 inflammasome

Colchicine

COLCOT72

4,500

Positive

Post ACS

IL-6, TNF

Methotrexate

CIRT

4,786

No effect

CAD + diabetes/MS

Neutrophil chemotaxis/NLRP3 inflammasome

Colchicine

LoDoCo269

5,522

Positive

Stable CAD

ACS = acute coronary syndrome; CAD = coronary artery disease; IL = interleukin; LDL = low-density lipoprotein; LpPLA2 = lipoprotein-associated phospholipase A2; MAPK = mitogen-activated protein kinase; MS = metabolic syndrome; NLRP3 = nucleotide-binding oligomerisation domain, leucine-rich repeat and pyrin domain containing protein 3; PCI = percutaneous coronary intervention; sPLA2 = secretory phospholipase A2 TNF = tumour necrosis factor.

CAD and either type 2 diabetes or metabolic syndrome. Thus, no benefit was observed in CV results with the use of LD-MTX (HR 0.96, 95% CI [0.79–1.16]; p=0.67) and no difference in all-cause mortality was observed between the groups. It is important to note that, in contrast to canakinumab, LD-MTX did not reduce IL-6, CRP or IL-1β levels and there was no reduction in CV events compared with placebo.64 The study populations in CANTOS and CIRT were similar but with a key difference. In the CANTOS trial all participants had a basal CRP ≥2 mg/l, they qualified as a population with high inflammatory risk (with a median basal hs-CRP of 4.2 mg/l), while in CIRT the median basal hs-CRP level was 1.6 mg/l. Another crucial difference was the inflammatory pathway affected by the pharmacological intervention. Canakinumab used in the CANTOS trial specifically inhibits IL-1β, resulting in a significant reduction in CRP, IL-6 and IL-1β levels. In contrast, LD-MTX used in CIRT had no effect on these biomarkers or inflammatory mediators, which may explain the lack of clinical benefit in these stable populations with atherosclerotic CAD.65

Colchicine

Colchicine, a broad-spectrum anti-inflammatory agent previously used to treat inflammatory disorders such as gout and recurrent pericarditis, is also a treatment option for atherosclerosis. Colchicine is a widely available, inexpensive and generally well-tolerated medication. Among several anti-inflammatory mechanisms, colchicine appears to block cholesterol crystal-induced activation of the NLRP3 inflammasome, which decreases the secretion of the pro-inflammatory cytokines IL-1β and IL-18 leading to downstream reductions in interleukin-6 and CRP, thus providing a reason to test this classical drug in patients with CAD.66–68 Colchicine also reduces the mobility and deformability of neutrophils and decreases their adhesion to endothelial cells and atherosclerotic lesions, features that can improve plaque morphology.69,70 The LoDoCo trial tested colchicine in a cohort of 532 patients with stable coronary disease receiving aspirin and/or clopidogrel and statins. The treatment with 0.5 mg/day of colchicine significantly reduced the

prevalence of CV events (4.5%) compared to placebo (16.0%), although a small percentage of patients showed intestinal intolerance toward colchicine.71 Similarly, in the COLCOT study, treatment with colchicine of 0.5 mg per day compared to placebo over a two-year period in 4,745 patients after MI, resulted in a 23% relative reduction in the primary endpoint of the study, including MI, stroke, resuscitated cardiac arrest, hospitalisation for angina leading to urgent revascularisation and CV death (HR 0.77; 95% CI [0.61–0.96]; p=0.02). Despite the benefit obtained from colchicine being significant only for the components of coronary revascularisation and the endpoint stroke, all CV outcomes were positively affected. However, it should be noted that colchicine has been associated with increased cases of pneumonia and gastrointestinal disturbances.72 Finally, evidence from the recent LoDoCo2 trial has shown that the antiinflammatory effects of colchicine reduce the risk of CV events in patients with chronic coronary disease. The study, randomised 5,522 patients with chronic stable coronary disease and compared a daily dosage of 0.5 mg colchicine against placebo. After an average follow-up of 2.4 years, the primary endpoint (CV death, non-fatal MI, non-fatal stroke and coronary revascularisation) decreased by 31% (HR 0.69; 95% CI [0.57–0.83]; p<0.001) in those treated with colchicine.73 A recent meta-analysis examined four randomised clinical trials, including 11,594 patients (colchicine n=5,774; placebo/no colchicine n=5,820) in two studies in stable CAD – LoDoCo and LoDoCo2 – and two in ACS – COLCOT and the Australian COPS Randomized Clinical Trial.74 Compared with placebo or no drug, colchicine was associated with a statistically significant reduction in the incidence of the primary composite endpoint (pooled HR 0.68; 95% CI [0.54-0.81]; I2 = 37.7%).75 Convincing evidence now supports the use of colchicine for secondary prevention in patients with recent MI or chronic CAD that has continued at residual CV risk despite good blood pressure control and an adequate reduction of atherogenic lipid.76 The features of this drug may contribute

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Anti-inflammatory Treatment and Cardiovascular Outcomes in different ways to its atheroprotective effects but many of these still need to be elucidated.77 In addition, further randomised and controlled studies will be needed to determine the long-term tolerability and efficacy of low-dose colchicine for secondary prevention in patients with CAD before its widespread use can be recommended.78 Indeed, two relevant randomised clinical trials are still running: CLEAR SYNERGY (NCT03048825) in ACS patients and CONVINCE (NCT02898610) for secondary prevention after stroke, that is expected to have the results shortly. Multiple pathways have been identified as potential objectives for the prevention and treatment of CV diseases. In Table 1, several trials of agents that modulate a specific pathway are summarised including some that have been extensively analysed. Most clinical trials targeting specific downstream targets, such as those with oxidation of LDL, secretory phospholipase A2 (sPLA2) and lipoprotein associated phospholipase A2 (LpPLA2), P-selectin, the IL-1b inhibitor anakinra, losmapimod to inhibit p38 MAP kinase and methotrexate failed to meet their primary endpoints with respect to a decrease in CV events or a selected surrogate endpoint.64,79–85 Nevertheless, a spectrum of possibilities has now opened up for exploring new anti-inflammatory therapies to target inflammation in the prevention of atherosclerosis, although it is clear that more research is still needed on the role of anti-inflammatory and immunomodulatory 1. Ross R. Atherosclerosis – an inflammatory disease. N Engl J Med 1999;340:115–26. https://doi.org/10.1056/ nejm199901143400207; PMID: 9887164. 2. Liuzzo G, Biasucci LM, Gallimore JR, et al. The prognostic value of C-reactive protein and serum amyloid a protein in severe unstable angina. N Engl J Med 1994;331:417–24. https://doi.org/10.1056/nejm199408183310701; PMID: 7880233. 3. Libby P. Molecular bases of the acute coronary syndromes. Circulation 1995;91:2844–50. https://doi.org/10.1161/01. cir.91.11.2844; PMID: 7758192. 4. Maseri A, Crea F. The elusive cause of instability in unstable angina. Am J Cardiol 1991;68:16b–21b. https://doi. org/10.1016/0002-9149(91)90380-4; PMID: 1892062. 5. Ridker PM. Inflammation, atherosclerosis, and cardiovascular risk: an epidemiologic view. Blood Coagul Fibrinolysis 1999;10:S9–12. PMID: 10070810. 6. Crea F, Biasucci LM, Buffon A, et al. Role of inflammation in the pathogenesis of unstable coronary artery disease. Am J Cardiol 1997;80:10e–6. https://doi.org/10.1016/s00029149(97)00483-9; PMID: 9296463. 7. Ruparelia N, Chai JT, Fisher EA, Choudhury RP. Inflammatory processes in cardiovascular disease: a route to targeted therapies. Nat Rev Cardiol 2017;14:133–44. https://doi. org/10.1038/nrcardio.2016.185; PMID: 27905474. 8. Libby P. Inflammation in atherosclerosis – no longer a theory. Clin Chem 2021;67:131–42. https://doi.org/10.1093/ clinchem/hvaa275; PMID: 33393629. 9. Viola J, Soehnlein O. Atherosclerosis – a matter of unresolved inflammation. Semin Immunol 2015;27:184–93. https://doi.org/10.1016/j.smim.2015.03.013; PMID: 25865626. 10. Sakamoto A, Virmani R, Finn AV. Coronary artery calcification: recent developments in our understanding of its pathologic and clinical significance. Curr Opin Cardiol 2018;33:645–52. https://doi.org/10.1097/ hco.0000000000000558; PMID: 30307412. 11. Panh L, Lairez O, Ruidavets JB, et al. Coronary artery calcification: from crystal to plaque rupture. Arch Cardiovasc Dis 2017;110:550–61. https://doi.org/10.1016/j. acvd.2017.04.003; PMID: 28735837. 12. Nakahara T, Dweck MR, Narula N, et al. Coronary artery calcification: from mechanism to molecular imaging. JACC Cardiovasc Imaging 2017;10:582–93. https://doi.org/10.1016/j. jcmg.2017.03.005; PMID: 28473100. 13. Aikawa E, Nahrendorf M, Figueiredo JL, et al. Osteogenesis associates with inflammation in early-stage atherosclerosis evaluated by molecular imaging in vivo. Circulation 2007;116:2841–50. https://doi.org/10.1161/ circulationaha.107.732867; PMID: 18040026. 14. Andrews J, Psaltis PJ, Bartolo BAD, et al. Coronary arterial calcification: a review of mechanisms, promoters and imaging. Trends Cardiovasc Med 2018;28:491–501. https://doi. org/10.1016/j.tcm.2018.04.007; PMID: 29753636. 15. Ross R. The pathogenesis of atherosclerosis: a perspective

interventions in atherosclerotic CV disease to achieve a better understanding of the complex players involved in the inflammatory process.86 Finally, the development of new potentially more promising drug compounds is highly desirable.

Conclusion

Inflammation plays a key role in all steps of the atherosclerotic process, from the initial stage, when leukocytes are recruited at the sites of subendothelial cholesterol accumulation to the late events of plaque rupture and thrombosis. Chronic inflammation of the arterial wall is promoted by the innate and adaptive immune responses and is sustained by the complex mechanism involving pro-inflammatory cytokines. In the CANTOS study, designed specifically to demonstrate whether purely decreasing inflammation correlated with reducing clinical events, the expected proof of concept, the quarterly administration of the anti-IL1β monoclonal antibody canakinumab showed clear benefits. Most recently this concept was endorsed by the use of colchicine in COLCOT and LoDoCo2 studies, but further confirmation and careful evaluation of the balance between benefits and adverse events is still needed before international guidelines can endorse the use of colchicine for the secondary prevention of CV diseases.

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Anti-inflammatory Treatment and Cardiovascular Outcomes 43. Joshi NV, Vesey AT, Williams MC, et al. 18F-fluoride positron emission tomography for identification of ruptured and highrisk coronary atherosclerotic plaques: a prospective clinical trial. Lancet 2014;383:705–13. https://doi.org/10.1016/s01406736(13)61754-7; PMID: 24224999. 44. Hop H, de Boer SA, Reijrink M, et al. 18 F-sodium fluoride positron emission tomography assessed microcalcifications in culprit and non-culprit human carotid plaques. J Nucl Cardiol 2019;26:1064–75. https://doi.org/10.1007/s12350-0181325-5; PMID: 29943142. 45. Ridker PM, Danielson E, Fonseca FA, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 2008;359:2195–207. https:// doi.org/10.1056/NEJMoa0807646; PMID: 18997196. 46. Ridker PM, Danielson E, Fonseca FA, et al. Reduction in C-reactive protein and LDL cholesterol and cardiovascular event rates after initiation of rosuvastatin: a prospective study of the JUPITER trial. Lancet 2009;373:1175–82. https:// doi.org/10.1016/s0140-6736(09)60447-5; PMID: 19329177. 47. Bohula EA, Giugliano RP, Cannon CP, et al. Achievement of dual low-density lipoprotein cholesterol and high-sensitivity C-reactive protein targets more frequent with the addition of ezetimibe to simvastatin and associated with better outcomes in IMPROVE-IT. Circulation 2015;132:1224–33. https://doi.org/10.1161/circulationaha.115.018381; PMID: 26330412. 48. Ruscica M, Ferri N, Corsini A, Sirtori CR. PCSK9 antagonists and inflammation. Atherosclerosis 2018;268:235–6. https:// doi.org/10.1016/j.atherosclerosis.2017.10.022; PMID: 29102656. 49. Bohula EA, Giugliano RP, Leiter LA, et al. Inflammatory and cholesterol risk in the FOURIER trial. Circulation 2018;138:131–40. https://doi.org/10.1161/ circulationaha.118.034032; PMID: 29530884. 50. Puri R, Nicholls SJ, Shao M, et al. Impact of statins on serial coronary calcification during atheroma progression and regression. J Am Coll Cardiol 2015;65:1273–82. https://doi. org/10.1016/j.jacc.2015.01.036; PMID: 25835438. 51. Nissen SE, Tuzcu EM, Schoenhagen P, et al. Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: a randomized controlled trial. JAMA 2004;291:1071–80. https://doi. org/10.1001/jama.291.9.1071; PMID: 14996776. 52. Puri R, Libby P, Nissen SE, et al. Long-term effects of maximally intensive statin therapy on changes in coronary atheroma composition: insights from SATURN. Eur Heart J Cardiovasc Imaging 2014;15:380–8. https://doi.org/10.1093/ ehjci/jet251; PMID: 24448227. 53. Zacho J, Tybjaerg-Hansen A, Jensen JS, et al. Genetically elevated C-reactive protein and ischemic vascular disease. N Engl J Med 2008;359:1897–908. https://doi.org/10.1056/ NEJMoa0707402; PMID: 18971492. 54. Abbate A, Toldo S, Marchetti C, et al. Interleukin-1 and the inflammasome as therapeutic targets in cardiovascular disease. Circ Res 2020;126:1260–80. https://doi.org/10.1161/ circresaha.120.315937; PMID: 32324502. 55. Ridker PM, Everett BM, Thuren T, et al. Anti-inflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med 2017;377:1119–31. https://doi.org/10.1056/ NEJMoa1707914; PMID: 28845751. 56. Ridker PM, MacFadyen JG, Everett BM, et al. Relationship of C-reactive protein reduction to cardiovascular event reduction following treatment with canakinumab: a secondary analysis from the CANTOS randomised controlled trial. Lancet 2018;391:319–28. https://doi.org/10.1016/s01406736(17)32814-3; PMID: 29146124. 57. Ridker PM, Libby P, MacFadyen JG, et al. Modulation of the interleukin-6 signalling pathway and incidence rates of atherosclerotic events and all-cause mortality: analyses from the Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS). Eur Heart J 2018;39:3499–507.

https://doi.org/10.1093/eurheartj/ehy310; PMID: 30165610. 58. Ridker PM, MacFadyen JG, Glynn RJ, et al. Inhibition of interleukin-1β by canakinumab and cardiovascular outcomes in patients with chronic kidney disease. J Am Coll Cardiol 2018;71:2405–14. https://doi.org/10.1016/j.jacc.2018.03.490; PMID: 29793629. 59. Everett BM, Donath MY, Pradhan AD, et al. Anti-inflammatory therapy with canakinumab for the prevention and management of diabetes. J Am Coll Cardiol 2018;71:2392– 401. https://doi.org/10.1016/j.jacc.2018.03.002; PMID: 29544870. 60. Westlake SL, Colebatch AN, Baird J, et al. The effect of methotrexate on cardiovascular disease in patients with rheumatoid arthritis: a systematic literature review. Rheumatology (Oxford) 2010;49:295–307. https://doi. org/10.1093/rheumatology/kep366; PMID: 19946022. 61. Xie F, Chen L, Yun H, et al. Benefits of methotrexate use on cardiovascular disease risk among rheumatoid arthritis patients initiating biologic disease-modifying antirheumatic drugs. J Rheumatol 2020. https://doi.org/10.3899/ jrheum.191326; PMID: 33060309; epub ahead of press. 62. De Vecchis R, Baldi C, Palmisani L. Protective effects of methotrexate against ischemic cardiovascular disorders in patients treated for rheumatoid arthritis or psoriasis: novel therapeutic insights coming from a meta-analysis of the literature data. Anatol J Cardiol 2016;16:2–9. https://doi. org/10.5152/akd.2015.6136; PMID: 26467356. 63. Cronstein BN. Low-dose methotrexate: a mainstay in the treatment of rheumatoid arthritis. Pharmacol Rev 2005;57:163–72. https://doi.org/10.1124/pr.57.2.3; PMID: 15914465. 64. Ridker PM, Everett BM, Pradhan A, et al. Low-dose methotrexate for the prevention of atherosclerotic events. N Engl J Med 2019;380:752–62. https://doi.org/10.1056/ NEJMoa1809798; PMID: 30415610. 65. Lorenzatti AJ, Servato ML. New evidence on the role of inflammation in CVD risk. Curr Opin Cardiol 2019;34:418–23. https://doi.org/10.1097/hco.0000000000000625; PMID: 31033505. 66. Vaidya K, Martínez G, Patel S. The role of colchicine in acute coronary syndromes. Clin Ther 2019;41:11–20. https://doi. org/10.1016/j.clinthera.2018.07.023; PMID: 30185392. 67. Martínez GJ, Celermajer DS, Patel S. The NLRP3 inflammasome and the emerging role of colchicine to inhibit atherosclerosis-associated inflammation. Atherosclerosis 2018;269:262–71. https://doi.org/10.1016/j. atherosclerosis.2017.12.027; PMID: 29352570. 68. Martínez GJ, Robertson S, Barraclough J, et al. Colchicine acutely suppresses local cardiac production of inflammatory cytokines in patients with an acute coronary syndrome. J Am Heart Assoc 2015;4:e002128. https://doi.org/10.1161/ jaha.115.002128; PMID: 26304941. 69. Opstal TSJ, Hoogeveen RM, Fiolet ATL, et al. Colchicine attenuates inflammation beyond the inflammasome in chronic coronary artery disease: a LoDoCo2 proteomic substudy. Circulation 2020;142:1996–8. https://doi.org/10.1161/ circulationaha.120.050560; PMID: 32864998. 70. Vaidya K, Arnott C, Martínez GJ, et al. Colchicine therapy and plaque stabilization in patients with acute coronary syndrome: a CT coronary angiography study. JACC Cardiovasc Imaging 2018;11:305–16. https://doi.org/10.1016/j. jcmg.2017.08.013; PMID: 29055633. 71. Nidorf SM, Eikelboom JW, Budgeon CA, Thompson PL. Lowdose colchicine for secondary prevention of cardiovascular disease. J Am Coll Cardiol 2013;61:404–10. https://doi. org/10.1016/j.jacc.2012.10.027; PMID: 23265346. 72. Tardif JC, Kouz S, Waters DD, et al. Efficacy and safety of low-dose colchicine after myocardial infarction. N Engl J Med 2019;381:2497–505. https://doi.org/10.1056/NEJMoa1912388; PMID: 31733140. 73. Nidorf SM, Fiolet ATL, Mosterd A, et al. Colchicine in

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patients with chronic coronary disease. N Engl J Med 2020;383:1838–47. https://doi.org/10.1056/NEJMoa2021372; PMID: 32865380. 74. Tong DC, Quinn S, Nasis A, et al. Colchicine in patients with acute coronary syndrome: the Australian COPS randomized clinical trial. Circulation 2020;142:1890–900. https://doi. org/10.1161/circulationaha.120.050771; PMID: 32862667. 75. Samuel M, Tardif JC, Bouabdallaoui N, et al. Colchicine for secondary prevention of cardiovascular disease: a systematic review and meta-analysis of randomized controlled trials. Can J Cardiol 2020. https://doi.org/10.1016/j. cjca.2020.10.006; PMID: 33075455; epub ahead of press. 76. Fiolet ATL, Nidorf SM, Cornel JH. Colchicine for secondary prevention in coronary disease. Eur Heart J 2021;42:1060–6. https://doi.org/10.1093/eurheartj/ehaa974; PMID: 33346343. 77. Fiolet ATL, Thompson PL, Mosterd A. Colchicine in coronary disease: another renaissance of an ancient drug. Cardiovasc Res 2020;117:e4–6. https://doi.org/10.1093/cvr/cvaa342; PMID: 33426561. 78. Nidorf SM, Thompson PL. Why colchicine should be considered for secondary prevention of atherosclerosis: an overview. Clin Ther 2019;41:41–8. https://doi.org/10.1016/j. clinthera.2018.11.016; PMID: 30591286. 79. Tardif JC, McMurray JJ, Klug E, et al. Effects of succinobucol (AGI-1067) after an acute coronary syndrome: a randomised, double-blind, placebo-controlled trial. Lancet 2008;371:1761– 8. https://doi.org/10.1016/s0140-6736(08)60763-1; PMID: 18502300. 80. Nicholls SJ, Kastelein JJ, Schwartz GG, et al. Varespladib and cardiovascular events in patients with an acute coronary syndrome: the VISTA-16 randomized clinical trial. JAMA 2014;311:252–62. https://doi.org/10.1001/ jama.2013.282836; PMID: 24247616. 81. White HD, Held C, Stewart R, et al. Darapladib for preventing ischemic events in stable coronary heart disease. N Engl J Med 2014;370:1702–11. https://doi. org/10.1056/NEJMoa1315878; PMID: 24678955. 82. O’Donoghue ML, Braunwald E, White HD, et al. Effect of darapladib on major coronary events after an acute coronary syndrome: the SOLID-TIMI 52 randomized clinical trial. JAMA 2014;312:1006–15. https://doi.org/10.1001/ jama.2014.11061; PMID: 25173516. 83. Tardif JC, Tanguay JF, Wright SR, et al. Effects of the P-selectin antagonist inclacumab on myocardial damage after percutaneous coronary intervention for non-STsegment elevation myocardial infarction: results of the SELECT-ACS trial. J Am Coll Cardiol 2013;61:2048–55. https:// doi.org/10.1016/j.jacc.2013.03.003; PMID: 23500230. 84. Abbate A, Van Tassell BW, Biondi-Zoccai G, et al. Effects of interleukin-1 blockade with anakinra on adverse cardiac remodeling and heart failure after acute myocardial infarction [from the Virginia Commonwealth UniversityAnakinra Remodeling Trial (2) (VCU-ART2) pilot study]. Am J Cardiol 2013;111:1394–400. https://doi.org/10.1016/j. amjcard.2013.01.287; PMID: 23453459. 85. O’Donoghue ML, Glaser R, Cavender MA, et al. Effect of losmapimod on cardiovascular outcomes in patients hospitalized with acute myocardial infarction: a randomized clinical trial. JAMA 2016;315:1591–9. https://doi.org/10.1001/ jama.2016.3609; PMID: 27043082. 86. Ridker PM. From CANTOS to CIRT to COLCOT to clinic: will all atherosclerosis patients soon be treated with combination lipid-lowering and inflammation-inhibiting agents? Circulation 2020;141:787–9. https://doi.org/10.1161/ CIRCULATIONAHA.119.045256; PMID: 32150469. 87. Giles JT, Sattar N, Gabriel S, et al. Cardiovascular safety of tocilizumab versus etanercept in rheumatoid arthritis: a randomized controlled trial. Arthritis Rheumatol 2019;72:31– 40. https://doi.org/10.1002/art.41095; PMID: 31469238.

Dyslipidaemia

Management of Dyslipidaemia in Real-world Clinical Practice: Rationale and Design of the VIPFARMA ISCP Project Ricardo Lopez Santi ,1 Felipe Martinez,2 Adrian Baranchuk ,3 Alvaro Sosa Liprandi,4 Daniel Piskorz,5 Alberto Lorenzatti,6 Maria Pilar Lopez Santi1 and Juan Carlos Kaski;7 on behalf of the VIPFARMA ISCP Investigators 1. Division of Cardiology, Hospital Italiano de La Argentina, La Plata, Buenos Aires, Argentina; 2. Instituto Médico DAMIC-Fundacion Rusculleda, Cordoba, Argentina; 3. Department of Medicine, Queen’s University, Kingston, Ontario, Canada; 4. Division of Cardiology, Sanatorio Guemes, Buenos Aires, Argentina; 5. Cardiovascular Institute of the Rosario British Sanatorium, Santa Fe, Argentina; 6. DAMIC-Rusculleda Foundation, National University of Córdoba, Cordoba, Argentina; 7. Molecular and Clinical Sciences Research Institute, St George’s, University of London, London, UK

Abstract

Dyslipidaemia plays a major role in the pathogenesis of atherosclerosis. Every year, scientific institutions publish cardiovascular prevention guidelines with updated goals and recommendations based on new evidence. However, medical barriers exist that make achieving these goals difficult and gaps between guidelines and best daily clinical practice still persist. The International Society of Cardiovascular Pharmacotherapy designed the Surveillance of Prescription Drugs in the Real World Project (VIPFARMA ISCP), a survey for physicians who manage lipid disorders in high-risk patients. Seven clusters of questions will be analysed comprising demographics, institution profile, access to continuing medical education, clinical practice profile, attitude regarding use of statins, knowledge regarding proprotein convertase subtilisin/kexin type 9 inhibitors and attitudes regarding medical decisions about triglycerides. The present study will be the first part of a larger programme and aims to shed light on barriers between lipid-lowering drug therapy recommendations in the 2019 European Society of Cardiology guidelines and clinical practice in different countries.

Keywords

Clinical practice, drug treatment, dyslipidaemia, guidelines, PCSK9 inhibitors, triglycerides, statins Disclosure: The authors have no conflicts of interest to declare. Acknowledgement: The authors acknowledge the Argentinean Biochemical Foundation’s Procordis Program for its support and collaboration. Received: 23 October 2020 Accepted: 15 December 2020 Citation: European Cardiology Review 2021;16:e16. DOI: https://doi.org/10.15420/ecr.2020.42 Correspondence: Ricardo Lopez Santi, Calle 42 no 639, La Plata (ZIP 1900), Buenos Aires B1900, Argentina. E: lopezsan@live.com.ar Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Dyslipidaemia plays a major role in the pathogenesis of atherosclerosis and has become a permanently evolving area of clinical interest. Scientific societies periodically publish international guidelines for use as recommendations for daily practice in different regions of the world.1 Dyslipidaemia is a constantly changing field as a consequence of advances in understanding of the pathophysiological mechanisms of the relationship between lipid metabolism and atherogenesis, along with the development of new, potent, lipid-lowering therapies.2,3 Thus, concepts such as atherogenic dyslipidaemia or residual risk have become common subjects of analysis in the recent medical literature.4 Beyond LDL cholesterol, suboptimal levels of other atherogenic lipids and lipoproteins – including triglycerides, HDL cholesterol, non-HDL cholesterol (total cholesterol minus HDL cholesterol) and apolipoprotein B – also play a role.5

Statin Therapy: The Gap Between Guidelines and Real-world Clinical Practice

Statins, ezetimibe, the birth of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors and the rebirth of fibrates and omega 3 fatty acid therapies, have contributed to debate about the gap between theoretical

guidelines and clinical practice in the real world. The recently published EUROASPIRE V survey showed that a large majority of patients in primary care at high cardiovascular risk failed to achieve the lifestyle, blood pressure, lipid and glycaemic targets defined in the 2016 joint European societies’ guidelines, illustrating the wide gap that still exists.6 Despite the powerful concept of high cardiovascular risk in terms of mortality and events and the importance of achieving lipid goals, gaps in dyslipidaemia care have been reported among patients with established cardiovascular disease (CVD).7,8 Okerson et al. conducted a retrospective cohort study in 90,287 patients in the US with a diagnosis of clinical atherosclerotic CVD (ASCVD).9 The aim of the study was to evaluate the impact on clinical practice of the 2013 American College of Cardiology (ACC)/American Heart Association (AHA) guidelines.9 Their main finding was that statin use remained the same before and after the publication of the guidelines. There were no changes in mean LDL cholesterol levels. In patients who had received highintensity statins, statin use increased by 4% 1 year after the guidelines (p<0.001). In addition to these poor preliminary data, there was also criticism towards the guidelines as they changed the main concept: LDL

Dyslipidaemia in the Real World Figure 1: The VIPFARMA ISCP Project Guidelines

Clinical practice

Barriers to implementation: • Patient-related reasons • Medication-related reasons • Medical-related reasons VIPFARMA project: • 1,000 surveys • Population: cardiologists, clinicians and others • Seven clusters of questions • Demographics • Institution and city profile • Access to continuing medical education • Clinical practice profile • Attitudes regarding statins • Knowledge regarding PCSK9 inhibitors • Attitudes regarding triglycerides Main barriers to the translation of guideline recommendations into clinical practice and the seven clusters of questions in the survey. PCSK9 = proprotein convertase subtilisin/kexin type 9.

targeting to treatment based on the level of risk, and of the fact that the score proposed by the AHA/ACC overestimated the risk in regions outside the US.10 However, many years later, we have recognized the main contribution of guidelines. Statins are recommended by the UK’s National Institute for Health and Care Excellence (NICE) as first-line lipid-modifying therapy for the reduction of cardiovascular event risk in patients with ASCVD, as well as diabetes, familial hypercholesterolaemia, chronic kidney disease and other high-risk primary-prevention populations.11 Taking into consideration the availability of generic atorvastatin, the NICE guidelines recommended atorvastatin 80 mg for patients with ASCVD and atorvastatin ≥20 mg for those with most other high-risk conditions. However, in a cohort study that included 91,479 patients with ASCVD, 21% did not receive any statin and only 31% received a high-intensity statin.12 Up to 94% of patients with ASCVD and 85% of high-risk non-ASCVD individuals – representing approximately 3 million individuals in each group in the UK – would require statin up-titration or initiation to achieve full concordance with updated guidelines. The REPAR study was a multicentre, prospective observational study in Spain including 1,103 patients with stable coronary heart disease.13 Only 26% of patients had LDL cholesterol <1.8 mmol/l, while 55% received low- or moderate-intensity statin therapy. When patients had LDL cholesterol values >1.8 mmol/l the attitude of physicians was passive. Over 70% made no changes, 26% increased treatment and 3% decreased it. The authors identified differences according to age of physicians – with a more proactive attitude in older doctors – and by region, unrelated to patient profile. Problems in achieving lipid goals and applying guideline recommendations are not restricted to European and North American countries. The PURE study reported a low proportion of patients with coronary artery disease or antecedent of stroke treated with statins in South America (18% and 9.8%, respectively) and in South Asia (4.8% and 0.6%, respectively).14,15 The cross-sectional observational ICLPS was conducted in 452 centres

in 18 countries in Eastern Europe, Asia, Africa, the Middle East and Latin America, recruiting more than 9,000 patients.16 Patients who had been receiving a stable dose and type of lipid-lowering therapy for ≥3 months before enrolment and had their LDL cholesterol value measured while receiving stable lipid-lowering therapy in the previous 12 months were eligible. The percentage of patients who achieved the relevant target goals was 51.4% when estimated by physicians versus 39.9% when based on European Society of Cardiology (ESC)/European Atherosclerosis Society recommendations (p<0.001), demonstrating an important gap between guidelines and clinical practice. Overall findings in patients receiving stable lipid-lowering therapy from countries outside western Europe suggest that approximately one-third of very-high-risk patients and half of high-risk patients achieve their risk-based target goals, whereas over half to two-thirds of moderate-risk patients achieve their goal. Evidence supports the importance of the use of ezetimibe added to statin therapy to achieve goals and reduce events and cardiovascular risk. The results of the landmark IMPROVE-IT indicated that after acute coronary syndrome, ezetimibe 10 mg/simvastatin 40 mg was superior to simvastatin 40 mg alone in reducing cardiovascular events in high-risk patients.17 A reduction of recurrent events was observed. Patients with diabetes, prior stroke and prior coronary artery bypass graft appeared to have a greater treatment effect from ezetimibe than patients without diabetes. However, ezetimibe prescription is still lower than expected. In the FOURIER study population, 27,564 patients with established CVD and at least one major risk factor (diabetes, current smoking, age ≥65 years, MI or non-haemorrhagic stroke, or symptomatic peripheral artery disease) were treated with lipid-lowering therapy.18 At baseline, only 1,440 (5.3%) were receiving ezetimibe. More recently, the REDUCE-IT trial randomised 8,179 statin-treated patients with elevated triglycerides (≥3.5 mmol/l and <13 mmol/l), LDL cholesterol (>1.0 mmol/l and ≤2.6 mmol/l) and a history of atherosclerosis (71% of patients) or diabetes (29% patientsof ) to icosapent ethyl 4 g/day or placebo.19 Only 6.4% of patients were given ezetimibe.

The VIPFARMA ISCP Project

Apart from statin intensity and LDL cholesterol goals, there are some aspects of atherogenic dyslipidaemia that are often neglected.20 It is well known that atherogenic dyslipidaemia is associated with poor cardiovascular outcomes, but markers of this condition, such as triglycerides, are often ignored in clinical practice.21 Some aspects explain the barriers to implementing recommendations from guidelines into clinical practice worldwide. A decade ago, Erhardt et al. grouped the components of non-adherence into patient, physician and medication-related reasons.22 In order to improve continuing medical education programmes, it is essential to understand causes that relate to clinician attitudes. This underpins the rationale for the International Society of Cardiovascular Pharmacotherapy (ISCP) Surveillance of Prescription Drugs in the Real World Project (VIPFARMA ISCP; Figure 1).

Aim

The aim of the VIPFARMA ISCP survey is to obtain relevant and representative data on a specific population regarding prescriptions or adherence to pharmacological therapeutic protocols. In the first stage, the ISCP will focus on the pharmacological management of lipid disorders.

EUROPEAN CARDIOLOGY REVIEW Access at: www.ECRjournal.com

Dyslipidaemia in the Real World The pilot research will be conducted by the Argentinean chapter of the ISCP. Because updated Argentinean guidelines are yet to be published, the ESC 2019 recommendations will be used as a reference.23 While lifestyle habits regarding dyslipidaemia are recognised as crucially important, this study will focus on medical attitudes towards lipid-lowering drug therapies.

Methods Study Design

A cross-sectional online survey will be submitted to doctors in different specialties (internal medicine, cardiology, endocrinology, general medicine or other) who usually treat patients with dyslipidaemia in the range of 1–10 patients per week. Participants specify their sub-specialty when responding (preventive medicine, preventive cardiology, diabetes, arterial hypertension or other). Our research team will send personal invitations to peers and will post open invitations on social media. The pilot study aims to reach 1,000 returned surveys in Argentina. Reminders will also be sent. The questionnaire will include 30 questions with dichotomous, Likertscale, rank-order, and open-ended response choices (Supplementary Material Appendix 1). Questions will not be compulsory and respondents will be permitted to select multiple response choices depending on the question content.

Statistical Analysis

Data will be collected via Google Forms and exported to SPSS (version 24.0; IBM) for statistical analysis. Means and SD will be used for continuous variables and frequencies and percentages for categorical variables. Independent sample t-tests will be used to compare the normally distributed continuous variables, the Mann–Whitney U test will be used for non-normally distributed continuous variables, and the Pearson χ-squared test (or the Fisher’s Exact test, as appropriate) for categorical variables. A p value <0.05 will be considered statistically significant.

Survey Content and Rationale Demographics

This cluster of questions focuses on age, sex, number of years of practice, specialty and subspecialty. The PERCRO-DOC survey, conducted among 1,382 randomly selected physicians (general practitioners/family medicine specialists, internists and cardiologists) from different regions of Croatia, showed that primary care physicians generally use their own personal experience in prevention, while internists and cardiologists are more likely to use guidelines.24 Another aspect we will ask about is the possible influence of pharmaceutical marketing on the dissemination of guideline content and about the use of new drugs.25 In 2019, the ESC board published a position statement that highlighted the changes resulting from its new Codes of Practice for the Pharmaceutical and Medical Device Industry.26 Consequently, access to scientific updates could probably be facilitated in specific subgroups.

Institution and City Profile

The PURE study demonstrated clear differences between urban and rural populations regarding cardiovascular prevention treatments.27 Therefore, it is relevant to analyse the differences in attitude and knowledge of doctors according to institution characteristics, the size of their cities where they work and the geographical location. Disparities in access to training and education of healthcare professionals, in conjunction with societal factors, may contribute to significant differences in morbidity and mortality from CVD in cities and provinces of the same country.28

Access to Continuing Medical Education

Clinicians in today’s healthcare environment face an overwhelming volume of information, which requires continued education and lifelong learning. In order to determine access to continuing medical education, questions focus on academy activities, subscription to medical journals and recent reading of scientific articles. A Cochrane review of educational meetings examined 81 randomised controlled trials and concluded that there are differences in the improvement of professional practice and the health outcomes of patients according to the type of educational activity to which healthcare professionals have access.29 Nissen et al. demanded changes in the continuing medical education system due to the accelerating rate of change in medical knowledge, which represents an enormous challenge to physicians’ ability to offer patients high-quality care.30,31 Barriers to access these new educational platforms can determine different degrees of knowledge and application of the guidelines in clinical practice.

Clinical Practice Profile

These questions aim to determine the experience in the management of patients with two types of lipid disorders, both of which involve a high cardiovascular risk condition: familial hypercholesterolemia and atherogenic dyslipidaemia in secondary prevention patients. The first is usually under diagnosed and the second is associated with inadequate treatment.32,33 In particular, early identification of familial hypercholesterolaemia is important for the prevention of coronary artery disease.34 Frequency of care in this group of patients could determine professional behaviour in terms of the goal level to be proposed and the intensity of the treatments they will be comfortable to indicate.35 The experience of the physician may possibly be reflected in the type of decisions that they take in specific patients, such as those with familial dyslipidaemia.36

Attitudes Regarding Statins

Despite the large and consistent body of evidence on the benefits of statins in primary and secondary prevention, their proper use continues to be a huge challenge for public health.37,38 Misconceptions lead to medical decisions with undesirable consequences, such as non-adherence to treatment, insufficient doses or failure to reach goals. For this reason, these questions will ask about the clinicians’ experience of adverse effects and the combination of statins with other drugs, such as ezetimibe.17

Knowledge Regarding PCSK9 Inhibitors

Understanding of PCSK9 has revolutionised the management of dyslipidaemia and has prompted research into monoclonal antibodies that inhibit it, such as alirocumab and evolocumab.39,40 While these drugs are included in the new guidelines, the opinion of physicians on these high-cost biological drugs is unknown, particularly regarding the very low LDL cholesterol fraction that can be achieved. In the FOURIER trial, 48week outcomes showed that LDL cholesterol level in the evolocumab group was reduced to ≤1.8 mmol/l in 87% of patients, to ≤1.0 mmol/l in 67% of patients and to ≤0.65 mmol/l in 42% of patients. This compared with 18%, 0.5%, and <0.1%, respectively, in patients in the placebo group (p<0.001 for all comparisons, evolocumab versus placebo). The questions in this cluster are designed to establish the level of confidence and any concerns that physicians have regarding the use of these drugs.41

Attitudes Regarding Triglycerides

The final cluster of questions will address the attitude of physicians towards the interpretation and management of elevated triglycerides. It is now established that omega-3 and omega-6 fatty acids play important roles in human health and disease. Recent results from REDUCE-IT have impacted medical opinion because it addressed residual risk, finding a

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Dyslipidaemia in the Real World significant 25% relative risk reduction in first ischaemic events using icosapent ethyl 4 g daily versus placebo in statin-treated patients with triglycerides ≥135 mg/dl.42 Finally, we will ask about cut-off values to treat hypertriglyceridaemia and prescribing of fibrates or omega 3 fatty acids.

Conclusion

Dyslipidaemia plays a critical role in the pathogenesis of atherosclerosis. Proper pharmacological management of lipid disorders, especially familial 1. Patel N, Bhargava A, Kalra R, et al. Trends in lipid, lipoproteins, and statin use among U.S. adults: Impact of 2013 cholesterol guidelines. J Am Coll Cardiol 2019;74:2525– 8. https://doi.org/10.1016/j.jacc.2019.09.026; PMID: 31727291. 2. Libby P, Buring JE, Badimon L, et al. Atherosclerosis. Nat Rev Dis Primers 2019;5:56. https://doi.org/10.1038/s41572-0190106-z; PMID: 31420554. 3. Ray KK, Corral P, Morales E, Nicholls SJ. Pharmacological lipid-modification therapies for prevention of ischaemic heart disease: current and future options. Lancet 2019;394:697–708. https://doi.org/10.1016/S01406736(19)31950-6; PMID: 31448741. 4. Lorenzatti AJ, Toth PP. New perspectives on atherogenic dyslipidaemia and cardiovascular disease. Eur Cardiol 2020;15:e04. https://doi.org/10.15420/ecr.2019.06; PMID: 32180834. 5. Agarwala A, Shapiro MD. Emerging strategies for the management of atherogenic dyslipidaemia. Eur Cardiol 2020;15:e05. https://doi.org/10.15420/ecr.2019.16; PMID: 32180837. 6. Kotseva K, De Backer G, De Bacquer D, et al. Primary prevention efforts are poorly developed in people at high cardiovascular risk: a report from the European Society of Cardiology EURObservational Research Programme EUROASPIRE V survey in 16 European countries. Eur J Prev Cardiol 2020. https://doi.org/10.1177/2047487320908698; PMID: 32195597; epub ahead of press. 7. Rosenson RS, Kent ST, Brown TM, et al. Underutilization of high-intensity statin therapy after hospitalization for coronary heart disease. J Am Coll Cardiol 2015;65:270–7. https://doi.org/10.1016/j.jacc.2014.09.088; PMID: 25614424. 8. Halcox JP, Tubach F, Lopez-Garcia E, et al. Low rates of both lipid-lowering therapy use and achievement of low-density lipoprotein cholesterol targets in individuals at high-risk for cardiovascular disease across Europe. PLoS One 2015;10:e0115270. https://doi.org/10.1371/journal. pone.0115270; PMID: 25692692. 9. Okerson T, Patel J, DiMario S, et al. Effect of 2013 ACC/AHA blood cholesterol guidelines on statin treatment patterns and low-density lipoprotein cholesterol in atherosclerotic cardiovascular disease patients. J Am Heart Assoc 2017;6:e004909. https://doi.org/10.1161/JAHA.116.004909; PMID: 28314797. 10. Vaucher J, Marques-Vidal P, Waeber G, Vollenweider P. Population impact of the 2017 ACC/AHA guidelines compared with the 2013 ESH/ESC guidelines for hypertension management. Eur J Prev Cardiol 2018;25:1111–3. https://doi.org/10.1177/2047487318768938; PMID: 29637794. 11. National Institute for Health and Care Excellence. Cardiovascular disease: risk assessment and reduction, including lipid modification. London: NICE; 2016. http://www.nice.org. uk/guidance/cg181 (accessed 12 February 2021). 12. Steen DL, Khan I, Ansell D, et al. Retrospective examination of lipid-lowering treatment patterns in a real-world high-risk cohort in the UK in 2014: comparison with the National Institute for Health and Care Excellence (NICE) 2014 lipid modification guidelines. BMJ Open 2017;7:e013255. https:// doi.org/10.1136/bmjopen-2016-013255; PMID: 28213597. 13. Galve E, Cordero A, Cequier A, et al. Degree of lipid control in patients with coronary heart disease and measures adopted by physicians. REPAR study. Rev Esp Cardiol (Engl Ed) 2016;69:931–8. https://doi.org/10.1016/j.rec.2016.02.012; PMID: 27178117. 14. Avezum A, Oliveira GBF, Lanas F, et al. Secondary CV prevention in South America in a community setting: the PURE study. Glob Heart 2017;12:305–13. https://doi.

and atherogenic dyslipidaemia, constitutes one of the greatest challenges in cardiovascular prevention in high-risk patients. However, some medical barriers prevent patients from achieving goals, contributing to the perceived gap between guidelines and daily clinical practice. It is therefore relevant to determine the attitudes of physicians regarding lipid management. The results of the VIPFARMA ISCP project will allow the identification of obstacles that exist in the medical community and the setting of an agenda to improve continuing medical education programmes.

org/10.1016/j.gheart.2016.06.001; PMID: 27773540. 15. Gupta R, Islam S, Mony P, et al. Socioeconomic factors and use of secondary preventive therapies for cardiovascular diseases in South Asia: the PURE study. Eur J Prev Cardiol 2015;22:1261–71. https://doi.org/10.1177/2047487314540386; PMID: 24942224. 16. Danchin N, Almahmeed W, Al-Rasadi K, et al. Achievement of low-density lipoprotein cholesterol goals in 18 countries outside Western Europe: the International ChoLesterol management Practice Study (ICLPS). Eur J Prev Cardiol 2018;25:1087–94. https://doi.org/10.1177/2047487318777079; PMID: 29771156. 17. Giugliano RP, Cannon CP, Blazing MA, et al. Benefit of adding ezetimibe to statin therapy on cardiovascular outcomes and safety in patients with versus without diabetes mellitus: results from IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial). Circulation 2018;137:1571–82. https://doi.org/10.1161/ CIRCULATIONAHA.117.030950; PMID: 29263150. 18. Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med 2017;376:1713–22. https://doi. org/10.1056/NEJMoa1615664; PMID: 28304224. 19. Bhatt DL, Steg PG, Miller M, et al. Effects of icosapent ethyl on total ischemic events: from REDUCE-IT. J Am Coll Cardiol 2019;73:2791–802. https://doi.org/10.1016/j. jacc.2019.02.032; PMID: 30898607. 20. Halcox JP, Banegas JR, Roy C, et al. Prevalence and treatment of atherogenic dyslipidemia in the primary prevention of cardiovascular disease in Europe: EURIKA, a cross-sectional observational study. BMC Cardiovasc Disord 2017;17:160. https://doi.org/10.1186/s12872-017-0591-5; PMID: 28623902. 21. Skulas-Ray AC, Wilson PWF, Harris WS, et al. Omega-3 fatty acids for the management of hypertriglyceridemia: a science advisory from the American Heart Association. Circulation 2019;140:e673–91. https://doi.org/10.1161/ CIR.0000000000000709; PMID: 31422671. 22. Erhardt L, Mourad JJ. Adherence to antihypertensive and lipid-lowering therapy – impact on clinical practice. Eur Cardiol 2008;4:10–5. https://doi.org/10.15420/ ecr.2008.4.2.10. 23. Cosentino F, Grant PJ, Aboyans V, et al. 2019 ESC guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD. Eur Heart J 2020;41:255–323. https://doi.org/10.1093/eurheartj/ehz486; PMID: 31497854. 24. Reiner Z, Sonicki Z, Tedeschi-Reiner E. Physicians’ perception, knowledge and awareness of cardiovascular risk factors and adherence to prevention guidelines: the PERCRO-DOC survey. Atherosclerosis 201;213:598–603. https://doi.org/10.1016/j.atherosclerosis.2010.09.014; PMID: 20947087. 25. Schwartz LM, Woloshin S. Medical marketing in the United States, 1997-2016. JAMA.2019;321:80–96. https://doi. org/10.1001/jama.2018.19320; PMID: 30620375. 26. ESC Board. The future of continuing medical education: the roles of medical professional societies and the health care industry. Eur Heart J 2019;40:1720–7. https://doi.org/10.1093/ eurheartj/ehy003; PMID: 29506125. 27. Khatib R, McKee M, Shannon H, et al. Availability and affordability of cardiovascular disease medicines and their effect on use in high-income, middle-income, and lowincome countries: an analysis of the PURE study data. Lancet 2016;387:61–9. https://doi.org/10.1016/S0140-6736(15)004699; PMID: 26498706.

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28. GBD 2017 Causes of Death Collaborators. Global, regional, and national age-sex-specific mortality for 282 causes of death in 195 countries and territories, 1980-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet 2018;392:1736–88. https://doi.org/10.1016/ S0140-6736(18)32203-7; PMID: 30496103. 29. Forsetlund L, Bjørndal A, Rashidian A, et al. Continuing education meetings and workshops: effects on professional practice and health care outcomes. Cochrane Database Syst Rev 2009;2009:CD003030. https://doi.org/10.1002/ 14651858.CD003030.pub2; PMID: 19370580. 30. Nissen SE. Reforming the continuing medical education system. JAMA 2015;313:1813–4. https://doi.org/10.1001/ jama.2015.4138; PMID: 25965221. 31. Cullen MW, Geske JB, Anavekar NS, et al. Reinvigorating continuing medical education: meeting the challenges of the digital age. Mayo Clin Proc 2019;94:2501–9. https://doi. org/10.1016/j.mayocp.2019.07.004; PMID: 31806103. 32. Raal FJ, Hovingh GK, Catapano AL. Familial hypercholesterolemia treatments: Guidelines and new therapies. Atherosclerosis 2018;277:483–92. https://doi. org/10.1016/j.atherosclerosis.2018.06.859; PMID: 30270089. 33. Pedro-Botet J, Ascaso JF, Blasco M, et al. Triglycerides, HDL cholesterol and atherogenic dyslipidaemia in the 2019 European guidelines for the management of dyslipidaemias. Clin Investig Arterioscler 2020;32:209–18. https://doi. org/10.1016/j.arteri.2019.12.001; PMID: 32037300. 34. Alonso R, Perez de Isla L, Muñiz-Grijalvo O, et al. Hypercholesterolaemia diagnosis and management. Eur Cardiol 2018;13:14–20. https://doi.org/10.15420/ecr.2018:10:2; PMID: 30310464. 35. Presta V, Figliuzzi I, Miceli F, et al. Achievement of low density lipoprotein (LDL) cholesterol targets in primary and secondary prevention: Analysis of a large real practice database in Italy. Atherosclerosis 2019;285:40–8. https://doi. org/10.1016/j.atherosclerosis.2019.03.017; PMID: 31003091. 36. Lan NSR, Martin AC, Brett T, et al. Improving the detection of familial hypercholesterolaemia. Pathology 2019;51:213–21. https://doi.org/10.1016/j.pathol.2018.10.015; PMID: 30579649. 37. Akyea RK, Kai J, Qureshi N, et al. Sub-optimal cholesterol response to initiation of statins and future risk of cardiovascular disease. Heart 2019;105:975–81. https://doi. org/10.1136/heartjnl-2018-314253; PMID: 30988003. 38. Chen ST, Huang ST, Shau WY, et al. Long-term statin adherence in patients after hospital discharge for new onset of atherosclerotic cardiovascular disease: a population-based study of real world prescriptions in Taiwan. BMC Cardiovasc Disord 2019;19:62. https://doi. org/10.1186/s12872-019-1032-4; PMID: 30876393. 39. Warden BA, Fazio S, Shapiro MD. The PCSK9 revolution: current status, controversies, and future directions. Trends Cardiovasc Med 2020;30:179–85. https://doi.org/10.1016/j. tcm.2019.05.007; PMID: 31151804. 40. Furtado RHM, Giugliano RP. What lessons have we learned and what remains to be clarified for PCSK9 Inhibitors? A review of FOURIER and ODYSSEY outcomes trials. Cardiol Ther 2020;9:59–73. https://doi.org/10.1007/s40119-02000163-w; PMID: 32026310. 41. Giugliano RP, Mach F, Zavitz K, et al. Cognitive function in a randomized trial of evolocumab. N Engl J Med 2017;377:633– 43. https://doi.org/10.1056/NEJMoa1701131; PMID: 28813214. 42. Bhatt DL, Steg PG, Miller M, et al. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med 2019;380:11–22. https://doi.org/10.1056/ NEJMoa1812792; PMID: 30415628.

Coronary Physiology

Optimal Prognostication of Patients with Coronary Stenoses in the Pre- and Post-PCI setting: Comments on TARGET FFR and DEFINE-FLOW Trials Presented at TCT Connect 2020 Andreas Seitz,1 Stefan Baumann,2 Udo Sechtem1 and Peter Ong1 1. Department of Cardiology and Angiology, Robert-Bosch-Krankenhaus, Stuttgart, Germany; 2. Department of Cardiology, Pneumology and Angiology, University Hospital Mannheim, Mannheim, Germany

Abstract

The body of evidence for the use of coronary physiology assessments to guide percutaneous coronary intervention (PCI) has been growing continuously in recent decades. Two studies presented during TCT Connect 2020 added insights into the prognostic value of coronary physiology measurements in pre- and post-PCI settings. The first study, TARGET FFR, assessed whether a post-PCI fractional flow reserve (FFR)-guided incremental optimisation strategy (PIOS) was superior to angiography-guided PCI. The second study, DEFINE-FLOW, assessed the course of stenoses with fractional and coronary flow reserve (FFR+/CFR−) discordance when treated medically. This article summarises the main results from the TARGET FFR and the DEFINE-FLOW trials and puts them into the context of the existing literature.

Keywords

Coronary flow reserve, coronary physiology, fractional flow reserve, intermediate stenosis, microvascular dysfunction, post-percutaneous coronary intervention, prognosis Disclosure: The authors have no conflicts of interest to declare Received: 5 February 2021 Accepted: 8 February 2021 Citation: European Cardiology Review 2021;16:e17. DOI: https://doi.org/10.15420/ecr.2021.04 Correspondence: Peter Ong, Department of Cardiology, Robert-Bosch-Krankenhaus, Auerbachstrasse 110, 70376 Stuttgart, Germany. E: Peter.Ong@rbk.de Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Controversy continues over how to evaluate the haemodynamic and prognostic relevance of intermediate coronary stenoses in the catheter laboratory. Many years before the advent of pressure-derived indices, the concept of coronary flow reserve (CFR) was introduced as a measure of the haemodynamic relevance of coronary stenoses.1 However, since the DEFER and FAME trials, the field of stenosis severity evaluation has mostly been replaced by fractional flow reserve (FFR), a pressure-bound surrogate for CFR.2–4 More recently, non-hyperaemic coronary pressure measurements have been introduced into clinical practice.5 Meanwhile, several large trials have proven that FFR allows prognostication of patients with angiographically intermediate stenoses and that FFRguided percutaneous coronary intervention (PCI) is superior to PCI guided by angiography alone.6 According to contemporary guidelines on chronic coronary syndromes, risk stratification using FFR is now a class 1A recommendation in patients without documented ischaemia and insufficient symptom control by medical treatment and/or a high-risk profile.7 However, despite these data and recommendations, it is still a matter of debate whether FFR should be considered the invasive gold standard for stenosis assessment, particularly considering the substantial number of patients with FFR/CFR-discordant stenoses.9–11 Moreover, studies so far have failed to show a mortality benefit for FFR-guided PCI over angiography-guided PCI.12 The growing body of evidence suggesting a prognostic relevance of FFR not only derived from pre-PCI measurements but also in the immediate post-PCI setting has recently been reviewed.13

In this article, we will set into perspective two studies presented during the 2020 virtual Transcatheter Cardiovascular Therapeutics congress (TCT Connect 2020, 14–18 October), which focused on post-PCI FFR (An Evaluation of a Physiology-guided PCI Optimisation Strategy [TARGET FFR]) and FFR/CFR discordance (Combined Pressure and Flow Measurements to Guide Treatment of Coronary Stenoses [DEFINE-FLOW]).

TARGET FFR: Post-PCI FFR Ready for Clinical Use?

The first reports of a predictive value of post-PCI FFR in large patient cohorts were published almost 2 decades ago.14 Since then, several retrospective and prospective studies have confirmed the association of post-PCI FFR with future cardiovascular events.15–22 Different post-PCI FFR cut-off values have been proposed by these studies for optimal prognostication (most of them between 0.88 and 0.92) as well as the use of generally lower cut-off values for left anterior descending lesions.21 Nonetheless, the relevance of post-PCI FFR in routine clinical practice has been debated.18 In the TARGET FFR trial presented at TCT Connect 2020, Damien Collison et al. investigated whether a physiology (post-PCI FFR)-guided incremental optimisation strategy (PIOS) was superior to angiography-guided PCI only. This study was a single-centre, investigator-initiated, randomised controlled and partly blinded trial, which enrolled patients undergoing PCI because of stable angina or non-ST-segment elevation MI between February 2018 and November 2019. The primary endpoint was the rate of

Optimal Prognostication of Patients with Coronary Stenoses in the Pre- and Post-PCI Setting patients with an optimal post-PCI result, defined as a final FFR ≥0.90 at the end of the procedure. Secondary endpoints were the rate of patients with suboptimal final FFR <0.80, as well as symptom improvement after 3 months assessed by the Seattle Angina Questionnaire 7 (SAQ-7) and target vessel failure during follow-up. Initially, 721 patients consented to take part in the study. Almost 50% of participants dropped out because they were referred to the multidisciplinary team meeting (13.9%); were found to have unobstructed coronary arteries (9.8%) or FFR-negative lesions (7.6%); or a decision for either medical (12.5%) or surgical treatment (2.9%) had been made. Of the 371 patients who proceeded to PCI, 111 were excluded for reasons such as incomplete data, meeting the exclusion criteria or technical/ operational reasons. The remaining 260 patients underwent blinded post-PCI coronary physiology assessment using FFR and CFR followed by randomisation to either the angiography-guided control group or the PIOS intervention group. In patients randomised to the PIOS group, further PCI optimisation was intended if post-PCI FFR was <0.90. This included either post-dilatation of the employed stent if a trans-stent gradient ≥0.05 was present or additional PCI if a focal FFR step ≥0.05 was detected proximally or distally of the initially treated lesion. Patients in this study were on average 59 years old and predominantly male (87%). Patient and lesion characteristics were similar in both the control and the intervention group. In line with previous studies, Collison et al. observed suboptimal post-PCI FFR (<0.90) in the majority of patients. FFR pullback most frequently revealed diffuse atherosclerotic disease proximally or distally to the treated target lesion in 66% and 85%, respectively, followed by a trans-stent gradient ≥0.05 in 39% and focal lesions (proximal 7%; distal 15%). Among the 131 patients randomised to the PIOS group, 93 (71%) had a post-PCI FFR <0.90 and were thus eligible for further post-PCI FFR-guided optimisation. Eventually, PIOS was applied in only 40 patients (31%). The remaining patients were either felt to have rather diffuse disease or the operator or patient declined further optimisation. In the patients who finally underwent PIOS, FFR improved by 0.06 ± 0.07 (from 0.76 ± 0.08 to 0.82 ± 0.06; p<0.001) and CFR improved by 1.0 ± 2.2 (from 3.0 ± 1.6 to 4.0 ± 2.1; p=0.02). The primary outcome (proportion of patients with final FFR ≥0.90) was reached in 38.1% of patients in the PIOS group compared to 28.1% in the control group. This 10% difference was statistically not significant (p=0.099), so the study failed to demonstrate superiority of the PIOS intervention. Regarding the secondary endpoint (proportion of patients with final FFR ≤0.80), a significant result in favour of the PIOS intervention was observed (18.6% versus 29.8%; p=0.045). No difference was found regarding the change in symptom severity 3 months after PCI. During a mean follow-up of 1.7 ± 0.9 years, only a single event of target vessel failure was observed (PIOS group). In the as-treated analysis, Collison et al. observed a significant increase in FFR and CFR in patients in whom PIOS was actually performed. These results have several implications. First, they demonstrate how challenging it is to conduct randomised coronary physiology/interventional studies, as the intervention could be performed in only 31% of patients randomised to the PIOS group because of the above-mentioned reasons (diffuse atherosclerotic disease and physician/patient preference). In the sample size calculation, a substantial difference between intention-to-treat and as-treated because of the

absence of a target for additional optimisation measures was already expected in 60% of patients, which was even surpassed in the actual trial (69%).23 In addition, the investigators aimed to detect a 20% difference between groups regarding the primary endpoint.23 With regards to the p-value of 0.099 of the primary analysis, one can conclude that: the initially assumed effect of the intervention (PIOS) on final FFR was overestimated; and the study was underpowered considering the low rate of actual PIOS interventions performed. Second, the results of the secondary endpoint analyses are clinically much more relevant than the primary endpoint question regarding clinical value of post-PCI FFR measurements. The follow-up data demonstrate that this is a low-risk setting, given the an annual cardiovascular mortality in the overall study population was as low as 0.22%. Moreover, as described in the study design paper, the authors sought to eventually reduce the number of patients with persistent (or recurrent) symptoms after PCI by minimising suboptimal PCI results. With regards to the presented SAQ-7 results at 3 months, which show no difference between the PIOS and the control groups, clinicians should bear in mind that other mechanisms of post-PCI angina might be more relevant than suboptimal PCI results, such as disorders of vasomotor function including microvascular and vasospastic disease or structural alterations of the microvasculature accompanying diffuse epicardial disease.24,25 Finally, we need to acknowledge the additional procedural details – i.e. the longer procedure duration and fluoroscopy time, as well as higher contrast and adenosine doses with side-effects in the PIOS group. Nonetheless, additional data in the field of post-PCI FFR are most welcome and will be provided e.g. by the ongoing FFR REACT trial that evaluates a potential benefit of high-definition intravascular ultrasoundguided PCI optimisation in patients with a post-PCI FFR<0.90.26

DEFINE-FLOW: Renaissance of Coronary Flow Reserve in Guiding PCI?

As mentioned at the beginning, there is an ongoing controversy over whether the pressure-derived FFR or the original flow-derived CFR should be considered the gold standard for invasive assessment of epicardial coronary stenosis severity.10,25 The DEFINE-FLOW trial, which was presented at TCT 2020 by Nils Johnson, was a sponsor-initiated multicentre trial that was designed to investigate the natural course of patients with angiographically intermediate coronary stenoses and discordant FFR/CFR results. The hypothesis of this non-inferiority study was that patients with an epicardial stenosis with FFR <0.80 and CFR >2.0 (FFR+/CFR−) have a similar favourable prognosis as patients with concordant normal results of FFR >0.80 and CFR >2.0 (FFR−/CFR−) when treated medically. The rationale behind this hypothesis is that patients with a pathologic FFR <0.80 yet a normal CFR >2.0 have an intact coronary microvasculature. When challenged with adenosine, this healthy microvasculature dilates maximally, leading to an adequate increase in coronary blood flow. The physiological hyperaemic coronary blood flow response results in a high pressure drop across the stenosis, resulting in a pathologic FFR value despite preserved CFR. Hence, FFR may overestimate the haemodynamic relevance of the stenosis in this group of patients. The primary endpoint of the study was a combined major adverse cardiovascular event endpoint, including all-cause death, MI and PCI or

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Optimal Prognostication of Patients with Coronary Stenoses in the Pre- and Post-PCI Setting coronary artery bypass graft (CABG), and the follow-up period was 2 years. The secondary endpoint was target vessel failure, which included MI and repeat PCI or CABG of the target vessel. Of the 455 enrolled patients with angiographically intermediate (≥50% diameter) coronary stenosis, 430 were treated according to the study protocol. Patients were on average 67 years old, predominantly men (74%) and every other patient was already taking two or more anti-anginal drugs at enrolment. Patients were allocated to four groups according to the results of the coronary physiology assessment (FFR−/CFR−: n=207 patients with 236 lesions [44%]; FFR−/CFR+: n=108 patients with 123 lesions [23%]; FFR+/CFR−: n=74 patients with 74 lesions [14%], FFR+/CFR+: n=94 patients with 100 lesions [19%]). FFR+/CFR+ patients underwent revascularisation while all other patient groups did not undergo revascularisation and were treated medically. The lowest rate of the primary endpoint was observed in patients with concordant normal FFR/CFR results (FFR−/CFR−), while the highest rate was observed in patients who had concordant pathological results (FFR+/CFR+) despite undergoing revascularisation. Interestingly and contrary to the hypothesis of the investigators, the ‘natural course’ of medically treated patients with pathological FFR but normal CFR (FFR+/CFR−) was not non-inferior to the FFR−/CFR− group, with a difference in event rates of 5%, i.e. event rates of 10.8% versus 5.8%, respectively (p=0.065 for non-inferiority). Instead, the Kaplan-Meier curve for FFR+/CFR− rather parallels the curve for FFR−/CFR+, both ranging between the two FFR/CFR concordant groups. Regarding the secondary endpoint of ‘target vessel failure’, the FFR+/CFR− group even had the numerically highest rate of events during the 2-year follow-up period, although it must be taken into account that all FFR+/ CFR+ patients did undergo PCI as per protocol. Using a time-to-failure Cox mixed effects model, the authors found that FFR was a highly significant continuous predictor for events (HR <0.01; p=0.0067), while CFR was no significant predictor (HR 0.74; p=0.44). These results can be interpreted as a throwback for CFR in the battle against FFR for the gold standard of epicardial stenosis assessment. However, we need to keep in mind that there was no comparator arm of patients with FFR+/CFR− patients who underwent PCI, which must be considered the current standard of care, and we do not know what the prognosis of this group would have been. Conversely, it would have been interesting to see how PCI would have impacted on the prognosis in patients with FFR−/CFR+; however, this was also not part of the study design.27 Generally, in the current post-ISCHEMIA era, we need to acknowledge that the indication for PCI in chronic coronary syndromes with proof of ischaemia (excluding left main stenosis and a left ventricular ejection fraction <35%) is symptom control rather than the prevention of hard clinical endpoints.28 Therefore, it is reasonable to question whether 1. Gould KL, Lipscomb K, Hamilton GW. Physiologic basis for assessing critical coronary stenosis. Instantaneous flow response and regional distribution during coronary hyperemia as measures of coronary flow reserve. Am J Cardiol 1974;33:87–94. https://doi.org/10.1016/00029149(74)90743-7; PMID: 4808557. 2. Tonino PA, De Bruyne B, Pijls NH, et al. Fractional flow reserve versus angiography for guiding percutaneous coronary intervention. N Engl J Med 2009;360:213–24. https://doi.org/10.1056/NEJMoa0807611; PMID: 19144937.

future studies on chronic coronary syndromes should not be designed based on soft primary endpoints such as symptoms. In addition, the distribution of primary endpoint events (death, MI, any PCI/CABG) and whether they can be attributed to the untreated lesions or were driven by de novo lesions have not yet been reported by the investigators. The detailed results that will follow with the publication of the study will also hopefully give more insights into ‘softer’ endpoints of patients depending on their FFR/CFR status. Moreover, the following aspects should be taken into account when interpreting the results of the DEFINE-FLOW study:

• Compared to patients with FFR−/CFR+, the event rate in patients with

FFR+/CFR− was numerically lower. This could point towards the fact that the FFR in the FFR−/CFR+ group was at least in part false negative. Especially in patients with concomitant microvascular disease, disturbed autoregulation may prevent maximal vasodilatation in response to adenosine. Studies have shown that this may lead to higher and thus in some cases negative FFR values.29 • When analysing the differences between patients with FFR−/CFR− and those with FFR+/CFR− more detailed information regarding resting flow and flow under maximal hyperaemia is needed. Although CFR was >2.0 in both groups, the absolute flow values may still be statistically different. This could at least in part explain the different results between the two groups. • The observed difference in outcome between the patients with FFR−/ CFR− and FFR+/CFR− may also be explained by differences in coronary microvascular resistance. Although hyperaemic microvascular resistance was most likely assessed during the invasive procedures in the DEFINE-FLOW study, these values have not yet been reported. However, increased microvascular resistance – despite a CFR of >2.0 – may be a marker for adverse outcome. Taking the findings together, the study should be seen as hypothesis generating. Despite the non-significant results, the good news is that the trial proves the feasibility of a multicentre study focusing on intracoronary Doppler flow measurements, which is the base for future coronary physiology studies that will probably focus more on coronary microvascular disease than on obstructive epicardial disease.

Conclusion

The field of invasive coronary physiology assessments is continuously moving forward. The data from TARGET FFR show that post-PCI FFR is not yet ready for use in daily clinical practice. The DEFINE-FLOW study has shown excellent feasibility of a multicentre study using a combination of intracoronary Doppler flow and pressure measurements. It has opened avenues for new coronary physiology research aiming at comprehensive assessments of the epicardial coronary arteries as well as the coronary microcirculation. However, its results also indicate that PCI of lesions with pathological FFR values is currently still the way to go.

3. De Bruyne B, Pijls NH, Kalesan B, et al. Fractional flow reserve-guided PCI versus medical therapy in stable coronary disease. N Engl J Med 2012;367:991–1001. https:// doi.org/10.1056/NEJMoa1205361; PMID: 22924638. 4. Bech GJ, De Bruyne B, Pijls NH, et al. Fractional flow reserve to determine the appropriateness of angioplasty in moderate coronary stenosis: a randomized trial. Circulation 2001;103:2928–34. https://doi.org/10.1161/01. CIR.103.24.2928; PMID: 11413082. 5. van de Hoef TP, Lee JM, Echavarria-Pinto M, et al. Nonhyperaemic coronary pressure measurements to guide

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coronary interventions. Nat Rev Cardiol 2020;17:629–40. https://doi.org/10.1038/s41569-020-0374-z; PMID: 32409779. 6. Zimmermann FM, Omerovic E, Fournier S, et al. Fractional flow reserve-guided percutaneous coronary intervention vs. medical therapy for patients with stable coronary lesions: meta-analysis of individual patient data. Eur Heart J 2019;40:180–6. https://doi.org/10.1093/eurheartj/ehy812; PMID: 30596995. 7. Knuuti J, Wijns W, Saraste A, et al. 2019 ESC guidelines for the diagnosis and management of chronic coronary syndromes. Eur Heart J 2020;41:407–77. https://doi.

Optimal Prognostication of Patients with Coronary Stenoses in the Pre- and Post-PCI Setting org/10.1093/eurheartj/ehz425; PMID: 31504439. 8. van de Hoef TP, Siebes M, Spaan JA, et al. Fundamentals in clinical coronary physiology: why coronary flow is more important than coronary pressure. Eur Heart J 2015;36:3312– 9a. https://doi.org/10.1093/eurheartj/ehv235; PMID: 26033981. 9. Soares A, Brown DL. The fallacies of fractional flow reserve. Int J Cardiol 2020;302:34–5. https://doi.org/10.1016/j. ijcard.2019.12.040; PMID: 31889563. 10. Stegehuis VE, Wijntjens GWM, Nijjer SS, et al. Objective identification of intermediate lesions inducing myocardial ischemia using sequential intracoronary pressure and flow measurements. J Am Heart Assoc 2020;9:e015559. https:// doi.org/10.1161/JAHA.119.015559; PMID: 32573324. 11. van de Hoef TP, van Lavieren MA, Damman P, et al. Physiological basis and long-term clinical outcome of discordance between fractional flow reserve and coronary flow velocity reserve in coronary stenoses of intermediate severity. Circ Cardiovasc Interv 2014;7:301–11. https://doi. org/10.1161/CIRCINTERVENTIONS.113.001049; PMID: 24782198. 12. Xaplanteris P, Fournier S, Pijls NHJ, et al. Five-year outcomes with PCI guided by fractional flow reserve. N Engl J Med 2018;379:250–9. https://doi.org/10.1056/ NEJMoa1803538; PMID: 29785878. 13. Rimac G, Fearon WF, De Bruyne B, et al. Clinical value of post-percutaneous coronary intervention fractional flow reserve value: a systematic review and meta-analysis. Am Heart J 2017;183:1–9. https://doi.org/10.1016/j.ahj.2016.10.005; PMID: 27979031. 14. Pijls NH, Klauss V, Siebert U, et al. Coronary pressure measurement after stenting predicts adverse events at follow-up: a multicenter registry. Circulation 2002;105:2950– 4. https://doi.org/10.1161/01.CIR.0000020547.92091.76; PMID: 12081986. 15. Hwang D, Lee JM, Yang S, et al. Role of post-stent physiological assessment in a risk prediction model after coronary stent implantation. JACC Cardiovasc Interv 2020;13:1639–50. https://doi.org/10.1016/j.jcin.2020.04.041;

PMID: 32703590. 16. Shin D, Lee SH, Lee JM, et al. Prognostic implications of post-intervention resting Pd/Pa and fractional flow reserve in patients with stent implantation. JACC Cardiovasc Interv 2020;13:1920–33. https://doi.org/10.1016/j.jcin.2020.05.042; PMID: 32819481. 17. Lee JM, Hwang D, Choi KH, et al. Prognostic impact of residual anatomic disease burden after functionally complete revascularization. Circ Cardiovasc Interv 2020;13:e009232. https://doi.org/10.1161/ CIRCINTERVENTIONS.120.009232; PMID: 32895005. 18. Piroth Z, Toth GG, Tonino PAL, et al. Prognostic value of fractional flow reserve measured immediately after drugeluting stent implantation. Circ Cardiovasc Interv 2017;10:e005233. https://doi.org/10.1161/ CIRCINTERVENTIONS.116.005233; PMID: 32895005. 19. Li SJ, Ge Z, Kan J, et al. Cutoff value and long-term prediction of clinical events by FFR measured immediately after implantation of a drug-eluting stent in patients with coronary artery disease: 1- to 3-year results from the DKCRUSH VII registry study. JACC Cardiovasc Interv 2017;10:986–95. https://doi.org/10.1016/j.jcin.2017.02.012; PMID: 28456699. 20. Lee JM, Hwang D, Choi KH, et al. Prognostic implications of relative increase and final fractional flow reserve in patients with stent implantation. JACC Cardiovasc Interv 2018;11:2099– 109. https://doi.org/10.1016/j.jcin.2018.07.031; PMID: 30336814. 21. Hwang D, Lee JM, Lee HJ, et al. Influence of target vessel on prognostic relevance of fractional flow reserve after coronary stenting. EuroIntervention 2019;15:457–64. https:// doi.org/10.4244/EIJ-D-18-00913; PMID: 30561367. 22. van Bommel RJ, Masdjedi K, Diletti R, et al. Routine fractional flow reserve measurement after percutaneous coronary intervention. Circ Cardiovasc Interv 2019;12:e007428. https://doi.org/10.1161/ CIRCINTERVENTIONS.118.007428; PMID:31018666. 23. Collison D, McClure JD, Berry C, et al. A randomized controlled trial of a physiology-guided percutaneous

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coronary intervention optimization strategy: rationale and design of the TARGET FFR study. Clin Cardiol 2020;43:414– 22. https://doi.org/10.1002/clc.23342; PMID: 32037592. 24. Crea F, Bairey Merz CN, Beltrame JF, et al. Mechanisms and diagnostic evaluation of persistent or recurrent angina following percutaneous coronary revascularization. Eur Heart J 2019;40:2455–62. https://doi.org/10.1093/eurheartj/ ehy857; PMID: 30608528. 25. van de Hoef TP, Echavarria-Pinto M, Meuwissen M, et al. Contribution of age-related microvascular dysfunction to abnormal coronary: hemodynamics in patients with ischemic heart disease. JACC Cardiovasc Interv 2020;13:20–9. https:// doi.org/10.1016/j.jcin.2019.08.052; PMID: 31918939. 26. van Zandvoort LJC, Masdjedi K, Tovar Forero MN, et al. Fractional flow reserve guided percutaneous coronary intervention optimization directed by high-definition intravascular ultrasound versus standard of care: rationale and study design of the prospective randomized FFR-REACT trial. Am Heart J 2019;213:66–72. https://doi.org/10.1016/j. ahj.2019.03.017; PMID: 31128504. 27. Stegehuis VE, Wijntjens GWM, van de Hoef TP, et al. Distal evaluation of functional performance with intravascular sensors to assess the narrowing effectcombined pressure and Doppler FLOW velocity measurements (DEFINE-FLOW) trial: Rationale and trial design. Am Heart J 2020;222:139–46. https://doi. org/10.1016/j.ahj.2019.08.018; PMID: 32062172. 28. Maron DJ, Hochman JS, Reynolds HR, et al. Initial invasive or conservative strategy for stable coronary disease. N Engl J Med 2020;382:1395-407. https://doi.org/10.1056/ NEJMoa1915922; PMID: 32227755. 29. Wiegerinck EM, van de Hoef TP, Rolandi MC, et al. Impact of aortic valve stenosis on coronary hemodynamics and the instantaneous effect of transcatheter aortic valve implantation. Circ Cardiovasc Interv 2015;8:e002443. https://doi.org/10.1161/CIRCINTERVENTIONS.114.002443; PMID: 26245891.

Inflammation

Atherosclerotic Cardiovascular Disease in Rheumatoid Arthritis: Impact of Inflammation and Antirheumatic Treatment Anne Mirjam Kerola ,1,2 Silvia Rollefstad

and Anne Grete Semb

1. Preventive Cardio-Rheuma Clinic, Division of Rheumatology and Research, Diakonhjemmet Hospital, Oslo, Norway; 2. Department of Rheumatology, Päijät-Häme Joint Authority for Health and Wellbeing, Lahti, Finland

Abstract

Patients with rheumatoid arthritis (RA) are at approximately 1.5-fold risk of atherosclerotic cardiovascular disease (CVD) compared with the general population, a phenomenon resulting from combined effects of traditional CVD risk factors and systemic inflammation. Rheumatoid synovitis and unstable atherosclerotic plaques share common inflammatory mechanisms, such as expression of proinflammatory cytokines interleukin (IL)-1, tumour necrosis factor (TNF)-α and IL-6. RA patients are undertreated in terms of CVD prevention, and structured CVD prevention programmes are warranted. Alongside management of traditional risk factors, suppressing systemic inflammation with antirheumatic medication is fundamental for the reduction of CVD risk among this high-risk patient group. Many antirheumatic drugs, especially methotrexate, TNF-αinhibitors and IL-6-inhibitors are associated with reduced risk of CVD in observational studies among RA patients, but randomised controlled trials with hard CVD endpoints are lacking. In patients without rheumatic disease, anti-inflammatory therapies targeting nucleotide-binding oligomerisation domain, leucine-rich repeat and pyrin domain-containing protein 3 inflammasome and the IL-1/IL-6 pathway arise as potential therapies after an atherosclerotic CVD event.

Keywords

Rheumatoid arthritis, cardiovascular disease, atherosclerosis, inflammation, antirheumatic agents Disclosure: This work was supported by research grants from the Foundation for Research in Rheumatology (FOREUM; AMK) and by grants from the South Eastern Regional Health Authorities of Norway (2016063 for SR and 2013064 for AGS). AMK has received speaker’s fees or congress sponsorship from Boehringer-Ingelheim, Pfizer, Celgene, UCB Pharma and Mylan, and attended advisory boards of Pfizer, Gilead and Boehringer-Ingelheim. AGS has received speaker honoraria and/or consulting fees from Sanofi, AbbVie, Novartis, Bayer and Lilly. SR has no conflicts of interest to declare. Received: 21 November 2020 Accepted: 19 February 2021 Citation: European Cardiology Review 2021;16:e18. DOI: https://doi.org/10.15420/ecr.2020.44 Correspondence: Anne Kerola, Preventive Cardio-Rheuma Clinic, Division of Rheumatology and Research, Diakonhjemmet Hospital, Diakonveien 12, 0370 Oslo, Norway. E: anne.kerola@helsinki.fi Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Atherosclerotic cardiovascular disease (ASCVD) is an important cause of disability and is the leading cause of death globally.1 Targeting modifiable cardiovascular risk factors, such as diabetes, hypercholesterolaemia, hypertension, smoking, physical inactivity and obesity, improves CVD outcomes in individuals with established CVD or those at high risk of CVD. Rheumatoid arthritis (RA) is a chronic inflammatory joint disease (IJD) with a prevalence of 0.5–1%. It is characterised by symmetric polyarthritis and, in the majority of RA patients, formation of autoantibodies, such as rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPA). Similar to diabetes, RA is recognised as an independent risk factor for CVD and the key underlying pathology is systemic inflammation. During the past few decades, mounting evidence on CVD risk in RA has led to substantial advances in CVD risk management in this patient population.2 RA patients are still undertreated in terms of primary and secondary CVD prevention.3,4 Alongside targeting traditional CVD risk factors, suppressing disease activity and inflammation with antirheumatic treatment is expected to reduce CVD burden in these patients. Inflammation plays a major role in atherosclerosis and it has been recognised that among well-treated ASCVD patients without IJD,

low‑grade inflammation is a key determinant of residual CVD risk.5 Groundbreakingly, anti-inflammatory therapies are being studied for the treatment of ASCVD outside the context of IJDs. In this review, we summarise the evidence on CVD risk in RA with emphasis on inflammation and the impact of antirheumatic treatment on CVD risk. We also discuss the current knowledge on anti-inflammatory therapies for secondary prevention of ASCVD from a rheumatological point of view.

Epidemiology of CVD in RA

People with RA have an approximate 1.5-fold risk of cardiovascular events and mortality compared to the general population.6,7 This excess cardiovascular burden is comparable to that of people with diabetes, although it is not as well recognised or structurally managed.8 According to a meta-analysis of observational studies, the risk of MI in people with RA compared to the general population is increased by 70% with no differences in the relative risk for men and women.6 The increase in the risk of coronary heart disease (CHD) seems to occur early on in the

Rheumatoid Arthritis and Atherosclerotic Cardiovascular Disease Figure 1: Central Inflammatory Mediators in Rheumatoid Synovitis and Atherosclerosis

Colchicine COLCOT94 and LoDoCo295

NLRP3 Inflammasome

MMPs oxLDL

LDL

IL-1

Anakinra

TNF inhibitors

Canakinumab CANTOS86

IL-6 IL-1 TNF-α

TNF-α

ate ex otr 69 h t T Me CIR

IL-6

IL-6 inhibitors

TNF-α IL-6 MMPs

otr

th Me

ate

CRP

10 3 2 1

3 2 1 CRP

CRP

NLRP3 inflammasome activates the conversion of pro-IL-1β to biologically active IL-1β. IL-1β promotes production of downstream cytokines TNF-α and IL-6. IL-6 induces hepatic production of acute phase reactants such as CRP. Vascular inflammation in atherosclerosis is usually associated with normal or only slightly increased CRP (low-grade inflammation), whereas active rheumatoid arthritis often results in high-grade systemic inflammation that accelerates atherosclerosis. Antirheumatic drugs that are used to target the central proinflammatory cytokines IL-1, TNF-α and IL-6 are depicted in white arrows, whereas anti-inflammatory therapies that have been investigated in secondary prevention of ASCVD are depicted in grey arrows. ASCVD = atherosclerotic cardiovascular disease; CRP = C-reactive protein; IL = interleukin; LDL = low-density lipoprotein; MMPs = matrix metalloproteinases; NLRP3 = nucleotide-binding oligomerisation domain, leucine-rich repeat and pyrin domain-containing protein 3; oxLDL = oxidised low-density lipoprotein; TNF = tumour necrosis factor.

course of RA, or according to some studies, even before RA is diagnosable.10 Patients with RA are less likely to report symptoms of angina and more likely to experience unrecognised MI and sudden cardiac death than the general population, suggesting an overrepresentation of vulnerable coronary plaques in patients with RA.10 After an MI, RA patients have impaired prognosis compared to the general population in terms of recurrent ischaemia and mortality.11,12 In general, cardiovascular mortality rates have declined during the past 50 years and this has also translated into better survival in RA. Presumably due to marked advances in RA pharmacotherapy and improved control of disease activity, recent studies suggest that the gap in cardiovascular mortality between RA patients diagnosed in the 2000s and the general population may be narrowing or even closing.13,14 Risk of cerebrovascular accidents is increased among RA patients by 40% compared to the general population.6 Alongside ASCVD, RA patients are at increased risk of other types of CVD, such as AF and heart failure.2 Heart failure in RA may partly result from increased prevalence of CHD, but the risk of non-ischaemic heart disease and diastolic dysfunction is also aggravated.15

Traditional Risk Factors do not Fully Explain Excess CVD Risk in RA

RA patients are more likely to suffer from insulin resistance, abnormal fat distribution, be physically inactive and smoke cigarettes compared to nonRA controls.16 Tobacco smoking is the strongest environmental risk factor for RA. A large international RA cohort study demonstrated that about a quarter of cardiovascular events were attributable to smoking (population attributable risk being 37.2% for men and 18.1% for women).17 Diabetes may be more prevalent in RA than in controls, although significant heterogeneity exists between studies.16 Data regarding overrepresentation of hypertension among RA patients is controversial, but most reports indicate no difference.16 Traditional CVD risk factors, however, do not fully explain the observed excess cardiovascular morbidity and mortality in RA. RA-related factors, such as disease activity and burden, extra-articular disease manifestations, elevated inflammatory markers and RF/ACPA positivity attribute to about 30% of the 10-year risk of cardiovascular events.17 A well-powered USbased registry study examined the relationship between longitudinally measured RA disease activity and the risk of CVD and demonstrated that treating RA from high disease activity to remission was associated with an approximate 50% reduction in risk of cardiovascular events.18 Both

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Rheumatoid Arthritis and Atherosclerotic Cardiovascular Disease exposure to each RA flare and cumulative disease activity seem to lead to an increased risk of CVD.19 In some studies, excess cardiovascular mortality risk has been confined only to seropositive RA patients.20

Figure 2: The Inverse Relationship Between Changes in Inflammatory and Lipid Parameters CRP (or inflammation)

Inflammation Drives CVD Risk in RA and the General Population

Development of an atherosclerotic plaque is not passive deposition of cholesterol in the vascular wall but an active inflammatory process involving the innate and adaptive immune system. Next, we will highlight the role of selected inflammatory mediators, which are central to pathogenesis of RA, on the development of atherosclerosis, such as nucleotide-binding oligomerisation domain, leucine-rich repeat and pyrin domain-containing protein 3 (NLRP3) inflammasome, and proinflammatory cytokines interleukin 1 (IL-1), tumour necrosis factor alpha (TNF-α) and interleukin 6 (IL-6). These inflammatory mediators are all interconnected in signalling pathways and they are targets for drugs that are used to treat rheumatic diseases and have gained interest as potential drugs for secondary prevention of ASCVD (Figure 1). Similar to high-sensitivity C-reactive protein (hsCRP), the role of IL-6 in prediction of cardiovascular events in the general population has been confirmed in primary and secondary prevention cohorts.5 To highlight a few studies, increased levels of IL-6 were associated with the risk of future MI in a prospective study with almost 15,000 apparently healthy men.21 In a secondary analysis of the CIRT study, IL-6 and hsCRP predicted major recurrent cardiovascular events in patients with prior MI or multivessel CHD who also had diabetes or metabolic syndrome, despite modern CVD preventive polypharmacotherapy and high rates of coronary revascularisation.22 IL-6 is also a marker of poor prognosis in acute coronary syndrome (ACS).23 Based on two Mendelian randomisation analyses, IL-6 signalling may have a causal role in the development of ASCVD.24,25 In MI patients, IL-6 production occurs at the site of plaque rupture, as indicated by higher concentration of IL-6 locally compared to levels in systemic circulation.26 IL-6 may also be involved in ischaemia-reperfusion myocardial injury.27 In contrast, CRP is produced in the liver in response to IL-6, and in fact, hsCRP seems to be an easy-to-use downstream marker of IL-6 activation rather than a causal agent in atherogenesis. NLRP3 inflammasome is a macromolecular protein complex of the innate immune system, which can be activated by many stimuli, such as urate crystals in gout or cholesterol crystals within an atherosclerotic plaque.28 IL-1β and NLRP3 inflammasome are important IL-6 upstream activators. Preclinical evidence links IL-1 to impaired vasodilatation, oxidative stress, plaque formation, growth and rupture.29 IL1-α may contribute to infarct size, whereas IL-1β is associated to adverse cardiac remodelling.29 Based on an ex vivo rodent model of myocardial ischaemia reperfusion, NLRP3 inflammasome may contribute to infarct size.30 Levels of TNF-α have also been demonstrated to predict future cardiovascular events.31 TNF-α is an important regulator of vascular homeostasis and contributes to the development of endothelial dysfunction and a prothrombotic state.32 Among RA patients, increased concentrations of both TNF-α and IL-6 are associated with increased prevalence of coronary artery calcification, independently of Framingham risk score or the presence of diabetes.33

Systemic Inflammation in RA Modifies Traditional CVD Risk Factors

The associations of lipids with CVD risk in RA are complex and essentially linked with inflammation. The levels of total cholesterol (TC), HDL

Increase in inflammation is associated with decrease in lipids (observed in other chronic inflammatory conditions post-MI, postsurgery and cancer treatment)

Lipid levels

Pre-RA: raised CRP and dyslipidaemia

Level of inflammatory suppression by different RA treatments may inversely affect the level of lipid elevations

Dampening of inflammation and tight disease control with RA treatment

Usually, before treatment of RA is initiated and when RA disease activity is high, inflammatory markers may increase and lipid levels decrease. Antirheumatic treatment suppresses synovial and systemic inflammation effectively and lipid levels increase. Similar outbursts of inflammatory markers and concomitant reductions in lipid levels can occur during flares of rheumatoid arthritis. CRP = C-reactive protein; RA: rheumatoid arthritis. Source: Choy et al. 2014.96 Reproduced with permission from Oxford University Press.

cholesterol (HDL-C) and LDL cholesterol (LDL-C) during active RA and ongoing inflammation typically decrease (Figure 2), a trend that is seen also in septicaemia and other inflammatory states.34 Low lipid levels during inflammation are, however, not associated with lower CVD risk, but rather the opposite.34 This phenomenon is referred to as the lipid paradox.35 In 2011, a retrospective cohort study among 651 RA patients reported a non-linear association of CVD risk and TC levels, with increasing CVD risk at TC levels below 4 mmol/l.35 Recently, this finding was confirmed in a study pooling four of the largest North American RA cohorts with information on coronary arterial calcium (CAC) scores: in contrast to controls, the association of LDL-C with CAC score in RA patients was U-shaped and the largest relative difference in coronary atherosclerosis between the RA and control groups was found among those with an LDL-C lower than 1.8 mmol/l.36 In addition, it was shown that CAC scores were higher in RA patients than in controls across LDL-C levels.36 A possible mechanism for the increased CVD risk despite low LDL-C is that inflammation promotes the oxidation of LDL-C, which is proatherogenic.37 HDL-C particles of RA patients may be unable to prevent LDL oxidation more often than those in controls.38 In addition to lipid levels, inflammation modifies other CVD risk factors such as insulin resistance, body composition and blood pressure (Figure 3). A 2020 study exploring the effects of CRP levels on systolic blood pressure in both an RA cohort and a large non-RA outpatient cohort revealed a biphasic association of systolic blood pressure with CRP (with a positive association at CRP <6 mg/l and inverse at CRP >6 mg/l).39 Body mass index (BMI) may also have a paradoxical effect on mortality in RA: patients with the lowest BMI seem to have the highest mortality rates.40 This might be due to the presence of rheumatoid cachexia, sarcopenia and frailty among those with prolonged high disease activity and hence higher CVD risk. Proinflammatory cytokines TNF-α and IL-6 induce insulin resistance, and many antirheumatic agents, including hydroxychloroquine, TNF-α-, IL-1- and IL-6-inhibitors, seem to improve markers of glucose metabolism in RA patients.41

Prevention of CVD in RA Estimation of Cardiovascular Risk

The accurate estimation of CVD risk in RA and other IJDs is challenging and remains an area of active research. Patients tend to underestimate

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Rheumatoid Arthritis and Atherosclerotic Cardiovascular Disease Figure 3: The Interplay Between Synovial and Systemic Inflammation and Cardiovascular Risk Factors in Rheumatoid Arthritis

internal validation, but failed to improve discrimination compared to established risk calculators in external validation.49,50

Insulin resistance in skeletal muscle Changes in lipid levels, structure and function

Synovial inflammation

Circulatory TNF-α IL-1 and IL-6

Oxidative stress Prothrombotic state Endothelial dysfunction Changes in blood pressure Changes in body composition; cachexia

IL = interleukin; TNF = tumour necrosis factor.

their CVD risk, warranting more patient education on this topic.42 In 2017, the European League Against Rheumatism (EULAR) published an update on recommendations for CVD risk management in RA and other IJDs.43 These recommendations emphasise that the rheumatologist is responsible for making sure that CVD risk management is addressed in patients with RA and suggest CVD risk assessment for all RA patients at least once every 5 years and reconsidered after major changes in antirheumatic therapy. Lipids should ideally be measured when RA is in remission due to the impact of inflammation on lipoprotein levels.43 CVD risk management among RA patients is performed either by rheumatologists during outpatient visits, GPs collaborating with rheumatologists or, less often, cardiologists cooperating with rheumatologists in a cardio-rheumatology clinic.44 A simple suggestion for CVD risk assessment in rheumatology clinics is that if blood pressure and lipids are recorded along with the already standardised recording of gender, age and smoking status, CVD risk can be calculated based on the Systematic Coronary Risk Evaluation (SCORE) or other CVD risk prediction algorithms. If the recommended treatment threshold is exceeded, patients could be referred to their primary care physician or a cardiologist for CVD prevention measures.45 Most established CVD risk calculators, such as SCORE, and the Reynolds and Framingham risk scores, incorporate only traditional risk factors and underestimate CVD risk among RA patients.46 QRISK2 and QRISK3 include RA as an independent CVD risk factor with a weight of 1.4 and have been shown to inaccurately predict CVD risk in RA.46 The 2018 American College of Cardiology and American Heart Association (ACC/AHA) guidelines on the management of blood cholesterol suggest that RA should be considered as a ‘risk enhancer’, promoting statin therapy in patients with intermediate or borderline risk.47 The 2015/2016 EULAR recommendations state that CVD risk scores should be adapted for patients with RA by a 1.5 multiplication factor if RA is not already included in the algorithm in use.43 Substantial efforts have been made to develop an RA-specific CVD risk prediction model, but with only modest results. An international consortium – A Trans-Atlantic Cardiovascular Consortium for Rheumatoid Arthritis (ATACC-RA) – including 13 RA cohorts from 10 countries developed two risk prediction models that included either a measure of disease activity or functional status but disappointingly, have been found to not improve discrimination when compared with established CVD prediction models.48 A similar well-powered registry study from North America presented a model incorporating measures of disease activity, disability, daily use of prednisolone and disease duration.49 It performed well in

Ultrasonography of carotid arteries is a promising non-invasive method to improve CVD risk prediction in RA. It is already incorporated into clinical practice in a few rheumatology clinics. Multiple studies have concluded that RA patients have higher prevalence of asymptomatic carotid atherosclerosis than non-RA controls.51 Carotid ultrasound may markedly improve CVD risk evaluation in RA as was shown in a study of 355 patients with IJDs where 30–60% of patients with an estimated low-to-moderate CVD risk according to established CVD risk calculators had carotid plaques and it was therefore reclassified to very high-risk category with an indication for lipid-lowering therapy.52

Management of Traditional Cardiovascular Risk Factors

Management of traditional CVD risk factors among RA patients is fundamental and includes advice about maintaining a healthy diet, regular exercise, weight control, smoking cessation and treatment with antihypertensive and lipid-lowering agents. Compelling evidence comparing different primary prevention strategies in RA are lacking and risk factor management is recommended to be carried out according to national guidelines.2,43 This means that treatment strategies, thresholds and targets for antihypertensive, anti-diabetic and lipid-lowering therapies are the same in RA and the general population. It may be asked whether primary prevention of CVD with statins could be beneficial to RA patients irrespective of their estimated CVD risk. A multicentre randomised controlled trial (RCT) TRACE-RA compared the effect of 40 mg daily atorvastatin versus placebo on hard CVD endpoints in RA patients.53 Due to unexpectedly low cardiovascular event rates, the study was terminated prematurely after recruiting only 3,002 RA patients with a median follow-up of 2.5 years. The reduction in cardiovascular events in the atorvastatin versus the placebo arm was estimated to be 34% but was not statistically significant probably due to lack of power caused by short observation period and low number of patients. Although, most importantly, this large risk reduction of 34% has been found in other large statin studies with hard CVD endpoints.54 Statins seem to be equally safe and effective among RA patients and the general population. A post hoc analysis of two large secondary prevention trials demonstrated that the effect of statins on reduction of lipids and cardiovascular event rates among patients with and without IJDs was comparable, despite lower baseline lipid levels in the IJD group.55 Statins may also ameliorate RA disease activity and reduce CRP and erythrocyte sedimentation rate (ESR) levels through their pleiotropic effects.56 Smoking cessation in patients with RA is of utmost importance. An international multicenter study showed that smoking cessation among RA patients is a predictor of reduced rate of cardiovascular events (for former versus current smokers HR 0.70; 95% CI [0.51–0.95]; p=0.02, and for never versus current smokers HR 0.48 ; 95% CI [0.34–0.69]; p<0.001).57 Smoking cessation was also associated with lower disease activity.57 A trial of intensive smoking cessation intervention on RA disease activity (NCT02901886) is currently under way. Every RA patient who smokes should receive advice for smoking cessation and, in our opinion, smoking cessation programmes would ideally be implemented in rheumatology clinics. Patient education is the key to lifestyle modifications. All patients should receive sufficient information on CVD risk associated with RA in oral and

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Rheumatoid Arthritis and Atherosclerotic Cardiovascular Disease written form. Heart friendly diet recommendations are the same for RA patients as for the general population. Even brief standardised advice on a heart friendly diet may result in a change in nutritional habits, as implied by a small pilot study among IJD patients.58 Barriers to physical activity in RA include pain, fatigue and stiffness, but on the other hand, exercise may aid symptom management, pain relief and joint function.59

Antirheumatic Treatment and Cardiovascular Risk in RA and Beyond

The antirheumatic medications used in the treatment of RA comprise conventional synthetic disease-modifying antirheumatic drugs (DMARDs) such as methotrexate, biological DMARDs such as TNF-α-, IL-6- or IL-1inhibitors, and targeted synthetic DMARDs, such as Janus kinase (JAK) inhibitors. The pharmacodynamics for conventional synthetic DMARDs is not fully elucidated, whereas biological and targeted synthetic DMARDs affect specific stages of inflammatory signalling. Suppression of disease activity with antirheumatic treatment is fundamental in lowering CVD risk. Although the mechanisms remain poorly understood, observational studies demonstrate an association of many DMARDs and lowered CVD risk in RA. An increasing number of clinical trials have also shown positive effects of several DMARDs on surrogate markers of CVD among RA patients, but RCTs with hard CVD endpoints are lacking.60–63 In the following sections, we will discuss the cardiovascular effects of DMARDs among RA patients and summarise the published RCTs that explore anti-inflammatory therapies in secondary prevention of ASCVD in patients without IJD. Potential anti-inflammatory therapies for ASCVD, which are not used in the treatment of RA and do not target the central IL-1, TNF-α and IL-6 pathways are not included in this review.

Methotrexate

Methotrexate is the anchor drug of RA treatment and the most important part of the initial antirheumatic treatment strategy. It can be combined with other synthetic or biological DMARDs. Its effects may be mediated at least partly via increased cellular adenosine release.64 Methotrexate may also have direct atheroprotective effects: in a model of cholesterol-fed rabbits, methotrexate reduced the size of atherosclerotic lesions by 75% and also diminished macrophage migration and presence of apoptotic cells in the vessel wall.65 From the beginning of the 2000s, mounting evidence from observational studies among RA cohorts point to an association of methotrexate use and reduced cardiovascular morbidity and mortality. In one prospective study of 1,240 RA patients with a mean follow-up of 6 years, after adjustment for relevant prognostic factors, cardiovascular mortality was reduced by as much as 70% and overall mortality by 60% in patients on methotrexate versus those never treated with methotrexate.66 According to a 2015 meta-analysis, methotrexate use for IJDs was associated with a 28% reduction in fatal and non-fatal cardiovascular events, based on eight observational studies.67 A recently published, wellpowered retrospective study using Medicare claims data on RA patients who were initiating biological DMARDs showed that concomitant methotrexate use was associated with a decreased risk of cardiovascular events also among biological DMARD users.68 Unmeasured confounding is naturally a threat to the validity of these findings. Ridker et al. conducted a large RCT of low-dose methotrexate compared with placebo in 4,786 patients with previous MI or multivessel CHD and

either type 2 diabetes or metabolic syndrome (CIRT).69 The study was terminated after a median follow-up of 2.3 years and methotrexate did not affect the rate of a composite CVD endpoint or the levels of IL-1β, IL-6 and CRP. It may be speculated whether an enrichment strategy with hsCRP to guide enrollment of patients into the study would have affected the outcome of the trial (median hsCRP at randomisation was only 1.6 mg/l). In contrast to ASCVD patients with low-grade inflammation, high RA disease activity often results in high-grade inflammation, which in most patients is well-controlled with methotrexate. Thus, it seems logical that the effect of methotrexate on CVD endpoints in RA is different from patients without IJD.

Other Conventional Synthetic DMARDs

Hydroxychloroquine, originally an antimalarial drug, may have cardioprotective effects through favourable changes in lipid and glucose metabolism.70 A safety pilot study of hydroxychloroquine compared with placebo for patients with MI to prevent recurrent cardiovascular events (NCT02648464) has now recruited 125 patients and if no important safety signals arise, the study will most likely be expanded to involve 2,500 patients. In one cross-sectional cohort of 4,363 patients with RA from 15 countries, use of not only methotrexate and biological DMARDs but also use of leflunomide and sulfasalazine was associated with a reduction in the risk of cardiovascular events.71 Leflunomide causes hypertension, and blood pressure must be monitored during treatment.72

TNF-α Inhibitors

If treatment with conventional synthetic DMARDs fails and RA disease activity is high, there is an indication for treatment with biological DMARDs. The most frequently prescribed biological DMARDs are TNF-α inhibitors, which have been in clinical use for two decades. In a 2015 meta-analysis of observational cohort studies among patients with IJD, anti-TNF-α therapy was associated with a 30% reduction in all cardiovascular events, 41% reduction in MIs, 43% reduction in strokes and up to 70% reduction in major adverse cardiac events (MACEs) when compared to other antirheumatic treatments.67 However, the decrease in ACS risk may not be similar in all patients treated with TNF-α inhibitors but conditional to treatment response. In a Swedish registry study among TNF-α inhibitor initiators with RA, 1-year risk of ACS was reduced by 50% among those with good treatment response compared to nonresponders.73 In addition, compared with the general population, nonresponders had a doubled risk of ACS but those with a good response had equal risk. TNF-α inhibitors may improve endothelial function and carotid intimamedia thickness among RA patients.61,63 However, in contrast to RA patients with high disease activity, patients with low disease activity or remission present no difference in carotid ultrasound findings or arterial stiffness compared with non-RA controls, suggesting that deceleration of these pre-atherosclerotic changes may be related to effective disease control rather than a certain DMARD.74 In the 1990s, preclinical data suggested that TNF-α played a role in the evolution and progression of heart failure. However, RCTs on TNF-α inhibitors etanercept and infliximab for moderate-to-severe heart failure did not show a beneficial effect on hospitalisation or death due to chronic heart failure.75,76 In fact, in the group with the highest infliximab dose of 10 mg/kg, the combined risk of death or hospitalisation for heart failure through 28 weeks compared to placebo was almost tripled.76 As a consequence, New York Heart Association III–IV heart failure is a contraindication for TNF-α inhibitors.

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Rheumatoid Arthritis and Atherosclerotic Cardiovascular Disease IL-6 Inhibitors

Tocilizumab and sarilumab are anti-IL-6 receptor monoclonal antibodies that are used in the treatment of RA. They are highly effective in suppressing systemic inflammation and normalising the production of acute phase reactants, especially CRP. IL-6 inhibitors increase lipid levels, which has raised concerns about their cardiovascular safety. A Phase IV non-inferiority trial addressed this issue by comparing tocilizumab to etanercept among 3,080 patients with seropositive RA and at least one CVD risk factor. During a mean follow-up of 3.2 years, the occurrence of MACE did not differ between the groups.77 Recently, signs of an atheroprotective effect of IL-6 receptor blockade in RA have been published. A meta-analysis of observational studies suggested that exposure to tocilizumab was associated with a lower risk of MACE but not stroke compared to exposure to TNF-α inhibitors.78 Despite elevations in TC, HDL-C and LDL-C, tocilizumab treatment incurs no change in TC/HDL-C ratio, and it may modify HDL particles towards an anti-inflammatory composition and also reduce lipoprotein (a) levels, which altogether may modify the risk towards a more favourable CVD outcome.60,79 Concomitant statin treatment with tocilizumab seems to be effective for lipid reduction.80 Of note, in patients using IL-6 inhibitors treatment with fluvastatin, pravastatin or rosuvastatin should be chosen, since IL-6 inhibitors may affect cytochrome P450 3A4 (CYP3A4) activity and thus the efficacy of other statins.2 The effect of IL-6 receptor blockade has also been explored for ACS. In an RCT including 121 patients with non-ST-elevation MI (STEMI) scheduled for coronary angiography, a single dose of tocilizumab not only lowered hsCRP levels as expected, but also attenuated the increase in troponin T during hospitalisation, suggesting a smaller infarct size.81 These findings are being further explored in an ongoing study (NCT03004703), in which 200 patients with first-time STEMI will be randomised to receive either tocilizumab or placebo prior to percutaneous coronary intervention with a primary endpoint of myocardial salvage index measured by cardiac MRI 3–7 days after the intervention.

IL-1 inhibitors

There are currently three IL-1 inhibitors available on the market: the IL-1 receptor antagonist anakinra, the soluble decoy receptor rilonacept and the monoclonal IL-1β antibody canakinumab. Of these, only anakinra is approved for the treatment of RA and its efficacy compared to other biological DMARDs is limited. In contrast, IL-1 inhibitors are highly effective in the treatment of certain autoinflammatory diseases. Evidence from rather small clinical trials imply that anakinra may reduce glycated haemoglobin levels among RA patients with diabetes and improve cardiac function, i.e. left ventricular longitudinal strain and coronary flow reserve.82,83 Cardiovascular effects of anakinra have been explored outside rheumatic diseases. In an RCT among 182 non-STEMI patients, 14-day treatment with anakinra attenuated inflammatory response following MI.84 In two pilot studies with a total of 70 patients hospitalised for STEMI, anakinra not only blunted inflammatory response but also improved left ventricle systolic volume index in cardiac MRI and seemed to reduce the incidence of newonset heart failure compared to placebo, suggesting a favourable effect on left ventricle remodelling and function.85 A pivotal proof-of-concept trial for the inflammatory hypothesis of atherothrombosis, CANTOS, recruited 10,061 patients with prior MI and persistent elevation of hsCRP >2 mg/l. Canakinumab 150 mg, but not 50 mg, reduced the incidence of a combined endpoint of stroke, MI or CVD

death by 15% (HR 0.85; 95% CI [0.74–0.98]; p=0.021) compared with placebo over 48 months of follow-up.86 A similar reduction in the primary endpoint was observed for canakinumab 300 mg, but this did not meet the prespecified threshold for statistical significance.

Other Biological DMARDs and JAK Inhibitors

Abatacept, an inhibitor of co-stimulation of T-cells, was found to be associated with a decreased risk of a composite CVD endpoint compared to conventional DMARDs in a large prospective observational study from the US.87 A similar effect was not observed for rituximab, a monoclonal anti-CD20 antibody. JAK inhibitors are targeted synthetic DMARDs that modulate the cytokine receptor-mediated intracellular signalling cascades. In phase II and III RCTs, a safety signal of a dose-dependent increase in the risk of venous thromboembolism (VTE) was identified with JAK inhibitor tofacitinib.88 However, a recent meta-analysis of RCTs reporting JAK inhibitor safety data revealed no increased risk of all CVD, MACE or VTE, with the exception that baricitinib 2 mg daily was safer than 4 mg with regard to all CVD.89 Caution should be taken when prescribing JAK inhibitors to patients with risk factors for VTE. Similar to IL-6 inhibitors, JAK inhibitors increase cholesterol levels, a side-effect that can be well-controlled with statins.90

Non-steroidal Anti-inflammatory Drugs, Glucocorticoids and Colchicine

Non-steroidal anti-inflammatory drugs (NSAIDs) are often used for rheumatic pain. Long-term use of NSAIDs, especially cyclo-oxygenase-2 selective inhibitors, has been associated with increased risk of CVD. This also holds true in patients with IJD.67 NSAIDs should be used with caution, especially in the presence of CVD risk factors or CVD.43,91 Glucocorticoids have well-known side-effects that amplify CVD risk, including weight gain, hypertension and insulin resistance. Observational studies have demonstrated that low-dose glucocorticoid use in IJD is associated with an approximate 50% increase in CVD risk.67 This association is dependent on glucocorticoid dosage and cumulative exposure.92 It is unclear, however, to which extent these results are affected by confounding by indication. This question may be answered by the GLORIA study which is assessing the harm, benefit and costs of 5 mg prednisolone daily versus placebo added to standard care in RA patients >65 years (NCT02585258). Glucocorticoids should be used for RA with the minimum effective dosage and tapered in case of remission or low disease activity. Although not used in the treatment of RA but in gout, colchicine, an antiinflammatory drug that inhibits tubulin polymerisation, microtubule generation and putatively also NLRP3 inflammasome activation, deserves attention (Figure 1).93 Two large RCTs have shown that colchicine reduces the risk of cardiovascular events compared to placebo after acute MI and in chronic CHD.94,95

Conclusion

RA patients have an increased ASCVD burden that is linked to disease activity, systemic inflammation, traditional CVD risk factors and a paradoxical decrease in lipid levels. Rheumatoid synovitis and unstable atherosclerotic plaque share common inflammatory pathophysiological mechanisms, such as expression of proinflammatory cytokines IL-1, TNF-α and IL-6. Increased CVD risk in RA may be reduced by addressing CVD risk factors and suppression of inflammation with effective antirheumatic

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Rheumatoid Arthritis and Atherosclerotic Cardiovascular Disease therapy. However, awareness of this phenomenon is still low in RA patients and healthcare professionals and CVD risk factors often remain undertreated in this high-risk population.

to RA patients with regard to their individual CVD risk. Furthermore, RA patients would most probably benefit from more structured CVD prevention programmes, such as in diabetes care.

Several DMARDs, especially methotrexate, TNF-α inhibitors and IL-6 inhibitors, seem to improve various biomarkers of CVD and reduce cardiovascular events in observational studies among RA cohorts. It is uncertain, however, whether these observations are due to reduced disease activity in general or to specific atheroprotective effects. The former theory is supported by the notion that CVD risk and its surrogate markers seem to correlate with treatment response to antirheumatic medication. More research is warranted on tailoring of DMARD treatment

Anti-inflammatory therapies – especially IL-1 inhibitors and colchicine – are promising agents to reduce inflammation-mediated residual risk of recurrent cardiovascular events among ASCVD patients. Further evaluation of IL-6 and IL-1 inhibitors as adjunct therapy for MI is warranted. Lessons from RA, a natural model of high-grade inflammation, can be used to understand the inflammatory mechanisms of atherosclerosis also in the general population and to identify novel targets for ASCVD treatment.

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cytokines and risk of coronary heart disease: new prospective study and updated meta-analysis. Eur Heart J 2014;35:578–89. https://doi.org/10.1093/eurheartj/eht367; PMID: 24026779. 32. Dixon WG, Symmons DP. What effects might anti-TNFα treatment be expected to have on cardiovascular morbidity and mortality in rheumatoid arthritis? A review of the role of TNFα in cardiovascular pathophysiology. Ann Rheum Dis 2007;66:1132–6. https://doi.org/10.1136/ard.2006.063867; PMID: 17251223. 33. Rho YH, Chung CP, Oeser A, et al. Inflammatory mediators and premature coronary atherosclerosis in rheumatoid arthritis. Arthritis Rheum 2009;61:1580–5. https://doi. org/10.1002/art.25009; PMID: 19877084. 34. Robertson J, Peters MJ, McInnes IB, et al. Changes in lipid levels with inflammation and therapy in RA: a maturing paradigm. Nat Rev Rheumatol 2013;9:513–23. https://doi. org/10.1038/nrrheum.2013.91; PMID: 23774906. 35. Myasoedova E, Crowson CS, Kremers HM, et al. Lipid paradox in rheumatoid arthritis: the impact of serum lipid measures and systemic inflammation on the risk of cardiovascular disease. Ann Rheum Dis 2011;70:482–7. https://doi.org/10.1136/ard.2010.135871; PMID: 21216812. 36. Giles JT, Wasko MCM, Chung CP, et al. Exploring the lipid paradox theory in rheumatoid arthritis: associations of low circulating low-density lipoprotein concentration with subclinical coronary atherosclerosis. Arthritis Rheumatol 2019;71:1426–36. https://doi.org/10.1002/art.40889; PMID: 30883031. 37. Fernandez-Ortiz AM, Ortiz AM, Perez S, et al. Effects of disease activity on lipoprotein levels in patients with early arthritis: can oxidized LDL cholesterol explain the lipid paradox theory? Arthritis Res Ther 2020;22:213–8. https://doi. org/10.1186/s13075-020-02307-8; PMID: 32917272. 38. McMahon M, Grossman J, FitzGerald J, et al. Proinflammatory high-density lipoprotein as a biomarker for atherosclerosis in patients with systemic lupus erythematosus and rheumatoid arthritis. Arthritis Rheum 2006;54:2541–9. https://doi.org/10.1002/art.21976; PMID: 16868975. 39. Yu Z, Kim SC, Vanni K, et al. Association between inflammation and systolic blood pressure in RA compared to patients without RA. Arthritis Res Ther 2018;20:107–9. https:// doi.org/10.1186/s13075-018-1597-9; PMID: 29855349. 40. Escalante A, Haas RW, del Rincon I. Paradoxical effect of body mass index on survival in rheumatoid arthritis: role of comorbidity and systemic inflammation. Arch Intern Med 2005;165:1624–9. https://doi.org/10.1001/ archinte.165/14/1624; PMID: 16043681. 41. Nicolau J, Lequerre T, Bacquet H, et al. Rheumatoid arthritis, insulin resistance, and diabetes. Joint Bone Spine 2017;84:411–6. https://doi.org/10.1016/j.jbspin.2016.09.001; PMID: 27777170. 42. Alonso-Molero J, Prieto-Pena D, Mendoza G, et al. Misperception of the cardiovascular risk in patients with rheumatoid arthritis. Int J Environ Res Public Health 2020;17:5954. https://doi.org/10.3390/ijerph17165954; PMID: 32824469. 43. Agca R, Heslinga SC, Rollefstad S, et al. EULAR recommendations for cardiovascular disease risk management in patients with rheumatoid arthritis and other forms of inflammatory joint disorders: 2015/2016 update. Ann Rheum Dis 2017;76:17–28. https://doi.org/10.1136/ annrheumdis-2016-209775; PMID: 27697765. 44. Weijers JM, Semb, AG, Rollefstad S, et al. Strategies for implementation of guideline recommended cardiovascular risk management for patients with rheumatoid arthritis: results from a questionnaire survey of expert rheumatology centers. Rheumatol Int 2020;40:523–7. https://doi.

Rheumatoid Arthritis and Atherosclerotic Cardiovascular Disease org/10.1007/s00296-020-04533-4; PMID: 32088752. 45. Semb AG, Rollefstad S, van Riel P, et al. Cardiovascular disease assessment in rheumatoid arthritis: a guide to translating knowledge of cardiovascular risk into clinical practice. Ann Rheum Dis 2014;73:1284–8. https://doi. org/10.1136/annrheumdis-2013-204792; PMID: 24608403. 46. Arts EE, Popa C, Den Broeder AA, et al. Performance of four current risk algorithms in predicting cardiovascular events in patients with early rheumatoid arthritis. Ann Rheum Dis 2015;74:668–74. https://doi.org/10.1136/ annrheumdis-2013-204024; PMID: 24389293. 47. Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/ AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation 2019;139:e1046–81. https://doi.org/10.1161/CIR.0000000000000624; PMID: 30423391. 48. Crowson CS, Rollefstad S, Kitas GD, et al. Challenges of developing a cardiovascular risk calculator for patients with rheumatoid arthritis. PLoS One 2017;12:e0174656. https://doi. org/10.1371/journal.pone.0174656; PMID: 28334012. 49. Solomon DH, Greenberg J, Curtis JR, et al. Derivation and internal validation of an expanded cardiovascular risk prediction score for rheumatoid arthritis: a Consortium of Rheumatology Researchers of North America registry study. Arthritis Rheumatol 2015;67:1995–2003. https://doi. org/10.1002/art.39195; PMID: 25989470. 50. Crowson CS, Gabriel SE, Semb AG, et al. Rheumatoid arthritis-specific cardiovascular risk scores are not superior to general risk scores: a validation analysis of patients from seven countries. Rheumatology (Oxford) 2017;56:1102–10. https://doi.org/10.1093/rheumatology/kex038; PMID: 28339992. 51. Jamthikar AD, Gupta D, Puvvula A, et al. Cardiovascular risk assessment in patients with rheumatoid arthritis using carotid ultrasound B-mode imaging. Rheumatol Int 2020;40:1921–39. https://doi.org/10.1007/s00296-02004691-5; PMID: 32857281. 52. Semb AG, Ikdahl E, Hisdal J, et al. Exploring cardiovascular disease risk evaluation in patients with inflammatory joint diseases. Int J Cardiol 2016;223:331–6. https://doi. org/10.1016/j.ijcard.2016.08.129; PMID: 27543704. 53. Kitas GD, Nightingale P, Armitage J, et al. A multicenter, randomized, placebo-controlled trial of atorvastatin for the primary prevention of cardiovascular events in patients with rheumatoid arthritis. Arthritis Rheumatol 2019;71:1437–49. https://doi.org/10.1002/art.40892; PMID: 30983166. 54. Pedersen TR, Kjekshus J, Berg K, et al. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994;344:1383–9. https://doi.org/10.1016/S01406736(94)90566-5; PMID: 7968073. 55. Semb AG, Kvien TK, DeMicco DA, et al. Effect of intensive lipid-lowering therapy on cardiovascular outcome in patients with and those without inflammatory joint disease. Arthritis Rheum 2012;64:2836–46. https://doi.org/10.1002/ art.34524; PMID: 22576673. 56. Lv S, Liu Y, Zou Z, et al. The impact of statins therapy on disease activity and inflammatory factor in patients with rheumatoid arthritis: a meta-analysis. Clin Exp Rheumatol 2015;33:69–76. PMID: 25327393. 57. Roelsgaard IK, Ikdahl E, Rollefstad S, et al. Smoking cessation is associated with lower disease activity and predicts cardiovascular risk reduction in rheumatoid arthritis patients. Rheumatology (Oxford) 2020;59:1997–2004. https:// doi.org/10.1093/rheumatology/kez557; PMID: 31782789. 58. Fagerhøi MG, Rollefstad S, Olsen SU, Semb AG. The effect of brief versus individually tailored dietary advice on change in diet, lipids and blood pressure in patients with inflammatory joint disease. Food Nutr Res 2018;62. https:// doi.org/10.29219/fnr.v62.1512; PMID: 30202399. 59. Veldhuijzen van Zanten JJ, Rouse PC, Hale ED, et al. Perceived barriers, facilitators and benefits for regular physical activity and exercise in patients with rheumatoid arthritis: a review of the literature. Sports Med 2015;45:1401– 12. https://doi.org/10.1007/s40279-015-0363-2; PMID: 262619268. 60. McInnes IB, Thompson L, Giles JT, et al. Effect of interleukin-6 receptor blockade on surrogates of vascular risk in rheumatoid arthritis: MEASURE, a randomised, placebo-controlled study. Ann Rheum Dis 2015;74:694–702. https://doi.org/10.1136/annrheumdis-2013-204345; PMID: 24368514. 61. Del Porto F, Lagana B, Lai S, et al. Response to anti-tumour necrosis factor alpha blockade is associated with reduction of carotid intima-media thickness in patients with active

rheumatoid arthritis. Rheumatology (Oxford) 2007;46:1111–5. https://doi.org/10.1093/rheumatology/kem089; PMID: 17449484. 62. Li HZ, Xu XH, Lin N, Lu HD. Metabolic and cardiovascular benefits of hydroxychloroquine in patients with rheumatoid arthritis: a systematic review and meta-analysis. Ann Rheum Dis 2019;78:e21. https://doi.org/10.1136/ annrheumdis-2018-213157; PMID: 29453218. 63. Hurlimann D, Forster A, Noll G, et al. Anti-tumor necrosis factor-alpha treatment improves endothelial function in patients with rheumatoid arthritis. Circulation 2002;106:2184–7. https://doi.org/10.1161/01. cir.0000037521.71373.44; PMID: 12390945. 64. Chan ES, Cronstein BN. Methotrexate – how does it really work? Nat Rev Rheumatol 2010;6:175–8. https://doi. org/10.1038/nrrheum.2010.5; PMID: 20197777. 65. Bulgarelli A, Martins Dias AA, Caramelli B, et al. Treatment with methotrexate inhibits atherogenesis in cholesterol-fed rabbits. J Cardiovasc Pharmacol 2012;59:308–14. https://doi. org/10.1097/FJC.0b013e318241c385; PMID: 22113347. 66. Choi HK, Hernan MA, Seeger JD, et al. Methotrexate and mortality in patients with rheumatoid arthritis: a prospective study. Lancet 2002;359:1173–7. https://doi.org/10.1016/S01406736(02)08213-2; PMID: 11955534. 67. Roubille C, Richer V, Starnino T, et al. The effects of tumour necrosis factor inhibitors, methotrexate, non-steroidal antiinflammatory drugs and corticosteroids on cardiovascular events in rheumatoid arthritis, psoriasis and psoriatic arthritis: a systematic review and meta-analysis. Ann Rheum Dis 2015;74:480–9. https://doi.org/10.1136/ annrheumdis-2014-206624; PMID: 25561362. 68. Xie F, Chen L, Yun H, et al. Benefits of methotrexate use on cardiovascular disease risk among rheumatoid arthritis patients initiating biologic disease-modifying antirheumatic drugs. J Rheumatol 2020. https://doi.org/10.3899/ jrheum.191326; PMID: 33060309; epub ahead of press. 69. Ridker PM, Everett BM, Pradhan A, et al. Low-dose methotrexate for the prevention of atherosclerotic events. N Engl J Med 2019;380:752–62. https://doi.org/10.1056/ NEJMoa1809798; PMID: 30415610. 70. Rempenault C, Combe B, Barnetche T, et al. Metabolic and cardiovascular benefits of hydroxychloroquine in patients with rheumatoid arthritis: a systematic review and metaanalysis. Ann Rheum Dis 2018;77:98–103. https://doi. org/10.1136/annrheumdis-2017-211836; PMID: 28970215. 71. Naranjo A, Sokka T, Descalzo MA, et al. Cardiovascular disease in patients with rheumatoid arthritis: results from the QUEST-RA study. Arthritis Res Ther 2008;10:R30. https:// doi.org/10.1186/ar2383; PMID: 18325087. 72. Rozman B, Praprotnik S, Logar D, et al. Leflunomide and hypertension. Ann Rheum Dis 2002;61:567–9. https://doi. org/10.1136/ard.61.6.567; PMID: 12006342. 73. Ljung L, Rantapaa-Dahlqvist S, Jacobsson LT, et al. Response to biological treatment and subsequent risk of coronary events in rheumatoid arthritis. Ann Rheum Dis 2016;75:2087–94. https://doi.org/10.1136/ annrheumdis-2015-208995; PMID: 26984007. 74. Arida A, Protogerou, AD, Konstantonis G, et al. Atherosclerosis is not accelerated in rheumatoid arthritis of low activity or remission, regardless of antirheumatic treatment modalities. Rheumatology (Oxford) 2017;56:934–9. https://doi.org/10.1093/rheumatology/kew506; PMID: 28160488. 75. Mann DL, McMurray JJ, Packer M, et al. Targeted anticytokine therapy in patients with chronic heart failure: results of the Randomized Etanercept Worldwide Evaluation (RENEWAL). Circulation 2004;109:1594–602. https://doi. org/10.1161/01.CIR.0000124490.27666.B2; PMID: 15023878. 76. Chung ES, Packer M, Lo KH, et al. Randomized, doubleblind, placebo-controlled, pilot trial of infliximab, a chimeric monoclonal antibody to tumor necrosis factor-alpha, in patients with moderate-to-severe heart failure: results of the anti-TNF Therapy Against Congestive Heart Failure (ATTACH) trial. Circulation 2003;107:3133–40. https://doi.org/10.1161/01. CIR.0000077913.60364.D2; PMID: 12796126. 77. Giles JT, Sattar N, Gabriel S, et al. Cardiovascular safety of tocilizumab versus etanercept in rheumatoid arthritis: a randomized controlled trial. Arthritis Rheumatol 2020;72:31– 40. https://doi.org/10.1002/art.41095; PMID: 31469238. 78. Singh S, Fumery M, Singh AG, et al. Comparative risk of cardiovascular events with biologic and synthetic diseasemodifying antirheumatic drugs in patients with rheumatoid arthritis: a systematic review and meta-analysis. Arthritis Care Res (Hoboken) 2020;72:561–76. https://doi.org/10.1002/ acr.23875; PMID: 30875456. 79. Cacciapaglia F, Anelli MG, Rinaldi A, et al. Lipids and atherogenic indices fluctuation in rheumatoid arthritis patients on long-term tocilizumab treatment. Mediators

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Inflamm 2018;2018:2453265. https://doi. org/10.1155/2018/2453265; PMID: 30405318. 80. Soubrier M, Pei J, Durand F, et al. Concomitant use of statins in tocilizumab-treated patients with rheumatoid arthritis: a post hoc analysis. Rheumatol Ther 2017;4:133–49. https://doi.org/10.1007/s40744-016-0049-8; PMID: 27900570. 81. Kleveland O, Kunszt G, Bratlie M, et al. Effect of a single dose of the interleukin-6 receptor antagonist tocilizumab on inflammation and troponin T release in patients with non-STelevation myocardial infarction: a double-blind, randomized, placebo-controlled phase 2 trial. Eur Heart J 2016;37:2406– 13. https://doi.org/10.1093/eurheartj/ehw171; PMID: 27161611. 82. Ruscitti P, Masedu F, Alvaro S, et al. Anti-interleukin-1 treatment in patients with rheumatoid arthritis and type 2 diabetes (TRACK): a multicentre, open-label, randomised controlled trial. PLoS Med 2019;16:e1002901. https://doi. org/10.1371/journal.pmed.1002901; PMID: 31513665. 83. Ikonomidis I, Pavlidis G, Katsimbri P, et al. Differential effects of inhibition of interleukin 1 and 6 on myocardial, coronary and vascular function. Clin Res Cardiol 2019;108:1093–101. https://doi.org/10.1007/s00392-019-01443-9; PMID: 30859382. 84. Morton AC, Rothman AM, Greenwood JP, et al. The effect of interleukin-1 receptor antagonist therapy on markers of inflammation in non-ST elevation acute coronary syndromes: the MRC-ILA Heart Study. Eur Heart J 2015;36:377–84. https://doi.org/10.1093/eurheartj/ehu272; PMID: 25079365. 85. Abbate A, Van Tassell BW, Biondi-Zoccai G, et al. Effects of interleukin-1 blockade with anakinra on adverse cardiac remodeling and heart failure after acute myocardial infarction [from the Virginia Commonwealth UniversityAnakinra Remodeling Trial (2) (VCU-ART2) pilot study. Am J Cardiol 2013;111:1394–400. https://doi.org/10.1016/j. amjcard.2013.01.287; PMID: 23453459. 86. Ridker PM, Everett BM, Thuren T, et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med 2017;377:1119–131. https://doi.org/10.1056/ NEJMoa1707914; PMID: 28845751. 87. Ozen G, Pedro S, Michaud K. The risk of cardiovascular events associated with disease-modifying antirheumatic drugs in rheumatoid arthritis. J Rheumatol 2020. https://doi. org/10.3899/jrheum.200265; PMID: 32801134; epub ahead of press. 88. Sandborn WJ, Panes J, Sands BE, et al. Venous thromboembolic events in the tofacitinib ulcerative colitis clinical development programme. Aliment Pharmacol Ther 2019;50:1068–76. https://doi.org/10.1111/apt.15514; PMID: 31599001. 89. Xie W, Huang Y, Xiao S, et al. Impact of Janus kinase inhibitors on risk of cardiovascular events in patients with rheumatoid arthritis: systematic review and meta-analysis of randomised controlled trials. Ann Rheum Dis 2019;78:1048– 54. https://doi.org/10.1136/annrheumdis-2018-214846; PMID: 31088790. 90. Taylor PC, Kremer JM, Emery P, et al. Lipid profile and effect of statin treatment in pooled phase II and phase III baricitinib studies. Ann Rheum Dis 2018;77:988–95. https:// doi.org/10.1136/annrheumdis-2017-212461; PMID: 29463520. 91. Lindhardsen J, Gislason GH, Jacobsen S, et al. Non-steroidal anti-inflammatory drugs and risk of cardiovascular disease in patients with rheumatoid arthritis: a nationwide cohort study. Ann Rheum Dis 2014;73:1515–21. https://doi.org/10.1136/ annrheumdis-2012-203137; PMID: 23749610. 92. Avina-Zubieta JA, Abrahamowicz M, De Vera MA, et al. Immediate and past cumulative effects of oral glucocorticoids on the risk of acute myocardial infarction in rheumatoid arthritis: a population-based study. Rheumatology (Oxford) 2013;52:68–75. https://doi.org/10.1093/ rheumatology/kes353; PMID: 23192907. 93. Demidowich AP, Davis AI, Dedhia N, et al. Colchicine to decrease NLRP3-activated inflammation and improve obesity-related metabolic dysregulation. Med Hypotheses 2016;92:67–73. https://doi.org/10.1016/j.mehy.2016.04.039; PMID: 27241260. 94. Tardif JC, Kouz S, Waters DD, et al. Efficacy and safety of low-dose colchicine after myocardial infarction. N Engl J Med 2019;381:2497–505. https://doi.org/10.1056/NEJMoa1912388; PMID: 31733140. 95. Nidorf SM, Fiolet ATL, Mosterd A, et al. Colchicine in patients with chronic coronary disease. N Engl J Med 2020;383:1838–47. https://doi.org/10.1056/NEJMoa2021372; PMID: 32865380. 96. Choy E, Ganeshalingam K, Semb AG, et al. Cardiovascular risk in rheumatoid arthritis: recent advances in the understanding of the pivotal role of inflammation, risk predictors and the impact of treatment. Rheumatology (Oxford) 2014;53:2143–54. https://doi.org/10.1093/ rheumatology/keu224; PMID: 24907149.

Ischaemic Heart Disease

The Association Between Psoriasis and Cardiovascular Diseases Ahmed Zwain ,1 Mohanad Aldiwani

and Hussein Taqi

1. North West Deanery, Aintree University Hospital, Liverpool, UK; 2. East Midlands Deanery, University Hospitals of Leicester NHS Trust, Leicester, UK. 3. East Midlands Deanery, Royal Derby Hospital, Derby, UK

Abstract

Cardiovascular diseases and psoriasis have been well established as separate entities, however, there is uncertainty with regards to a link between the two diseases. A few environmental, psychological and social factors have been implicated as potential common risk factors that may exacerbate the two diseases, and an array of complex immune and non-immune inflammatory mediators can potentially explain a plausible link. Pharmacotherapy has also played a role in establishing a potential association, especially with the advent of biological agents which directly act on inflammatory factors shared by the two diseases. This review will look at existing evidence and ascertain a potential correlation between the two.

Keywords

Psoriasis, psoriasis vulgaris, cardiovascular risk, ischaemic heart disease, MI, vascular disease, atherosclerosis, hyperlipidaemia, pathophysiology, inflammation, cytokines Disclosure: The authors have no conflicts of interest to declare. Received: 29 April 2020 Accepted: 16 February 2021 Citation: European Cardiology Review 2021;16:e19. DOI: https://doi.org/10.15420/ecr.2020.15.R2 Correspondence: Ahmed Zwain, Aintree University Hospital, Liverpool L9 7AL, UK. E: dr_zwain@yahoo.com Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Psoriasis is a chronic inflammatory skin disorder, and one of the most common skin diseases that presents in everyday dermatology practice. It is characterised by overgrowth of keratinocytes in the skin tissue, with complex underlying inflammatory processes playing a role in its pathogenesis.1 An extensive inflammatory response in different body systems aggravated by a dysregulated immune system is thought to play a pivotal role in its pathogenesis.2–4 The correlation between these complicated immune and non-immune responses have been thoroughly investigated to establish an appropriate management strategy for the disease and to set up a foundation for its multifactorial association with other systemic comorbidities, most importantly cardiac diseases.5 According to the General Practice Research Database (GPRD) there is a strong suggestion that there is an increased independent association between cardiovascular disease (CVD) and severe psoriasis, particularly in younger patients.6 This was further confirmed in a study performed by Ludwig et al., who suggested that psoriasis could act as an independent risk factor for composite cardiovascular outcomes.7 However, this suggestion was soon opposed by another GPRD database study by Parisi et al. who abandoned the hypothesis of the relationship between the two entities even after the adjustment for traditional risk factors.8 Nevertheless, the prevalence of CVDs as a leading cause for higher mortality rates among patients with psoriasis compared to other causes such as infection or end-stage disease.2,3,9 Hypertension, diabetes, hyperlipidaemia and non-alcohol fatty liver disease are all modifiable risk factors in CVDs and they have been reported in psoriasis with a parallel rise in accordance with disease severity.2,3,10,11 This is of paramount importance among all systemic comorbidities caused by psoriasis, due to

its direct effect on life expectancy, especially in advanced cases.2 The disease is not only confined to the skin tissue. It has various systematic, cellular, immune and non-immune mechanisms referred to as psoriasis march.12 This concept was first introduced in 2011 as a notion that severe psoriatic inflammation may lead to insulin resistance and vascular dysfunction preceding acute MI and stroke development.13 However, there is still an independent association between psoriasis and CVD.

Epidemiology

Psoriasis is a chronic inflammatory multisystemic skin condition, primarily affecting skin and joints.14 It is characterised by scaly skin lesions in the form of patches, plaques or pustules with episodes of relapse and remission. The prevalence of psoriasis is approximately 2% worldwide, with more than 50% of the cases presenting in the first three decades of life.15 There are two common ages for its predominance: the initial presentation is usually experienced during the second decade of life while the second presentation often occurs in the patient’s fifties.16 The prevalence of psoriasis varies according to geographical location, with higher rates among Caucasians when compared with other ethnicities.10 It is also argued that countries located away from the equator have shown a higher prevalence of the disease when compared to warmer climates where the reported cases are relatively lower.17 This variation is thought to be related to various degrees of genetic and environmental factors.10 Nevertheless, cardiac diseases are also more common in these geographical locations and that could be attributed to similar risk factors. The life expectancy of people with psoriasis was reported to be nearly 5 years lower compared to control groups, with cardiovascular problems being the main cause of death.9 The disease also has a significant impact

The Relationship Between Psoriasis and Cardiovascular Diseases on physical and mental well-being, with a subsequent impact on heart disease as a result.18,19 The majority of deaths for people with psoriasis are related to cardiovascular or cerebrovascular morbidities, such as MI or stroke, and not solely to renal diseases or infection as previously thought.9 There is evidence of an increased risk of major cardiovascular events in patients with psoriasis and it has a direct and linear relationship with disease severity.20 Ahlehoff et al. noted that the risk of cardiovascularrelated death was higher with severe psoriasis (RR 1.39; 95% CI [1.11–1.74]) rather than with a mild form of psoriasis (RR 1.03; 95% CI [0.86–1.25]).21

Risk Factors in Psoriasis and CVD Genetic

The association between psoriasis and CVD has led researchers to further investigate the links between the two in the hope of discovering genetic loci shared between them. However, to date, there is no established genetic association between psoriasis and CVD shown in the Genomewide Association Studies. Observational studies have shown that psoriasis patients have high levels of homocysteine, resulting from demethylation of DNA. It was found that polymorphism of methylenetetrahydrofolate reductase can lead to DNA methylation, and several studies have demonstrated that homocysteine is an independent risk factor in CVD.22 The caspase recruitment domain-containing protein 14 (CARD14) gene has been investigated for its mutation and the link with psoriasis. CARD14 is mainly expressed in dermal keratinocytes and some unidentified dermal cells.23 A study by Harden et al. highlighted the expression of CARD14 in aortic endothelial cells, which might indicate a relation between CVD and psoriasis; this is an area that requires further research.24

Environmental

Obesity has been thought to be a key contributor in the development of both diseases. A strong link between high BMI and the development of both diseases has been explained in a robust systematic review which demonstrated that the incidence and prevalence of obesity are higher in patients with psoriasis and it is independently associated with CVD.25 Furthermore, obesity is linked to the metabolic syndrome, which induces a systemic inflammation caused by five pathological mechanisms: abdominal obesity, impaired glucose tolerance, hypertriglyceridaemia, hypertension and low levels of HDL cholesterol. A meta-analysis conducted by Choudhary et el. demonstrated that 30.3% of patients with psoriasis had metabolic syndrome.26 Similarly, Mottillo et al. reported that the metabolic syndrome is associated with a twofold increase in cardiovascular outcomes and a 1.5-fold increase in all-cause mortality.27 Visceral adipose tissue triggers the release of adipokines, which in turn lead to the development of insulin resistance and endothelial cell damage. This cascade of events prompts the formation of atherosclerotic plaques which enhances the process of CVD.28

Psychological

Stress is another factor implicated in the aetiology of both diseases, with its negative sequelae in leukocyte catalysis and surge of inflammatory factors in the tissue areas. It was thought that patients with higher levels of stress can have severe psoriatic flare ups. However, recent studies have not revealed a strong link between perceived stress and the severity degree of psoriasis.29

Social

Smoking is a strongly recognised risk factor for CVD. It is also implicated in the disease process of psoriasis. The disease prevalence is higher among smokers and continues to rise despite smoking cessation. It has been demonstrated that patients who smoke more than 20 cigarettes per

day are associated with a twofold risk of severe psoriasis with more cases reported of pustular psoriasis.30,31 Moreover, the relationship between alcohol and CVD is well established, whereas it is more complex with psoriasis. A higher consumption of alcohol has been seen in patients with severe psoriasis and studies have confirmed a rise in CVD in these subgroups.32,33

The Pathogenic Connection Between Psoriasis and Vascular Disease

The precise correlation between psoriasis and CVD is not yet fully understood. The hypothesis of the impact of deep inflammatory processes at cellular level has been postulated.4 Inflammatory mediators with various cytokines have been identified as playing a major role in psoriasis, including interleukins (IL)-1,4,6,8 and 12 and tumour necrosis factor-α (TNF-α).34

Atherosclerosis

Atherosclerosis is a progressive disease caused by the deposition of lipid with a superimposed fibrous cap. This often occurs over decades, eventually leading to cardiovascular and cerebrovascular diseases, such as MI and stroke.35 Studies have also found that the underlying inflammation plays an essential role in the progression of atheroma and the eventual rapture of the plaque.36 At cellular level, atherosclerosis is associated with inflammatory cytokines, such as TNF-α and IL-1, which overlap with the same markers implicated in psoriasis (Figure 1).37 This process initially starts with T-helper cells 1 (Th1), which are a subdivision of active T-cells and the main active T-cells in psoriasis followed by the activation of macrophages, neutrophils and CD8 cytotoxic T-lymphocyte.38,39 In psoriatic plaque, Th1 cytokines, interferon-y (INF-y), IL-2, and TNF-α catalyse keratinocytes and stimulate the production of inflammatory cytokines (TNF-α, IL-1β and IL-6) and chemokines ligands 8, 9, 10, 11 and 20.40 Following this, the migrated T-cells to the dermis require upregulation of adhesive molecules and once E-selectin is upregulated in the dermal microvasculature of inflamed cutaneous tissue, it acts as a ligand for the cutaneous lymphocyte antigen in the memory T-cells. Consequently, the binding of T-cells to the adhesion molecules will further enhance the migration of more T-cells into the dermis and hence provoke more inflammation. Simultaneously, the raised levels of circulating Th1 cytokines such as TNF-α also lead to endothelial dysfunction and extravasation of T-cells into the site of atherosclerotic plaque.41 The activated dendritic cells produce IL-12, which will later activate transcription factor signal transducer and activator of transcription 4 and subsequently trigger the release of large amounts of INF-y, leading to further Th1 differentiation. The activation of Th1 enhanced by IL-12 is well recognised in psoriasis and atherosclerosis, therefore, there would be assumptions that downstream release of cytokines are shared in the pathogenesis of the two conditions.35 More recent studies have shown that patients with psoriasis have an increased non-calcified lipid-rich atherosclerotic coronary plaque burden (NCB). This NCB has been reported to be mediated by immunological abnormalities and impaired HDL function.42 In fact, psoriasis patients have significantly higher levels of oxidation-modified lipids (OMLs), including oxidised LDL (oxLDL), HDL (oxHDL) and lipoprotein (a) – oxLp(a) – which promote a proatherogenic lipoprotein profile and an impaired HDLcholesterol efflux capacity (CEC).42 Furthermore, oxLDL initiates a cascade of biochemical reactions leading to endothelial cell dysfunction and atherosclerotic plaque formation.43 Additionally, in vitro experiments have shown low doses of oxLDL to be sufficient to activate macrophages and

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The Relationship Between Psoriasis and Cardiovascular Diseases mast cells to synergistically increase monocyte-endothelium adhesion, which contributes to endothelial dysfunction and early atherogenesis.44

Psoriatic plaque

Thickened epidermis

Dermis

4 AT ST

Neutrophils Macrophages IL-12

Platelets are also immune cells that trigger and regulate immune and inflammatory processes and their dysfunction is deeply involved in the pathogenesis of psoriasis.48 Liu et al. demonstrated that platelets from patients with psoriasis showed a significantly increased percentage of platelet aggregation, which is positively correlated with disease severity. Additionally, activated platelets could stimulate an inflammatory environment by releasing biologically active molecules in some skin disorders, such as psoriasis, systemic lupus erythematous and multiple sclerosis.49 Cytokines released by activated platelets are reported to play a key role in psoriasis. Platelets are the major source of IL-1β, and an increased IL-1 level is involved in the development and progression of inflammation in psoriasis. Serotonin derived from platelet-dense granules is also expressed in psoriatic skin to modulate the immune response.50

Psoriasis and Coronary Microvascular Dysfunction

The chronic exposure to systemic inflammation in patients with severe psoriasis can result in coronary microvascular dysfunction (CMD). This may lead to the impairment of the coronary arteries’ ability to augment coronary blood flow (vasodilatory abnormality) and/or in a reduction in coronary blood flow (coronary microvascular spasm).51 Piaserico et al. showed that CMD was associated with severe psoriasis in 15% of the 153 patients in their study (n=23; OR 3.1, p=0.03).52 Similarly, the prevalence of CMD has been assessed in psoriasis patients in a cohort study by Weber et al. to quantify myocardial perfusion and myocardial flow reserve (MFR) using positron emission tomography imaging. It was reported that the prevalence of CMD (defined as MFR <2) was 61.3% in patients with psoriatic disease, compared to 38.4% in a matched control population (p=0.004). Additionally, psoriasis patients had a more drastic reduction in adjusted MFR (2.3 ± 0.81 versus 1.92 ± 0.65, p=0.001, respectively).53 Endothelial dysfunction is a key mechanism for obstructive and nonobstructive forms of coronary artery disease. It is referred to the imbalance between the release of vasoprotective vasorelaxant mediators, such as nitric oxide (NO), prostacyclin (PGI2), endothelium-derived hyperpolarising factors, and pathological vasoconstricting substances, such as endothelin-1 (ET-1), superoxide, hydrogen peroxide and thromboxanes.54 To evaluate endothelium-independent microvascular functional status, the coronary flow reserve (CFR) can be measured, which is defined by the rate of coronary blood flow at hyperaemia compared to baseline. The cutoff for an abnormal CFR is ≤2.5 or 2.0, depending on the technique that is being used.55 In 2012, Osto et al. reported that in patients with psoriasis, CFR was

Keratinocytes

Th1 cell

Atherosclerotic plaque rupture Fibrous cap

TNF-α Lipid core

IL-12

IFN-y

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Dendritic cells T-active cells

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T-cell migration and upregulation

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous group of progenitor and immature myeloid cells, which are produced in a variety of conditions such as cancer, infectious diseases and autoimmune disorders. Studies have demonstrated that the population of MDSCs has expanded in psoriasis patients, where cytokines including IL-23, IL-1β and CCL4 have been produced.45,46 It is now appreciated that myeloid dendritic cells are key cells in the pathogenesis of psoriasis. Inflammatory myeloid cells release IL-23 and IL-12 to activate IL-17-producing T-cells, Th1 cells and Th22 cells to where psoriatic cytokines IL-17, IFN-γ, TNF and IL-22 have been generated. These cytokines express effects on keratinocytes to amplify psoriatic inflammation.47 Myeloid cells expressing 6-sulfo-LacNAc (Slan) have also been thought to be inflammatory DC precursors in psoriasis, driving strong T-helper cells (Th17) and Th1 responses.

Figure 1: The Pathogenesis of Psoriasis and its Association with Atherosclerotic Plaque in the Endothelial Vessel

CLA

IL-1B TNF-α CD-8 IL-6 cells

E-selectin

Endothelial vessel

CD-8 cells: cytotoxic T-cells; CLA: cutaneous lymphocyte antigen; IFN-y: interferon-gamma; IL-1B: interleukin-1B; IL-12: interleukin-12; IL-2: interleukin-2; IL-6: interleukin-6; Th1 cell: T-helper cells; TNF- TNF-α: tumour necrosis factor-alpha; STAT4: signal transducer and activator of transcription 4. Created with Biorender.com by Hussein Taqi.

lower than in controls (3.2 ± 0.9 versus 3.7 ± 0.7, p=0.02). The CFR was abnormal (≤2.5) in 12 patients (22% versus 0% controls, p<0.0001). Moreover, in patients with CFR ≤2.5, the psoriasis area severity index (PASI) score, a clinical score for psoriasis severity was higher (11 ± 6 versus 7 ± 3, p=0.006) compared to patients with CFR >2.5. At multivariable analysis, PASI remained the only determinant of CFR ≤2.5 (p=0.02).56 Amplified adrenoreceptor-mediated vasoconstrictor responsiveness is another factor contributing to vascular dysfunction in pathological conditions characterised by systemic inflammation such as psoriasis.57 Increased arterial stiffness has also been reported in patients with psoriasis.58

Interleukin-17

Another cytokine which is a key element in the pathogenesis of both conditions is IL-17 (Figure 2). This is a pro-inflammatory cytokine released by Th17, which similarly produces IL-6, IL-21, IL-22 and TNF-α. All these factors are involved in inflammatory diseases such as psoriasis and atherosclerosis. Th17 plays a crucial role in the atherosclerotic process with larger levels measured in patients with CVDs.59 Its release into endothelial and vascular smooth muscle cells will render arteries vulnerable to a pro-inflammatory feedback loop.60 Once there is an endothelial injury, there is a release of cytokines that stimulates more Th17 which in turn fuels its release in positive feedback. This process consequently potentiates the release of further pro-inflammatory cytokines, such as TNF-α, adhesion molecules and chemokines. Eventually, TNF-α and IL-17 work collaboratively to upregulate other key cytokines, such as IL-6. It has been demonstrated that these inflammatory cascades enhance local oxidative stress, which causes the plaque to be less stable. Th1 cells are thought to have a role in the pathophysiology of ischaemic heart diseases in psoriasis.61

Nitric Oxide

Various studies have suggested that NO is released in many inflammatory

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The Relationship Between Psoriasis and Cardiovascular Diseases Figure 2: The Role of IL-17 in the Destabilisation of Atherosclerotic Plaque

influences the inflammatory process of atherosclerosis. Additionally, ET-1 can cause accelerated hypertension by affecting the vascular endothelium which acts as an intermediate border in the circulation and its levels are higher with more severe cases.67

Psoriatic plaque

Pharmacotherapy in Psoriasis and its Correlation with Cardiovascular Diseases

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IL-17: interleukin-17; IL-21: interleukin-21; IL-22: interleukin-22; Th17 cells: T-helper cells 17; TNF-α: tumour necrosis factor-α. Created with Biorender.com by Hussein Taqi.

diseases with psoriasis being one of them.62 The synthesis of induced NO is shown to be correlated with an increased release of NO-forming enzymes in psoriasis. Similarly, the involvement of NO in the function of endothelial cells suggests that it is implicated in the pathogenesis of the disease.63 NO is highly involved in the activation of IL-1β, cyclo-oxygenase and TNF-α, which are major contributors in psoriasis and the inflammatory processes of atherosclerosis. This hypothesis is further enhanced due to the abundance of NO in a diseased tissue compared to normal samples. NO also plays an important role in the pathology of atherosclerosis by affecting the arterial wall through catalysing inflammatory cells such as macrophages and leukocytes. NO affects the resting vascular tone, permeability and alters the metabolism that is associated with the inflammation in psoriasis patients. This led to the assumption that induction of NO synthesis by the high level of enzymes in psoriasis and its action in cells outside the skin, such as endothelial cells, could alter vascular function and lead to CVD.64

Oxidative Stress

Oxidative stress tends to have a key element in the development of CVD in patients with psoriasis. It is thought that this phenomenon participates in the process of atherosclerosis by the effect of oxygen metabolites, which modifies oxidatively LDL cholesterol and the antioxidant capacity is consequently overwhelmed. The resulting oxidative stress leads to oxidative damage to the lipids and proteins.65 This discrepancy between oxidant and antioxidant factors is involved in the pathogenesis of the accelerated atherosclerosis in psoriasis.66

Angiotensin-converting Enzyme, Renin and Endothelin-1

High levels of angiotensin-converting enzyme levels, renin and ET-1 in psoriasis are associated with an increased risk of hypertension. It is believed that the adipose tissue in psoriatic patients acts as a source of angiotensinogen that is converted to angiotensin II.11 It has been observed that angiotensin II has a dual function in this condition; it retains salt in the kidneys and participates in the proliferation of T-cells, which consequently

The pharmacotherapy used in psoriasis has a dual effect on patients’ cardiovascular risk profile (Figure 2). Ciclosporin is an effective treatment in psoriasis but it has been strongly linked to the worsening of hypertension. The underlying reason for the predominance of essential hypertension due to systemic ciclosporin is primarily due to the development of chronic kidney disease.68 Ciclosporin also alters vascular endothelial function by suppressing vasodilators such as prostacyclin and NO, whereas vasoconstrictors are being catalysed by increasing levels of endothelin. The cumulative effects of vasoconstriction, sodium retention and the reduction of glomerular filtration collectively act as a precursor for worsening hypertension. It has been argued that calcineurin inhibitors enhance the action of the thiazide-sensitive sodium chloride co-transport through a direct effect on the tissue kinase activity resulting in high rates of hypertension.69 For that reason, it is strongly advised to use ciclosporin only for a short period and there should be an intention to substitute it with another systemic agent once the flare up has improved.70 Steroids have an effective role in the treatment of psoriasis but they are implicated in heart diseases. They can potentially cause hypertension by various mechanisms which include increased systemic vascular resistance, extracellular volume and cardiac contractility. They also cause sodium retention, hypokalaemia and hypertension by altering the blood pressure regulatory system.71 Similarly, the non-steroidal anti-inflammatory drugs have similar consequences mainly by causing salt and water retention, aggravating peripheral vascular resistance and the activation of the renin-angiotensin-aldosterone system.72 Acitretin, which is a vitamin A analogue used in the treatment of psoriasis, has unfavourable effects by increasing the levels of serum triglycerides and LDL cholesterol and reducing HDL levels in the blood.73 A growing body of evidence pointing mainly towards the shared pathophysiology of psoriasis and CVD has raised an important question about the possibilities that treatment of the cutaneous disease can reduce the development of cardiovascular risk (Table 1). This hypothesis mainly suggests that inflammatory cascades in psoriasis, specifically those related to atherosclerosis, could be prevented by certain medications and reduce major adverse cardiovascular events (MACE) as a consequence. For example, methotrexate is one of the oldest systemic agents used in the treatment of psoriasis and was thought to have new promises in reducing vascular diseases in patients who suffer from psoriasis if matched to the control group in some studies.34 However, the CIRT trial showed that low-dose methotrexate did not reduce IL-1β, IL-6, C-reactive protein (CRP) or cardiovascular events compared with placebo among patients with established coronary artery disease and either diabetes or metabolic syndrome or both.74 The biological agents that are commonly used in moderate-to-severe psoriasis have shown neutral outcomes in reducing MACE in the short term.12 Their effects have been questioned despite their direct action on the same cytokines involved in the pathogenesis of psoriasis and atherosclerosis such as TNF-α, IL-12, 23 and 17. Furthermore, the link between biological medications and the development of MACE is still

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The Relationship Between Psoriasis and Cardiovascular Diseases unclear as shown in multiple meta-analyses, therefore, more robust longterm studies are required in this field.75,76

Table 1: The Effects of Psoriasis Medications on Cardiovascular Disease

In 2019, a 5-year study showed that tumour necrosis factor inhibitor (TNFi) can significantly reduce the risk of MACE, which is cumulative and can reach up to 11% reduction in cardiovascular events in 2 years.77 In the VIP trials, adalimumab was compared with phototherapy and showed a reduction in inflammatory markers such as glycoprotein acetylation in comparison with phototherapy. However, adalimumab did not have an effect on vascular inflammation.78 In contrast, when ustekinumab was compared with placebo in VIP trials, patients assigned to ustekinumab had a -6.58% (95% CI -13.64–0.47%) reduction in aortic vascular inflammation (AVI) at week 12 compared with baseline, whereas patients assigned to placebo had a 12.07% (95% CI 3.26–20.88%) increase in AVI during the same time period.79

Drugs with an adverse CVD outcome

Drugs with a neutral or debated CVD outcome

• Calcineurin inhibitors • Acitretin • Steroids • NSAIDs

• Biological agents • Methotrexate

The effect of TNF-α on major cardiovascular events was investigated in a meta-analysis and a net benefit in reducing adverse events was reported compared to methotrexate, warranting further randomised controlled trials to validate these findings.80 Notably, elevated levels of TNF-α and soluble TNF-α receptors were found in the severe psoriatic skin lesions, which likewise reflect the same findings in heart failure.81 TNF-α activation can result in different consequences: the development of atherosclerosis; deterioration in the heart function; and remodelling of the vascular endothelium. Anti-TNF-α can minimise CRP, vascular endothelial growth factor (VEGF) and an array of chemotactic co-factors – epithelial cell adhesion molecule-1, IL-8, E-selectin and monocyte chemoattractant protein-1 – in addition to the Th17 levels in the peripheral blood of patients with psoriasis.82 Although there are multiple studies that contributed to the body of evidence of effectiveness of TNFi in reducing systemic inflammation, it is still an area of debate with regards to its effectiveness in reducing CVD. Boehncke et al. revealed that patients who have been commenced on TNFi not only showed improvement in PASI score, but they also demonstrated a decline in CVD biomarkers (CRP, VEGF and resistin levels) after 6 months of therapy.78 Additional studies also endorsed the improvement of endothelial function and insulin sensitivity after starting etanercept (a TNFi) in severe psoriatic patients.83,84 The same authors also 1. Griffiths CE, Barker JN. Pathogenesis and clinical features of psoriasis. Lancet 2007;370:263–71. https://doi.org/10.1016/ S0140-6736(07)61128-3; PMID: 17658397. 2. Armstrong AW, Harskamp CT, Armstrong EJ. The association between psoriasis and obesity: a systematic review and meta-analysis of observational studies. Nutr Diabetes 2012;2:e54. https://doi.org/10.1038/nutd.2012.26; PMID: 23208415. 3. Takeshita J, Wang S, Shin DB, et al. Effect of psoriasis severity on hypertension control: a population-based study in the United Kingdom. JAMA Dermatology 2015;151:161–9. https://doi.org/10.1001/jamadermatol.2014.2094; PMID: 25322196. 4. Binus AM, Han J, Qamar AA, et al. Associated comorbidities in psoriasis and inflammatory bowel disease. J Eur Acad Dermatol Venereol 2012;26:644–50. https://doi. org/10.1111/j.1468-3083.2011.04153.x; PMID: 21689167. 5. Lowes MA, Bowcock AM, Krueger JG. Pathogenesis and therapy of psoriasis. Nature 2007;445:866–73. https://doi. org/10.1038/nature05663; PMID: 17314973. 6. Gelfand JM, Neimann AL, Shin DB, et al. Risk of myocardial infarction in patients with psoriasis. JAMA 2006;296:1735– 41. https://doi.org/10.1001/jama.296.14.1735; PMID: 17032986. 7. Ludwig RJ, Herzog C, Rostock A, et al. Psoriasis: a possible risk factor for development of coronary artery calcification. Br J Dermatol 2007;156:271–6. https://doi.org/10.1111/ j.1365-2133.2006.07562.x; PMID: 17223866. 8. Parisi R, Rutter MK, Lunt M, et al. Psoriasis and the risk of major cardiovascular events: cohort study using the clinical

10.

11.

12.

13.

14.

approved the reduction in the serum retinol binding protein 4 (RBP4) in the treated psoriatic patients who received TNFi.85 RBP4 has a strong link on the other side with subclinical atherosclerosis.86 Another clinical trial, which is based on echocardiographic assessment of the heart function for 18 patients receiving TNFi showed an improvement in the cardiac systolic function.87 Similarly, a small study consisting of 44 patients showed an improvement in the right ventricular systolic function in 33 patients treated with TNFi.88 On the contrary, a larger study of 1,500 patients with symptomatic heart failure treated with etanercept showed no improvement in mortality or hospitalisation.89 Despite the wide difference and interpretation of TNFi’s impact on CVD profile, which is mainly due to the different methodological approaches, there are some data that revealed a positive role for TNFi in the reduction of CVD, which could prompt researchers to investigate its effectiveness in future.12

Conclusion

Various studies have explored the link between cardiovascular complications and psoriasis. Different aspects have been investigated, such as genetic, environmental and social risk factors. The possible pathogenic and pharmacological connection between the two diseases has also been investigated. It can be concluded that a relation between CVD and psoriasis is possible, but there are other avenues that need to be explored and more in-depth research on a wider scale is required. It is imperative that GPs recognise early signs of cardiovascular complications of psoriasis and seek advice from cardiology specialists when indicated. Formulating an appropriate follow-up plan and encouraging joint management would improve patient outcome through early detection and management of those complications.

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Inflammation

Inflammation and Cardiovascular Disease: The Future Natalie Arnold,1,2 Katharina Lechner,3,4 Christoph Waldeyer,1,2 Michael D Shapiro

and Wolfgang Koenig

3,4,6

1. Department of Cardiology, University Heart and Vascular Center Hamburg; Hamburg, Germany; 2. German Center for Cardiovascular Research (DZHK), Partner Site Hamburg/Kiel/Luebeck, Hamburg, Germany; 3. Deutsches Herzzentrum München, Technische Universität München, Munich, Germany; 4. German Centre for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, Munich, Germany; 5. Center for Prevention of Cardiovascular Disease, Section on Cardiovascular Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina, US; 6. Institute of Epidemiology and Medical Biometry, University of Ulm, Ulm, Germany

Abstract

Despite considerable advances in reducing the global burden of atherosclerotic cardiovascular disease by targeting conventional risk factors, significant residual risk remains, with low-grade inflammation being one of the strongest risk modifiers. Inflammatory processes within the arterial wall or systemic circulation, which are driven in a large part by modified lipoproteins but subsequently trigger a hypercoagulable state, are a hallmark of atherosclerotic cardiovascular disease and, in particular, its clinical complications. Extending conventional guideline-based clinical risk stratification algorithms by adding biomarkers of inflammation may refine phenotypic screening, improve risk stratification and guide treatment eligibility in cardiovascular disease prevention. The integration of interventions aimed at lowering the inflammatory burden, alone or in combination with aggressive lipid-modifying or even antithrombotic agents, for those at high cardiovascular risk may hold the potential to reduce the still substantial burden of cardiometabolic disease. This review provides perspectives on future clinical research in atherosclerosis addressing the tight interplay between inflammation, lipid metabolism and thrombosis, and its translation into clinical practice.

Keywords

Atherosclerosis, inflammation, dyslipidaemia, cardiovascular prevention, residual risk, novel treatment strategies Disclosure: KL has received speaker’s honoraria from Goerlich Pharma, Novo Nordisk, Sanofi and Amgen. CW has received lecture fees from Amgen, Daiichi Sankyo, Sanofi and Novartis. MDS reports scientific advisory activities with Alexion, Amgen, Esperion and Novartis. WK reports receiving consulting fees and lecture fees from AstraZeneca, Novartis and Amgen, consulting fees from Pfizer, the Medicines Company, DalCor Pharmaceuticals, Kowa, Corvidia Therapeutics, Genentech, Esperion, Novo Nordisk and Daiichi Sankyo, lecture fees from Berlin-Chemie, Bristol-Myers Squibb and Sanofi, and grant support and provision of reagents from Singulex, Abbott, Roche Diagnostics and Dr Beckmann Pharma; he has also been a member of the executive steering committees of JUPITER, CANTOS, SPIRE, GLAGOV and COLCOT. NA has no conflicts of interest to declare. Received: 14 December 2020 Accepted: 24 January 2021 Citation: European Cardiology Review 2021;16:e20. DOI: https://doi.org/10.15420/ecr.2020.50 Correspondence: Wolfgang Koenig, Deutsches Herzzentrum München, Technische Universität München, Lazarettstrasse 36, 80636 Munich, Germany. E: koenig@dhm.mhn.de Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Although significant improvements in the treatment of atherosclerotic cardiovascular disease (ASCVD), including early mechanical intervention and polypharmacotherapy with aggressive lipid modification, have been achieved in recent decades, there is still considerable residual cardiovascular (CV) risk.1 The latest trials have underlined the role of inflammation in CV disease (CVD), showing that lowering the inflammatory burden results in a reduction of future CV events.2–4 The aims of this review are to discuss the role of inflammation in CVD and to provide perspectives on future questions that need to be addressed with regard to treatment allocation.

Atherosclerosis as an Interplay Between Lipoproteins and Inflammation: Biology and Mechanisms

Canonically, atherosclerosis has been considered as a lipoprotein-driven disease, which is amplified and modified by the host immune cellular response to retained lipoproteins.5–7 The primary steps in early lesion formation are the accumulation and subsequent chemical modification

(e.g. by lipolysis, proteolysis, glycation, aggregation or, most importantly, oxidation) of apolipoprotein B (apoB) containing lipoproteins, principally LDL in the subendothelial matrix with subsequent foam cell formation.8 Oxidised lipoproteins possess a variety of biological actions and consequences, including injury to endothelial cells, upregulation of the expression of adhesion molecules, recruitment and retention of leukocytes that recognise them as possible triggers of local inflammatory processes within the atherosclerotic plaque. Interestingly, the potential of apoB lipoproteins to trigger inflammatory processes in the arterial wall may differ profoundly across apoB particles.7–10 Given this, certain metabolic conditions, such as an elevated hepatic triglyceride pool, or a genetic predisposition, such as LPA variants, significantly modulate the formation and/or metabolic disposition of atherogenic apoB lipoproteins, ultimately resulting in a more proinflammatory apoB phenotype.11,12 In addition, oxidised LDLs can both mimic damage-associated molecular pattern molecules (DAMPs), a wellknown substrate for pattern recognition receptors on macrophages, and/

Inflammation and Cardiovascular Disease or participate in the generation of intracellular crystalline cholesterol, thereby initiating an innate immune response through coactivation of a NLRP3 (NOD [nucleotide oligomerisation domain], LRR [leucine-rich repeat]-containing and PYD [pyrin domain]-containing protein 3) inflammasome within macrophages.13–16 In line with these mechanistic findings, observational evidence has demonstrated that elevated levels of circulating inflammatory biomarkers such as high-sensitivity C-reactive protein (hsCRP) or interleukin-6 (IL-6) independently predict the risk of ASCVD.17–20 Chronic low-grade inflammation accompanies all stages of atherosclerotic disease from its onset to the overt disease with manifest ischaemic syndromes, thereby potentially offering a new and important therapeutic option.

Inflammation as a Target for Intervention: Lipid-modifying and Anti-inflammatory Agents

The initial evidence that systemic inflammation can be modified pharmacologically stems from the lipid-lowering trials of the early 2000s, which demonstrated that statin therapy significantly reduced circulating levels of hsCRP, thereby confirming at least partially the interplay between inflammatory pathways and lipid metabolism.21–23 Since then, several landmark statin trials have clearly demonstrated that lowering hsCRP concentrations translated into a significant reduction of future CV events.24–26 Importantly, the reduction in hsCRP was found to be of similar magnitude to that seen with LDL-cholesterol (LDL-C) reduction. Additionally, these trials highlighted the fact that patients who demonstrated statin-associated reductions both in LDL-C to below 70 mg/dl and in hsCRP levels below 2 mg/l had a larger CV benefit than those who achieved substantial LDL-C lowering alone.24–26 Among other factors, this has led to the ‘residual inflammatory risk’ concept, defined as persistently elevated hsCRP despite sufficient atherogenic lipid lowering, a phenomenon seen among 30–40% of all statin trial participants.1 Interestingly, both a recent meta-analysis of 2,546 patients who were treated with a novel non-statin lipid-lowering drug class, namely PCSK9 (pro-protein convertase subtilisin-kexin type 9) inhibitors, as well as the two large PCSK9 inhibitor outcome trials FOURIER and ODYSSEY OUTCOMES demonstrated PCSK9 inhibitors had no significant effect on hsCRP despite profound LDL-C reduction (up to 50–60%).27–29 Nonetheless, post-hoc data from FOURIER and SPIRE in patients at high risk on statin treatment consistently documented that inflammation still plays an important prognostic role, even in subjects with very low LDL-C concentrations (<20 mg/dl), in whom hsCRP was able to independently modify CV risk.30,31 This supports the notion that additional antiinflammatory treatment in these patients might provide benefit beyond aggressive lipid lowering. To date, the pharmacological inhibition of various pathways involved in inflammation has been investigated in several clinical trials among patients with manifest ASCVD, who were already on statin therapy (>90% of all participants).32 Proof of principle that pharmacological lowering of persistent low-grade inflammation in the absence of lipid modification resulted in a reduction of incident ASCVD came from the CANTOS trial.2 This involved 10,061 stable patients with a history of MI and elevated baseline concentrations of hsCRP (≥2 mg/l) despite maximally tolerated statin treatment. Canakinumab, a fully human monoclonal antibody directed against IL-1β, not only significantly reduced concentrations of IL-6 and hsCRP by up to 40–60%, but was also associated with a significant reduction in the primary outcome (major adverse CV events [MACE] including non-fatal MI or stroke and CV death) overall by 15% and by 25%

in those with on-treatment hsCRP level <2 mg/l.2,33 The CV protection achieved by canakinumab was identical in magnitude to that observed in major trials of PCSK9 inhibition (relative risk reduction of 15–20% over 2–3 years’ follow-up). In contrast, the results from the large CIRT study were rather disappointing.34 Here, 4,786 stable high-risk patients, either post-MI or presenting with multivessel disease and diabetes or metabolic syndrome on standard secondary prevention care, were randomly allocated to treatment with low-dose methotrexate versus placebo. Methotrexate therapy (15–20 mg weekly) neither decreased MACE over 5 years (HR 1.01; 95% CI [0.82–1.25]; p=0.91 versus placebo) nor lowered the concentration of inflammatory markers, particularly hsCRP.34 A third compound with potent anti-inflammatory properties tested in two large clinical trials was colchicine.3,4 In the COLCOT study, Tardif et al. demonstrated that colchicine at a low dose of 0.5 mg daily was able to reduce the risk of ischaemic ASCVD events (primary endpoint of death, resuscitated cardiac arrest, acute coronary syndrome, stroke and urgent hospitalisation for angina requiring revascularisation) by 23% compared with placebo in patients recruited in the first 30 days after an MI (n=4,755).3 When stratified according to time to randomisation, participants who received colchicine within 3 days of the index event sustained a 48% relative risk reduction in the primary endpoint.35 More recently, Nidorf et al. extended the COLCOT observations to patients with stable coronary artery disease (CAD) in the LoDoCo2 study (n=5,522).4 LoDoCo2, following the earlier open-label LoDoCo trial of low-dose colchicine involving only 532 patients with stable CAD, demonstrated – similar to COLCOT – a therapeutic benefit with colchicine 0.5 mg daily, with a 31% lower relative risk of the primary CVD endpoint compared to placebo after a median follow-up of 28.6 months.36 Unfortunately, neither COLCOT (measured in <3% of the study population) nor LoDoCo2 (not measured) provided sufficient insights into the inflammatory burden at baseline or on-treatment represented by hsCRP or IL-6 levels.3,4 Although colchicine seems to confer a clinical benefit in secondary prevention, clarification is still needed on optimal dosing and/ or what therapeutic regimens should be chosen for optimal prevention of recurrent events, as discussed later.

NLRP3 Inflammasome: Linking Lipoproteins and Inflammation

One common feature of the above-discussed anti-inflammatory drugs for CV event reduction relates to their interaction with the canonical pathway of the NLRP3 inflammasome to IL-1/ IL-6/ CRP.15,16 Although a central action of colchicine and canakinumab is related to the inactivation of the NLRP3 inflammasome sequelae, these compounds target different components of the above mentioned pathway. Canakinumab has a specific mechanism of action, selectively targeting IL-1β and leaving IL-1α untouched.37 Colchicine, in contrast, has much broader effects on inflammation, predominantly as a consequence of the inhibition of tubulin polymerisation.38 However, its most important properties in the context of ASCVD are related to the suppression of caspase 1 activity, which prevents IL-1β cleavage from its precursor.39 In contrast, methotrexate has been shown to have no specific effects on the IL-1β/IL-6 pathway and to act via inhibition of aminoimidazole-4-carboximaide ribonucleotide with subsequent elevations in adenosine levels, and exhibited no reduction in CV endpoints.34,40 The results of the above trials suggests that inflammation related to atherogenesis may be pathway specific rather than a generalised inflammatory process. So far, it appears the NLRP3 inflammasome is linked to ASCVD.

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Inflammation and Cardiovascular Disease Most importantly, these data further highlight activation of the NLRP3 inflammasome as a mechanistic link between vascular inflammation and the cholesterol pathway. Indeed, several components of lipid metabolism, such as oxidised LDL, cholesterol crystals, apoC3 and/or palmitic acid (C16:0) are pivotal regulators of the NLRP3-inflammasome either via dimerisation and activation of pattern recognition receptors such as toll-like receptors (TLR) 2 and TLR 2/4 or (especially in the case of cholesterol crystals) by lysosomal damage, enhanced potassium ion efflux, mitochondrial dysfunction and reactive oxygen species release (Figure 1).11,41–48 Once activated, the NLRP3 complex activates caspase-1, which, in turn, leads to IL-1 family cytokine production and the release of the highly proinflammatory cytokine IL-1β, the key mediator of atherosclerosis.16,49,50 IL-1β acts as a chemotactic agent for other inflammatory cells, resulting in a chronic, maladaptive inflammatory response dominated by macrophages and T-cells.7,8,15,49,50 Moreover, it induces the IL-6/IL-18 pathway and stimulates protein synthesis in the liver, which results in a characteristic shift towards an acute phase pattern characterised by elevated levels of not only CRP, but also serum amyloid A (SAA), fibrinogen, plasminogenactivator inhibitor-1 (PAI-1) and others.49–51 This vicious cycle sustains an inflammatory environment and mediates the ongoing cellular recruitment with the generation of foam cells and fatty streaks, eventually leading to the development of complex plaques.52 The seminal role of the NLRP3 inflammasome and the IL-1β pathway in atherosclerosis have recently been reviewed in detail.17,53,54

Lipoproteins, Inflammation and Thrombosis: a Dangerous Triad?

Figure 1: NLRP3 Inflammasome Pathway and Therapeutic Targets Sterile danger (danger-associated molecular patterns): extracellular ATP, silica, asbestos, high glucose, amyloid-β, CPPD, hyaluronan, necrotic cells, cholesterol crystals, oxidised LDL, uric acid

Pathogen-associated molecular patterns

K+

ATP P2X7

NLRP3 Procaspase-1

ASC

Mitochondrial dysfunction

Cathepsin B

Signal 1 priming

Lysosomal rupture

NLRPsinflammasome inhibitors Colchicine

Signal 2 activation

NF-KB

Pro-IL-18 Pro-IL-1β

Activate caspase-1 IL-18 IL-1β

IL-1β

Canakinumab Anakinra Colchicine

IL-6

Tocilizumab Ziltivekimab Sarilumab

CRP

Viewed from another perspective, inflammation per se might be a key regulator of hepatic lipoprotein metabolism, supporting the concept of a bidirectional relationship.55 Lipoproteins such as apoC3-enriched very LDL (VLDL) particles and oxidised phospholipid (OxPL)-enriched lipoprotein(a) (Lp(a)) particles have the potential to trigger distinct inflammatory/immune responses.44,45,56 On the other hand, acute or chronic systemic inflammatory signals such as increased levels of tumour necrosis factor-α (TNF-α) cause rapid upregulation of lipid synthesis, secretion of VLDL particles into the plasma and reduced apoB degradation.57 This conserved lipoprotein response to infection and/or hyperinflammatory states may have served important evolutionary purposes in that the increased transport of lipids and the resulting hyperlipidaemia as part of the host’s protective response may have enhanced acute tissue repair after injury and fast energy delivery to tissues. In our current environment, it may rather be seen as a maladaptive response to chronic low-grade inflammatory conditions such as metabolic syndrome, visceral adiposity and diabetes, and may contribute to the vicious cycle of inflammation and dyslipidaemia. One prominent example of a tight link between dyslipidaemia and vascular inflammation is illustrated by Lp(a). Lp(a) is an LDL-like particle with apo(a) bound covalently to apoB by a disulphide bridge.58 It has several features that render it more pathogenic and proatherogenic. Due to its homology with plasminogen, apo(a) has the prothrombotic properties of Lp(a).59 Furthermore, apo(a) has a distinct proatherogenic potential which is mainly attributable to its pro-inflammatory properties resulting in cytokine expression and release, as well as increased monocyte chemotaxis, which seems to be mediated in a large part by an enrichment in oxidised phospholipids (oxPLs).12,56 Indeed, Lp(a) is the major reservoir of oxPLs in human plasma.60,61

Fibrinogen

Proclotting

PAI-1

–

Antifibrinolytic

Canonical NLRP3-inflammasome pathway in atherosclerotic disease and potential targets for emerging therapeutic anti-inflammatory agents. ASC = apoptosis associated with speck-like protein; ATP = adenosine triphosphate; CPPD = calcium pyrophosphate dihydrate; CRP = C-reactive protein; Fib = fibrinogen; IL = interleukin; NF-κB = nuclear factor κB; NLRP3 = NOD(nucleotide oligomerisation domain), LRR (leucine-rich repeat), PYD (pyrin domain)-containing protein 3; P2X7 = purinoceptor 7; PAI-1 = plasminogen activator inhibitor 1; ROS = reactive oxygen species. Source: Some of the icons in this image are reproduced from Servier Medical Art by Servier. Reproduced from Servier Medical Art by Servier under a Creative Commons (CC BY 4.0) licence.

Moreover, recent ex vivo data has demonstrated that, on an equimolar basis, Lp(a) has much higher inflammatory potency than LDL-C.12 On the other hand, Lp(a) has been documented as an acute phase reactant, likely because the LPA gene contains an IL-6 response element, which suggests proinflammatory stimuli are involved in its regulation.62,63 The specificity of the IL-6 pathway in regulating Lp(a) production is further reflected by the fact that monoclonal antibodies directed against IL-6 (e.g. tocilizumab or sarilumab) reduced Lp(a) levels by 30–40%, whereas the antibody directed against TNF-α (adalimumab) did not affect Lp(a) levels substantially.64–66

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Inflammation and Cardiovascular Disease Figure 2: Treatment of Residual Cardiovascular Risk Randomised clinical trial: 2 × 2 factorial design Intensified lipid-lowering (LL) Rx

Placebo (optimal guideline-directed Rx including statins/ezetimibe)

Intensified LL, adding e.g. a PCSK9i or inclisiran + Anti-inflammatory (e.g. colchicine)

Anti-inflammatory (e.g. colchicine) + Placebo

Intensified LL, adding e.g. a PCSK9i or inclisiran + Placebo

LDL-C Inflammation Lp(a) Triglyceride

Placebo + Placebo

What to use Critical questions

Anti-inflammatory Rx

Patients with very high cardiovascular risk and optimal guideline-directed Rx including statins/ezetimibe

Thrombosis

‘Placebo’

Residual cardiovascular risk

Diabetes

Drug selection In whom to use Patient stratification When to use Treatment modalities

This figure shows an ideal way to overcome essential issues related to the treatment of residual cardiovascular risk. This randomised clinical trial with 2 × 2 factorial design would include an arm with intensified lipid-lowering (LL) adding e.g. a PCSK9i or inclisiran, a siRNA, on top of optimal guideline-directed therapy including statins/ezetimibe (stated as ‘placebo’) versus e.g. colchicine as an aggressive anti-inflammatory regimen versus PCSK9i/statins/ezetimibe without colchicine, versus colchicine plus statins/ezetimibe versus no colchicine but statins/ezetimibe. CV = cardiovascular; LDL-C = LDL cholesterol; Lp(a) = lipoprotein (a); PCSK9i = pro-protein convertase subtilisin-kexin type 9 inhibitors; Rx = treatment.

Of interest, a prespecified secondary analysis of the ACCELERATE trial showed that elevated Lp(a) levels were associated with CV death, MI and stroke only in patients with hsCRP levels >2 mg/l but not in patients with hsCRP levels ≤2 mg/l.67 The interdependence of Lp(a) and systemic inflammation may have important clinical implications in terms of selecting patients who might benefit the most from Lp(a)-mediated ASCVD risk reduction, namely those with residual inflammatory risk. However, these results need to be confirmed by other studies. In general, subjects with elevated Lp(a) exhibit increased inflammatory activity in the arterial wall, as demonstrated by PET or CT.68 However, whether inflammation, at least partially, triggers Lp(a) production or Lp(a) induces an important immune response is still not entirely clear. The results from Puri et al. suggest an involvement of inflammatory stimuli in Lp(a) regulation, which is in line with the above-mentioned genetic regulation of Lp(a) in response to IL-6.67 On the other hand, treatment with an antisense oligonucleotide, a gene-based therapy aimed at silencing the translation of apo(a) that is associated with an approximately 80% Lp(a) reduction, was able to attenuate the pro-inflammatory state of circulating monocytes on the transcriptional as well as functional level in patients with elevated Lp(a), suggesting their reciprocal relation.69,70 Innate immunity is also tightly linked to a prothrombotic phenotype, a process now referred to as thromboinflammation.71 Several lines of evidence suggest an inflammatory response has a pivotal role in tissue factor expression, activation of platelets, hyperfibrinogenaemia and of PAI-I associated impaired fibrinolytic function (Figure 2).71,72 On the other hand, coagulation can also increase inflammation, thereby acting in a positive feedback loop.72 Interestingly, the recent introduction of platelet lipidomics reemphasised the role of circulatory lipids in inflammationdriven thrombosis.73 Several components of lipid metabolism, such as oxidised LDL and especially Lp(a), are thought to promote potent prothrombogenic activity.12,56,61 Moreover, rosuvastatin might have an additional pleiotropic effect beyond its anti-inflammatory properties by reducing platelet membrane cholesterol, as well as by diminishing levels of tissue factor, factor VII and factor X.74 In addition, a new player in lipidology, PCSK9, might also contribute to impaired platelet function and a procoagulatory state, as depicted by recent in vivo data.74 For instance, PCSK9 deletion in mice resulted in

reduced formation of both arterial and venous thrombi, whereas overexpression of PCSK9 in septic mice promoted a hypercoagulable state, as reflected by elevated thrombin–antithrombin values in conjunction with reduced protein C.74 Circulating lipoproteins appear to affect both inflammation and thrombosis, although the exact mechanisms behind such complex interplay within this dangerous triad are still unclear.

Residual Cholesterol Versus Residual Inflammatory Risk: Rationale Applying a 2 × 2 Factorial Design for a Trial

As discussed, lipoprotein metabolism and low-grade inflammation are interrelated in their contribution to atherogenesis.54 Whether they act synergistically, potentiate their actions or have additional, independent effects still needs to be evaluated. However, there is clear evidence that using a combination of inflammatory and lipid parameters improves our ability to predict future ASCVD events. In CIRT, which represented a contemporary, optimally treated population at very high risk, the combination of IL-6 (or hsCRP) and LDL-C resulted in an up to threefold better prediction of future MACE than did a single biomarker alone.75 Comparing the participants in the top quartile (Q) of IL-6 and the LDL-C distribution with those in the bottom quartile resulted in an adjusted HR of 6.4 (95% CI [2.9–14.1]). The risk estimate for increased hsCRP and LDL-C was similar at 4.9 (95% CI [2.6–9.4]). In contrast, HRs for a single biomarker (Q4 versus Q1, fully adjusted model) varied from 1.79 for hsCRP, 2.11 for IL-6 and 2.38 for LDL-C. These observations have significant clinical implications. First, they highlight the presence of both residual cholesterol risk and residual inflammatory risk despite aggressive, guideline-directed medical therapy, including statins and coronary revascularisation. Second, they indicate the equal importance of these two different types of residual risk. Finally, they support the need for a more comprehensive ‘dual pathway’ approach that goes beyond statins and simultaneously targets both dyslipidaemia and inflammation. The latter is of particular importance, since trials using a PCSK9 inhibitor or anti-inflammatory agents separately from each other resulted only in a 20–30% reduction in CV risk. This leaves considerable residual risk that needs to be addressed.

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Inflammation and Cardiovascular Disease The important question is whether a combination of both aggressive lipidlowering and anti-inflammatory therapy, which should be given only as ‘add-on’ therapy to optimal guideline-directed secondary prevention, not only might result in a more profound reduction of recurrent ASCVD events, but also may exceed the sum of the parts. Such an assumption can only be tested in the context of a cardiovascular outcomes trial employing a 2 × 2 factorial design. However, it is not clear yet how to optimally design such a clinical trial. Indeed, three central questions need to be answered first – what to use? who to use? and when to use? – reflecting drug selection, patient stratification and treatment modality (Figure 2).

Which Compounds to Select?

The first question to be answered by the research community is which drug/drug combination will provide an optimal choice? What is clear to date is that a combination of conventional lipid-lowering medication (maximally tolerated high-intensity statin and ezetimibe) with an antiinflammatory drug would represent an ‘anti-inflammatory + placebo’ arm of the 2 × 2 trial (Figure 2; upper right panel of 2 × 2 table). However, the question remains as to which additional lipid-lowering therapy should be chosen for more aggressive LDL-C reduction (Figure 2; left panel of 2 × 2 table), particularly as the trial design would employ significantly lower LDL-C thresholds than those in current guideline recommendations. Would compounds antagonising PCSK9 or bempedoic acid be a promising approach for this purpose? A clear limitation of PCSK9 inhibitors is their cost but their negligible effect on hsCRP concentration make them ideal candidates for an unbiased estimate of 2 × 2 effects on risk reduction. A combination of bempedoic acid with ezetimibe, which has been recently approved, might have LDL-C lowering effects only similar to moderate intensity statin therapy; moreover, CV outcomes data are still awaited.76 Another possible choice among forthcoming novel lipid-lowering agents might be inclisiran, a small interfering RNA molecule that reduces hepatic PCSK9 production by approximately 50%.77 In addition, inclisiran administration twice yearly might be a major advance in lipid-lowering strategies.78 There is unequivocal evidence that direct inhibition of the inflammatory pathway targeting the NLRP-3 inflammasome has the potential to become a cornerstone therapy for atherosclerotic disorders. However, in contrast to a plethora of compounds used for lipid management, only two antiinflammatory drugs – canakinumab and colchicine – have been shown to improve cardiovascular outcomes. To date, there has been no head-tohead comparison between canakinumab and colchicine and whether such a trial would ever be conducted is questionable, especially taking into account the huge differences in treatment costs and route of administration (oral daily versus subcutaneous every 3 months). In general, colchicine, being an oral, well-tolerated, rapid-acting and, most importantly, highly cost-effective drug compared to canakinumab might be the only feasible anti-inflammatory compound to date to be used in a 2 × 2 factorial trial.79 Its further advantage may be related to its broader mechanism of action compared to canakinumab. For instance, the recently published LoDoCo2 proteomic substudy demonstrated that 30-day colchicine treatment reduced not only the level of NLRP3 inflammasome-related cytokines, such as IL-1/IL-6/IL-18, but also resulted in the reduction of 11 inflammasomeunrelated proteins, such as myeloblastin, carcinoembryonic antigenrelated cell adhesion molecule 8, azurocidin and myeloperoxidase.80 In addition, upregulation of 23 biomarkers with potent anti-atherosclerotic effects, such as fibroblast growth factor and insulin-like growth factor-

binding protein, has also been shown.80 However, whether these additional beneficial effects of colchicine might result in a more pronounced event reduction than that seen in canakinumab therapy alone remains unknown. Recently, Ridker et al. showed that patients on canakinumab were still at substantial residual inflammatory risk.81 Despite significant IL-6 lowering (43.2% from baseline on a 300 mg dose of canakinumab), each tertile increase in IL-6 concentration, measured 3 months after canakinumab initiation, was associated with a 42% higher risk for MACE (95% CI [26– 59%]; p<0.0001). Weaker results have been obtained for IL-18 (15% increase in risk; 95% CI [3–29%]; p=0.016), although canakinumab did not alter IL-18 levels at 3 months significantly. Do we need novel anti-inflammatory agents that affect the upstream NLRP3-inflammasome, reducing both IL-1β and IL-18? Theoretically, yes, and there are several NLRP3-inflammasome inhibitors already under development.82 However, more safety data are needed, since such profound, systemic inhibition of inflammatory pathways always bears potential risks due to interaction with immune homeostasis. In CANTOS, direct targeting of IL-1β by canakinumab was associated with a small but statistically significant risk for fatal infections (0.31 versus 0.18 events per 100 person-years; p=0.02).2 Whether targeting a downstream molecule of the NLRP3-inflammasome by directly inhibiting IL-6 is a better solution – especially taking into account that IL-6 is causally involved in atherogenesis, as shown by Mendelian randomisation analysis – is an issue of ongoing investigation.83 Currently, several IL-6 pathway inhibitors are under investigation, including a monoclonal antibody against IL-6 (e.g. tocilizumab) or its receptor (e.g. sarilumab).51,84 Furthermore, ziltivekimab, a human monoclonal antibody targeting IL-6 is being evaluated in the Phase IIb study, RESCUE (NCT03926117), which is testing the value of inflammation reduction in patients with chronic kidney disease. This is of particular importance as colchicine is contraindicated in patients with chronic kidney disease, which indicates a clear need for an alternative antiinflammatory drug for the subgroup with renal dysfunction.

Which Patients Might Benefit Most?

Selection of patients is critical. Should LDL-C levels be reduced to less than 55 mg/dl prior to initiating anti-inflammatory therapy? Furthermore, should anti-inflammatory therapy be applied to all ASCVD patients or only to those with residual inflammatory risk? Certainly, from a pathophysiologic standpoint, this would make sense and has been shown to work in JUPITER and CANTOS.2,26 However, it is not clear as to which biomarkers would be the best to use to identify those at high risk. The CANTOS trial included only patients with a high residual inflammatory risk, reflected by a hsCRP-concentration above 2 mg/l despite statin treatment.2 In contrast, the COLCOT trial did not use hsCRP as an inclusion criterion although, in a relatively small subset of patients, the median concentration was found to be very similar to that in the CANTOS trial at about 4 mg/l.3 Whether this hsCRP concentration, measured in such a small subset of patients, is representative of the hsCRP concentration in a trial population is not known. In CIRT – a negative trial that did not require an elevated hsCRP for inclusion – the median hsCRP concentration was much lower than in CANTOS (1.5 mg/l at randomisation).34 Nonetheless, a ‘responder’ analysis from CANTOS provided evidence that those who achieved a hsCRP of less

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Inflammation and Cardiovascular Disease than 2 mg/l benefited most from anti-inflammatory treatment, with a 25% reduction in MACE (HR 0.75; 95% CI [0.66–0.85]; p<0.0001), whereas in ‘non-responders’ only marginal treatment effects were observed (HR 0.90; 95% CI [0.79–1.02]; p=0.11).33 Even more convincing data were obtained for IL-6 ‘responders’ who achieved on-treatment IL-6 levels below 1.65 ng/l and demonstrated a 32% reduction in MACE.33

When to Treat and How Long to Treat?

Other issues that need to be addressed are related to the regimen of antiinflammatory treatment such as time of treatment initiation or duration (life-long, e.g. aspirin and statins, versus intermediate- or long-term, e.g. P2Y12 receptor inhibitors). Are time-dependent treatment effects to be expected? Will targeting inflammation translate into improved cardiovascular outcomes in the short term or will the impact of this approach reveal its full potential over the long run? Are we dealing with permanent suppression of inflammation or should we anticipate a recurrence in MACE after cessation of therapy? We still do not know how long anti-inflammatory treatment needs to be continued and further research in this direction is urgently needed. More recently, a secondary analysis of the CANTOS trial revealed intriguing results.85 Regarding canakinumab therapy, Everett at al. assessed the total (initial and subsequent) number of CV events, since patients remained on their assigned treatment for the total duration of the trial, even if they experienced a primary endpoint.85 In contrast to the primary analysis, a significant reduction of total major CV events was seen among all therapeutic regimens, including patients who were randomised to the lowest dose of canakinumab (RR 0.80; 95% CI [0.69–0.93]; RR 0.79; 95%CI [0.68–0.92]; and RR 0.78 (95% CI: 0.67–0.91) for 50 mg, 150 mg and 300 mg treatment groups, respectively. Moreover, significant benefits of anti-inflammatory therapy were demonstrated even among subjects who did not achieve a hsCRP concentration below 2 mg/l or an IL-6 concentration below 1.65 ng/l. Interesting results have been also provided by the COLCHICINE-PCI study, which tested a strategy of preprocedural administration of a much higher colchicine dose of 1.8 mg among 400 subjects with chronic or acute PCI.86 Although an acute rise in IL-6 and hsCRP could be prevented by shortterm colchicine administration, no significant risk reduction in PCI-related myocardial injury/MI or MACE within 30 days was seen. Theoretically, the data above might favour prolonged anti-inflammatory treatment, at least among those at high risk for recurrent CV events (e.g. the PEGASUS trial) but, in practice, we are still far away from having solid data on the required duration of anti-inflammatory treatment.87 Another question related to treatment modality is: at what stage of the disease (acute or chronic) would targeting inflammation be most beneficial? Canakinumab was investigated only among patients who had experienced a documented MI at least 30 days before randomisation, whereas colchicine demonstrated its efficacy in those with acute MI as well as in patients with stable CAD.2–4 On the other hand, a time-totreatment initiation (TTI) analysis within COLCOT highlighted the 1. Dhindsa DS, Sandesara PB, Shapiro MD, et al. The evolving understanding and approach to residual cardiovascular risk management. Front Cardiovasc Med 2020;13;7:88. https://doi. org/10.3389/fcvm.2020.00088; PMID: 32478100. 2. Ridker PM, Everett BM, Thuren T, et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med 2017;377:1119–31. https://doi.org/10.1056/ NEJMoa1707914; PMID: 28845751.

importance of early initiation of colchicine therapy for favourable CV outcomes after MI.35 Patients in whom treatment with colchicine was initiated within the first 3 days of the index event demonstrated a profound 48% reduction of the composite primary endpoint (HR 0.52; 95% CI [0.32– 0.84]; p=0.007) compared to patients whose treatment started within 4–7 days (HR 0.96; 95% CI [0.53–1.75]; p=0.896) or >8 days (HR 0.82; 95% CI [0.61–1.11]; p=0.200), respectively. While the role of combined lipid-lowering and anti-inflammatory therapy might become a cornerstone in the prevention and treatment of ASCVD, it is also prudent to promote lifestyle modification that might have antiinflammatory potential.88 A recent simulation study revealed that optimisation of modifiable lifestyle risk factors such as body weight, smoking, physical inactivity and diet would shift almost 40% of patients with CAD and a high inflammatory burden beneath the considered treatment threshold of hsCRP >2mg/l.89 The ketone body ß-hydroxybutyrate (BHB), an endogenous inhibitor of the NLRP-3 inflammasome, is a promising molecule in this regard. Its physiological and transient elevation can be achieved by vigorous physical activity, (intermittent) fasting and dietary carbohydrate restriction.90,91 BHB promotes its anti-inflammatory properties by inhibiting the assembly of the NLRP-3 inflammasome and further reduction of expression of its downstream mediators (i.e. the IL-1β/IL-6 axis).83 In line with this, low carbohydrate dietary patterns that result in nutritional ketosis have been shown to reduce broad, systemic inflammation and most biomarkers of ASCVD risk in the insulin-resistant phenotype.92 Overall, elevated levels of BHB in plasma seem to shift tissue cross-talk from a proinflammatory milieu conducive to high-risk atherosclerosis to an anti-atherogenic milieu so might be a promising non-pharmacological therapeutic avenue for addressing residual inflammatory risk.

Conclusion

To date, varying inflammatory and/or atherogenic potential across different apoB phenotypes is not fully addressed by strategies directed at apoB/ LDL-C lowering alone and results in residual inflammatory risk despite optimal lipid-lowering therapy. This highlights the importance of moving beyond assessment and treatment of a single marker such as apoB/LDL-C to comprehensively address all drivers of atherosclerotic risk, including inflammation. Pharmacologically, a variety of compounds are under investigation, primarily those targeting the NLRP3-IL1-β/IL-6 pathway, which might be best tested in high-risk post-MI patients, optimally identified on the basis of an increased inflammatory burden. However, time of initiation and duration of treatment have still to be determined. As discussed in this review, a large trial based on a 2 × 2 factorial design applying aggressive LDL-C lowering and aggressive anti-inflammatory (anticytokine) treatment to fully evaluate the potential additional value of reducing inflammation in the presence of ultra-low LDL-C concentrations may further optimise outcomes. Moreover, it may be important to go beyond these targets and simultaneously address residual risk related to elevated triglycerides, elevated Lp(a) and thrombotic burden. This comprehensive approach to residual risk management has the potential to revolutionise the prevention of cardiovascular disease. Nonetheless, we are still at the beginning of this journey with plenty of questions that need to be adequately addressed.

3. Tardif JC, Kouz S, Waters DD, et al. Efficacy and safety of low-dose colchicine after myocardial infarction. N Engl J Med 2019;381:2497–505. https://doi.org/10.1056/NEJMoa1912388; PMID: 31733140. 4. Nidorf SM, Fiolet ATL, Mosterd A, et al. Colchicine in patients with chronic coronary disease. N Engl J Med 2020;383:1838–47. https://doi.org/10.1056/NEJMoa2021372; PMID: 32865380.

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Atrial Fibrillation

Mapping Technologies for Catheter Ablation of Atrial Fibrillation Beyond Pulmonary Vein Isolation Giulio La Rosa ,1,2 Jorge G Quintanilla ,1,2,3 Ricardo Salgado ,2 Juan José González-Ferrer,2,3 Victoria Cañadas-Godoy,2,3 Julián Pérez-Villacastín,2,3,4 Nicasio Pérez-Castellano,2,3,4 José Jalife 1,3 and David Filgueiras-Rama1,2,3 1. Centro Nacional de Investigaciones Cardiovasculares (CNIC), Myocardial Pathophysiology Area, Madrid, Spain; 2. Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Cardiovascular Institute, Madrid, Spain; 3. Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain; 4. Fundación Interhospitalaria para la Investigación Cardiovascular (FIC), Madrid, Spain

Abstract

Catheter ablation remains the most effective and relatively minimally invasive therapy for rhythm control in patients with AF. Ablation has consistently shown a reduction of arrhythmia-related symptoms and significant improvement in patients’ quality of life compared with medical treatment. The ablation strategy relies on a well-established anatomical approach of effective pulmonary vein isolation. Additional anatomical targets have been reported with the aim of increasing procedure success in complex substrates. However, larger ablated areas with uncertainty of targeting relevant regions for AF initiation or maintenance are not exempt from the potential risk of complications and pro-arrhythmia. Recent developments in mapping tools and computational methods for advanced signal processing during AF have reported novel strategies to identify atrial regions associated with AF maintenance. These novel tools – although mainly limited to research series – represent a significant step forward towards the understanding of complex patterns of propagation during AF and the potential achievement of patient-tailored AF ablation strategies for the near future.

Keywords

AF, catheter ablation, instantaneous frequency modulation, mapping technologies, rotors Disclosure: DFR, JGQ, JPV and NPC are inventors of the patent #EP3636147A1. All other authors have no conflicts of interest to declare. Funding: The CNIC is supported by the Spanish Ministry of Science and Innovation and the Pro-CNIC Foundation, and is a Severo Ochoa Center of Excellence (SEV-20150505). This study was supported by the European Regional Development Fund and the Spanish Ministry of Science and Innovation (PID2019-109329RB-I00). The study was also partially supported by the Fundación Interhospitalaria para la Investigación Cardiovascular and the Fundación Salud 2000. Received: 7 October 2020 Accepted: 25 January 2021 Citation: European Cardiology Review 2021;16:e21. DOI: https://doi.org/10.15420/ecr.2020.39 Correspondence: David Filgueiras-Rama, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Myocardial Pathophysiology Area, Melchor Fernández Almagro 3, 28029 Madrid, Spain. E: david.filgueiras@cnic.es Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Despite substantial advancements in rhythm control strategies during the last decade, AF remains a daily clinical problem with a steadily growing socio-economic burden worldwide.1 In the last few years, long-term success rates of ablation procedures have stood between 60% and 80% for paroxysmal AF (PxAF) and between 50% and 60% for persistent AF (PersAF), depending on the ablation strategy.2 Current international consensus on AF ablation has established the minimal acceptable 12-month AF-free rate off antiarrhythmic drugs after PersAF ablation at 40%.2 Catheter-based pulmonary vein isolation (PVI) is the standard invasive approach for AF ablation. However, the optimal ablation strategy beyond pulmonary vein isolation (PVI) for PersAF remains unclear.3 A wide variety of adjunctive ablation strategies have been explored, such as linear ablation, posterior wall isolation, ganglionic plexus ablation, isolation of the left atrial appendage, or substrate modification of areas with low voltage and fibrosis among others.4–9 While incremental benefit has been reported with some of these approaches, other studies have failed to show any advantage. The latter is probably related to the intrinsic

limitations of anatomical approaches, which pay scant attention to the underlying mechanisms of complex wave propagation dynamics during AF. This lack of incremental benefit with additional anatomical-based ablation strategies goes against a classically accepted hypothesis of random propagation dynamics and non-hierarchical organisation in human PersAF.10 Recently, other approaches aimed at localising and targeting AF sources have led to the recognition of specific spatio-temporal patterns underlying what apparently turns out to be a chaotic and unstable rhythm.11 Experimental studies have demonstrated that AF can be sustained by high frequency drivers or sources, which can potentially be targeted to terminate the arrhythmia.12–14 During the last few years, novel mapping approaches have been implemented in the clinic aiming to identify AF drivers in complex PersAF cases. These mechanistic-based approaches have the potential to enable translational insights from experimental animal models into further improved specificity of ablation procedures and long-term freedom from AF (Table 1).15,16

Novel Approaches for AF Ablation Table 1: Clinical Data of Selected Studies Using Novel Mapping Systems in Patients with Persistent AF* Study

Type of AF

Study Design

Acute Response Follow-up Freedom (AF Termination)† (Months) from AT/AF

Major Periprocedural Complications‡

ECGI15

103

81% PersAF 19% long-lasting PersAF

Prospective: Highest driver activity ablation 80% and sequentially in the decreasing order of arrhythmogenic density ± linear lesions on the LA roof and MI until AF termination or linear block in sinus rhythm versus control (matched group for patients whose AF terminated, n=82): PVI + EGM-based linear lesions until AF termination

64% overall Not reported 85% patients with AF termination were AF free versus 87% control population (p=ns)

FIRM29

28% PxAF 72% PersAF

RCT: FIRM ± PVI ± LA roof line versus PVI ± LA roof line

56% versus 9% (p<0.001)

82.4% versus 44.9% (p<0.001)

Three cardiac tamponades (one versus two), four vascular complications (one versus three), PV stenosis (one in group 2)

68% versus 27% (p=0.001)

18 ± 8

82.4% versus 58.8% (AF only, p=0.03)

One cardiac tamponade in PVI + CFAE arm

RCT: PVI alone versus PVI + high-frequency 26% versus 46% source ablation (for patients with PersAF) (p=ns)

63% versus 67% (p=ns)

Two cardiac tamponade and one vascular complication in high-frequency arm

70%

One decompensated heart failure None

Electrogram 68 similarity/phasemapping combined technique30

68% PersAF Prospective: PVI + SI and phase mapping 32% long-lasting versus PVI + CFAE PersAF

Spectral analysis 232 and DF mapping62

49.5% PxAF

CARTOFINDER55

100% longstanding PsAF

Prospective: PVI + Rotor ablation

Spatiotemporal dispersion64

152

22% PxAF

78% PersAF

Prospective: Ablation of spatio-temporal 95% versus 62% dispersion of EGMs in AF versus PVI ± CFAE (p<0.01) and linear ablation (step-wise approach)

55% versus 36% (p=0.026)

RRa

100% PersAF

RCT: PVI + RRa ablation versus PVI alone

61% versus 30%; (p<0.007)

73.2% versus 50% Two femoral pseudo (p=0.03) aneurysm (one per group)

RADAR system70

83% PersAF Single-arm prospective trial: PVI + drivers 17% long-standing identified by RADAR system PersAF

55%

12.6 ± 0.8

66%

None

Charge/dipole density75

127

100% PersAF

98% in total (32% 12 without cardioversion)

72.5%

Two cardiac tamponades, one stroke, one air embolism, one femoral arteriovenous fistula and one femoral lymphocele.

None

16 (step 3)

Two out of three None (step 3) patients (one patient displayed too large leading areas to be safely targeted by catheter-based ablation)

Electrographic flow 25 mapping77

iAM/iFM mapping algorithm63

50.5% PersAF

Prospective: PVI + charge density identified targets

15%

96% PersAF Prospective: NA 4% long-standing Step 1: PVI + FIRM PersAF Step 2: EGMs re-analysis using electrographic flow mapping after the procedure to identify active AF sources and discriminate from passive rotational phenomena Animal and human study: Step 2: 92.3% Step 1: test of the single-signal algorithms Step 3: 33% to detect rotational-footprints in optical movies from five ex vivo Langendorffperfused PersAF sheep hearts and in computer simulations Step 2: in vivo high-density electroanatomical atrial mapping in 16 pigs with PersAF to perform leading driver and rotational footprint maps to guide ablation Step 3: iAM/iFM-guided mapping and ablation in three patients with PersAF despite ≥1 previous PVI procedures

*The studies were selected based on the following criteria: RCT or prospective series with more specific targets on the study design, large sample numbers, and a follow-up of at least 12 months when available. †AF termination rate may show limitations to predict freedom from AF in the long-term follow-up.56 ‡Major complications were defined as those that were likely to result in permanent injury, prolongation of hospitalisation, requirement of intervention for treatment, or death. AT = atrial tachycardia; BSM = body surface mapping; CFAE = complex fractionated atrial electrogram; CL = cycle length; DF = dominant frequency; ECGI = electrocardiographic imaging; EGMs = electrograms; FIRM = focal impulse and rotor modulation; iAM/iFM = instantaneous amplitude modulation/instantaneous frequency modulation; LA = left atrium; MI = mitral isthmus; n = number; NA = not applicable; ns = not significant; PersAF = persistent AF; PxAF = paroxysmal AF; PV = pulmonary vein; PVI = pulmonary vein isolation; RA = right atrium; RRa = repetitive-regular activities; RCT = randomised clinical trial; SI = similarity index.

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Novel Approaches for AF Ablation Here, we summarise the state-of-the-art of mapping methods to identify AF drivers and potentially improve ablation outcomes. We review the main available clinical data facing the main controversies and possible solutions towards near-future directions, in the quest to increase the specificity of ablation strategies and a more personalised AF treatment.

Since then, several non-invasive (electrocardiographic imaging; ECGI) and invasive (focal impulse and rotor modulation [FIRM] and electrogram similarity/phase-mapping combined techniques) mapping approaches have used phase-mapping to guide driver detection and ablation (Tables 1 and 2, Figure 1).15,29,30

Experimental Bases and Clinical Tools to Identify Drivers of AF

Electrocardiographic Imaging

To date, a wide variety of methodological approaches have been used to identify AF drivers with the aim of increasing AF specificity in catheterbased ablation procedures, especially in complex clinical cases with recurrences despite PVI.11 Although the high spatio-temporal resolution of optical mapping would be the ideal scenario to map wave propagation dynamics during AF, in vivo optical mapping is still at early development stages in experimental settings, and we are still far from achieving further technological advances for clinical application.17 However, other approaches using novel hardware and software tools, unipolar or bipolar electrograms, sequential or simultaneous electrogram acquisitions have been developed to decrease the gap between the gold-standard optical mapping and current clinically available technology.

Optical Mapping and Phase Mapping to Identify Drivers of AF

The advent of ex-vivo high-resolution optical mapping techniques has enabled visualisation of complex propagation dynamics with submillimeter resolution on simultaneously mapped large myocardial areas.18 This experimental mapping technology represents the current gold standard technique to study cardiac electrophysiology in whole heart preparations.17,18 In particular, the use of voltage-sensitive probes and high-resolution video imaging in isolated animal hearts has provided support for the hypothesis that AF may be driven by a single or a few highfrequency functional reentrant sources called rotors.12,19,20 Leading rotors can give rise to daughter rotational patterns and produce fibrillatory conduction by waves breaking against refractory barriers.21 Rotational drivers that maintain AF have been described as those with the highest frequency of rotation and whose domain of 1:1 activation is the narrowest.22 Rotors can be identified by the presence of scroll waves that span the atrial wall with different shapes of their 3D rotational axis (i.e. filament). In 2D, the most commonly described linear I-shape filament is on the epicardial or endocardial surface as a wave of excitation propagating around a point of uncertain phase called a phase singularity (the tip of the filament).23 The dynamics of the phase singularity may be determined by phase mapping the activation/recovery cycle (i.e., the action potential) at each time point (Figure 1A). In a phase map of functional reentry all the phases of the action potential converge at the phase singularity with a continuous progression of phase from −π to +π.24 Thus, the phase singularity is the pivot of the rotating pattern and its trajectory may circulate continuously around a small central region forming a circle (the core).20 The phase singularity trajectory may also meander (precess) around the same spot, or even drift never returning to the same point.24,25 Phase mapping forms the basis of many wave propagation analyses to identify phase singularities and rotational activity in current mechanistically based mapping methodologies used in clinical electrophysiology.26 Those studies have adapted the Hilbert transformation as a practical way to derive the signal phase from the voltage-time series, and to demonstrate rotational drivers underlying AF maintenance in PxAF, PersAF and longlasting PersAF.26–28 In 80% of cases with non-PxAF, the drivers have been identified as rotors, which often colocalised with focal breakthroughs.15,16,29

Electrocardiographic imaging is based on a vectorial body surface representation of the cardiac electric field.31 This technology enables to investigate non-invasively different patterns of cardiac activation that may be relevant for the understanding of AF dynamics.32–34 Electrical signals from the patients’ torso are acquired using a high-density multielectrode array applied to the chest wall via a wearable vest. These signals are processed using sophisticated computer back-extrapolation (inverse solution) to deduce electrical activity on the heart surface.35 Both rotors and focal sources can be observed using ECGI (Figure 1B).36 Moreover, the complexity of wave propagation patterns increases with the duration of AF history, which is consistent with the expected effects of atrial remodelling. Body surface potentials face significant challenges during complex arrhythmia such as AF. The potential field diminishes with distance from the epicardium to the body surface, which becomes problematic in the case of atrial signals, especially during wave propagation patterns like fibrillation.33,37 This results in low signal-to-noise ratios for recordings on the body surface, which may diffuse the interpretation of underlying atrial sources.33 The limitations of body surface recordings are further compounded when inverse solutions with regularisation methods are applied to minimise the effects of small errors in data collection (measurement noise, geometry errors, inaccurate conductivity values) that would otherwise cause significant errors in the solution.34 Despite these challenges, plausible source localisation has been obtained (Table 2), albeit with drawbacks associated with limited spatial resolution or the inability to distinguish endocardial from epicardial activation patterns.15

Focal Impulse and Rotor Modulation

Narayan et al. pioneered the clinical identification of rotational and focal impulses as a potential target to increase specificity in AF ablation procedures.38 The approach was based on experimental data in isolated animal hearts reporting that AF can be sustained by a few or small number of rotational drivers, which can also be observed as focal activity when the 3D filament is parallel to the endocardial or epicardial wall.39 Narayan et al. used simultaneous unipolar recordings from multielectrode basket catheters positioned in the left and right atrial cavities.38 Despite the low spatial resolution of the basket catheters to resolve the rotor core at the tip of a spiral wave, the authors calculated that based on knowledge of the human action potential duration and conduction velocity restitution curves, the minimal wavelength for reentry is 4–5 cm, which would be sufficient to resolve the rotating arms of the spiral wave emanating from the core of a rotor (Figure 1C).40–42 Narayan and co-authors enrolled 92 patients (107 consecutive ablation procedures) with highly symptomatic PxAF or PersAF in a two-arm 1:2 design with ablation of AF sources (FIRM-guided) followed by conventional ablation (mainly PVI; n=36), or conventional ablation alone (n=71; FIRMblinded; Table 1).29 The data showed that FIRM ablation at patient-specific sources could acutely terminate or slow the AF cycle length and improve clinical outcomes. Although the initial results and long-term follow-up of this trial were promising, subsequent studies have shown more controversial results.43 Together with a high operator-dependent variability and technical limitations, the fact that active and passive sources cannot

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Novel Approaches for AF Ablation be discriminated by this technology might play an additional role regarding the controversial efficacy of AF driver elimination during FIRMguided ablation.11,44

Similarity Index and Phase-mapping Combination

AF electrograms are characterised by wide temporal and spatial disparities, which make it difficult to visually identify any organised wave propagation patterns in real time. Complex fractionated atrial electrograms (CFAE) have been proposed to be associated with the surrounding of rotational activity.45 However, CFAEs have been proven to be highly unspecific, especially when using bipolar recordings, because multiple functional and structural irregularities in the atria can lead to CFAEs that are irrelevant to AF mechanisms.46–48 Such a lack of specificity has resulted in no incremental benefit when CFAEs are ablated after conventional PVI.49 Moreover, CFAE ablation may increase the risk of atypical atrial flutter due to lesion-related structural borders that may generate the substrate for other atrial arrhythmias.50 Lin et al. have proposed to improve CFAEs analysis using nonlinear-based waveform similarity analysis to identify the morphological repetitiveness of waveform patterns in fractionated electrograms (termed similarity index).51 The similarity index distribution can be displayed on the 3D electroanatomical mapping system in real time as similarity index vector fields, which can be obtained from the values between pairs of the nearest electrodes to show the average wave propagation (Table 2, Figure 1D). The analysis also enables to identify different wave propagation patterns including rotational activity.30 Lin et al. tested the clinical value of a combined methodology, including similarity index and phase mapping, in a prospective randomised trial that enrolled 68 patients with PersAF undergoing substrate modification after PVI (Table 1). AF had not terminated after PVI in any of the patients enrolled in the study. Patients were randomly allocated to group 1, undergoing similarity index and phase mapping-guided ablation, and group 2 receiving conventional CFAE ablation.30 In group 1, the authors identified an average of 2.6 ± 0.89 similarity index regions per chamber (rotors and focal sources in 65% and 77% of patients, respectively). Patients allocated to group 1 showed higher termination rates and lower AF recurrences than patients in group 2. Among potential limitations, it is worth mentioning that the interelectrode size of different catheters might have affected the bipolar recordings used for analysis. Moreover, sequential mapping might have affected the options to detect rotors compared with simultaneous mapping.38

Spectral Analysis and Advanced Electrogram Processing for Mapping AF

The use of phase mapping to identify the underlying dominant atrial region sustaining the overall fibrillation dynamics is subject to intrinsic limitations. Low spatial resolution of electrical recordings during clinical procedures makes interpolation of phases inherently biased toward rotor detection, since phase mapping algorithms are mainly devised to show rotational activity.29,52 Other mapping alternatives using spectral analysis of electrical recordings or advanced signal processing of intracardiac electrograms have been proposed to identify regions with specific temporal characteristics associated with AF drivers (Figures 2 and 3).

The CARTOFINDER

Recently, a novel module of the Carto System (Biosense Webster) called CARTOFINDER has been developed to map potential AF drivers through identifying repetitive activation patterns either focal or reentrant.53–55

Sequential and panoramic mapping can be achieved using a PentaRay catheter and a 64-pole-basket catheter, respectively (Figure 1E and Figure 2A), to acquire 30-second segments of unipolar signals at different atrial positions.53–55 Signal processing using the CARTOFINDER tool results in wavefront propagation maps (with or without associated frequency analysis) in an open format, where location points and electrograms can be further reviewed by the operator (Table 2).53,55 In particular, for each unipolar signal, two bipolar signals are created by pairing the electrode with the nearest two electrodes. A bipolar electrogram window is then applied to the unipolar signals that range from earliest onset to the latest offset of the two bipolar electrograms. Atrial signals within the bipolar electrogram window are then annotated, whereas areas outside this window are excluded. Atrial signals are annotated at the point of the maximum negative unipolar slope (peak negative dv/dt) using wavelet analysis to determine local activation time. In patients with PersAF (average AF duration 13.5 ± 6.2 months) undergoing AF ablation, Honarbakhsh et al. have described transient but recurrent rotational activity in approximately two-thirds of instances, mostly confined to low-voltage zones.53 The remaining one-third of focal activity did not show any predilection for low-voltage zones. CARTOFINDER-guided AF driver ablation yielded a positive response (in terms of AF termination or cycle length slowing ≥30 ms) in 84.6% of cases, with at least one driver with a positive response to ablation in all patients.53 More specifically, Honarbakhsh et al. described AF termination in 12 of 19 patients after the ablation of driver sites. Although AF termination rate may be considered an endpoint of acute procedural success, recent data have questioned its potential to predict freedom from AF in the long-term follow-up and should therefore be considered with caution.2,56 This acute ablation success to terminate AF was much lower in a previous study by Calvo et al., who also used the CARTOFINDER system in patients with long-standing PersAF (Table 1). In this more complex setting, AF termination was only achieved in two of 13 patients after targeting rotor domains, which were defined as areas with rotational activity lasting for ≥three consecutive rotations and with repetitive patterns over a 30-s acquisition period.55

Spectral Analysis and Dominant Frequency Mapping

Spectral analysis and dominant frequency (DF) have been proposed as a robust method to identify AF driver regions associated with hierarchically activated atrial domains.12,57 Irrespective of the predominant wave propagation patterns, either rotors or focal activity, spectral analysis can identify the regions with the fastest frequency domain, which likely maintain the overall arrhythmia. Although this activation rate hierarchy is particularly evident in PxAF, in more complex scenarios like PersAF, atrial frequency domains tend to be more homogeneous and difficult to distinguish.57,58 The latter complicates the identification of a single atrial region that might correspond to the dominant AF driving source. In fact, in advanced remodelling stages, it is common to observe more than one atrial region with high-frequency AF drivers.59 The most common approach to identify atrial regions with the fastest activation rates (i.e. the shortest cycle lengths) is to perform spectral analysis to identify the DF. Briefly, the spectrum of a signal displays its energy/power distribution in the frequency domain. The frequency of the highest peak in the spectrum at each spatial location is called DF (Figure 2B), which is often used as a surrogate for the average activation rate (i.e. the inverse of the cycle length) at that location.60 Spectral analysis becomes particularly useful when the activation rate is difficult to measure in the time domain, as may be the case with fragmented signals during AF.37

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Novel Approaches for AF Ablation Figure 1: Panoramic and Sequential Phase-mapping Approaches in Experimental Settings and in Patients With AF A

CCD camera

Linear analyses

Nonlinear analysis

Interval analysis for fractionation (frequency, CFAE)

Morphological repetitiveness of the waveform patterns Similarity index

Upstroke

High SI

Low SI

Calculation of the average of the SI between a pair of the nearest electrodes SI vector field (average wave propagation)

Curl and divergence are applied to analyse the SI vector field

Curl

LAA LSPV LIPV

RSPV Indicates whether a vector field is rotational

RIPV

1 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0

Divergence Represents how a vector field spreads out from a source or converges toward a sink

E Unipolar EGMs are used to construct an isopotential snapshot at any time point

Activation time

MAPs (indicating repolarisation) are used to calibrate unipolar EGMs Multiple isopotential maps to generate movies with specific activation patterns

A: Schematic of optical mapping and phase mapping of AF in experimental settings using isolated Langendorff-perfused heart preparations and voltage sensitive dyes; B: Main steps and information obtained using electrocardiographic imaging; C: Focal impulse and rotor modulation mapping approach; D: Main processing steps and schematic representation of mapping data using the electrogram similarity/phase-mapping technique; E: Schematic of the CARTOFINDER system using sequential acquisitions to generate phase maps. CFAE = complex fractionated atrial electrogram; EGM = electrogram; LA = left atrium; LAA = left atrial appendage; LIPV = left inferior pulmonary vein; LSPV = left superior pulmonary vein; RIPV = right inferior pulmonary vein; RSPV = right superior pulmonary vein; SI = similarity index.

However, DF analysis is sensitive to bias when using a fully automatic approach that can be affected by harmonic peaks.61 Moreover, the more complex the signal is the more complex the spectrum will be. Thus, spectral peaks with similar power may make it difficult to select the peak associated with the underlying intrinsic activation rate of a specific atrial spot. Some of these limitations may have affected the results of the multicentre randomised clinical trial RADAR-AF (Table 1). In PersAF patients, the study reported no incremental benefit on freedom from AF at 6 months of followup after PVI plus DF-guided high-frequency source ablation compared with PVI alone.62 In addition, the RADAR-AF trial used the analysis of bipolar signals (Table 2), which are more prone to be fractionated with more complex spectra compared with unipolar recordings.63

Spatio-temporal Dispersion of Electrograms

Another approach involving the analysis of fractionated electrograms has suggested that fractionation occurring in a non-simultaneous fashion at neighbouring electrode locations (time dispersion) and organised in welldefined clusters (spatial dispersion) may indicate the presence of an underlying source of AF (Tables 1 and 2).64 As described by Seitz et al., the approach takes advantage of using a traditional high-resolution electroanatomic mapping obtained with a multielectrode catheter, sequentially positioned in various atrial regions for a minimum acquisition time-period of 2.5 seconds. Then, the data are visually analysed to identify atrial locations displaying spatiotemporal dispersion on bipolar electrograms. Areas with dispersion have been defined as clusters of electrograms, either fractionated or non-fractionated, that display inter-

electrode time and space dispersion at a minimum of three adjacent bipoles such that activation spreads over all the AF cycle length (Figure 2C).64 Seitz et al. tested this approach in a prospective study including 105 patients undergoing AF ablation (non-PxAF; 77.2%). The authors used a Pentaray catheter to map under electroanatomical guidance with the Carto system. The ablation was performed only in regions displaying electrogram dispersion criteria during AF, which terminated (mainly initial conversion to atrial tachycardia; 85%) in 95% of patients. These results were obtained after the ablation of 7.5 ± 2.5% (10.1 ± 4% of the left atrial surface) and 15 ± 4% of the total atrial surface (29 ± 9.7% of the left atrial surface) in PersAF and long-standing PersAF, respectively. After 18 months of follow-up, atrial arrhythmia recurrences were reported in 15% of patients. These results were complemented with 2D computational simulations and optical mapping data from ovine atrial scar-related AF. In this experimental setting, pseudomultipolar electrograms exhibiting dispersion were specifically recorded in the vicinity of rotors. Moreover, dispersion was larger in the presence of interstitial fibrosis.64 Although encouraging, these results will need to be confirmed by other groups. Ablation of large atrial areas (up to 30% of the left atrial surface) may reflect a potential lack of specificity. Moreover, using visual inspection to identify areas with spatio-temporal dispersion of electrograms makes it difficult to follow an objective criterion for ablation. Map stability and reproducibility of target sites have not been addressed either, which raises the concern of potential significant variability on target sites as may happen for CFAE regions.65

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Narayan et al. 201229

Lin et al. 201630

Atienza et al. 201462

Calvo et al. 201755

Seitz et al. 201764

FIRM

Electrogram similarity/ phase-mapping combined technique

Spectral analysis and DF mapping

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CARTOFINDER

Spatiotemporal dispersion

Bipolar

Unipolar

Bipolar

Uni/Bipolar

Unipolar

ECGI

Haissaguerre et al. 201415

Type of Signal (Uni/ Bipolar)

Mapping Systems Study

Minimum of 2.5 s LA 927 ± 436 RA 512 ± 325

30 s LA 64.9 ± 20% RA 67.4 ± 21%

>10 min

9±1s

Recording Time/Mapping Coverage†

Sequential PentaRay NAV 4-4-4 mm (Biosense Webster)

Sequential PentaRay NAV (Biosense Webster)

Sequential Irrigated 3.5 mm tip catheter

Panoramic 64-pole basket catheter (Constellation, Boston Scientific)

Panoramic 252-electrode vest (ECVUE, CardioInsight Technologies Inc) combined with non-contrast thoracic computed tomography scan, with localisation accuracy of 6 mm

with inter-electrode time and space dispersion at a minimum of 3 adjacent bipoles such that activation spread over all the AF cycle length

• Dispersion areas: clusters of EGMs

meandering singularity point undergoing at least 3 consecutive complete rotations with a pattern of recurrence

• Rotational activity organised by a

power at each recording site

207

2.1 ± 1 sources per patients

4720

Number of Drivers‡

• DF: the frequency with the largest

curvature force and divergence • Focal sources: high SI, low curvature force and high divergence

• Rotational events: high SI, high

clockwise or counterclockwise activation contours around a centre of rotation • Focal sources: centrifugal activation contours from an origin

• Rotational events: sequential

fully rotated around a centre on phase progression • Focal sources: centrifugal activation originated from a point or an area

• Rotational events: at least 1 wave

Mapping Tool Definition of Driver (Sequential/Panoramic)

Table 2: Technical Considerations of Selected Studies Using Novel Mapping Systems in Patients With Persistent AF* Type of Drivers (rotational/ focal)

Rotational

38%/62%

70%/30%

79%/42% NA (% of patients with dispersion areas)

63%/37%

77%/23%

89%/11%

76%/24%

Rotational 80.5%/19.5% events: 69%/31% Focal sources: 71%/29%

Location of Drivers (LA/RA)

Transient, recurring and with high frequency

Stable

Limited spatial precession, consistent in multiple recordings over >10 min

Not sustained, substantially meandering but repetitively recurring in the same region

Characteristics of Drivers

Novel Approaches for AF Ablation

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Quintanilla et al. 201963

iAM/iFM mapping algorithm

Unipolar

8s 4,920 (IQR, 4,435–5,855) per biatrial map

19 ms

Sequential PentaRay catheter 4-4-4 mm (20 poles, Biosense Webster)

Panoramic FIRMap (Abbott, 50–70 mm 64-pole basket)

Panoramic The ultrasound and charge density imaging and mapping catheter AcQMap (Acutus Medical)

Sequential AFocusII catheter (20-pole, Abbott)

3 firings from the same location

2.5 (IQR, 2.0–4.0) per biatrial CS/LA NA map floor (76.9%) LA free wall/LAA (50%) LAPW/PVs (42.3%) Upper half of the RA (92.3%)

than surrounding average iFM

97%/3%

• Leading-drivers: regions with higher

65%/35%

40 (compared with 44 identified with FIRM)

flow directions adjoin and from where the arrows represent excitation velocity vectors, pointing in all directions

Spatiotemporal repetitive areas in border zones

Temporal and spatial stability

60% active 40% passive

44.1% Stable localised irregular activation, 31% focal and 24.4% rotational activation

73%/27%

• Quadripoint centres (singularities),

spiraling >270° around a confined central zone

• Localised rotational activation

100% LA (RA mapping not performed)

710

in the Probabilistic Atrial Driver Assessment map (voltage data and driver density maps)

• Localised, irregular activation • Focal activation, requiring at least

100% LA (RA mapping not performed)

252 (only LA drivers, RA data 100% LA (RA not provided) data not provided)

479

• Rotational activity and focal impulses

with a mean CL ≤220 ms and a CL standard deviation between 0 to 30 ms.

• Repetitive and regular activations

*The studies were selected based on the following criteria: RCT or prospective series with more specific targets on the study design, large sample numbers, and a follow-up of at least 12 months when available. †When available, mapping coverage data (either % of surface coverage or mapping points number) for sequential mapping systems is indicated. ‡Represents the total number of drivers identified in the study, unless the number of drivers per patient or per mapping is indicated. CS = coronary sinus; DF = dominant frequency; ECGI = electrocardiographic imaging; EGMs = electrograms; FIRM = focal impulse and rotor modulation; iAM/iFM = instantaneous amplitude modulation/instantaneous frequency modulation; IQR = interquartile range; LA = left atrium; LAA = left atrial appendage; LAPW = left atrial posterior wall; NA = not applicable; PV = pulmonary vein; RA = right atrium; RRa = repetitive-regular activities; RCT = randomised clinical trial; SI = similarity index.

Bellman et al. 201877

Electrographic flow mapping

Willems et al. 201975

Charge/dipole density

20 s

5–10 s LA 2,367 ± 936

Intracardiac Anatomic potential field ultrasound image (cavitary <5 minutes voltage) Activation maps ≈5 s

Choudry et al. Unipolar 202070

The RADAR system

Bipolar

Pappone et al. 201866

RRa

Novel Approaches for AF Ablation

Novel Approaches for AF Ablation Figure 2: Schematics of Basket and Sequential Electrogram-based Mapping Approaches in Patients With AF

A: CARTOFINDER system using a basket catheter for mapping; B: Dominant frequency mapping; C: Spatiotemporal dispersion mapping; D: Repetitive-regular activities mapping approach; E: RADAR system; F: Instantaneous amplitude and frequency modulation mapping. CL = cycle length; CS = coronary sinus; CV = conduction velocity; DF = dominant frequency; EGMs = electrograms; iAM/iFM = instantaneous amplitude modulation/instantaneous frequency modulation; LAT = local activation time; RRa = repetitive-regular activities.

Repetitive-regular Activities

Other alternatives may provide novel options to identify areas with fast atrial activation rates and unravel the hierarchical patterns of complex AF dynamics. On this line, Pappone et al. have proposed a new method based on cycle length analysis, variability of electrograms and conduction velocity vectors to identify the direction of wavefront propagation, the speed of the repetitive-regular activations and the fractionation index, which is measured by an automatic algorithm to show the regions exhibiting fragmented electrograms (Table 1, Figure 2D).66 The regions showing repetitive and regular activations with a mean cycle length ≤220 ms and a cycle length standard deviation between 0 and 30 ms were considered as ablation targets. These regions showed distinct peak– peak activations, small variation in activation cycle length, consistent electrogram morphology, flat isoelectric interval between consecutive activations and consistent activation sequences on the multielectrode mapping catheter over time. The methodology excluded irregular activations (>30 ms variability), fractionation (60–120 ms cycle length) and regions with voltage <0.05 mV from the analysis to identify AF sources (Table 2).66 The approach of Pappone et al. was tested in a prospective, single-centre randomised trial, in which PersAF patients undergoing AF ablation were randomly allocated to ablation of repetitive-regular activations followed by PVI (mapping group; n=41) or PVI alone (control group; n=40). The regions exhibiting repetitive-regular activities were 479 in 81 patients (5.9 ± 2.4 per patient), and 39% of repetitive regular activities were identified within the PVs. Ablation of repetitive-regular activities resulted in higher arrhythmia termination rates compared with conventional PVI (61% versus

30%). After 1 year of follow-up, 73.2% of patients in the mapping group were free from AF recurrences versus 50% in the control group.66 The mapping criteria excluded irregular yet repetitive electrograms patterns and fast temporal activations, which might also have potential mechanistic value. This could have led to missing relevant AF driver regions, which may have affected the sensitivity to detect AF sources. The authors did not map the right atrium either, which may also have affected study outcomes in this cohort of patients with PersAF and more complex substrates.67

New Approaches to Improve Spatial Resolution During AF Mapping

Spatial resolution represents a significant problem during AF mapping, specially using simultaneous mapping with low-density multipolar catheters. This limitation makes it difficult to identify AF drivers in real time.29 Moreover, most rotational activity associated with driver regions has been described with drifting behaviour in experimental settings using high-resolution optical mapping, and only occasionally a driver can be recorded remaining stable in the same position for long recording periods.12,13,19 Therefore, limited spatial resolution in the clinic may cause rotors to be missed, improperly localised, or artefactually created due to highly interpolated maps.68,69 Two innovative systems have been recently developed to potentially overcome these technical limitations and provide real-time and more panoramic insights.

Real-time Electrogram Analysis for Drivers of AF

The Real-time Electrogram Analysis for Drivers of Atrial Fibrillation (RADAR) system (AFTx, Inc.) uses high-density electroanatomical maps, created with

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Novel Approaches for AF Ablation standard mapping equipment and unipolar signals.70 Local unipolar atrial electrograms and electrode positions are extracted from the mapping system and matched to the corresponding simultaneous coronary sinus pattern, or phase (not to be confused with the aforementioned phase mapping approach), which is used as a reference. Electrograms from different anatomical locations are processed to create a high-resolution panoramic 3D conduction vector map for each coronary sinus phase. This enables to calculate conduction vectors using the distance between electrodes on the mapping system and the depolarisation timings at each electrode. Thus, the system identifies sites with spatiotemporal repetition of drivers and generates driver density maps, which are the result of analysing individual vector maps (Table 2, Figure 2E). Areas of voltage transition can also be identified to specifically highlight rotational or focal activity localised in these areas. To date, clinical outcomes reported with this system mainly rely on a clinical series conducted by Choudry et al.70 The study included 64 patients with PersAF or long-standing PersAF undergoing AF ablation with the RADAR system. After PVI, the system was used to target and ablate all driver domains. If the patient remained in AF after ablation of all driver domains, additional RADAR maps could be created in the left or right atrium at the discretion of the operator. The authors reported acute AF termination in 55% of patients (Table 1). After 1-year follow-up 68% remained free of AF off all antiarrhythmic drugs.70

Figure 3: Other Basket Electrogram-based Mapping Systems in Patients With AF A

B Green's minimal energy algorithm Voltage shapes Horn-Schunck Flow algorithm

Non-contact Charge Density Mapping

Complex wave propagation patterns as those documented during AF may require simultaneous or very rapid high-resolution mapping of both atrial chambers to identify relevant regions sustaining the overall arrhythmia.12,71,72 This would be crucial if fibrillation dynamics were completely random and driver regions were not stable during sequential mapping. A novel mapping approach has been proposed to address this potential limitation of conventional sequential mapping in the clinic. The method uses a combination of ultrasound-based real time reconstruction of the endocardial surface with simultaneous acquisition of intracardiac unipolar voltage. Inverse and forward algorithms are then applied to the intracardiac voltage to obtain the distribution of positive and negative ionic charges and display electrical activation on the generated anatomical shell (Figure 3A).73,74 The maps obtained with this method provide an average fourfold improvement in spatial and temporal resolution compared with conventional voltage maps. This relies not only on the panoramic acquisition of the electrode positions but also on the integration of high-resolution real-time anatomical data of the ultrasound transducers, which minimise errors due to motion, and provide accurate distance measurements for overall system stability.74 The UNCOVER-AF trial has recently confirmed the feasibility and safety of this novel system during AF ablation (Tables 1 and 2).75 Thirteen centres across Europe and Canada prospectively enrolled 129 patients with PersAF undergoing de novo catheter ablation combining PVI + charge density-guided ablation. The main results of the study showed that after 1-year follow-up a single procedure achieved 72.5% freedom from AF on or off antiarrhythmic drugs. The primary safety outcome was 98% with no device-related major adverse events.

In Search of Greater Specificity in the AF Ablation Strategy

Targeting passive atrial structures with catheter ablation might result in unnecessary scar formation, potentially increasing the likelihood of iatrogenic atrial tachyarrhythmias, loss of contractile function and other sequelae without a significant impact on long-term ablation success.76 Interesting novelties in the field may improve characterisation of AF drivers and decrease unnecessary ablation sites.

Average flow behaviour Schematics of the charge/dipole density mapping system (A) and the electrographic flow mapping approach (B). US = ultrasound.

Electrographic Flow Mapping

This novel technology provides the ability for a full spatial and temporal reconstruction of electrographic potentials and their flow, derived from endocardial unipolar electrogram data collected with a 64-pole basket catheter.77 Electrographic flow mapping designates the matrix of velocity vectors describing the average propagation of action potentials by acquisition of unipolar recordings (Table 2, Figure 3B). The system is not affected by limitations of spatial resolution due to the algorithm providing triangulation between the electrodes as long as electrode distance is larger than the excitation wavelength. Each electrographic flow map is automatically analysed to discriminate between active and passive drivers. Active drivers are characterised by vectors spreading away from an AF source. Conversely, passive drivers show flow phenomena around a distinct area with the vectors running towards this area. Clinical data have shown that electrographic flow mapping was able to identify the majority of AF sources detected with FIRM, although 40% of them were classified as passive flow phenomena (Table 1).77 Therefore, electrographic flow mapping may potentially increase specificity on ablating AF drivers although validation warrants further confirmation in dedicated series.

The Instantaneous Amplitude Modulation and Instantaneous Frequency Modulation Mapping Algorithm

Quintanilla et al. have recently proposed a new algorithm capable of distinguishing the dominant drivers in AF, which may also increase the specificity of AF ablation in complex PersAF cases (Table 1).63 Based on the assumption that the amplitude and frequency modulations used for radio broadcasting are naturally present in signals during cardiac fibrillation,78 the combined analysis of the instantaneous frequency modulation (iFM) and instantaneous amplitude modulation (iAM) of single-signals (optical

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Novel Approaches for AF Ablation action potentials or unipolar atrial signals) during PersAF could detect AF drivers and display their hierarchical organisation without costly panoramic multielectrode acquisition systems (Table 2 and Figure 2F). The authors used a completely translational approach, including computer simulations, optical mapping of isolated Langendorff-perfused sheep hearts with PersAF, in vivo electroanatomical mapping of a clinicallyrelevant porcine model of long-term self-sustained PersAF, and complementary studies in patients with PersAF. The results showed that both rotational-footprint and spatiotemporally stable leading-driver regions can be identified using the iFM/iAM algorithm without panoramic multielectrode acquisition systems. In the pig model of long-term PersAF, the arrhythmia terminated during the ablation of leading-driver regions in 92.3% ablation procedures after a median of 16.9 minutes of radiofrequency delivery. Importantly, despite the fact that all the leading-driver regions displayed rotational-footprints, they only constituted around a quarter of total rotational-footprint positive locations. This demonstrates that rotational activations are sensitive but not specific to guide AF ablation. All identified leading-driver regions were targeted in two of the three patients of the interventional group, with subsequent freedom from AF recurrence after 16 months of follow-up off antiarrhythmic drugs.63 Unlike phase mapping, which requires multiple signals to detect rotations,79 the iFM/iAM algorithm detects rotational-footprints for each signal independently. Also different from DF mapping, iFM tracks dynamic changes in the local activation rate during acquisition, enabling the detection of intervals with rotational-footprint or high-frequency short bursts that would be easily missed by DF analysis.63 Furthermore, this new algorithm relies on unipolar signals from 1 mm electrodes after advanced signal processing and careful ventricular farfield minimisation/rejection, instead of bipolar signals whose amplitudes depend on wavefront orientation. Although promising, this novel algorithm needs further validation in larger sets, also to quantify its potential synergistic value with respect to PVI.

Main Clinical Evidence Using Novel Mapping Methods For AF Ablation

The steady increase in the number of mapping techniques to identify and ablate potential AF drivers has raised the need to assess their effectiveness and safety in large clinical trials, either if performed as a complementary step after PVI (e.g. in PersAF cases) or instead of PVI (e.g. in PxAF cases). Currently, the main clinical evidence comes from the pioneering approach of Narayan et al. using FIRM.16,38 Initial meta-analyses focused on studies comparing PVI alone and PVI plus FIRM ablation. In particular, Parameswaran et al. included 11 observational studies (four studies with PxAF patients and 10 with PersAF patients) with a total of 556 patients (166 PxAF and 390 PersAF patients).80 The data showed wide variation in reported efficacy, which could not be explained by clear differences between the studies. Single procedure freedom from AF was 37.8% for PxAF and 59.2% for PersAF at a mean follow-up of 13.8 and 12.9 months, respectively. These data suggest the possibility that FIRM-guided ablation may have pro-arrhythmic effects in PxAF. Another meta-analysis by Mohanty et al. did not show any therapeutic benefit of PVI plus FIRM ablation compared with PVI alone.81 Both meta-

analyses show limitations to report stronger results. Thus, the majority of studies included in the analyses were uncontrolled with a relatively small sample size (<200 patients) and marked heterogeneity and variability in success rates among different centres performing FIRM ablation. Such variability in results may reflect a complex procedure that requires additional skills for mapping, acquisition and interpretation before ablation. Beyond the FIRM approach, other meta-analyses have supported the potential benefit of a combined strategy involving other phase-mapping and electrogram-based techniques with PVI in improving both acute AF termination rates and single-procedure freedom from AF. This can be achieved with similar rates of procedural complications as in conventional PVI.82,83 Remarkably, in controlled trials, the addition of AF driver ablation to PVI supports the possible benefit of this combined approach to improve AF ablation outcomes. A step towards better understanding of the clinical impact of different AF driver mapping methodologies has recently been performed by Lin et al. in patients with PersAF.28 Their meta-analysis confirmed that adjunctive driver-guided ablation in addition to PVI could improve one-year AF freedom and increase acute AF termination rate without a significant increase in potential complications. The benefit in PersAF ablation seems to be more evident using phase-mapping methodologies rather than electrogram-based driver mapping.28 From the foregoing, although the data from meta-analyses provide some support to target and ablate driver regions plus PVI in PersAF patients, the evidence mainly comes from uncontrolled and non-randomised studies, with substantial heterogeneity in reported outcomes. In addition, the analyses are based on the premise that these mapping tools are adequate for detecting AF drivers. However, the considerable heterogeneity among AF driver mapping technologies precludes data analysis from drawing firm conclusions on driver-guided ablation. Actually, only a few studies have compared different driver-based mapping approaches. These data show some agreement on target sites between phase mapping and other methods as electrographic flow mapping or a method that reconstructs AF signals using sinusoids in an attempt not to detect false rotational activations.84,85 However, to the best of our knowledge, actual validation in experimental settings using optical mapping comparisons of the current wide range of methodologies has not been performed. Data variability on reported outcomes may be affected by clinical and procedural differences, and among individual operators. In particular, evidence against the effectiveness of any specific driver-guided AF ablation strategy need not undermine its validity, but may instead reflect some shortcomings of the technology or even differences in atrial debulking among operators. Overall, evidence for the efficacy of AF driver ablation remains inconclusive. Further prospective randomised studies with standardised driver identification and validation are warranted.

Conclusion

Rotors/focal sources are an important mechanism for sustaining AF in animal models and they are increasingly being demonstrated in human AF by a variety of mapping approaches. However, other mechanisms may certainly be involved in initiation and maintenance of specific cases.86 Recent studies using different novel mapping approaches to identify,

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Novel Approaches for AF Ablation target and ablate potential AF sources have been reported with promising results. Such mechanistic-based ablation techniques have evolved thanks to insights into wave propagation dynamics during AF provided by experimental optical mapping studies and computer-based simulations. Still, current mechanistic-based ablation strategies have provided conflicting results, often linked to technical limitations of the methodology and also partial knowledge of AF pathophysiology. In the near future, the development of more specific and reliable ablation methods is an important goal to improve overall safety and clinical outcomes of AF ablation. This will help to decrease the substrate for subsequent development of macroreentrant atrial arrhythmias and minimise the extent of atrial ablation so as to preserve atrial contraction. 1. Hindricks G, Potpara T, Dagres N, et al. 2020 ESC guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association of Cardio-Thoracic Surgery (EACTS). Eur Heart J 2021;42:373– 498. https://doi.org/10.1093/eurheartj/ehaa612; PMID: 32860505. 2. Calkins H, Hindricks G, Cappato R, et al. 2017 HRS/EHRA/ ECAS/APHRS/SOLAECE expert consensus statement on catheter and surgical ablation of atrial fibrillation: executive summary. Europace 2018;20:157–208. https://doi. org/10.1093/europace/eux275; PMID: 29016841. 3. la Rosa G, Quintanilla JG, Salgado R, et al. Anatomical targets and expected outcomes of catheter-based ablation of atrial fibrillation in 2020. Pacing Clin Electrophysiol 2020;44:341–59. https://doi.org/10.1111/pace.14140; PMID: 33283883. 4. Sanders P, Hocini M, Jais P, et al. Complete isolation of the pulmonary veins and posterior left atrium in chronic atrial fibrillation. Long-term clinical outcome. Eur Heart J 2007;28:1862–71. https://doi.org/10.1093/eurheartj/ehl548; PMID: 17341503. 5. Dixit S, Marchlinski FE, Lin D, et al. Randomized ablation strategies for the treatment of persistent atrial fibrillation: RASTA study. Circ Arrhythm Electrophysiol 2012;5:287–94. https://doi.org/10.1161/CIRCEP.111.966226; PMID: 22139886. 6. Vogler J, Willems S, Sultan A, et al. Pulmonary vein isolation versus defragmentation: the CHASE-AF Clinical Trial. J Am Coll Cardiol 2015;66:2743–52. https://doi.org/10.1016/j. jacc.2015.09.088; PMID: 26700836. 7. Driessen AHG, Berger WR, Krul SPJ, et al. Ganglion plexus ablation in advanced atrial fibrillation: the AFACT Study. J Am Coll Cardiol 2016;68:1155–65. https://doi.org/10.1016/j. jacc.2016.06.036; PMID: 27609676. 8. Di Biase L, Burkhardt JD, Mohanty P, et al. Left atrial appendage isolation in patients with longstanding persistent AF undergoing catheter ablation: BELIEF trial. J Am Coll Cardiol 2016;68:1929–40. https://doi.org/10.1016/j. jacc.2016.07.770; PMID: 27788847. 9. Rolf S, Kircher S, Arya A, et al. Tailored atrial substrate modification based on low-voltage areas in catheter ablation of atrial fibrillation. Circ Arrhythm Electrophysiol 2014;7:825–33. https://doi.org/10.1161/CIRCEP.113.001251; PMID: 25151631. 10. Moe GK, Abildskov JA. Atrial fibrillation as a self-sustaining arrhythmia independent of focal discharge. Am Heart J 1959;58:59–70. https://doi.org/10.1016/0002-8703(59)902741; PMID: 13661062. 11. Quintanilla JG, Perez-Villacastin J, Perez-Castellano N, et al. Mechanistic approaches to detect, target, and ablate the drivers of atrial fibrillation. Circ Arrhythm Electrophysiol 2016;9:e002481. https://doi.org/10.1161/CIRCEP.115.002481; PMID: 26729850. 12. Filgueiras-Rama D, Price NF, Martins RP, et al. Long-term frequency gradients during persistent atrial fibrillation in sheep are associated with stable sources in the left atrium. Circ Arrhythm Electrophysiol 2012;5:1160–7. https://doi. org/10.1161/CIRCEP.111.969519; PMID: 23051840. 13. Yamazaki M, Avula UMR, Berenfeld O, et al. Mechanistic comparison of “nearly missed” versus “on-target” rotor ablation. JACC Clinical Electrophysiology 2015;1:256–69. https://doi.org/10.1016/j.jacep.2015.04.015; PMID: 29759314. 14. Hansen BJ, Zhao J, Csepe TA, et al. Atrial fibrillation driven by micro-anatomic intramural re-entry revealed by

Clinical Perspective

• Current long-term success rates after catheter ablation of

persistent AF are not higher than 60%, highlighting the need for more effective strategies. • A wide variety of adjunctive anatomical ablation strategies have been explored, without convincing evidence of benefit and with potential risk of pro-arrhythmia and higher complication rates. • Developments in mapping tools and computational methods for advanced signal processing have provided novel strategies to identify atrial regions potentially associated with AF maintenance. • These novel mapping tools represent a significant step forward towards the understanding of complex patterns of propagation during AF and the potential achievement of patient-tailored ablation strategies in the near future.

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71. Krummen DE, Hayase J, Morris DJ, et al. Rotor stability separates sustained ventricular fibrillation from selfterminating episodes in humans. J Am Coll Cardiol 2014;63:2712–21. https://doi.org/10.1016/j.jacc.2014.03.037; PMID: 24794115. 72. Krummen DE, Hayase J, Vampola SP, et al. Modifying ventricular fibrillation by targeted rotor substrate ablation: Proof-of-concept from experimental studies to clinical VF. J Cardiovasc Electrophysiol 2015;26:1117–26. https://doi. org/10.1111/jce.12753; PMID: 26179310. 73. Grace A, Verma A, Willems S. Dipole density mapping of atrial fibrillation. Eur Heart J 2017;38:5–9. https://doi. org/10.1093/eurheartj/ehw585; PMID: 28110304. 74. Grace A, Willems S, Meyer C, et al. High-resolution noncontact charge-density mapping of endocardial activation. JCI Insight 2019;4. https://doi.org/10.1172/jci. insight.126422; PMID: 30895945. 75. Willems S, Verma A, Betts TR, et al. Targeting nonpulmonary vein sources in persistent atrial fibrillation identified by noncontact charge density mapping: UNCOVER AF Trial. Circ Arrhythm Electrophysiol 2019;12:e007233. https://doi. org/10.1161/CIRCEP.119.007233; PMID: 31242746. 76. Zaman JA and Narayan SM. Ablation of atrial fibrillation: how can less be more? Circ Arrhythm Electrophysiol 2015;8:1303–5. https://doi.org/10.1161/CIRCEP.115.003495; PMID: 26671931. 77. Bellmann B, Lin T, Ruppersberg P, et al. Identification of active atrial fibrillation sources and their discrimination from passive rotors using electrographical flow mapping. Clin Res Cardiol 2018;107:1021–32. https://doi.org/10.1007/s00392018-1274-7; PMID: 29744616. 78. Quintanilla JG, Moreno J, Archondo T, et al. KATP channel opening accelerates and stabilizes rotors in a swine heart model of ventricular fibrillation. Cardiovasc Res 2013;99:576– 85. https://doi.org/10.1093/cvr/cvt093; PMID: 23612586. 79. Kuklik P, Zeemering S, Maesen B, et al. Reconstruction of instantaneous phase of unipolar atrial contact electrogram using a concept of sinusoidal recomposition and Hilbert transform. IEEE Trans Biomed Eng 2015;62:296–302. https:// doi.org/10.1109/TBME.2014.2350029; PMID: 25148659. 80. Parameswaran R, Voskoboinik A, Gorelik A, et al. Clinical impact of rotor ablation in atrial fibrillation: a systematic review. Europace 2018;20:1099–106. https://doi.org/10.1093/ europace/eux370; PMID: 29340595. 81. Mohanty S, Mohanty P, Trivedi C, et al. Long-term outcome of pulmonary vein isolation with and without focal impulse and rotor modulation mapping: Insights from a metaanalysis. Circ Arrhythm Electrophysiol 2018;11:e005789. https:// doi.org/10.1161/CIRCEP.117.005789; PMID: 29545360. 82. Ramirez FD, Birnie DH, Nair GM, et al. Efficacy and safety of driver-guided catheter ablation for atrial fibrillation: A systematic review and meta-analysis. J Cardiovasc Electrophysiol 2017;28:1371–8. https://doi.org/10.1111/jce.13313; PMID: 28800192. 83. Baykaner T, Rogers AJ, Meckler GL, et al. Clinical implications of ablation of drivers for atrial fibrillation: a systematic review and meta-analysis. Circ Arrhythm Electrophysiol 2018;11:e006119. https://doi.org/10.1161/ CIRCEP.117.006119; PMID: 29743170. 84. Swerdlow M, Tamboli M, Alhusseini MI, et al. Comparing phase and electrographic flow mapping for persistent atrial fibrillation. Pacing Clin Electrophysiol 2019;42:499–507. https://doi.org/10.1111/pace.13649; PMID: 30882924. 85. Navara R, Leef G, Shenasa F, et al. Independent mapping methods reveal rotational activation near pulmonary veins where atrial fibrillation terminates before pulmonary vein isolation. J Cardiovasc Electrophysiol 2018;29:687–95. https:// doi.org/10.1111/jce.13446; PMID: 29377478. 86. Heijman J, Voigt N, Nattel S, Dobrev D. Cellular and molecular electrophysiology of atrial fibrillation initiation, maintenance, and progression. Circ Res 2014;114:1483–99. https://doi.org/10.1161/CIRCRESAHA.114.302226; PMID: 24763466.

Coronary Physiology

TCT Connect 2020 Trial Update: FORECAST, COMBINE OCT-FFR and DEFINE-PCI Kevin Cheng

and Ranil de Silva

National Heart and Lung Institute, Imperial College London, Royal Brompton and Harefield NHS Foundation Trust, London, UK

Abstract

Recent studies reported at TCT Connect 2020 have investigated a number of open clinical questions regarding the role of coronary physiology and the assessment of plaque morphology for diagnosis (FORECAST), risk stratification (COMBINE OCT-FFR) and treatment evaluation (DEFINEPCI) of patients with coronary artery disease. In this article, the authors provide a critical appraisal of these studies and evaluate how they add to the current evidence base for management of patients with epicardial coronary artery disease. Furthermore, they discuss their potential impact on clinical practice, limitations of these studies and unanswered clinical questions that are areas for future research.

Keywords

Trials, coronary physiology, coronary artery disease Disclosure: The authors have no conflicts of interest to declare. Received: 18 February 2021 Accepted: 8 March 2021 Citation: European Cardiology Review 2021;16:e22. DOI: https://doi.org/10.15420/ecr.2021.07 Correspondence: Ranil de Silva, NHLI (Brompton Campus), Imperial College London, Sydney St, London SW3 6NP, UK. E: r.desilva@imperial.ac.uk Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

FORECAST Trial

The UK’s National Institute for Health and Care Excellence (NICE) has recommended CT coronary angiography (CTCA) as the first-line investigation for patients with suspected cardiac chest pain.1,2 Recent developments now enable physiological lesion assessment in epicardial coronary arteries to be performed using computational fluid dynamic simulations based on 3D coronary arterial geometries derived from CT coronary angiograms.3,4 Adoption of this technology into the routine clinical algorithm for investigation of patients with suspected cardiac chest pain has been advocated primarily on the basis of cost-effectiveness modelling.5 The FFR-CT RIPCORD study of 200 consecutive patients with stable chest pain in whom CTCA was performed as a first-line non-invasive investigation for CAD evaluated the impact of the addition of FFR-CT on top of conventional CTCA analysis.6 The primary endpoint was the difference between a consensus management plan derived from CTCA information versus CTCA combined with FFR-CT. The investigators showed that disclosure of FFR-CT data substantially affected the categorisation of CAD severity and changed management in 36% of patients, driven mainly by re-classifying patients from treatment with PCI to medical therapy. Analyses from this study also suggested that FFR-CT might lead to a cost saving of £214 per patient and reduce the need for invasive coronary angiography, its associated costs and potential complications.5 The preliminary data from FFR-CT RIPCORD were used to inform the design of the prospective FORECAST trial, which randomised 1,400

patients presenting to 11 UK rapid-access chest pain clinics.7,8 It compared resource utilisation using an algorithm incorporating FFR-CT if a >40% stenosis was identified on CTCA (31.5%) against a conventional chest pain assessment pathway involving CTCA (60.1%), stress echocardiography (14.7%) and treadmill exercise ECG (10.0%).7,8 At 9 months, the number of invasive angiograms in the FFR-CT arm was reduced by 14% compared to the reference group (p=0.02) with 22% fewer patients undergoing invasive investigation (p=0.01). The utilisation of non-invasive tests was also higher in the conventional arm. However, these differences did not translate to a reduction in the FFR-CT arm of per-patient resource utilisation (£1,491.46 with conventional versus £1,605.50 with FFR-CT; p=0.962), major adverse cardiovascular events, revascularisation or improved angina class or quality of life. While these neutral results may appear on the surface somewhat disappointing and discrepant with previous cost-effectiveness modelling, there are reasons for optimism. The reduction in referral for invasive angiography using the FFR-CT strategy, without any compromise of clinical outcomes, symptom status and quality of life, will be welcome to patients. Further analyses should help to refine the CTCA criteria which trigger referral for FFR-CT analysis and the price point at which FFR-CT can achieve cost-effectiveness. This technology is likely to form an important addition to an algorithm of initial non-invasive CTCA-driven diagnosis, risk stratification and medical therapy as demonstrated in the ISCHEMIA trial.9 In other clinical scenarios, potential advantages of FFR-CT when coupled with improved CT scanning platforms are being investigated and have the potential to change practice. These include its utility in revascularisation decision-making by the heart team, as well as procedure planning of PCI.10

COMBINE OCT-FFR Trial

Identification of patients and plaques at risk of future cardiovascular death, MI or worsening angina remains an important unmet clinical need.11

Trial Update: FORECAST, COMBINE OCT-FFR and DEFINE-PCI Studies using intracoronary imaging by intravascular ultrasound (IVUS),12 optical coherence tomography (OCT)13 and near-infrared spectroscopyIVUS (NIRS-IVUS)14 have been reported to identify lesion characteristics associated with increased future adverse clinical events. Previous studies have demonstrated that mild to moderate non-flow-limiting lesions are often responsible for subsequent MI.15 Coronary lesions with FFR >0.8 and iFR >0.92 are safe to defer and lesions with FFR <0.8 have not been associated with an increased risk of death or MI.16–20 Furthermore, patients with diabetes remain a high-risk group at increased risk of future MACE.21 Against this backdrop, the COMBINE OCT-FFR study was an international multicentre observational prospective study in 547 patients with diabetes presenting with either acute or chronic coronary syndromes, which evaluated whether further stratification of coronary lesions (40–80% angiographic diameter stenosis) with FFR >0.8 (n=423) according to the presence (n=98) or absence (n=292) of thin-cap fibroatheroma defined by OCT (OCT-TCFA) was associated with differences in risk of future adverse clinical events. Only two patients were lost to follow-up and evaluable OCT was acquired in 92% of cases. At 18 months, the primary composite endpoint of target lesion MACE (cardiac death, target vessel MI, clinicallydriven target lesion revascularisation, or hospitalisation due to unstable or progressive angina) was significantly higher among patients with OCTTCFA compared with those without OCT-TCFA: 13.3% versus 3.1% (HR 4.7; 95% CI [2.0–10.9], p=0.0004). The major drivers for increased MACE were clinically driven target lesion revascularisation and hospitalisation in patients with OCT-TCFA rather than the hard endpoints of death or MI. People with diabetes are a known high-risk group. While the results of this study are certainly of interest, they do not demonstrate that additional OCT evaluation is either necessary or significantly alters their risk assessment or approach to management. Patients with diabetes require intensive guideline-directed medical therapy for blood pressure, lipid, and glycaemic control combined with antiplatelet therapy and these should be the primary goals when managing non-flow limiting coronary lesions. For instance, previous studies have shown the disease-modifying effects of intensive lipid lowering which can promote the development of increased fibrous cap thickness which can be considered a more favourable plaque morphology.22 At the current time, despite the results of early studies, such as PROSPECT-ABSORB (TCTMD2020), there is no indication to consider pre-emptive percutaneous intervention of high-risk lesions defined by intracoronary imaging to reduce future clinical risk, though results from studies, such as PREVENT (NCT02316886), will provide further insights.

DEFINE-PCI at 1 Year

In contemporary interventional practice, clinical guidelines recommend invasive wire-based coronary physiology lesion assessment using fractional flow reserve (FFR) or instant wave free ratio (iFR), to stratify revascularisation decisions for relief of symptomatic angina in patients with chronic coronary syndromes.18,19,16,20,23 However, angina persists in up to 30% of patients after ‘successful’ PCI, adjudicated by angiographic criteria. Persistence of angina may be caused by stent failure, inaccurate identification of the segment of epicardial coronary disease requiring treatment resulting in residual ischaemia, incomplete revascularisation, e.g. residual chronic total occlusion, diffuse small vessel epicardial disease or coronary microvascular dysfunction. DEFINE-PCI was a prospective study of 467 patients who had successful PCI and documented post-procedure iFR data. Twenty-four per cent of patients had residual haemodynamically significant lesions, defined as

iFR <0.90, mostly due to a focal treatable stenosis. In a post-hoc analysis, investigators identified a post-PCI iFR value of ≥0.95 being associated with fewer clinical events. The investigators now present the 1-year outcomes data for this group using an iFR ≥0.95 cutoff. At 1 year, patients with post-PCI iFR <0.95 had a rate of cardiac death, spontaneous MI, or clinically-driven target vessel revascularisation of 5.7% compared with 1.8% in those with an iFR ≥0.95 (HR 3.38; 95% CI [0.99–11.6]; log-rank p=0.04). The secondary endpoint of death or spontaneous MI occurred in 3.2% in patients with an iFR <0.95 compared to 0% in those with higher iFR values. This was a small study with a small number of events and the difference in outcomes between the two groups can only be considered hypothesis generating. The unanswered question remains as to why adverse events occur in patients with iFR values that are above the ischaemic threshold. Furthermore, the additional intervention that may be required to provide an optimised PCI by iFR may incur a risk of added procedural complication and additional cost due to increased procedure time and the need to employ additional adjunctive technologies, such as IVUS or OCT. Previous studies have suggested the importance of intracoronary imaging guidance to optimise PCI.24,25 The ULTIMATE trial randomised all-comers undergoing PCI to either IVUS-guided or angiography-guided PCI and investigated a primary outcome of target vessel failure at 12 months.25 IVUS-guided PCI was superior (2.9% MACE rate) compared to angiographyguided PCI (5.4%; p=0.019). These improved outcomes with IVUS-guided PCI are durable, out to 3 years, mainly due to reduced clinically-driven target vessel revascularisation.26 Similarly, the ILUMIEN series of studies has demonstrated the benefit of OCT in PCI planning and stent optimisation.24,27–29 Although ILUMIEN I showed that OCT-driven PCI optimisation did not significantly improve post-PCI FFR (0.86 ± 0.07 to 0.90 ± 0.10; p=0.1209), the study demonstrated that an optimal post-PCI FFR (>0.80) following OCT-guided PCI was achieved in a high proportion of patients.27 Similarly, the DOCTORS study, a multicentre randomised study of 240 patients with NSTEACS undergoing PCI, also showed that OCT-guidance resulted in significantly greater FFR values compared to angiography (0.94 ± 0.04 versus 0.92 ± 0.05; p=0.05) with a greater proportion of patients achieving a post-procedure FFR >0.90 with OCT guidance (p=0.0001).30 In our view, the current evidence base would support use of physiological lesion assessment for selection of location and length of ischaemiacausing lesions that may benefit from PCI for relief of symptomatic angina. Techniques such as iFR pullback combined with angiographic coregistration may well facilitate this strategy. The DEFINE GPS trial (NCT04451044) is an international multicentre 3,000 patient study, which will investigate whether iFR co-registration reduces target vessel failure or rehospitalisation for progressive or unstable ischaemia at 2 years. Pending the results of this study, PCI procedural optimisation may currently be guided better by an intracoronary imaging modality. New hybrid technologies that enable combined lesion morphology and haemodynamic assessment by OCT may play an important role in the future.31

Future Directions

The studies presented at TCT Connect 2020 add to the current evidence base for management of patients with epicardial CAD. They affirm the complementary and clinically valuable information offered by coronary lesion morphology by intracoronary imaging and wire-based functional haemodynamic assessment for diagnosis, risk stratification, and treatment of symptomatic patients with atherosclerotic epicardial CAD.

EUROPEAN CARDIOLOGY REVIEW Access at: www.ECRjournal.com

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syndromes. Eur Heart J 2020;41:407–77. https://doi. org/10.1093/eurheartj/ehz425; PMID: 31504439. 24. Ali ZA, Maehara A, Généreux P, et al. Optical coherence tomography compared with intravascular ultrasound and with angiography to guide coronary stent implantation (ILUMIEN III: OPTIMIZE PCI): a randomised controlled trial. Lancet 2016;388:2618–28. https://doi.org/10.1016/S01406736(16)31922-5; PMID: 27806900. 25. Zhang J, Gao X, Kan J, et al. Intravascular ultrasound versus angiography-guided drug-eluting stent implantation: the ULTIMATE trial. J Am Coll Cardiol 2018;72:3126–37. https://doi. org/10.1016/j.jacc.2018.09.013; PMID: 30261237. 26. Gao X-F, Ge Z, Kong X-Q, et al. 3-year outcomes of the ULTIMATE trial comparing intravascular ultrasound versus angiography-guided drug-eluting stent implantation. JACC: Cardiovascular Interventions 2021;14:247–57. https://doi. org/10.1016/j.jcin.2020.10.001. PMID: 33541535. 27. Wijns W, Shite J, Jones MR, et al. Optical coherence tomography imaging during percutaneous coronary intervention impacts physician decision-making: ILUMIEN I study. Eur Heart J 2015;36:3346–55. https://doi.org/10.1093/ eurheartj/ehv367; PMID: 26242713. 28. Maehara A, Ben-Yehuda O, Ali Z, et al. Comparison of stent expansion guided by optical coherence tomography versus intravascular ultrasound: the ILUMIEN II study (Observational Study of Optical Coherence Tomography [OCT] in Patients Undergoing Fractional Flow Reserve [FFR] and Percutaneous Coronary Intervention). JACC Cardiovasc Interv 2015;8:1704–14. https://doi.org/10.1016/j.jcin.2015.07.024; PMID: 26585621. 29. Ali Z, Landmesser U, Karimi Galougahi K, et al. Optical coherence tomography-guided coronary stent implantation compared to angiography: a multicentre randomised trial in PCI - design and rationale of ILUMIEN IV: OPTIMAL PCI. EuroIntervention 2021;16:1092–9. https://doi.org/10.4244/EIJD-20-00501; PMID: 32863246. 30. Meneveau N, Souteyrand G, Motreff P, et al. Optical coherence tomography to optimize results of percutaneous coronary intervention in patients with non-ST-elevation acute coronary syndrome: results of the multicenter, randomized DOCTORS study (Does Optical Coherence Tomography Optimize Results of Stenting). Circulation 2016;134:906–17. https://doi.org/10.1161/ CIRCULATIONAHA.116.024393; PMID: 27573032. 31. do31. Yu W, Huang J, Jia D, et al. Diagnostic accuracy of intracoronary optical coherence tomography-derived fractional flow reserve for assessment of coronary stenosis severity. EuroIntervention 2019;15:189–97. https://doi. org/10.4244/EIJ-D-19-00182; PMID: 31147309. 32. Gulati M, Cooper-DeHoff RM, McClure C, et al. Adverse cardiovascular outcomes in women with nonobstructive coronary artery disease: a report from the Women’s Ischemia Syndrome Evaluation Study and the St James Women Take Heart Project. Arch Intern Med 2009;169:843– 50. https://doi.org/10.1001/archinternmed.2009.50; PMID: 19433695.

APSC Consensus Recommendations

Direct Oral Anticoagulants in Asian Patients with Atrial Fibrillation: Consensus Recommendations by the Asian Pacific Society of Cardiology on Strategies for Thrombotic and Bleeding Risk Management Daniel TT Chong,1 Felicita Andreotti,2 Peter Verhamme,3 Jamshed J Dalal,4 Noppacharn Uaprasert,5 Chun-Chieh Wang,6 Young Keun On,7 Yi-Heng Li,8 Jun Jiang,9 Koji Hasegawa,10 Khalid Almuti,11 Rong Bai,12 Sidney TH Lo,13 Rungroj Krittayaphong,14 Lai Heng Lee,15 David KL Quek,16 Sofian Johar,17 Swee-Chong Seow,18 Christopher J Hammett19 and Jack WC Tan1,15,20 1. National Heart Centre, Singapore; 2. Fondazione Policlinico Universitario A Gemelli IRCCS, Rome, Italy; 3. University of Leuven, Leuven, Belgium; 4. Kokilaben Hospital, Mumbai, India; 5. Chulalongkorn University and King Chulalongkorn Memorial Hospital, Bangkok, Thailand; 6. Chang Gung Memorial Hospital, Linkou and Chang Gung University College of Medicine, Taoyuan City, Taiwan; 7. Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea; 8. National Cheng King University Hospital, Taiwan; 9. Second Affiliated Hospital Zhejiang University School of Medicine, Zhejiang, China; 10. Translational Research, National Hospital Organization Kyoto Medical Center, Kyoto, Japan; 11. Cleveland Clinic Abu Dhabi, United Arab Emirates; 12. Beijing Anzhen Hospital, Capital Medical University, Beijing, China; 13. Liverpool Hospital, Sydney, Australia; 14. Siriraj Hospital, Mahidol University, Bangkok, Thailand; 15. Singapore General Hospital, Singapore; 16. Pantai Hospital Kuala Lumpur, Kuala Lumpur, Malaysia; 17. Ripas Hospital, Brunei; 18. National University Hospital, Singapore; 19. Royal Brisbane and Women’s Hospital, Brisbane, Australia; 20. Sengkang General Hospital, Singapore

Abstract

The disease burden of AF is greater in Asia-Pacific than other areas of the world. Direct oral anticoagulants (DOACs) have emerged as effective alternatives to vitamin K antagonists (VKA) for preventing thromboembolic events in patients with AF. The Asian Pacific Society of Cardiology developed this consensus statement to guide physicians in the management of AF in Asian populations. Statements were developed by an expert consensus panel who reviewed the available data from patients in Asia-Pacific. Consensus statements were developed then put to an online vote. The resulting 17 statements provide guidance on the assessment of stroke risk of AF patients in the region, the appropriate use of DOACs in these patients, as well as the concomitant use of DOACs and antiplatelets, and the transition to DOACs from VKAs and vice versa. The periprocedural management of patients on DOAC therapy and the management of patients with bleeding while on DOACs are also discussed.

Keywords

AF, Asia, bleeding, consensus, non-vitamin K antagonist oral anticoagulants, vitamin K antagonist, haemostasis Disclosure: This work was funded through the Asian Pacific Society of Cardiology with unrestricted educational grants from Abbott Vascular, Amgen, AstraZeneca, Bayer and Roche Diagnostics. DC has received honoraria from Abbott, Biotronik, Boston Scientific, Boehringer Ingelheim, Johnson & Johnson, Medtronic and Pfizer. FA has received honoraria outside the present work from Amgen, Bayer, BI, BMS, Daiichi Sankyo and Pfizer. PV has received honoraria from Bayer, BI, BMS, Daiichi Sankyo, Leo Pharma, Pfizer and Portola; and research grants from Bayer, Boehringer Ingelheim and Bristol Meyers Squibb. JJD has received honoraria from Bayer and Pfizer. CCW has received honoraria and research grants from Bayer, BI, Daiichi Sankyo and Pfizer. YHL has received honoraria from Amgen, AstraZeneca, Bayer, BI, Daiichi Sankyo, Roche and Sanofi. JJ has received honoraria from Abbott Vascular, Amgen, AstraZeneca, Bayer, Boston Scientific, Medtronic and Pfizer. STHL has received honoraria and travel support from Abbott, Bayer, Bioexcel, BI, Boston Scientific, Medtronic and Pfizer. LHL has received education and travel grants from Sanofi. DQ has received honoraria from Bayer and Pfizer. SJ has received honoraria from Biosense Webster and Medtronic. SCS has received honoraria from Abbott, Bayer, Biotronik and Medtronic. CJH has received honoraria from Amgen, Bayer, BI and Pfizer-MSD. JWCT has received honoraria from Abbott Vascular, Amgen, AstraZeneca, Bayer, Boston Scientific, BI, Medtronic, Orbus Neich and Biotronik; and research grants from Abbott Diagnostics and Beckmann. All other authors have no conflicts of interest to declare. Acknowledgement: Medical writing support was provided by Tan Ee Min and Ivan Olegario of MIMS Pte Ltd. Received: 23 October 2020 Accepted: 27 December 2020 Citation: European Cardiology Review 2021;16:e23. DOI: https://doi.org/10.15420/ecr.2020.43 Correspondence: Jack Wei Chieh Tan, National Heart Centre, 5 Hospital Dr, Singapore 169609, Singapore. E: jack.tan.w.c@singhealth.com.sg Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

With a proportionally larger older population, the disease burden of AF is greater in the Asia-Pacific region than other areas of the world. By 2050, approximately 72 million people in the area will have AF.1 Despite the potential risks of major bleeding, oral anticoagulation (OAC) has a clear net benefit as it is highly effective in preventing ischaemic strokes in AF patients.2 Direct oral anticoagulants (DOACs) have emerged

as alternatives to vitamin K antagonists (VKA) for the prevention of thromboembolic events (TEE) in AF patients. DOACs interfere with thrombus formation by direct inhibition of thrombin or through inhibition of factor Xa (FXa), which converts prothrombin to thrombin.3 Dabigatran etexilate mesylate is a competitive direct thrombin inhibitor, while rivaroxaban, apixaban and edoxaban are FXa inhibitors.

APSC Consensus Recommendations on DOACs in Asian Patients with AF Table 1: Recommended Indications and Contraindications for Direct Oral Anticoagulant Use in AF Patients Conditions

Eligibility for DOAC Therapy

Recommended for use AF in the absence of moderate-to-severe Included in DOAC trials mitral stenosis or mechanical heart valves Mild-to-moderate other native valvular disease (e.g. mild to moderate aortic stenosis or regurgitation, degenerative mitral regurgitation etc)

Included in DOAC trials

Bioprosthetic valve (>3 months postoperatively)

Acceptable for degenerative mitral regurgitation or in the aortic position Not advised if rheumatic mitral stenosis

Consider for use, although limited data Mitral valve repair (>3 months postoperatively)

Some patients included in some DOAC trials

Severe aortic stenosis

Limited data (excluded in RE-LY trial)59

Percutaneous transluminal aortic valvuloplasty; transcatheter aortic valve implantation

No published prospective data yet May require combination with single or dual antiplatelet therapy

Hypertrophic cardiomyopathy

Limited data but patients may be eligible for DOAC

Contraindicated Mechanical prosthetic valve

Contraindicated

Moderate-to-severe mitral stenosis (usually rheumatic origin)

Contraindicated

Pregnant women and children

No data available, not recommended

DOAC = Direct oral anticoagulants. Source Steffel et al. 2018.25 Adapted with permission from Oxford University Press.

This consensus aims to guide clinicians to manage AF with reference to issues pertinent to Asia, such as the underuse of OAC and inappropriate dose reduction of DOAC. The authors were part of the guideline working committee and the guidelines were based on available evidence that were appraised based on the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) as: 1. High (authors have high confidence that the true effect is similar to the estimated effect). 2. Moderate (authors believe that the true effect is probably close to the estimated effect). 3. Low (true effect might be markedly different from the estimated effect). 4. Very low (true effect is probably markedly different from the estimated effect).4 Each author then indicated their agreement to each statement (agree, neutral or disagree) via an online poll. Consensus was considered to have been reached when 80% of votes were agree or neutral.

Indication for Direct Oral Anticoagulants in Patients with AF Statement 1. DOAC use is recommended over warfarin in DOACeligible AF patients. Level of evidence: High. Level of agreement: 100% agree, 0% neutral, 0% disagree.

Consistent evidence from the RE-LY, ROCKET-AF, ARISTOTLE and the ENGAGE AF-TIMI 48 randomised controlled trials (RCTs), comparing DOACs with warfarin in AF patients demonstrated at least non-inferiority of DOACs for reducing stroke or systemic embolism (S/SE) risk, and a superior safety profiles with reduced intracranial haemorrhage (ICH) rates.5–8 Meta-analysis of these RCTs showed that DOACs significantly reduced S/SE risk compared with warfarin driven, at least in part, by reducing haemorrhagic strokes.9 DOACs significantly reduced all-cause mortality and ICH but with increased risk of gastrointestinal bleeding. These results show that, compared with warfarin, DOACs have a favourable risk-benefit profile. The relative efficacy and safety of DOACs were consistent across a wide range of patients. Concurring real-world evidence showed that DOACs were associated with reduced ICH risk and similar rates of S/SE compared with warfarin.10 Consistent with other AF management guidelines and consensuses, this panel recommends DOAC use over warfarin in Asian DOAC-eligible AF patients.11–14 This is supported by multiple Asian studies and systematic reviews documenting the efficacy and added safety of DOACs in preventing S/SE among AF patients.15–21 Statement 2. DOACs can be used in patients with valvular disease in the absence of moderate-to-severe mitral stenosis or mechanical heart valves. Level of evidence: High. Level of agreement: 100% agree, 0% neutral, 0% disagree. The inclusion and exclusion criteria of pivotal trials have been summarised elsewhere.22 Patients with concomitant moderate-to-severe mitral stenosis or prosthetic/mechanical heart valves were excluded from pivotal RCTs.5–8 It was demonstrated that compared to warfarin, dabigatran use increased TEE rates and bleeding complications in AF patients with mechanical heart valves; hence there is a lack of benefit and excess risk.23 Conversely, patients with valvular heart disease who did not meet the exclusion criteria were included in pivotal trials.5–8,22 An ongoing trial, INVICTUS-VKA (NCT02832544), aims to evaluate DOAC efficacy and safety compared with warfarin in patients with rheumatic heart disease. Patients with non-AF indications for anticoagulation were excluded and few AF patients with hypertrophic cardiomyopathy (HCM) were included in these DOAC trials.5–8 Large retrospective studies have demonstrated that DOAC-treated AF patients with HCM have comparable rates of S/SE and major bleeding and lower mortality than warfarin-treated patients.24 Despite limited prospective data, AF patients with HCM may be eligible for DOACs. DOACs have not been evaluated for use in pregnant women and children and should not be used for these patients. Table 1 summarises the recommended indications and contraindications for DOACs in AF patients.25 Statement 3. The CHA2DS2-VASc score is well-validated; the CHA2DS2-VA score can be considered for use in practice. Level of evidence: Low. Level of agreement: 95% agree, 0% neutral, 5% disagree.

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APSC Consensus Recommendations on DOACs in Asian Patients with AF Stroke risk assessment forms a critical part of AF management.11–14 The identification of AF patients at elevated stroke risk would allow targeted prescription of oral anticoagulation to the appropriate subgroup of AF patients with a favourable benefit-risk ratio.26 Multiple clinical, anatomical and biochemical risk factors for stroke have been identified in AF patients.27 However, a simple, reliable and widely accepted risk score such as the CHA2DS2-VASc would be more practical for front-line clinicians than a more complex risk score involving multiple other non-clinical factors, even if the latter is more accurate (with a marginally higher C statistic).28,29 Clinicians also need to be aware of the dynamic nature of individual components of the CHA2DS2-VASc risk score.30,31 Almost half of AF patients initially at low stroke risk (CHA2DS2-VASc 0 or 1) are no longer low risk after a mean follow-up of 4 years.32 The CHA2DS2-VASc score increases in about 12% of initially low-risk AF patients each year – hence it would be reasonable to reassess this risk score more frequently.33 Recent studies have attempted to improve the accuracy of the CHA2DS2VASc score in several east Asian populations. Lower ages have been proposed for the scoring and hence initiation of anticoagulation.34,35 If the tipping point for DOAC use was a stroke risk of 0.9% per year, there would be different age thresholds for Asian AF patients with different other single risk factors beyond gender.26,36 However, having multiple age thresholds would increase the complexity of the CHA2DS2-VASc score. Until further data is available and a more widespread consensus develops among Asian AF physicians, it is reasonable to continue to use the traditional CHA2DS2VASc score (as published in the 2020 European Society of Cardiology guidelines for the diagnosis and management of AF) for Asian patients.37 Sex category (Sc) in the CHA2DS2-VASc score is a stroke risk modifier rather than a risk factor per se.38,39 If a more accurate stroke risk prediction is desired, the CHA2DS2-VASc score should be used.40,41 However, if the intent of the physician in using the risk score is to determine when anticoagulation is indicated, as will be discussed in statement 4, and the threshold is determined to be CHA2DS2-VASc ≥1 for men and ≥2 for women, then Sc becomes unnecessary and CHA2DS2-VA can be reasonably used with a recommendation to start DOAC anticoagulation when CHA2DS2-VA ≥1.42 This would provide a simplified and consistent threshold recommendation for both sexes as per the Australian AF guidelines.43 Statement 4. DOAC use is recommended in Asian AF patients with CHA2DS2-VA ≥1 or CHA2DS2-VASc ≥1 (for men) and ≥2 (for women). Level of evidence: Moderate. Level of agreement: 90% agree, 5% neutral, 5% disagree. The annual incidence of stroke in Asians is generally higher than in white people, particularly for patients with CHA2DS2-VASc scores of 0–1 (Supplementary Table 1). Thus, while American and European guidelines recommend that OAC be considered in patients with >1 risk factor for stroke (besides being a woman), this panel recommends that DOACs be used in Asian patients with CHA2DS2-VA score ≥1.11,14,37 If clinicians use the CHA2DS2-VASc score, then we recommend OAC be considered when CHA2DS2-VASc ≥1 (for men) and ≥2 (for women) as per current major AF guidelines. It should be noted that HCM patients with a CHA2DS2-VASc / CHA2DS2-VA score of 0 should still be anticoagulated.14

Statement 5. Elderly patients should not be excluded from anticoagulation for stroke prevention and DOAC use is recommended over warfarin. Level of evidence: High. Level of agreement: 100% agree, 0% neutral, 0% disagree. Post-hoc analyses of pivotal DOAC trials have been reviewed in another position paper; stroke risk-reduction benefits of DOACs, compared with warfarin, were maintained in both older and younger patients with no significant difference in overall major bleeding and ICH rates across all age groups.44 These studies demonstrated that major bleeding risk markedly increased with age, underscoring the need for anticoagulation strategies with improved safety profiles to mitigate bleeding risk.44 A meta-analysis of the four RCTs also showed that, compared with warfarin, DOACs decreased S/SE risk in people aged ≥75 years, without significant differences in the overall risk of major bleeding.9 A retrospective observational study in elderly Taiwanese AF patients (aged ≥90 years) showed that, compared with warfarin, DOACs (dabigatran, rivaroxaban and apixaban) were associated with lower ICH risk and no difference in ischaemic stroke risk.45 These results, as well as those from other Asian studies, show that efficacy and safety of DOACs are preserved in elderly populations.45,46 Since stroke and major bleeding risks increase with age, DOAC use is likely to yield greater absolute risk reduction and greater net clinical benefit in elderly populations when compared with warfarin. In very old patients who may otherwise be considered ineligible for oral anticoagulation therapy due to frailty, some countries may consider lowering the dose if well-designed clinical trials have demonstrated the effectiveness of this strategy. A Phase III, multicentre, randomised, double-blind, placebo-controlled trial that included Japanese patients aged ≥80 years found low-dose edoxaban (15 mg once daily) reduced the risk of S/SE compared with placebo (p<0.001) although gastrointestinal bleeding was also increased in the edoxaban group.47 However, in the absence of such compelling clinical data, the approved recommended doses should be used. Statement 6. Aspirin or other antiplatelet agents should not be used for stroke risk management in AF patients. Level of evidence: Moderate. Level of agreement: 100% agree, 0% neutral, 0% disagree. Current evidence does not support the use of aspirin and other antiplatelet agents for the management of the risk of stroke in AF patients.48,49 A meta-analysis (n=13,000) showed that dose-adjusted warfarin was substantially more efficacious than antiplatelet therapy for stroke risk reduction in AF patients.48 Warfarin was also superior to aspirin in preventing S/SE in AF patients ≥75 years without increasing major bleeding rates.44,50 With alternative therapeutic options available, such as warfarin, and DOACs having greater efficacy in stroke risk reduction and comparable overall safety profiles with aspirin, antiplatelet therapy should not be used for stroke-risk management in AF patients. This recommendation is consistent with other guidelines and consensus.12–14

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APSC Consensus Recommendations on DOACs in Asian Patients with AF Figure 1: Direct Oral Anticoagulant Dosing with Respect to Renal Function 95 ml/min

50 ml/min

30 ml/min

15 ml/min Haemodialysis

CrCl§

Peritoneal dialysis

Clinicians should also be mindful of the potential interaction of DOACs with other drugs, including herbal medicines and traditional Chinese medicine, especially those that modulate CYP3A4 and P-glycoprotein activity although data on these potential interactions are limited.57 The clinical impact of these potential interactions is still not established, however, a literature review found 194 verified reports of interactions with anticoagulants or antiplatelets with 79.9% attributable to pharmacodynamic interactions.58 Some of these interactions (mostly associated with danshen, dong quai, ginger, ginkgo, licorice, and turmeric) resulted in increased bleeding risks.

110 mg* twice daily

Dabigatran

150 mg twice daily

Edoxaban

60 mg daily

30 mg daily

Rivaroxaban

20 mg daily

15 mg† daily

Statement 8. Rivaroxaban, apixaban and edoxaban can be used in patients with severe renal impairment – creatine clearance (CrCl) 15–29 ml/min – with appropriate dose adjustment. Level of evidence: Low. Level of agreement: 90% agree, 5% neutral, 5% disagree.

5 mg twice daily Apixaban

Except in countries where population-specific evidence demonstrated that reduced doses of DOACs are effective for thromboembolic risk reduction, trial-approved doses of DOACs should be used, even in Asian populations. Recommendations for DOAC dosing regimens with respect to approved dose-reduction criteria and renal function are summarised in Figure 1.

2.5 mg twice daily‡

If at least two out of three criteria: age ≥80 years, body weight ≤60 kg, creatine ≥1.5 mg/dl

CrCl§ Legend:

Consider for use in selected patients

Not recommended

*150 mg twice daily may be considered in suitable patients with low bleeding risk. †In appropriate countries where 10 mg dose is approved, 10 mg may be considered in suitable patients with high bleeding risk. ‡In patients with CrCl 15–29 ml/min, recommended dose is 2.5 mg twice daily independent of age or body weight. § Creatinine clearance estimated by the Cockcroft-Gault equation. CrCl = creatinine clearance.

Dose Regimens of Direct Oral Anticoagulants Statement 7. Trial-approved doses of DOACs and/or doses recommended in respective country guidelines/regulations should be used, i.e. DOAC dose should not be reduced inappropriately. Level of evidence: Low. Level of agreement: 100% agree, 0% neutral, 0% disagree. Only doses of DOACs evaluated in pivotal trials have been demonstrated to be at least non-inferior to warfarin in thromboembolic risk-reduction efficacy, with superior safety profiles in terms of reduced ICH risk.5–8 A meta-analysis of landmark DOAC trials also demonstrated the safety profile of DOACs over warfarin in Asians and non-Asians with significant reductions in major bleeding and ICH.51 Nonetheless, patients are frequently underdosed. A retrospective cohort study of about 15,000 AF patients treated with DOAC showed that 13.3% of patients with no renal indication for dose reduction were potentially underdosed.52 The study also found that apixaban underdosing was associated with a fourfold increase in stroke risk with no statistically significant difference in major bleeding risk.52 Several real-world studies in Asia also reported much higher rates of underdosing, ranging from 27% to 36% of patients with suboptimal outcomes.53–56 Underdosed patients were generally found to have a higher ischaemic stroke risk compared to those receiving appropriate doses.

Safety and efficacy of DOACs relative to warfarin in patients with creatinine clearance (CrCl) 30–59 ml/min were consistent with that of patients with normal renal function.59,60 All DOACs can be used in Asian patients with CrCl ≥30 ml/min (Figure 1). The RE-LY trial showed that the 110 mg twice daily dose of dabigatran had similar thromboembolic risk reduction efficacy and lower major bleeding rates than warfarin.5 The European Medicines Agency recommended that dabigatran be used at 110 mg twice daily in patients with CrCl 30–50 ml/min with high bleeding risk. Since Asians have higher risks of major bleeding and ICH compared with non-Asians, this panel recommends that dabigatran be used at 110 mg twice daily in AF patients with CrCl 30–50 ml/min.44 Since dabigatran is predominantly (80%) eliminated via renal excretion, dabigatran use in patients with CrCl <30 ml/min is not recommended in agreement with European guidelines.3,14 DOAC RCTs mostly excluded patients with CrCl <30 ml/min and limited randomised data are available regarding DOAC use in patients with CrCl 15–29 ml/min. However, based on pharmacokinetic studies and renal excretion characteristics, FXa inhibitors have been approved in Europe for AF patients with CrCl 15–29 ml/min. Evidence from small retrospective studies also showed that reduced doses of FXa inhibitors in patients with CrCl 15–29 ml/min did not lead to increases in major bleeding or thrombotic events.61,62 Similar to other guidelines, this panel recommends that reduced doses of rivaroxaban, apixaban and edoxaban, but not dabigatran, can be considered for patients with CrCl 15–29 ml/min.13,25 Various formulae to estimate CrCl result in slightly different values: the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) and Modification of Diet in Renal Disease (MDRD) formulae generally result in higher values among patients with advanced age or low body weight compared with the Cockcroft-Gault (CG) formula.63,64 These variability may lead to

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APSC Consensus Recommendations on DOACs in Asian Patients with AF inappropriate dosing with the use of CKD-EPI or MDRD among these subgroups. Hence, guidelines recommend the use of the CG formula in CrCl estimation.37,43,63 Statement 9. Rivaroxaban and apixaban may be used in patients with end-stage renal disease on haemodialysis. Level of evidence: Very low. Level of agreement: 64% agree, 27% neutral, 9% disagree. Pharmacokinetic studies showed no significant change in systemic exposure to FXa inhibitors pre- or post-haemodialysis, indicating that haemodialysis did not significantly impact FXa inhibitor clearence.65 Apixaban undergoes approximately 27% renal clearance.65 Compared with subjects with normal renal function, systemic exposure of apixaban increased 36% with no increase in maximum plasma concentration in patients with end-stage renal disease (ESRD) (CrCl <15 ml/min) on haemodialysis. Rivaroxaban undergoes approximately 33% renal clearance and, compared with subjects with normal renal function, systemic exposure to rivaroxaban increased 56% in ESRD subjects on haemodialysis, an extent similar to patients with severe renal impairment (CrCl 15–29 ml/min) not undergoing dialysis.65 Recent registry-based studies also showed that compared with warfarin, rivaroxaban and apixaban use in AF patients with severe renal impairment or undergoing haemodialysis is associated with significantly less major bleeding events but no significant reduction in thromboembolic risk.66,67 However, these studies did not specify the duration of OAC treatment and whether warfarin-treated patients were within therapeutic range. The RENAL-AF trial, which compared apixaban with warfarin in ESRD patients on haemodialysis, was terminated early with inconclusive findings relative to bleeding and stroke rates.68 Despite the current lack of prospective data, pharmacokinetic studies and real-world evidence suggest that rivaroxaban and apixaban may be used in ESRD patients on haemodialysis. Conversely, clinical and observational data to support edoxaban use in these patients are relatively lacking. Although the pharmacokinetic profile of edoxaban in ESRD patients on haemodialysis is similar to that of other FXa inhibitors, FDA labelling states that edoxaban is not recommended in patients with CrCl <15 ml/min.65,69 This position may change should further evidence emerge, perhaps from the ongoing AXADIA study (NCT02933697).

Concomitant DOAC and Antiplatelet Use in AF Patients with Acute Coronary Syndrome or Who Have Undergone Percutaneous Coronary Intervention Statement 10. Following percutaneous coronary intervention, triple therapy (DOAC + aspirin + P2Y12 inhibitor) is recommended for up to 1 month (keeping it as short as possible), and dual therapy (DOAC + P2Y12 inhibitor) is recommended for up to 12 months, after which the patient may be maintained on DOAC monotherapy. Level of evidence: High. Level of agreement: 95% agree, 5% neutral, 0% disagree.

Statement 11. The duration of triple therapy may be lengthened or shortened depending on the patient’s thrombotic and bleeding risks. Level of evidence: Very low. Level of agreement: 100% agree, 0% neutral, 0% disagree.

Early Triple Antithrombotic Therapy with DOAC + Aspirin + P2Y12 Inhibitor

Although optimal combination and duration of antithrombotic therapy in AF patients who have undergone percutaneous coronary intervention (PCI) are not well-established, expert consensus have recommended a short period of triple antithrombotic therapy in suitable patients.11–14 Four RCTs of AF patients who underwent PCI and/or presented concomitant acute coronary syndrome (ACS) showed that, compared with standard triple therapy (STT) of dose-adjusted warfarin plus dual antiplatelet therapy (DAPT), DOACs + P2Y12 inhibitor led to lower rates of major or clinically relevant bleeding.70–74 Clinically significant bleeding occurred in 16.1% of aspirin-treated patients compared with 9% of patients receiving aspirin-matched placebo (p<0.001) in the AUGUSTUS trial.71 Although not statistically significant, the rates of stent thrombosis in placebo-treated patients was almost twice that of patients treated with aspirin.71 Stent thrombosis rates in the ENTRUST-AF PCI trial were also higher in the dual therapy group (edoxaban + P2Y12 inhibitor) than the STT group. However, these studies were not powered to detect statistically significant differences in stent thrombosis rates between treatment groups.74 Recent meta-analyses showed significantly increased stent thrombosis rates with early-dual versus triple antithrombotic therapy, which do not support the use of dual therapy immediately after PCI in Asian AF patients.73 This panel recommends a short duration of triple therapy, of up to 1 month (keeping it as short as possible), following PCI in AF patients; duration of triple therapy may be tailored based on the relative thrombotic and bleeding risks before transitioning to dual therapy. For AF patients with ACS not undergoing PCI, early dual antithrombotic therapy (DOAC + P2Y12 inhibitor) is reasonable (Figure 2).

Mid-term Dual Antithrombotic Therapy with DOAC + P2Y12 Inhibitor

Several trials have demonstrated that dual therapy with DOAC + P2Y12 inhibitor reduced bleeding risk compared with STT.70–72,74 Consistent with other guidelines, dual therapy is recommended for up to 12 months, corresponding to the duration evaluated in most trials (Figure 2).13,14

Long-term Monotherapy with Direct Oral Anticoagulants

The AFIRE trial in AF patients with chronic coronary artery disease showed that, compared with the combination group (rivaroxaban + single antiplatelet), rivaroxaban alone resulted in no significant difference in TEE but reduced bleeding events and mortality.75 Global guidelines also recommend OAC monotherapy 12 months after PCI or ACS in AF patients.12–14,25 DOAC monotherapy is recommended for most patients after 12 months post-PCI in line with statement 1, (Figure 2).

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APSC Consensus Recommendations on DOACs in Asian Patients with AF Periprocedural Management

Figure 2: Antithrombotic Therapy in AF patients with Acute Coronary Syndrome or Post-percutaneous Coronary Intervention PCI

AF + elective PCI

AF + ACS with PCI

AF + medically treated ACS

1 month Triple therapy

DOAC C A Shorten

Triple therapy

DOAC P2Y12 inhibitor A Shorten • Uncorrectable high-risk bleeding • Low atherothrombotic risk

P2Y12 inhibitor

+6 months Dual therapy

DOAC C

Statement 14. Avoid unnecessary or prolonged interruption of DOAC therapy for surgical procedures in AF patients. Level of evidence: Moderate. Level of agreement: 100% agree, 0% neutral, 0% disagree.

+1 year Monotherapy

DOAC

Lengthen Dual therapy

DOAC P2Y12 inhibitor

Monotherapy

DOAC

Lengthen • First generation DES • High atherothrombotic risk and low bleeding risk

Dual therapy

DOAC P2Y12 inhibitor

Monotherapy

DOAC

A = aspirin; ACS = acute coronary syndrome; DES = drug eluting stent; C = clopidogrel; PCI = percutaneous coronary intervention.

Transitioning to Direct Oral Anticoagulants from VKA and Vice Versa Statement 12. When switching from VKA to DOAC, DOAC can be started the same day if the international normalised ratio (INR) <2 or the next day if INR is 2–3. If INR >3, INR should be reassessed after an appropriate interval as determined by the clinician, before deciding on when to switch from VKA to DOAC. Level of evidence: Very low. Level of agreement: 90% agree, 10% neutral, 0% disagree. Major bleeding risk in patients with INR >3 is twice that of when INR = 2–3 while TEE risk increases by at least two-fold with INR <2.14 Given the quick onset of action and short half-life of DOACs, these agents can be started on the same day if INR <2, or the following day if the patient is in the therapeutic INR range (2–3).3 If INR >3, DOACs should be withheld until the INR is at the indicated threshold (Supplementary Figure 1). Statement 13. When switching from DOAC to VKA, VKA should be started while the patient is on DOAC. DOAC can then be stopped once the INR >2 (if target INR is 2–3). INR should be reassessed 1–2 days after stopping DOAC. Level of evidence: Very low. Level of agreement: 95% agree, 5% neutral, 0% disagree. VKAs have a slow onset of action and it may take days before the INR is in therapeutic range. Thus, DOAC and VKA should be administered concomitantly until the INR is in the appropriate therapeutic range. DOACs present in the body may also affect the accuracy of INR measurements.25 Depending on the patient’s renal function, INR should be reassessed 1–2 days after DOAC discontinuation to ascertain INR levels while solely on VKA and ensure adequate anticoagulation.

Statement 15. Parenteral anticoagulation overlap with DOAC therapy is not advised. Level of evidence: Very low. Level of agreement: 100% agree, 0% neutral, 0% disagree. Unnecessary prolonged interruption of DOACs should be avoided given that periprocedural interruption/cessation of DOACs increased TEE risk by around 20-fold.76 Patient characteristics, including age, renal function, history of bleeding complications and concomitant medications, should also be considered when deciding to discontinue or restart DOACs. Recent evidence from the PAUSE cohort study, evaluating the safety of a standardised perioperative DOAC management strategy, showed that omitting FXa inhibitors one day before a procedure with a low-risk of bleeding and two days before a procedure with a high risk of bleeding was associated with a 30-day postoperative major bleeding rate of <2% and a stroke rate of <1%.77 Figure 3 summarises the bleeding risks associated with common elective procedures and the recommended intervals for DOAC interruption prior to these procedures. Less invasive procedures have a relatively low risk of severe bleeding and may not necessitate discontinuation; omitting one dose of DOAC before low-risk procedures may be considered to avoid nuisance bleeding episodes, which can contribute to DOAC therapy non-adherence. Consistent with other guidelines, complex left-sided ablation procedures may proceed with uninterrupted anticoagulation or after omitting one dose of DOAC.78 In patients with renal impairment, a longer duration of DOAC interruption is recommended before procedures with moderate and high bleeding risk. As dabigatran undergoes extensive renal clearance, dabigatran should be stopped earlier than FXa inhibitors in patients with impaired renal function for these procedures.3 The quick onset of action of DOACs makes it feasible to time the interruption of DOACs before a procedure with a predictable decline of its anticoagulation effects.3 Perioperative overlap of DOAC therapy with parenteral anticoagulation (‘bridging’) is not necessary and has been shown to increase major bleeding complications rates without reduction in cardiovascular events.79 DOACs can be resumed after the procedure when the bleeding risk is deemed acceptable. As with thrombotic risk, bleeding risk is also dynamic, as demonstrated by a Taiwanese study that included 19,566 AF patients treated with warfarin. After a follow-up of 93,783 person years, 61.8% of patients had a change in HAS-BLED score, and an increased score was associated with major bleeding.80 This underscores the need to reassess bleeding risk before deciding to alter anticoagulant therapy.

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APSC Consensus Recommendations on DOACs in Asian Patients with AF Figure 3: Periprocedural Management of Patients on Direct Oral Anticoagulants Days before/after elective procedures* -6

-5

-4

-3

-2

-1

Low bleeding risk Non-cardiac procedures

Cardiac procedures

• Dental interventions

• Coronary angiogram (radial approach)

• Complex left-sided ablation e.g AF†/VT

• Pacemaker or ICD implantation (unless complex anatomical setting e.g. congenital heart disease)

• Prostate or bladder biopsy

• Percutaneous coronary intervention

Dabigatran with CrCl 31–50 ml/min

Factor X inhibitors with CrCL >30 ml/min

Factor X inhibitors with CrCL 15–30 ml/min

Ensure adequate haemostasis

• Endoscopy with biopsy

Dabigatran with CrCl >50 ml/min

Surgery

Cardiac procedures

Discontinue all anticoagulation

Non-cardiac procedures

Restart

Moderate bleeding risk

Restart

• Superficial surgery e.g. abscess incision, small dermatologic excisions

Restart

• Endoscopy without biopsy or resection

Continue anticoagulation but consider missing one dose or performing procedure at trough drug concentration

• Electrophysiological study/ablation

Restart

• Cataract or glaucoma surgery

• Major vascular surgery e.g aortic aneurysm repair

• Major cardiac surgery e.g. coronary artery bypass, valve replacement or repair

• Major orthopaedic surgery e.g. hip arthroplasty or hip fracture repair • Other major cancer or reconstructive/ abdominal/thoracic surgery

Dabigatran with CrCl >50 ml/min

Restart

Cardiac procedures

Dabigatran with CrCl 31–50 ml/min

Restart

Non-cardiac procedures

Restart

High bleeding risk

Factor X inhibitors with CrCL >30 ml/min

Restart

• Spinal/epidural anaesthesia Factor X inhibitors with CrCL 15–30 ml/min

• Liver, kidney biopsies

* For emergency life-saving procedures, the medical/surgical team should weigh the risk-benefit ratio and may proceed without delay. Reversal agents may be considered in this scenario. † Continue with uninterrupted anticoagulation therapy despite moderate bleeding risk due to elevated thromboembolic risk.

LEGEND:

Patient receiving anticoagulant

CrCl = creatinine clearance; ICD = implantable cardioverter defibrillator; VT = ventricular tachycardia.

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Patient may continue/ restart anticoagulant if judged appropriate

Anticoagulation to be stopped. No bridging necessary

APSC Consensus Recommendations on DOACs in Asian Patients with AF Figure 4: Strategies for Bleeding Management While on Direct Oral Anticoagulants

Figure 5: Management Strategy After Major Bleeding Episode

Bleeding while using an DOAC

Enquire about last DOAC intake

Mild bleeding

Rapid coagulation assessment including plasma drug levels (if available)

Major bleeding episode

Blood sample to determine creatinine (clearance), haemoglobin, platelets etc

Yes

Has cause of bleed been found and reversed?

Discussion to decide on individualised strategy, weighing thrombotic risk and risk of recurrent bleeding

• Delay or discontinue next dose • Investigate and treat underlying cause Supportive measures:

Non lifethreatening major bleeding

Immediately lifethreatening bleeding

• Mechanical compression • Endoscopic haemostasis • Surgical haemostasis • Volume expansion • Blood transfusion • Adjuvant tranexamic acid • Consider use of appropriate direct reversal agents (idarucizumab or andexanet alfa) if available • Use appropriate direct reversal agents if available (idarucizumab or andexanet alfa) • Otherwise consider PCC or aPCC

aPCC = activated prothrombin complex concentrates; PCC = prothrombin complex concentrates.

Management of Bleeding That Occurs While on Direct Oral Anticoagulants Statement 16. An institution-specific policy should be developed for managing bleeding events, placing focus on the (pro)haemostatic agents available as direct reversal agents which are not widely available for use. Level of evidence: Very low. Level of agreement: 100% agree, 0% neutral, 0% disagree. DOAC-related bleeding events will inevitably increase as the number of patients using DOACs rises. This panel recommends that hospitals implement institution-specific protocols for managing bleeding events as reversal agents are not uniformly available in Asia-Pacific hospitals and a wide diversity of (pro)haemostatic agents are available. Physicians may refer to the HAS-BLED score for identification and modification of bleeding risk factors such as adequate hypertension control, labile INR (on warfarin), excessive alcohol intake and concomitant antiplatelet therapy or non-steroidal anti-inflammatory drugs.25 Managing these modifiable risk factors further minimises bleeding risk. Bleeding management strategies for DOAC-treated patients depend on bleeding severity and on individual patient factors such as time of last DOAC intake. Figure 4 summarises the recommended management strategies for bleeding complications. Fresh frozen plasma (FFP) may be considered for volume expansion in major bleeding complications but FFP does not reverse DOAC anticoagulation. Use of direct reversal agents may be considered. Idarucizumab, a monoclonal antibody that binds dabigatran with a

Consider restarting DOAC

Yes

Decision to restart anticoagulation? No

Timing of restart and dose of DOAC to be determined after discussion

Consider no anticoagulation versus LAA occlusion

LAA = left atrial appendage.

higher affinity than thrombin, reverses the anticoagulant effect of dabigatran within minutes when administered intravenously.25 IV administration of andexanet alfa, a recombinant modified FXa decoy protein, neutralises the effects of direct and indirect FXa inhibitors immediately.25 Where direct reversal agents are unavailable, data from observational studies suggest that coagulation factors such as activated prothrombin complex concentrates may be used to achieve haemostasis in patients who experience life-threatening bleeding while on DOACs.25

Post-bleed Management of AF Patients Statement 17. Following a major bleeding episode, DOAC should be restarted after the cause of bleed has been corrected. If the cause of bleed is not found, an interdisciplinary consensus should be reached for an individualised anticoagulation strategy. Level of evidence: Low. Level of agreement: 100% agree, 0% neutral, 0% disagree. Whether to restart DOAC therapy after major bleeding episodes, such as ICH, gastrointestinal bleeding or a fall/trauma, is a common dilemma. OAC resumption in AF patients after ICH was associated with reduced TEE risk and overall mortality without increased risk of recurrent ICH compared with patients who did not resume OAC.81 Although anticoagulation is contraindicated in those with a history of spontaneous ICH, the panel recommends that DOAC therapy be restarted if the cause of bleed, such as uncontrolled hypertension, has been reversed (Figure 5). Evidence is lacking about when to restart DOACs and timing and dose of DOACs when restarted after a major bleeding episode should be determined after a multidisciplinary discussion. If the cause of the bleed has not been reversed, an individualised strategy for thrombotic risk management should be reached after a

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APSC Consensus Recommendations on DOACs in Asian Patients with AF multidisciplinary discussion, weighing the patient’s thrombotic and recurrent bleeding risks. Left atrial appendage occlusion may be considered as an alternative in AF patients unsuitable for long-term anticoagulation (Figure 5). 1. Wong CX, Brown A, Tse HF, et al. Epidemiology of atrial fibrillation: The Australian and Asia-Pacific perspective. Heart Lung Circ 2017;26:870–9. https://doi.org/10.1016/j. hlc.2017.05.120; PMID: 28684096. 2. Singer DE, Chang Y, Fang MC, et al. The net clinical benefit of warfarin anticoagulation in atrial fibrillation. Ann Intern Med 2009;151:297–305. https://doi.org/10.7326/0003-4819-151-5200909010-00003; PMID: 19721017. 3. Raval AN, Cigarroa JE, Chung MK, et al. Management of patients on non-vitamin K antagonist oral anticoagulants in the acute care and periprocedural setting: a scientific statement from the American Heart Association. Circulation 2017;135:e604–33. https://doi.org/10.1161/ CIR.0000000000000513; PMID: 28167634. 4. Balshem H, Helfand M, Schünemann HJ, et al. GRADE guidelines: 3. Rating the quality of evidence. J Clin Epidemiol 2011;64:401–6. https://doi.org/10.1016/j.jclinepi.2010.07.015; PMID: 21208779. 5. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139–51. https://doi.org/10.1056/NEJMoa0905561; PMID: 19717844. 6. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011;365:883–91. https://doi.org/10.1056/NEJMoa1009638; PMID: 21830957. 7. Granger CB, Alexander JH, McMurray JJ, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011;365:981–92. https://doi.org/10.1056/ NEJMoa1107039; PMID: 21870978. 8. Giugliano RP, Ruff CT, Braunwald E, et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2013;369:2093–104. https://doi.org/10.1056/ NEJMoa1310907; PMID: 24251359. 9. Ruff CT, Giugliano RP, Braunwald E, et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a metaanalysis of randomised trials. Lancet 2014;383:955–62. https://doi.org/10.1016/S0140-6736(13)62343-0; PMID: 24315724. 10. Ntaios G, Papavasileiou V, Makaritsis K, et al. Real-world setting comparison of nonvitamin-K antagonist oral anticoagulants versus vitamin-K antagonists for stroke prevention in atrial fibrillation: a systematic review and meta-analysis. Stroke 2017;48:2494–503. https://doi. org/10.1161/STROKEAHA.117.017549; PMID: 28716982. 11. January CT, Wann LS, Calkins H, et al. 2019 AHA/ACC/HRS focused update of the 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society in Collaboration With the Society of Thoracic Surgeons. Circulation 2019;140:e125–51. https:// doi.org/10.1161/CIR.0000000000000719; PMID: 30686041. 12. Joung B, Lee JM, Lee KH, et al. 2018 Korean guideline of atrial fibrillation management. Korean Circ J 2018;48:1033– 80. https://doi.org/10.4070/kcj.2018.0339; PMID: 30403013. 13. Chiang CE, Okumura K, Zhang S, et al. 2017 consensus of the Asia Pacific Heart Rhythm Society on stroke prevention in atrial fibrillation. J Arrhythm 2017;33:345–67. https://doi. org/10.1016/j.joa.2017.05.004; PMID: 28765771. 14. Kirchhof P, Benussi S, Kotecha D, et al. 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS. Eur Heart J 2016;37:2893–962. https://doi.org/10.1093/eurheartj/ ehw210; PMID: 27567408. 15. Kohsaka S, Katada J, Saito K, et al. Safety and effectiveness of non-vitamin K oral anticoagulants versus warfarin in realworld patients with non-valvular atrial fibrillation: a retrospective analysis of contemporary Japanese administrative claims data. Open Heart 2020;7:e001232. https://doi.org/10.1136/openhrt-2019-001232; PMID: 32341789. 16. Ohshima A, Koyama T, Ogawa A, et al. Oral anticoagulants usage in Japanese patients aged 18–74 years with nonvalvular atrial fibrillation: a retrospective analysis based on insurance claims data. Fam Pract 2019;36:685–92. https:// doi.org/10.1093/fampra/cmz016; PMID: 31329899. 17. Koretsune Y, Yamashita T, Yasaka M, et al. Comparative effectiveness and safety of warfarin and dabigatran in patients with non-valvular atrial fibrillation in Japan: A claims

Conclusion

The 17 statements in this paper provide guidance to front-line physicians on select contemporary issues in Asia, such as the underuse of OAC and inappropriate dose reduction of DOACs.

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https://doi.org/10.1097/FJC.0000000000000750; PMID: 31599783. 34. Turc G, Maïer B, Naggara O, et al. Clinical scales do not reliably identify acute ischemic stroke patients with largeartery occlusion. Stroke 2016;47:1466–72. https://doi. org/10.1161/STROKEAHA.116.013144; PMID: 27125526. 35. Choi SY, Kim MHH, Lee KM, et al. Age-dependent anticoagulant therapy for atrial fibrillation patients with intermediate risk of ischemic stroke: A nationwide population-based study. Thromb Haemost 2020. https://doi. org/10.1055/a-1336-0476; PMID: 33307565; epub ahead of press. 36. Chao TF, Lip GYH, Lin YJ, et al. Age threshold for the use of non-vitamin K antagonist oral anticoagulants for stroke prevention in patients with atrial fibrillation: insights into the optimal assessment of age and incident comorbidities. Eur Heart J 2019;40:1504–14. https://doi.org/10.1093/eurheartj/ ehy837; PMID: 30605505. 37. Hindricks G, Potpara T, Dagres N, et al. 2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association of Cardio-Thoracic Surgery (EACTS). Eur Heart J 2020. https://doi.org/10.1093/eurheartj/ehaa612; PMID: 32860505; epub ahead of press. 38. Nielsen PB, Skjoth F, Overvad TF, et al. Female sex is a risk modifier rather than a risk factor for stroke in atrial fibrillation: should we use a CHA2DS2-VA score rather than CHA2DS2-VASc? Circulation 2018;137:832–40. https://doi.org/10.1161/CIRCULATIONAHA.117.029081; PMID: 29459469. 39. Wu VCC, Wu M, Aboyans V, et al. Female sex as a risk factor for ischaemic stroke varies with age in patients with atrial fibrillation. Heart 2019;106:534–40. https://doi.org/10.1136/ heartjnl-2019-315065; PMID: 31558571. 40. Nielsen PB, Overvad TF. Female sex as a risk modifier for stroke risk in atrial fibrillation: using CHA2DS2-VASc versus CHA2DS2-VA for stroke risk stratification in atrial fibrillation: a note of caution. Thromb Haemost 2020;120:894–8. https://doi.org/10.1055/s-0040-1710014; PMID: 32316064. 41. Overvad TF, Potpara TS, Nielsen PB. Stroke risk stratification: CHA2DS2-VA or CHA2DS2-VASc? Heart Lung Circ 2019;28:e14–e5. https://doi.org/10.1016/j.hlc.2018.08.012; PMID: 30220482. 42. Chao TF, Liu CJ, Wang KL, et al. Should atrial fibrillation patients with 1 additional risk factor of the CHA2DS2-VASc score (beyond sex) receive oral anticoagulation? J Am Coll Cardiol 2015;65:635–42. https://doi.org/10.1016/j. jacc.2014.11.046; PMID: 25677422. 43. National Heart Foundation of Australia (NHFA), Cardiac Society of Australia and New Zealand (CSANZ). NHFA and CSANZ: Australian clinical guidelines for the diagnosis and management of atrial fibrillation 2018. Heart Lung Circ 2018;27:1209–66. https://doi.org/10.1016/j.hlc.2018.06.1043; PMID: 30077228. 44. Andreotti F, Rocca B, Husted S, et al. Antithrombotic therapy in the elderly: expert position paper of the European Society of Cardiology Working Group on Thrombosis. Eur Heart J 2015;36:3238–49. https://doi.org/10.1093/eurheartj/ehv304; PMID: 26163482. 45. Chao TF, Liu CJ, Lin YJ, et al. Oral anticoagulation in very elderly patients with atrial fibrillation: a nationwide cohort study. Circulation 2018;138:37–47. https://doi.org/10.1161/ CIRCULATIONAHA.117.031658; PMID: 29490992. 46. Kitazono T, Ikeda T, Ogawa S, et al. Real-world outcomes of rivaroxaban treatment in elderly Japanese patients with nonvalvular atrial fibrillation. Heart Vessels 2020;35:399– 408. https://doi.org/10.1007/s00380-019-01487-x; PMID: 31492970. 47. Okumura K, Akao M, Yoshida T, et al. Low-dose edoxaban in very elderly patients with atrial fibrillation. N Engl J Med 2020;383:1735–45. https://doi.org/10.1056/NEJMoa2012883; PMID: 32865374. 48. Hart RG, Pearce LA, Aguilar MI. Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann Intern Med 2007;146:857–67. https://doi.org/10.7326/0003-4819-146-12200706190-00007; PMID: 17577005. 49. Sato H, Ishikawa K, Kitabatake A, et al. Low-dose aspirin for prevention of stroke in low-risk patients with atrial fibrillation: Japan Atrial Fibrillation Stroke Trial. Stroke

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function on outcomes with edoxaban in the ENGAGE AF-TIMI 48 trial. Circulation 2016;134:24–36. https://doi. org/10.1161/CIRCULATIONAHA.116.022361; PMID: 27358434. 61. Stanton BE, Barasch NS, Tellor KB. Comparison of the safety and effectiveness of apixaban versus warfarin in patients with severe renal impairment. Pharmacotherapy 2017;37:412– 9. https://doi.org/10.1002/phar.1905; PMID: 28117916. 62. Fazio G, Dentamaro I, Gambacurta R, et al. Safety of edoxaban 30 mg in elderly patients with severe renal impairment. Clin Drug Investig 2018;38:1023–30. https://doi. org/10.1007/s40261-018-0693-6; PMID: 30191509. 63. Lee KN, Choi JI, Kim YG, et al. Comparison of renal function estimation formulae for dosing direct oral anticoagulants in patients with atrial fibrillation. J Clin Med 2019;8:2034. https://doi.org/10.3390/jcm8122034; PMID: 31766393. 64. Chan YH, Chao TF, Lee HF, et al. Impacts of different renal function estimation formulas on dosing of DOACs and clinical outcomes. J Am Coll Cardiol 2020;76:1808–10. https:// doi.org/10.1016/j.jacc.2020.08.025; PMID: 33032742. 65. Turpie AGG, Purdham D, Ciaccia A. Nonvitamin K antagonist oral anticoagulant use in patients with renal impairment. Ther Adv Cardiovasc Dis 2017;11:243–56. https://doi. org/10.1177/1753944717714921; PMID: 28651452. 66. Coleman CI, Kreutz R, Sood NA, et al. Rivaroxaban versus warfarin in patients with nonvalvular atrial fibrillation and severe kidney disease or undergoing hemodialysis. Am J Med 2019;132:1078–83. https://doi.org/10.1016/j. amjmed.2019.04.013; PMID: 31054829. 67. Siontis KC, Zhang X, Eckard A, et al. Outcomes associated with apixaban use in patients with end-stage kidney disease and atrial fibrillation in the United States. Circulation 2018;138:1519–29. https://doi.org/10.1161/ CIRCULATIONAHA.118.035418; PMID: 29954737. 68. Pokorney S, Kumbhani DJ. RENAL-AF trial interim results. Presented at American Heart Association Annual Scientific Sessions, Philadelphia, PA, US. 16 November 2019. 69. Daiichi Sankyo. Savaysa™ (edoxaban) prescribing information. Daiichi Sankyo, Tokyo, Japan, 2019. 70. Gibson CM, Mehran R, Bode C, et al. Prevention of bleeding in patients with atrial fibrillation undergoing PCI. N Engl J Med 2016;375:2423–34. https://doi.org/10.1056/ NEJMoa1611594; PMID: 27959713. 71. Lopes RD, Heizer G, Aronson R, et al. Antithrombotic therapy after acute coronary syndrome or PCI in atrial fibrillation. N Engl J Med 2019;380:1509–24. https://doi. org/10.1056/NEJMoa1817083; PMID: 30883055. 72. Cannon CP, Bhatt DL, Oldgren J, et al. Dual antithrombotic therapy with dabigatran after PCI in atrial fibrillation. N Engl J Med 2017;377:1513–24. https://doi.org/10.1056/ NEJMoa1708454; PMID: 28844193. 73. Galli M, Andreotti F, Porto I, Crea F. Intracranial

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haemorrhages vs. stent thromboses with direct oral anticoagulant plus single antiplatelet agent or triple antithrombotic therapy: a meta-analysis of randomized trials in atrial fibrillation and percutaneous coronary intervention/ acute coronary syndrome patients. EP Europace 2020;22:538–46. https://doi.org/10.1093/europace/euz345; PMID: 31942971. 74. Vranckx P, Valgimigli M, Eckardt L, et al. Edoxaban-based versus vitamin K antagonist-based antithrombotic regimen after successful coronary stenting in patients with atrial fibrillation (ENTRUST-AF PCI): a randomised, open-label, phase 3b trial. Lancet 2019;394:1335–43. https://doi. org/10.1016/S0140-6736(19)31872-0; PMID: 31492505. 75. Yasuda S, Kaikita K, Akao M, et al. Antithrombotic therapy for atrial fibrillation with stable coronary disease. N Engl J Med 2019;381:1103–13. https://doi.org/10.1056/ NEJMoa1904143; PMID: 31475793. 76. Vene N, Mavri A, Gubenšek M, et al. Risk of thromboembolic events in patients with non-valvular atrial fibrillation after dabigatran or rivaroxaban discontinuation – data from the Ljubljana registry. PloS One 2016;11:e0156943-e. https://doi. org/10.1371/journal.pone.0156943; PMID: 27280704. 77. Douketis JD, Spyropoulos AC, Duncan J, et al. Perioperative management of patients with atrial fibrillation receiving a direct oral anticoagulant. JAMA Intern Med 2019;179:1469–78. https://doi.org/10.1001/jamainternmed.2019.2431; PMID: 31380891. 78. Calkins H, Hindricks G, Cappato R,et al. 2017 HRS/EHRA/ ECAS/APHRS/SOLAECE expert consensus statement on catheter and surgical ablation of atrial fibrillation: executive summary. J Arrhythm 2017;33:369–409. https://doi. org/10.1016/j.joa.2017.08.001; PMID: 29021841. 79. Beyer-Westendorf J, Gelbricht V, Forster K, et al. Periinterventional management of novel oral anticoagulants in daily care: results from the prospective Dresden NOAC registry. Eur Heart J 2014;35:1888–96. https://doi.org/10.1093/ eurheartj/eht557; PMID: 24394381. 80. Chao TF, Lin YJ, Chang SL, et al. Incident risk factors and major bleeding in patients with atrial fibrillation treated with oral anticoagulants: a comparison of baseline, follow-up and delta HAS-BLED scores with an approach focused on modifiable bleeding risk factors. Thromb Haemost 2018;47:768–77. https://doi.org/10.1055/s-0038-1636534; PMID: 29510426. 81. Nielsen PB, Larsen TB, Skjøth F, Lip GYH. Outcomes associated with resuming warfarin treatment after hemorrhagic stroke or traumatic intracranial hemorrhage in patients with atrial fibrillation. JAMA Intern Med 2017;177:563– 70. https://doi.org/10.1001/jamainternmed.2016.9369; PMID: 28241151.

ISCHEMIA Trial

The ISCHEMIA Trial: What is the Message for the Interventionalist? Emmanuel Ako ,1,2 Sukhjinder Nijjer ,1,3 Abtehale Al-Hussaini1,2 and Raffi Kaprielian1,3 1. Chelsea and Westminster NHS Trust, London, UK; 2. Royal Brompton NHS Hospital, London, UK; 3. Hammersmith Hospital, London, UK

Keywords

ISCHEMIA trial, coronary artery disease, intervention, revascularisation, medical therapy Disclosure: The authors have no conflicts of interest to declare. Received: 1 October 2020 Accepted: 5 March 2021 Citation: European Cardiology Review 2021;16:e24. DOI: https://doi.org/10.15420/ecr.2020.37 Correspondence: Emmanuel Ako, Chelsea and Westminster NHS Trust, 369 Fulham Rd, London SW10 9NH, UK. E: e.ako@ucl.ac.uk Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Was the International Study of Comparative Health Effectiveness with Medical and Invasive Approaches (ISCHEMIA) needed? The short answer is yes. Will it change practice? The answer should be no if your practice was already consistent with recent international guidance for chronic coronary syndrome.1–3 Coronary revascularisation should be considered if patients have recurrent symptoms of angina not controlled by optimal medical therapy (OMT). However, the timing of when to offer revascularisation – and whether it offers benefits beyond symptom control – has remained in question. While guidance has emphasised OMT, there are wide disparities in how the guidance is interpreted and applied between specialities, hospitals and countries. Real-world practice demonstrates there is often routine revascularisation for those with demonstrable ischaemia on non-invasive testing and medication titration has remained limited. To understand whether this is the right approach, a randomised controlled study was carried out to compare a routine early invasive strategy with a strategy of medical therapy alone. The headline message of the ISCHEMIA trial was that an invasive strategy was no better than medication for reduction in cardiovascular events. While this headline suggests conclusion of the debate, it is simplistic and misses the nuanced learning from the study. Albeit clearly an ambitious, large and costly study, questions remain on whether the study design was the most definitive approach. There are also concerns on whether the selected cohort represents the wider population of patients with chronic coronary syndromes. In this editorial, we will consider the ISCHEMIA study, along with older data, from the viewpoint of the interventionalist. Ischaemic heart disease (IHD) remains the leading cause of mortality and morbidity worldwide, causing more than 9 million deaths per year globally.4 Management requires a combination of medical therapy with or without revascularisation. Since both MI and chronic ischaemia have deleterious clinical events through vessel occlusion, it is intuitive to think that relieving severe coronary stenoses and thus improving blood flow would improve outcomes in IHD. Percutaneous coronary intervention (PCI) studies show that coronary intervention successfully removes or reduces ischaemia. This includes modern studies such as the doubleblind, randomised controlled trial ORBITA.5 Older studies using coronary artery bypass surgery, albeit before the advent of medical therapy, had shown a reduction in mortality.6–9 Older PCI studies had suggested

percutaneous revascularisation reduced cardiovascular mortality and MI.10 However, more recent studies have failed to show a mortality benefit. This includes large randomised controlled studies, such as COURAGE, BARI2D and FAME 2.11–13 Table 1 shows a summary of the key studies from 1992 to 2020.

Does Ischaemia Matter?

Previous interventional studies included patients based on severity of angiographic stenosis without confirmation of ischaemia. Invasive pressure wire studies have repeatedly demonstrated angiographic appearance relates poorly to ischaemia.11 It is likely that prior studies will have included patients without ischaemia and thus revascularisation would give minimal benefit; such recruitment would dilute signals of benefit. Those studies that did seek ischaemia demonstrated only relatively limited levels of it.14 This issue with prior studies formed the basis of the ISCHEMIA study, which originally aimed to recruit patients with moderate to severe levels of ischaemia. This is a valid study design strategy as it addresses the tightly held belief that forms the basis of the central paradigm in the management of IHD.15 Patients with angina are typically referred for non-invasive ischaemia testing according to the local availability (tests range from those with limited sensitivity and specificity, such as exercise stress ECG testing, to those with higher accuracy such as stress perfusion myocardial resonance imaging or PET). In some countries, repeated annual ischaemia testing generates a lot of routine elective activity.16,17 However, data relating ischaemia – or its improvement following revascularisation – with hard clinical events remain limited. Large observational studies have suggested limited value to routine revascularisation for ischaemia.18,19 On the other hand, a propensitymatched analysis in 39,131 Canadian patients with stable IHD undergoing early revascularisation (n=23,992) or treated conservatively (n=15,139) found, over 4 years of follow-up, a significant reduction in death and MI with revascularisation.20 The relationship between ischaemia and exercise capacity was also questioned in the small but well performed randomised placebo-controlled PCI study ORBITA. Although ORBITA demonstrated clear improvements in both invasive and non-invasive markers of ischaemia, there was no demonstrable improvement in treadmill exercise

What Is the Message That an Interventionalist Takes From the ISCHEMIA Trial? Table 1: Trials Comparing Optimal Medical Therapy and Revascularisation in Chronic Coronary Disease Trial

n (OMT/PCI)

Follow-up

Mortality

Angina Relief

RITA-2 200330

514/504

7 years

→

↑

ACME-1 1992

107/105

3 years

→

↑

ACME-2 1997

50/51

5 years

→

↑

MASS-I 199933

72/72

3 years

→

↑

MASS-II 2004

203/205

5 years

→

↑

COURAGE 200734

1,138/1,149

4.6 years

→

↑

BARI2D 2009

807/798

5 years

→

↑

ORBITA 20185

95/105

6 weeks

↑

2,591/2,588

3.3 years

→

↑

31 32

ISCHEMIA 2020

↑ = PCI statistically significant over OMT; → = no statistical significance between PCI and OMT; NA = not applicable; OMT = optimal medical therapy; PCI = percutaneous coronary intervention.

time between those treated with sham-PCI and those with true relief of the coronary stenosis. This was measured at 6 weeks and whilst there are those who suggest a longer follow-up would have altered outcomes, this is difficult to imagine since PCI relieves the stenosis and ischaemia immediately. At the end of the study, after blinding was removed, 80% of those in the sham arm chose to have coronary intervention. Many claim this is crossover: it is not. The patients had been advised to have PCI by their usual care practitioners before volunteering to participate in the study. They had expected to have PCI and their participation was prefaced with the expectation that they would get it within the usual waiting time built into the local healthcare system.

Does the Mode of Revascularisation Matter?

The debate over revascularisation approaches – specifically PCI versus coronary artery bypass grafting (CABG) – has remained fractious. In many ways, it was always a sign of great hubris that the two very different techniques are compared at all. CABG offers an entirely separate conduit to perfuse the myocardium beyond the stenosis while PCI offers a focal solution to a single narrowing. Intravascular imaging and physiology often reveal that coronary disease is rarely focal, undermining the PCI strategy. Inadequate technique undermines the longevity of a given stent. Older studies, such as COURAGE, will have used older PCI techniques and had older stent technologies more prone to failure. These events are more notable and are often clinically detected. While CABG provides a more optimal solution in many anatomical settings, such as those with a high SYNTAX score, the acceleration of native disease and high failure rates in saphenous vein grafts mean that many patients are left with chronic ischaemia with or without significant cardiac events.21,22 Graft attrition is not always clinically detectable. Even allowing for the very different mechanistic approaches, there are many technical or patient factors to favour one over the other, and these factors can drive outcome differences. In a study such as ISCHEMIA, where the mode of revascularisation was selected by the physician based on normal clinical criteria, one can draw limited value from comparing the mode of revascularisation. Importantly, ISCHEMIA excluded patients that would typically be referred for revascularisation with CABG such as patients with significant left main stem (LMS) disease or patients with severe coronary disease with left ventricular impairment.23 Although PCI and CABG were analysed as the same treatment in ISCHEMIA, patients that would have been referred for CABG in the real world based on evidence based guidance were excluded from the study.

What Does the ISCHEMIA Trial Add?

ISCHEMIA represents the culmination of an audacious and admirable research efforts of an international team, lasting more than 10 years, with more than US$100 million of National Institutes of Health funding. The design emphasised the use of careful core laboratory validation of ischaemia testing. It randomised chronic coronary syndrome patients with moderate to severe ischaemia to early invasive investigation or OMT after a CT coronary angiogram (CTCA) as detailed in Figure 1. Importantly, invasive assessment did not mean mandatory invasive treatment and physicians were free to treat according to the invasive findings and this included medical therapy, PCI or CABG. Physicians were encouraged to use the latest technologies, including pressure wires, but uptake remained low. This may be because of resource issues and because patients already had positive ischaemia tests to enter the study. The total number of patients enrolled in the trial was 5,179 (2,588 in the invasive group and 2,591 in the medical therapy group). Median duration of follow-up was 3.2 years and median patient age 64 years; 23% were women and 41% had diabetes. A total of 54% of participants had severe baseline inducible ischaemia on stress testing – this included ECG exercise stress testing, which was added to the study because of slow recruitment. Exclusion criteria included significant LMS stenosis (blinded CTCA), chronic kidney disease (CKD), significant symptom burden, severe left ventricular impairment or heart failure or recent revascularisation with 12 months. Interestingly, a significant proportion (34%) had no angina at baseline implying that they had non-invasive ischaemia testing for other reasons – perhaps work-up prior to other elective surgery. Rates of the primary outcome of cardiovascular death, MI, resuscitated cardiac arrest, hospitalisation for unstable angina or heart failure at 3.5 years were 13.3% in the invasive group versus 15.5% in the OMT group (p=0.34).23 There were also no differences in the primary outcome when stratified by subgroup, such as diabetes or single versus multivessel disease. Importantly, there was no association between degree of ischaemia and all-cause mortality. These results should be interpreted in the context of the short-term follow-up period. It is possible that the increased incidence of spontaneous MI in the OMT group may affect longer-term outcomes in favour of revascularisation. Indeed, a recent publication by the same group found that longer follow-up is needed to assess whether reduction of spontaneous MI in the revascularisation arm observed in their metaanalysis translates into improved patient outcomes.24

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What Is the Message That an Interventionalist Takes From the ISCHEMIA Trial? It is perhaps inevitable that these results led to striking headlines, such as “ISCHEMIA: invasive strategy no better than meds for CV events” and “ISCHEMIA: invasive treatment not better than meds in patients with stable ischemic heart disease”.25,26 However, it is worth noting that the randomisation was to early angiography and not to early invasive treatment per se. Eighty per cent had revascularisation, while 20% had treatment deferred. In the deferment group, two-thirds (66%) had normal coronary arteries, while a third had coronary vessels too severe for revascularisation. In the 80% who had revascularisation, 74% (around 1,532 patients) had PCI, while 26% (538) had bypass surgery. This is evident in the usage of dual antiplatelet therapy in the study: this peaks at 60%. Around 26% of patients in the medical arm underwent angiography with 21% being revascularised. It is also worth noting that of the PCI performed, only 93% was considered successful. Those patients with the most symptoms did better in the invasive arm having undergone revascularisation. Angina relief and quality of life were statistically better with the invasive strategy, durable out to 3 years of follow-up. The probability of rendering patients angina-free was greater in the higher symptom burden group, reflected by lower Seattle Angina Questionnaire scores. Both groups had similar numbers of non-fatal MI with the number of spontaneous MI higher in the conservative arm and a higher number of peri-procedural MIs in the invasive group. Although there was a higher number of peri-procedural MIs in the invasive group, it is important to note that this did not translate into mortality. Spontaneous infarctions however on the other hand confer a higher risk of subsequent death.27,28 ISCHEMIA-CKD, comprising 777 participants, was a pre-specified subgroup of the main study assessing those patients with CKD or end-stage renal failure. This is a higher-risk cohort of patients who are often under-treated because of concerns over kidney function. This subgroup also demonstrated no reduction in death or MI with routine invasive strategy compared to OMT in patients with severe CKD (i.e. estimated glomerular filtration rate <30 ml/min/1.73 m2).29

Application of ISCHEMIA in Real-world Practice

Patients remain the true winners in the ISCHEMIA debate. Those who meet the entry criteria – including a low symptom burden – can choose OMT, with an invasive strategy only required if there are on-going symptoms. The study also shows an increase in spontaneous MI after the first year in the conservative arm. Therefore, early invasive strategy should remain available for those that cannot tolerate medical therapy or those with worsening symptoms despite optimal therapy. Considering the safety of revascularisation and significant improvements seen in quality of life with interventions, we can make the argument to offer an invasive strategy early in the patient journey. In the past, cardiologists may have been eager to expedite invasive management of patients with low symptom burden but significant ischaemia. A key take away from ISCHEMIA study is that mortality in patients with chronic coronary syndromes is relatively low with OMT and treatment should be individualised to patients. Those who do not meet the entry criteria should be treated as per established pathways. Unstable angina and acute coronary syndromes

Figure 1: Design of the ISCHEMIA Trial Chronic coronary disease with moderate to severe ischaemia eGFR <30 ml/min/1.73m2 CIAO-ISCHEMIA trial Unobstructed coronaries ISCHEMIA-CKD trial

Conservative (OMT) n= 2,591

Blinded CTCA

Invasive (OMT + revascularisation*) n= 2,588

3.3-year follow-up Primary outcomes: CV death, MI, cardiac arrest, unstable angina, HF (NS) *Either PCI or CABG. CAGB = coronary artery bypass grafting; CTCA = CT coronary angiogram; CKD = chronic kidney disease; CV = cardiovascular; eGFR = estimated glomerular filtration rate; HF = heart failure; NS = not significant; OMT = optimal medical therapy; PCI = percutaneous coronary intervention.

were not included in the study. Those with intolerable angina were also not included. When using medical treatment, this should be as close to clinical studies to be able to claim results seen in studies. Outside of closely monitored research studies, this can be challenging to deliver. The ORBITA study had close one-to-one consultant supervision of medical therapy escalation – rarely possible in routine clinical practice. As interventionalists, we should do our best to communicate these results effectively to our patients and colleagues when discussing treatment options. The discussion that revascularisation may not prolong your life, but prevent spontaneous MI, alleviate symptoms and improve quality of life, is one we should continue to have with our patients. It is very important to stress that this is set against trial setting medical therapy. There will always be the group of patients who were excluded from ISCHEMIA and a heart team approach should always be best practice. These patients represent a group considered at significant risk because of significant LMS disease, severe heart failure or CKD. A key message for interventionalists and all physicians is that modifying the atherosclerotic disease process should be the cornerstone of management. Addressing cardiovascular risk factors with lifestyle modifications is an essential part of the treatment plan. The application of the ISCHEMIA trial results of moderate to severe ischaemia seen in chest pain clinics should strengthen the argument for initial optimal medical management offering an invasive strategy on an individual patient level. Results from longer term follow up of ISCHEMIA trial patients, ORBITA 2 and the debate of cost effectiveness of adding revascularisation to OMT is one that will need to be analysed more closely. This involves a more complex analysis qualityadjusted life years, burden on healthcare system and quality of life. The ISCHEMIA trial should inform the cardiologist and physician how to better communicate treatment options to patients with chronic coronary syndromes. OMT is the cornerstone of patient management.

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What Is the Message That an Interventionalist Takes From the ISCHEMIA Trial? 1. Deedwania PC, Carbajal EV. Getting with the ACC/AHA guidelines for the treatment of chronic angina as a disease state. Rev Cardiovasc Med 2009;10(Suppl 1):11–20. https://doi. org/10.1016/S0140-6736(17)32714-9; PMID: 19898283. 2. Joseph J, Velasco A, Hage FG, Reyes E. Guidelines in review: comparison of ESC and ACC/AHA guidelines for the diagnosis and management of patients with stable coronary artery disease. J Nucl Cardiol 2018;25:509–15. https://doi. org/10.1007/s12350-017-1055-0; PMID: 28884447. 3. Knuuti J, Wijns W, Achenbach S, et al. 2019 ESC guidelines for the diagnosis and management of chronic coronary syndromes. Eur Heart J 2020;41:407–77. https://doi. org/10.1093/eurheartj/ehz425; PMID: 31504439. 4. Nowbar AN, Gitto M, Howard JP, et al. Mortality from ischemic heart disease: analysis of data from the world health organization and coronary artery disease risk factors from NCD risk factor collaboration. Circ Cardiovasc Qual Outcomes 2019;12:e005375. https://doi.org/10.1161/ CIRCOUTCOMES.118.005375; PMID: 31163980. 5. Al-Lamee R, Thompson D, Dehbi HM, et al. Percutaneous coronary intervention in stable angina (ORBITA): a doubleblind, randomised controlled trial. Lancet 2018;391:31–40. https://doi.org/10.1016/S0140-6736(17)32714-9; PMID: 29103656. 6. Hueb W, Soares PR, Gersh BJ, et al. The Medicine, Angioplasty, or Surgery Study (MASS-II): a randomized, controlled clinical trial of three therapeutic strategies for multivessel coronary artery disease: one-year results. J Am Coll Cardiol 2004;43:1743–51. https://doi.org/10.1016/j. jacc.2003.08.065; PMID: 15145093. 7. Hueb W, Lopes N, Gersh BJ, et al. Ten-year follow-up survival of the Medicine, Angioplasty, or Surgery Study (MASS II): a randomized controlled clinical trial of 3 therapeutic strategies for multivessel coronary artery disease. Circulation 2010;122:949–57. https://doi.org/10.1161/ CIRCULATIONAHA.109.911669; PMID: 20733102. 8. Hueb W, Lopes NH, Gersh BJ, et al. Five-year follow-up of the Medicine, Angioplasty, or Surgery Study (MASS II): a randomized controlled clinical trial of 3 therapeutic strategies for multivessel coronary artery disease. Circulation 2007;115:1082–9. https://doi.org/10.1161/ CIRCULATIONAHA.106.625475; PMID: 17339566. 9. Velazquez EJ, Lee KL, Jones RH, et al. Coronary-artery bypass surgery in patients with ischemic cardiomyopathy. N Engl J Med 2016;374:1511–20. https://doi.org/10.1056/ NEJMoa1602001; PMID: 27040723. 10. Schömig A, Mehilli J, de Waha A, et al. A meta-analysis of 17 randomized trials of a percutaneous coronary interventionbased strategy in patients with stable coronary artery disease. J Am Coll Cardiol 2008;52:894–904. https://doi. org/10.1016/j.jacc.2008.05.051; PMID: 18772058. 11. Torosoff MT, Sidhu MS, Desai KP, et al. Revascularization options in stable coronary artery disease: it is not how to revascularize, it is whether and when to revascularize. J Comp Eff Res 2015;4:505–14. https://doi.org/10.2217/cer.15.37; PMID: 26387530. 12. Sedlis SP, Jurkovitz CT, Hartigan PM, et al. Optimal medical therapy with or without percutaneous coronary intervention for patients with stable coronary artery disease and chronic

kidney disease. Am J Cardiol 2009;104:1647–53. https://doi. org/10.1016/j.amjcard.2009.07.043; PMID: 19962469. 13. Torosoff MT, Sidhu MS, Boden WE. Impact of myocardial ischemia on myocardial revascularization in stable ischemic heart disease: lessons from the COURAGE and FAME 2 trials. Herz 2013;38:382–6. https://doi.org/10.1007/s00059013-3824-0; PMID: 23695652. 14. Shaw LJ, Weintraub WS, Maron DJ, et al. Baseline stress myocardial perfusion imaging results and outcomes in patients with stable ischemic heart disease randomized to optimal medical therapy with or without percutaneous coronary intervention. Am Heart J 2012;164:243–50. https:// doi.org/10.1016/j.ahj.2012.05.018; PMID: 22877811. 15. Hachamovitch R, Hayes SW, Friedman JD, et al. Comparison of the short-term survival benefit associated with revascularization compared with medical therapy in patients with no prior coronary artery disease undergoing stress myocardial perfusion single photon emission computed tomography. Circulation 2003; 107:2900–7. https://doi. org/10.1161/01.CIR.0000072790.23090.41; PMID: 12771008. 16. Bagai A, Eberg M, Koh M, et al. Population-based study on patterns of cardiac stress testing after percutaneous coronary intervention. Circ Cardiovasc Qual Outcomes 2017;10:e003660. https://doi.org/10.1161/ CIRCOUTCOMES.117.003660; PMID: 29017997. 17. Lucas FL, DeLorenzo MA, Siewers AE, Wennberg DE. Temporal trends in the utilization of diagnostic testing and treatments for cardiovascular disease in the United States, 1993–2001. Circulation 2006; 113:374–9. https://doi. org/10.1161/CIRCULATIONAHA.105.560433; PMID: 16432068. 18. Porter TR, Smith LM, Wu J, et al. Patient outcome following 2 different stress imaging approaches: a prospective randomized comparison. J Am Coll Cardiol 2013; 61:2446–55. https://doi.org/10.1016/j.jacc.2013.04.019; PMID: 23643501. 19. Katritsis DG, Ioannidis JPA. Percutaneous coronary intervention versus conservative therapy in nonacute coronary artery disease: a meta-analysis. Circulation 2005;111:2906–12. https://doi.org/10.1161/ CIRCULATIONAHA.104.521864; PMID: 15927966. 20. Wijeysundera HC, Bennell MC, Qiu F, et al. Comparativeeffectiveness of revascularization versus routine medical therapy for stable ischemic heart disease: a populationbased study. J Gen Intern Med 2014;29:1031–9. https://doi. org/10.1007/s11606-014-2813-1; PMID: 24610309. 21. Greenland P, Knoll MD, Stamler J, et al. Major risk factors as antecedents of fatal and nonfatal coronary heart disease events. J Am Med Assoc 2003;290:891–7. https://doi. org/10.1001/jama.290.7.891; PMID: 12928465. 22. Chesebro JH, Fuster V, Elveback LR, et al. Effect of dipyridamole and aspirin on late vein-graft patency after coronary bypass operations. N Engl J Med 1984;310:209–14. https://doi.org/10.1056/NEJM198401263100401; PMID: 6361561. 23. Maron DJ, Hochman JS, Reynolds HR, et al. Initial invasive or conservative strategy for stable coronary disease. N Engl J Med 2020;382:1395–407. https://doi.org/10.1056/ NEJMoa1915922; PMID: 32227755. 24. Bangalore S, Maron D, Stone G, et al. Routine revascularization versus initial medical therapy for stable

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ischemic heart disease: a systematic review and metaanalysis of randomized trials. Circulation 2020;142:841–57. https://doi.org/10.1161/CIRCULATIONAHA.120.048194; PMID: 32794407. 25. Wood S. ISCHEMIA: invasive strategy no better than meds for CV events. TCTMD 16 November 2019. https://www.tctmd. com/news/ischemia-invasive-strategy-no-better-meds-cvevents (accessed 10 May 2021). 26. Herman AO. ISCHEMIA: invasive treatment not better than meds in patients with stable ischemic heart disease. NEJM Journal Watch 18 November 2019. https://www.jwatch.org/ fw116042/2019/11/18/ischemia-invasive-treatment-not-bettermeds-patients-with (accessed 10 May 2021). 27. Prasad A, Gersh BJ, Bertrand ME, et al. Prognostic significance of periprocedural versus spontaneously occurring myocardial infarction after percutaneous coronary intervention in patients with acute coronary syndromes: an analysis from the ACUITY (Acute Catheterization and Urgent Intervention Triage Strategy) trial. J Am Coll Cardiol 2009;54:477–86. https://doi.org/10.1016/j.jacc.2009.03.063; PMID: 19628125. 28. Lansky AJ, Stone GW. Periprocedural myocardial infarction: prevalence, prognosis, and prevention. Circ Cardiovasc Interv 2010;3:602–10. https://doi.org/10.1161/ CIRCINTERVENTIONS.110.959080; PMID: 21156928. 29. Bangalore S, Maron DJ, O’Brien SM, et al. Management of coronary disease in patients with advanced kidney disease. N Engl J Med 2020; 382:1608–18. https://doi.org/10.1056/ NEJMoa1915925; PMID: 32227756. 30. Henderson RA, Pocock SJ, Clayton TC, et al. Seven-year outcome in the RITA-2 trial: coronary angioplasty versus medical therapy. J Am Coll Cardiol 2003;42:1161–70. https:// doi.org/10.1016/S0735-1097(03)00951-3; PMID: 14522473. 31. Parisi AF, Folland ED and Hartigan P. A comparison of Angioplasty with medical therapy in the treatment of singlevessel coronary artery disease. N Engl J Med 1992;326:10–6. https://doi.org/10.1056/NEJM199201023260102; PMID: 1345754. 32. Folland ED, Hartigan PM, Parisi AF et al. Percutaneous transluminal coronary angioplasty versus medical therapy for stable angina pectoris: outcomes for patients with double-vessel versus single-vessel coronary artery disease in a Veterans Affairs Cooperative randomized trial. J Am Coll Cardiol 1997;29:1505–11. https://doi.org/10.1016/S07351097(97)00097-1; PMID: 9180111. 33. Hueb WA, Soares PR, Almeida De Oliveira S et al. Five-year follow-up of MASS: a prospective, randomized trial of medical therapy, balloon angioplasty or bypass surgery for single proximal left anterior descending coronary artery stenosis. Circulation 1999;100(19 Suppl):II107–13. https://doi. org/10.1161/01.cir.100.supp_2.ii-107; PMID: 10567287. 34. Boden WE, O’Rourke RA, Teo KK et al. Optimal medical therapy with or without PCI for stable coronary disease. N Engl J Med 2007;356:1503–16. https://doi.org/10.1056/ NEJMoa070829; PMID: 17387127. Frye RL, August P,Brooks MM et al. A randomized trial of therapies for type 2 diabetes and coronary artery disease. N Engl J Med 2009;360:2503–15. https://doi.org/10.1056/ NEJMoa0805796; PMID: 19502645.

APSC Consensus Recommendations

Asian Pacific Society of Cardiology Consensus Recommendations on the Use of MitraClip for Mitral Regurgitation Khung Keong Yeo ,1 Jack Wei Chieh Tan ,1 David WM Muller ,2 Darren L Walters,3 JoAnn Lindenfeld,4 Michael Kang Yin Lee ,5 Angus Shing Fung Chui,5 Sai Satish,6 Teguh Santoso,7 Shunsuke Kubo,8 John Chan Kok Meng ,9 Kenny YK Sin,1 See Hooi Ewe,1 David Sim,1 Edgar Tay,10 Krissada Meemook,11 Shih-Hsien Sung,12 Quang Ngoc Nguyen ,13 Xiangbin Pan,14 Makoto Amaki,15 Masaki Izumo,16 Kentaro Hayashida,17 Jung Sun Kim,18 Do-Yoon Kang ,19 Gregg Stone20 and Takashi Matsumoto21 1. National Heart Centre, Singapore; 2. St. Vincent’s Hospital, Sydney, Australia; 3. St. Vincent’s Private Hospital Northside, Chermside, Australia; 4. Vanderbilt University Medical Center, Nashville, TN, US; 5. Queen Elizabeth Hospital, Hong Kong; 6. Apollo Hospitals, Chennai, India; 7. Medistra Hospital, Jakarta, Indonesia; 8. Kurashiki Central Hospital, Kurashiki, Japan; 9. CVSKL Hospital, Kuala Lumpur, Malaysia; 10. National University Heart Centre, Singapore; 11. Ramathibodi Hospital Mahidol University, Bangkok, Thailand; 12. Taipei Veterans General Hospital, Taipei, Taiwan; 13. Department of Cardiology, Hanoi Medical University, Vietnam National Heart Institute, Hanoi, Vietnam; 14. Fuwai Hospital CAMS & PUMC, National Center for Cardiovascular Diseases, Beijing, China; 15. National Cerebral and Cardiovascular Center, Suita, Japan; 16. St Marianna University School of Medicine, Kawasaki, Japan; 17. Keio University School of Medicine, Tokyo, Japan; 18. Yonsei University, Seoul, Korea; 19. Asan Medical Center, Seoul, Korea; 20. Icahn School of Medicine at Mount Sinai, New York, US; 21. Sendai Kousei Hospital, Sendai, Japan

Abstract

Transcatheter mitral valve repair with the MitraClip, a catheter-based percutaneous edge-to-edge repair technique to correct mitral regurgitation (MR), has been demonstrated in Western studies to be an effective and safe MR treatment strategy. However, randomised clinical trial data on its use in Asian-Pacific patients is limited. Hence, the Asian Pacific Society of Cardiology convened an expert panel to review the available literature on MitraClip and to develop consensus recommendations to guide clinicians in the region. The panel developed statements on the use of MitraClip for the management of degenerative MR, functional MR, and other less common indications, such as acute MR, dynamic MR, hypertrophic obstructive cardiomyopathy, and MR after failed surgical repair. Each statement was voted on by each panel member and consensus was reached when 80% of experts voted ‘agree’ or ‘neutral’. This consensus-building process resulted in 10 consensus recommendations to guide general cardiologists in the evaluation and management of patients in whom MitraClip treatment is being contemplated.

Keywords

Mitral regurgitation, Asia-Pacific, MitraClip, edge-to-edge, valve repair, transcatheter, consensus Disclosure: This work was funded through Asian Pacific Society of Cardiology by unrestricted educational grants from Abbott Vascular, Amgen, AstraZeneca, Bayer and Roche Diagnostics. YKK has received research funding from Medtronic, Boston Scientific, Amgen, AstraZeneca and Shockwave Medical (all significant, via institution); consulting or honoraria fees (all modest) from Medtronic, Boston Scientific, Abbott Vascular, Amgen, Bayer and Novartis; and speaker or proctor fees from Abbott Vascular, Boston Scientific, Medtronic, Philips, Shockwave Medical, Alvimedica, Menarini, AstraZeneca, Amgen and Bayer. JWCT has received honoraria from AstraZeneca, Bayer, Amgen, Medtronic, Abbott Vascular, Biosensors, Alvimedica, Boehringer Ingelheim and Pfizer; research and educational grants from Medtronic, Biosensors, Biotronik, Philips, Amgen, AZ, Roche, Ostuka, Terumo and Abbott Vascular; and consulting fees from Elixir, CSL Behring. ET and SHS have received honoraria from Abbott Vascular. JL has received research funding from AstraZeneca, Sensible Medical and Volumetrix; and consulting fees from Abbott, Amgen, AstraZeneca, Boehringer Ingelheim, Boston Scientific, CVRx, Edwards Lifesciences, Impulse Dynamics and VWave. XP has received proctor fees from Medtronic and Abbott Vascular. DWMM has received research funding and consulting or proctor fees from Abbott Vascular, Medtronic and Edwards Lifesciences. KM has received modest research funding and consulting or proctor fees from CSL Behring, Boston Scientific, Abbott Vascular, Medtronic, Thai Osuka, AstraZeneca and Daiichi Sankyo. SHE has received speaker fees from Edwards Lifesciences and Abbott Vascular. MA has received speaker fees from Abbott Medical Japan. JSK has received proctoring fees from Abbott Vascular and Occlutech. All other authors have no conflicts of interest to declare. Acknowledgement: Medical writing support was provided by Ivan Olegario of MIMS Pte Ltd. Received: 6 January 2021 Accepted: 5 February 2021 Citation: European Cardiology Review 2021;16:e25. DOI: https://doi.org/10.15420/ecr.2021.01 Correspondence: Jack Wei Chieh Tan, National Heart Centre, Singapore, 5 Hospital Dr, Singapore 169609, Singapore. E: jack.tan.w.c@singhealth.com.sg Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

APSC Consensus Recommendations for MitraClip in MR Transmitral valve repair can be performed with the MitraClip, a catheterbased percutaneous edge-to-edge repair technique to correct mitral regurgitation (MR), by connecting the anterior and the posterior leaflet of a regurgitant mitral valve. Data from the EVEREST II high-risk registry, as well as Asian registry data, demonstrate that the MitraClip procedure is feasible and safe.1–3 MitraClip was also evaluated in MITRA-FR and COAPT. Both these randomised controlled trials included patients with heart failure (New York Heart Association [NYHA] functional class ≥2 despite optimal guidelinedirected medical therapy [GDMT]), reduced ejection fraction, and moderate-to-severe or severe secondary MR who received medical treatment with or without MitraClip implantation. The MITRA-FR trial did not show a significant difference in the composite primary endpoint of death from any cause and unplanned hospitalisation for heart failure at 12 months (54.6% in the device group versus 51.3% in the medical group; p=0.53).4 In contrast, the COAPT trial showed that the primary endpoint of all hospitalisations for heart failure within 24 months was significantly lower in the device group than in the control group (35.8% versus 67.9%, p<0.001).5 The 2020 American College of Cardiology/American Heart Association guideline for the management of patients with valvular heart disease recommends the MitraClip in treating severely symptomatic patients with primary MR who are at high or prohibitive surgical risk.6 In Asia-Pacific, MitraClip has been reserved for patients who are at high or prohibitive surgical risk, although many Asian patients with intermediate or low surgical risk still refuse to undergo surgery.3 For these patients, the MitraClip may be a reasonable treatment option. However, published data on the use of the MitraClip among Asian populations are limited compared with the West.7 The multicentre retrospective MARS registry, involving eight sites in five Asia-Pacific countries, reported the early experience in Asia with 142 patients who underwent the MitraClip procedure from February 2011 to October 2013. In this study, the acute procedural success rate was 93.7%.2 Given the limited published clinical evidence on the use of MitraClip in the Asia-Pacific region, the Asian Pacific Society of Cardiology (APSC) developed these consensus recommendations to provide expert guidance on the potential role of MitraClip in the treatment of MR in the region. These consensus recommendations are intended to guide general cardiologists and internists practicing cardiology in managing MR and evaluating patient suitability for MitraClip repair. However, the consensus recommendations are not intended to replace clinical judgement.

Methods

appraised using the Grading of Recommendations Assessment, Development, and Evaluation system as follows: 1. High (authors have high confidence that the true effect is similar to the estimated effect). 2. Moderate (authors believe that the true effect is probably close to the estimated effect). 3. Low (true effect might be markedly different from the estimated effect). 4. Very low (true effect is probably markedly different from the estimated effect).9 The evidence was then discussed in two consensus meetings, held on 18 January 2020 and 27 June 2020. Consensus recommendations for the use of MitraClip in the management of degenerative mitral regurgitation (DMR), functional mitral regurgitation (FMR), and other less common indications in the Asia-Pacific setting were developed during the two meetings. The statements were each put to an online vote using a three-point scale (agree, neutral, or disagree). Consensus was reached when 80% of experts voted agree or neutral. When there was not consensus, the statements were further discussed via email then revised accordingly until the criteria for consensus were reached.

MitraClip Use in Degenerative Mitral Regurgitation Statement 1. Both symptomatic and asymptomatic patients with ≥3+ DMR, who meet the indications for surgery but are considered high risk by the Heart Team, should be considered for MitraClip implantation. Level of evidence: Moderate. Level of agreement: 80% agree, 16% neutral, 4% disagree. Statement 2. MitraClip use should be considered for symptomatic high-risk ≥3+ DMR patients with or without reduced left ventricular ejection fraction (LVEF). Level of evidence: Moderate. Level of agreement: 84% agree, 12% neutral, 4% disagree. Statement 3. MitraClip use should be considered for asymptomatic patients with high-risk ≥3+ DMR, with: • Reduced LVEF and/or LV dilatation; or • New onset AF or pulmonary hypertension. Level of evidence: Low. Level of consensus: 84% agree, 16% neutral, 0% disagree.

The APSC convened a 26-member panel to review the literature on the use of MitraClip in the management of MR, discuss gaps in the current management strategies, outline areas where further guidance is needed and, ultimately, develop consensus recommendations on the use of MitraClip. The experts were mostly members of the APSC who were nominated by national societies and endorsed by the APSC consensus board, as well as international experts in the MitraClip procedure. For these consensus recommendations, the expert panel decided to adapt the echocardiographic criteria from the American Society of Echocardiography guidelines, with a focus on parameters identifying severe MR patients suitable for MitraClip use (Figure 1), as the common definition for discussions during the consensus meeting.8

DMR, wherein one of the components of the mitral apparatus (leaflets, chords or papillary muscles) is affected, is often the result of degenerative mitral valve disease characterised by morphological changes in the connective tissue of the valve over time and resulting in MR.10,11 DMR may be either the result of fibroelastic deficiency or due to diffuse myxomatous disease.12,13 It may present across a spectrum ranging from isolated prolapse of a single leaflet scallop to bileaflet prolapse and annular dilation.10

A comprehensive literature search was conducted, with particular focus on Asian-centric studies. Selected applicable articles were reviewed and

Surgical mitral valve repair or replacement is still the gold standard for DMR, although transcatheter therapy may have a role in the management

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APSC Consensus Recommendations for MitraClip in MR Figure 1: Schematic Illustration of Echocardiographic Parameters for Mitral Regurgitation Assessment

AF ECG LA LA size Dilated: LA ≥60 ml/m2 Pulmonary vein flow pattern

Mild: Normal

Moderate: Severe: Systolic blunting Flow reversal

Rvol and RF Mild: Rvol <30 ml; RF <30% Moderate: RvoI 30–59 ml; RF 30–49% Severe: Rvol ≥60 ml; RF ≥50%

Vena contracta Mild: Width <0.3 cm Moderate: Width 0.3–0.69 cm Severe: Width ≥0.7 cm EROA Mild: EROA <0.2 cm2 Moderate: EROA 0.2–0.39 cm2 Severe: EROA ≥0.4 cm2

PASP Normal: Absence of pulmonary hypertension Elevated: Presence of pulmonary hypertension (PASP at rest >50 mmHg)

LVESD Normal: LVESD <4.0 cm Dilated: LVESD ≥4.0 cm

LVEF Normal: LVEF >60% Reduced: LVEF ≤60%

EROA = effective regurgitant orifice area; LA = left atrium; LVEF = left ventricular ejection fraction; LVESD = left ventricular end-systolic diameter; PASP = pulmonary artery systolic pressure; RF = regurgitant fraction; Rvol = regurgitant volume.

of a subset of patients.7,8,14,15 Data from MARS found that the acute procedural success rate for patients with DMR was 92%.3 The 30-day major adverse event rate was 14.7%, which was not significantly different from FMR patients (9.2%; p=0.555). Both FMR and DMR patients had significant improvements in the severity of MR and NYHA functional class after 30 days. There was a significantly greater reduction in LV enddiastolic diameter (p=0.002) and end-systolic diameter (p=0.017) in DMR than in FMR. In addition, the AVJ-514 trial also provided Asian evidence to support the use of MitraClip in DMR patients. AVJ-514 was a prospective, multicentre, single-arm study that included patients with symptomatic chronic moderate-to-severe (3+) or severe (4+) DMR (n=16) or FMR (n=14). Among DMR patients, the acute procedural success rate was 87.5% and 81.3% had MR grade ≤2+ at 30 days.16 The proportion of patients with NYHA functional class III/IV was reduced from 37.5% to 6.3%. No deaths were reported.

The panel agreed to recommend MitraClip for high-risk patients with symptomatic severe DMR with or without reduced LVEF; high-risk asymptomatic patients with severe DMR with reduced LVEF and LV dilatation; and those with new-onset AF or pulmonary hypertension, who meet the indications for surgery but are considered high risk by the Heart Team. However, some panellists underscored the absence of clinical data in asymptomatic patients, which then lowered the level of evidence for this subgroup. One dissenting opinion for Statement 1 explained that only asymptomatic patients with prohibitively high risk should be considered for MitraClip therapy. For Statement 2, one dissenting opinion explained that such patients should be considered for surgery first, and MitraClip should be limited to those with high surgical risk. While some experts stated their preference to treat early prior to deterioration or severe LV remodelling, the overall panel opinion was that there was no reason to intervene in asymptomatic patients with severe DMR with good LVEF and no LV dilatation (except those with new-onset AF

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APSC Consensus Recommendations for MitraClip in MR or pulmonary hypertension). These patients should continue to be observed closely.

adequately treated (i.e. revascularisation and medical therapy); MitraClip may then be considered for severe symptomatic residual FMR (≥3+).

MitraClip Use in Functional Mitral Regurgitation

As first suggested by the EVEREST II trial, MitraClip is a suitable alternative treatment option for symptomatic FMR patients.1 The definitive COAPT trial also showed that patients with moderate-to-severe (grade 3+) or severe (grade 4+) secondary MR had a significantly lower rate of all hospitalisations for heart failure (primary endpoint) within 24 months with MitraClip compared with controls (35.8% versus 67.9%; p<0.001).5 Allcause mortality was also significantly lower in the device group (29.1% versus 46.1%; p<0.001). The secondary endpoints of quality of life, functional capacity, MR grade and LV remodelling also favoured MitraClip over controls.

Statement 4. MitraClip should be considered for (≥3+) symptomatic FMR patients who are already on GDMT. FMR patients should receive at least 1 month of optimised GDMT, with reasonable attempts to uptitrate treatment, as well as cardiac resynchronisation therapy defibrillator (CRT-D) if indicated, before being evaluated for further intervention or MitraClip use. Level of evidence: High. Level of consensus: 88% agree, 8% neutral, 4% disagree. Statement 5. For patients with ischaemic FMR (≥3+), coronary anatomy, ischaemia evaluation and potential revascularisation should be performed before MitraClip consideration. If the coronary revascularisation strategy is percutaneous coronary intervention, staged MitraClip should be considered. If the coronary revascularisation strategy is coronary artery bypass graft (CABG), concomitant surgical mitral valve repair/replacement may be considered. Level of evidence: Low. Level of agreement: 100% agree, 0% neutral, 0% disagree. Statement 6. FMR patients should be monitored regularly (e.g. every 6 months) and referred early to the Heart Team (including a MitraClip specialist, heart failure specialist, echocardiologist and surgeon) for intervention, including MitraClip implantation. Discussions and endorsements of futility should be deferred to the Heart Team. Level of evidence: Low. Level of agreement: 100% agree, 0% neutral, 0% disagree. Statement 7. Symptomatic patients with ≥3+ FMR should be assessed by the Heart Team for possible MitraClip implantation. Level of evidence: High. Level of agreement: 100% agree, 0% neutral, 0% disagree. Statement 8. FMR patients who do not meet the eligibility criteria for MitraClip implantation (e.g. asymptomatic patients, those with MR severity of ≤2+, and those with less-optimised GDMT) should be closely monitored. These patients should be considered for MitraClip implantation once the eligibility criteria are met. Level of evidence: Low. Level of agreement: 100% agree, 0% neutral, 0% disagree. In FMR, the components of the mitral apparatus remain intact but there is resultant MR because of dysfunctional coaptation of the leaflets, usually as a result of ventricular or annular dilation.11 Patients with functional MR usually have LV dysfunction and most of them undergo medical treatment for the treatment of underlying conditions such as hypertension, dyslipidaemia, AF, coronary artery disease and heart failure. Guidelines recommend that these conditions be adequately treated – including the use of CRT-D when indicated – together with the management of the MR.14 Among those with FMR in Asia, 66% have an ischaemic aetiology.3 Hence, ischaemic evaluation is a crucial step in patient assessment. Coronary angiography is the preferred method of ischaemia assessment although the use of CT coronary angiography and other modalities would be acceptable in selected patients. Correctable ischaemia should be

The MITRA-FR trial did not show a significant difference in the composite primary endpoint of death from any cause and unplanned hospitalisation for heart failure at 12 months.4 On cursory examination, both the COAPT and MITRA-FR studies examined similar cohorts of FMR patients. However, there are several key differences in patient selection that have been instructive in the appropriate selection of the MitraClip and would also explain the differences between the two study outcomes. Firstly, the COAPT study is arguably a more robust study with a central inclusion committee, larger (almost double) sample size, detailed follow-up with echocardiography and functional studies (e.g. 6-minute walk test) and a requirement for stable doses of GDMT prior to enrolment, compared to the MITRA-FR. In addition, the COAPT study reported superior technical success rates and lower complication rates than the MITRA-FR study. Thirdly the criteria for MR severity also differed between COAPT and MITRA-FR, with the COAPT adopting more stringent criteria to qualify for severe MR. Finally, and perhaps most importantly, the COAPT study selected patients who had disproportionately severe MR compared to MITRA-FR patients who appeared to have more proportionate MR. The concept of disproportionate MR, first described by Grayburn et al. is beyond the scope of this paper, but in brief, refers to a situation where the MR is more severe relative to the LV volume.17 This implies a mechanical dysfunction of the mitral valve driving a significant element of the underlying heart failure. According to the ACCESS-EU registry, which included patients with significant MR (77% of whom had FMR), there was an improvement in the severity of MR at 12 months compared with baseline (p<0.0001), with 78.9% of patients free from MR of >2+ severity at 12 months.18 The 6-minute-walk-test improved by 59.5 ± 112.4 m and the 1-year survival rate was 81.8%. The MARS registry also reported that the acute procedural success rates of MitraClip for FMR was 95.5%.3 Among the 14 patients in the AVJ-514 trial with FMR, acute procedural success rate was 85.7% and 92.9% of patients had MR grade ≤2+ after 30 days. The proportion of patients with NYHA functional class III/IV was reduced from 35.7% to 0.0%.16 No deaths were reported. For patients with FMR, the panel recommended that MitraClip may be considered as long as medical therapy has already been dose-optimised for at least 1 month and, if appropriate, have had a CRT-D implanted. While a few panellists recommend observing on GDMT for up to 3 months, data from COAPT suggest that patients with more severe disease should probably not wait unnecessarily. FMR patients who are potential candidates for MitraClip therapy should be monitored regularly by the general cardiologist via echocardiography, then referred to the Heart Team (MitraClip specialist, heart failure

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APSC Consensus Recommendations for MitraClip in MR Figure 2: Flowchart for the Assessment and Initial Management of Patients With ≥3+ FMR

Table 1: Technical Considerations for MitraClip Use in Mitral Regurgitation Ideal

≥3+ FMR

• Pathology in segment 2

• Coronary anatomy and ischaemia evaluation with revascularisation if appropriate • Heart failure specialist to optimise medical therapy +/- CRT-D

• Valve area >4.0 cm2

If persistent ≥3+ FMR: Re-evaluate by echocardiogram, preferably TOE for defining aetiology and TTE for assessing severity

Complex

Inappropriate

• Pathology in segment 1 or 3 • Leaflet perforation • Posterior leaflet length • Active infective <7.0 mm

endocarditis

• Barlow’s syndrome • Moderate-to-severe mitral stenosis (valve • Mitral valve cleft area ≤2.0 cm2) • Severe calcification • Left atrial thrombus • Prior annuloplasty • Rheumatic leaflet thickening

Level of agreement: 100% agree, 0% neutral, 0% disagree. Refer to the Heart Team for MitraClip eligibility assessment

CRT-D = cardiac resynchronisation therapy defibrillator; FMR = functional mitral egurgitation; TOE = transoesophageal echocardiogram; TTE = transthoracic echocardiogram.

specialist, echocardiologist and surgeon) as soon as the patient fits the eligibility criteria (i.e. symptomatic moderate-to-severe FMR). All patients with LV dysfunction should undergo close surveillance. The panel recommends the use of transoesophageal echocardiogram (TOE) to define MR aetiology while transthoracic echocardiogram (TTE) would be more appropriate for severity assessment as TOE may be influenced by haemodynamic variables during sedation. TOE may be used alone only for instances where the use of TTE is challenging. Surgical risk should be considered by the Heart Team when deciding on the best treatment strategy, although surgical risk is not a predictor of MitraClip success or failure. Mitral valve surgery could be considered when concomitant CABG is required.14 In contrast, for severe FMR with LV dysfunction where no CABG is planned, MitraClip may be considered. Figure 2 shows a flowchart to guide the assessment and initial management of patients with ≥3+ FMR. Additionally, the panel outlined the technical considerations for the use of MitraClip in the treatment of DMR and FMR (Table 1). The MitraClip currently has a fourth-generation ‘G4’ device, which has been enhanced with an expanded range of four clip sizes (NTR, NTW, XTR, XTW), differentiated by clip arm length and width, independent leaflet grasping feature and real-time left atrial (LA) pressure monitoring capabilities.19,20 The G4 system is already available in parts of Asia and these new features could aid in the treatment of challenging anatomies.

Subgroups and Special Populations for MitraClip Use

The use of the MitraClip was also considered in subgroups and special patient groups, including atrial FMR, concomitant MR/tricuspid regurgitation (TR), acute MR and hypertrophic obstructive cardiomyopathy (HOCM). Statement 9. Patients with symptomatic atrial FMR should be evaluated by the Heart Team (including an electrophysiologist and heart failure specialist) and, if treatment has already been optimised, MitraClip may be considered. Level of evidence: Low. Level of agreement: 96% agree, 0% neutral, 4% disagree.

Although LA dilatation may occur in the absence of AF, a common cause of LA dilatation is long-standing AF.21 In patients with LA dilation due to AF, dilatation of the mitral annulus may lead to reduced leaflet coaptation and MR. Prominent LA dilation may cause posterior mitral leaflet tethering and restriction, which would result in atrial FMR.22 One study compared the effect of MitraClip therapy in AF patients with atrial FMR (n=38) with those with ventricular FMR (n=49). In this study, atrial FMR was defined as MR with preserved LV function (LVEF ≥50%) and normal LV wall motion, while ventricular FMR was defined as MR with LV dysfunction (LVEF<50%) or LV wall motion abnormality. The study found that MitraClip was associated with an improvement of MR, with an increase in leaflet coaptation and a greater reduction of anteroposterior diameter and mitral annular area in patients with atrial FMR than in ventricular FMR.23 Based on this study, the panel considered MitraClip a possible treatment option for symptomatic atrial FMR; hence, such patients should be evaluated by the Heart Team (including an electrophysiologist and heart failure specialist) for possible MitraClip implantation after other treatments have already been optimised. However, some panellists disagreed, pointing out that many patients with atrial FMR would be considered low risk for surgery, and maintained the role of surgical mitral valve repair in these patients. Nonetheless, for patients not amenable to surgery (e.g. some elderly patients), MitraClip is a reasonable option. Lastly, it is worth noting that atrial FMR is often associated with severe TR24, which may limit the clinical benefit of transcatheter mitral intervention. Hence, this concomitant condition should also be assessed. Statement 10. The expert panel acknowledges that MitraClip has been used in less common scenarios (e.g. acute MR, dynamic MR, HOCM, MR after failed surgical repair and TR) with reasonable reports of clinical success. However, enrolment into clinical trials or registries is preferred. Patients with these less common conditions should be evaluated by the Heart Team on a per-patient basis, with informed patient consent on the limited understanding available, to determine whether MitraClip use would be feasible and beneficial for them. Level of evidence: Low. Level of agreement: 100% agree, 0% neutral, 0% disagree. Case reports have documented the use of MitraClip in less common scenarios, such as acute MR, dynamic MR, HOCM, MR after failed surgical repair and TR, with reasonable reports of clinical success.25–32

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APSC Consensus Recommendations for MitraClip in MR In the IREMMI trial, a multicentre registry that reported the feasibility of using MitraClip to treat acute MR in patients with acute myocardial infarction (n=93), patients had a procedural success rate of over 90% and a 30-day mortality rate of 6.5%.25 Another study, which included 221 patients who underwent MitraClip implantation, found that patients with dynamic severe MR experienced similar clinical improvement as patients with severe MR at rest, and that the majority of patients with dynamic severe MR experienced clinical improvement from NYHA functional class III/IV to I/II, as did those with severe MR at rest (59% versus 56%; p=0.566).26 For TR, one study of 64 patients with severe TR on optimal medical treatment, who were unsuitable for surgery and so were treated with MitraClip implantation, found that TR was reduced by at least 1 grade in 91% of the patients.31 Patients also had significant reductions in effective regurgitant orifice area (p<0.001), vena contracta width (p=0.001), and regurgitant volume (p<0.001). The 6-minute walking distance also increased significantly (p=0.007). A second observational study showed that in 50 patients, MitraClip treatment was associated with a 44% increase in 6-minute walk distance (p<0.001) and a non-significant 16% increase in quality-of-life scores (p=0.056).30 Despite these successes, clinicians should be aware that a separate catheter-based intervention (TriClip) has been evaluated in an international, prospective, single arm, multicentre study. This study, TRILUMINATE, found that in patients with 1. Glower DD, Kar S, Trento A, et al. Percutaneous mitral valve repair for mitral regurgitation in high-risk patients. J Am Coll Cardiol 2014;64:172–81. https://doi.org/10.1016/j. jacc.2013.12.062; PMID: 25011722. 2. Yeo KK, Yap J, Yamen E, et al. Percutaneous mitral valve repair with the MitraClip: early results from the MitraClip Asia-Pacific Registry (MARS). EuroIntervention 2014;10:620–5. https://doi.org/10.4244/eijv10i5a107; PMID: 24425362. 3. Tay E, Muda N, Yap J, et al. The MitraClip Asia-Pacific registry: differences in outcomes between functional and degenerative mitral regurgitation. Catheter Cardiovasc Interv 2016;87:e275–81. https://doi.org/10.1002/ccd.26289; PMID: 26508564. 4. Obadia JF, Messika-Zeitoun D, Leurent G, et al. Percutaneous repair or medical treatment for secondary mitral regurgitation. N Engl J Med 2018;379:2297–306. https://doi.org/10.1056/NEJMoa1805374; PMID: 30145927. 5. Stone GW, Lindenfeld J, Abraham WT, et al. Transcatheter mitral-valve repair in patients with heart failure. N Engl J Med 2018;379:2307–18. https://doi.org/10.1056/NEJMoa1806640; PMID: 30280640. 6. Otto CM, Nishimura RA, Bonow RO, et al. 2020 ACC/AHA guideline for the management of patients with valvular heart disease. J Am Coll Cardiol 2021;77:e25–197. https://doi. org/10.1016/j.jacc.2020.11.018; PMID: 33332150. 7. Wong N, Yeo KK. MitraClip in Asia ― current adoption and regional data. Circ Rep 2019;1:397–400. https://doi. org/10.1253/circrep.cr-19-0074; PMID: 33693075. 8. Zoghbi WA, Adams D, Bonow RO, et al. Recommendations for noninvasive evaluation of native valvular regurgitation: a report from the American Society of Echocardiography developed in collaboration with the Society for Cardiovascular Magnetic Resonance. J Am Soc Echocardiogr 2017;30:303–71. https://doi.org/10.1016/j.echo.2017.01.007; PMID: 28314623. 9. Balshem H, Helfand M, Schünemann HJ, et al. GRADE guidelines: 3. Rating the quality of evidence. J Clin Epidemiol 2011;64:401–6. https://doi.org/10.1016/j.jclinepi.2010.07.015; PMID: 21208779. 10. McNeely CA, Vassileva CM. Long-term outcomes of mitral valve repair versus replacement for degenerative disease: a systematic review. Curr Cardiol Rev 2015;11:157–62. https://doi.org/10.2174/1573403x10666140827093650; PMID: 25158683. 11. Cubero-Gallego H, Hernandez-Vaquero D, Avanzas P, et al. Outcomes with percutaneous mitral repair. Ann Transl Med 2020;8:962. https://doi.org/10.21037/atm.2020.03.202; PMID: 32953762. 12. Adams DH, Rosenhek R, Falk V. Degenerative mitral valve regurgitation: best practice revolution. Eur Heart J 2010;31:1958–66. https://doi.org/10.1093/eurheartj/ehq222;

moderate or greater TR, the TriClip reduced TR to moderate or less in 71% of patients (versus 8% at baseline; p<0.0001).33 Patients also experienced significant clinical improvements in NYHA functional class I/II (p<0.0001), 6-minute walk test (p=0.0023) and Kansas City Cardiomyopathy Questionnaire score (p<0.0001). For HOCM, and MR after failed surgical repair, the current evidence has been limited to a few case reports.28,29,32 Beyond these reports, the use of MitraClip in these patients has not been evaluated in well-designed controlled trials so these patients should ideally be included in a clinical trial or patient registry. Should MitraClip be considered, patients with these less common conditions should be evaluated by the Heart Team on a per-patient basis, with informed patient consent on the limited understanding available, to determine whether MitraClip use would be feasible and beneficial for them. This opinion applies to patients who are not candidates for surgery, either due to surgical risk or due to lack of consent.

Conclusion

In all patients with MR, the aetiology, nature, and severity of the MR should be assessed, together with a thorough assessment of symptoms and overall surgical risk. Correctable underlying causes of MR should be adequately addressed together with the valvular problems. The determination of eligibility for MitraClip implantation requires a Heart Team approach to ensure a comprehensive benefit–risk assessment.

PMID: 20624767. 13. Antoine C, Mantovani F, Benfari G, et al. Pathophysiology of degenerative mitral regurgitation: new 3-dimensional imaging insights. Circ Cardiovasc Imaging 2018;11:e005971. https://doi.org/10.1161/CIRCIMAGING.116.005971; PMID: 29321211. 14. Bonow RO, O’Gara PT, Adams DH, et al. 2020 focused update of the 2017 ACC Expert Consensus decision pathway on the management of mitral regurgitation: a report of the American College of Cardiology Solution Set Oversight Committee. J Am Coll Cardiol 2020;75:2236–70. https://doi. org/10.1016/j.jacc.2020.02.005; PMID: 32068084. 15. Baumgartner H, Falk V, Bax JJ, et al. 2017 ESC/EACTS guidelines for the management of valvular heart disease. Eur Heart J 2017;38:2739–91. https://doi.org/10.1093/ eurheartj/ehx391; PMID: 28886619. 16. Hayashida K, Yasuda S, Matsumoto T, et al. AVJ-514 trial – baseline characteristics and 30-day outcomes following MitraClip® treatment in a Japanese cohort. Circ J 2017;81:1116–22. https://doi.org/10.1253/circj.CJ-17-0115; PMID: 28321004. 17. Grayburn PA, Sannino A, Packer M. Proportionate and disproportionate functional mitral regurgitation: a new conceptual framework that reconciles the results of the MITRA-FR and COAPT trials. JACC Cardiovasc Imaging 2019;12:353–62. https://doi.org/10.1016/j.jcmg.2018.11.006; PMID: 30553663. 18. Maisano F, Franzen O, Baldus S, et al. Percutaneous mitral valve interventions in the real world: early and 1-year results from the ACCESS-EU, a prospective, multicenter, nonrandomized post-approval study of the MitraClip therapy in Europe. J Am Coll Cardiol 2013;62:1052–61. https://doi. org/10.1016/j.jacc.2013.02.094; PMID: 23747789. 19. Chakravarty T, Makar M, Patel D, et al. Transcatheter edgeto-edge mitral valve repair with the MitraClip G4 system. JACC Cardiovasc Interv 2020;13:2402–14. https://doi. org/10.1016/j.jcin.2020.06.053; PMID: 33011141. 20. Lim DS. A contemporary, prospective study evaluating realworld experience of performance and safety for the next generation of MitraClip Devices. Presented at American College of Cardiology Virtual Conference, March 2020. 21. Deferm S, Bertrand PB, Verbrugge FH, et al. Atrial functional mitral regurgitation: JACC review topic of the week. J Am Coll Cardiol 2019;73:2465–76. https://doi.org/10.1016/j. jacc.2019.02.061; PMID: 31097168. 22. Machino-Ohtsuka T, Seo Y, Ishizu T, et al. Novel mechanistic insights into atrial functional mitral regurgitation 3-dimensional echocardiographic study. Circ J 2016;80:2240–8. https://doi.org/10.1253/circj.CJ-16-0435; PMID: 27535338. 23. Nagaura T, Hayashi A, Yoshida J, et al. percutaneous edgeEUROPEAN CARDIOLOGY REVIEW Access at: www.ECRjournal.com

to-edge repair for atrial functional mitral regurgitation: a real-time 3-dimensional transesophageal echocardiography Study. JACC Cardiovasc Imaging 2019;12:1881–3. https://doi. org/10.1016/j.jcmg.2019.02.018; PMID: 31005543. 24. Mutlak D, Khalil J, Lessick J, et al. risk factors for the development of functional tricuspid regurgitation and their population-attributable fractions. JACC Cardiovasc Imaging 2020;13:1643–51. https://doi.org/10.1016/j.jcmg.2020.01.015; PMID: 32305485. 25. Estévez-Loureiro R, Shuvy M, Taramasso M, et al. Outcomes of MitraClip in patients with acute mitral regurgitation in AMI with and without cardiogenic shock. IREMMI (International REgistry MitraClip in acute Myocardial Infarction). Presented at TCT Connect 2020, Virtual, 14–18 October 2020. 26. Spieker M, Hellhammer K, Spießhoefer J, et al. Percutaneous mitral valve repair with the MitraClip in patients with handgrip exercise-induced dynamic mitral regurgitation. Vessel Plus 2020;2020. https://doi. org/10.20517/2574-1209.2020.28. 27. Masumoto A, Kubo S, Ohya M, et al. MitraClip therapy for dynamic mitral regurgitation with repetitive heart failure exacerbation. JACC Cardiovasc Interv 2019;12:e215–7. https:// doi.org/10.1016/j.jcin.2019.09.021; PMID: 31786214. 28. Schäfer U, Kreidel F, Frerker C. MitraClip implantation as a new treatment strategy against systolic anterior motioninduced outflow tract obstruction in hypertrophic obstructive cardiomyopathy. Heart Lung Circ 2014;23:e131–5. https://doi. org/10.1016/j.hlc.2014.01.007; PMID: 24698439. 29. Sorajja P, Pedersen WA, Bae R, et al. First experience with percutaneous mitral valve plication as primary therapy for symptomatic obstructive hypertrophic cardiomyopathy. J Am Coll Cardiol 2016;67:2811–8. https://doi.org/10.1016/j. jacc.2016.03.587; PMID: 27311518. 30. Orban M, Besler C, Braun D, et al. Six-month outcome after transcatheter edge-to-edge repair of severe tricuspid regurgitation in patients with heart failure. Eur J Heart Fail 2018;20:1055–62. https://doi.org/10.1002/ejhf.1147; PMID: 29405554. 31. Nickenig G, Kowalski M, Hausleiter J, et al. Transcatheter treatment of severe tricuspid regurgitation with the edge-toedge MitraClip technique. Circulation 2017;135:1802–14. https://doi.org/10.1161/CIRCULATIONAHA.116.024848; PMID: 28336788. 32. Bianda D, Gaemperli O, Corti R, et al. Percutaneous treatment options for recurrent mitral valve disease after failed mitral valve surgery. J Cardiovasc Thoracic Surg 2017;2:1–8. 33. Lurz P, Stephan von Bardeleben R, Weber M, et al. Transcatheter edge-to-edge repair for treatment of tricuspid regurgitation. J Am Coll Cardiol 2021;77:229–39. https://doi. org/10.1016/j.jacc.2020.11.038; PMID: 33478646.

APSC Consensus Recommendations

2020 Asian Pacific Society of Cardiology Consensus Recommendations on Antithrombotic Management for High-risk Chronic Coronary Syndrome Jack Wei Chieh Tan ,1,2 Derek P Chew,3 David Brieger,4 John Eikelboom,5 Gilles Montalescot,6,7,8 Junya Ako,9 Byeong-Keuk Kim,10 David KL Quek,11 Sarah J Aitken ,12 Clara K Chow ,13,14 Sok Chour,15 Hung Fat Tse,16 Upendra Kaul,17 Isman Firdaus,18 Takashi Kubo,19 Boon Wah Liew,20 Tze Tec Chong,21 Kenny YK Sin,1 Hung-I Yeh ,22 Wacin Buddhari,23 Narathip Chunhamaneewat,24 Faisal Hasan,25 Keith AA Fox,26 Quang Ngoc Nguyen27 and Sidney TH Lo28 1. National Heart Centre, Singapore; 2. Sengkang General Hospital, Singapore; 3. College of Medicine and Public Health, Flinders University, Adelaide, Australia; 4. Concord Repatriation General Hospital, University of Sydney, Sydney, Australia; 5. McMaster University, Ontario, Canada; 6. Sorbonne University, Paris, France; 7. ACTION Study Group, France; 8. Pitié-Salpêtrière University Hospital (AP-HP), Paris, France; 9. Kitasato University and Hospital, Kanagawa, Japan; 10. Yonsei University College of Medicine, South Korea; 11. Pantai Hospital Kuala Lumpur, Kuala Lumpur, Malaysia; 12. University of Sydney, Sydney, Australia; 13. Westmead Applied Research Centre, University of Sydney, Sydney, Australia; 14. Westmead Hospital, Sydney, Australia; 15. Calmette Hospital, Phnom Penh, Cambodia; 16. Queen Mary Hospital, University of Hong Kong, Hong Kong, China; 17. Batra Hospital and Medical Research Center, New Delhi, India; 18. Faculty of Medicine, University of Indonesia, Jakarta, Indonesia; 19. Wakayama Medical University, Wakayama, Japan; 20. Changi General Hospital, Singapore; 21. Singapore General Hospital, Singapore; 22. MacKay Memorial Hospital, MacKay Medical College, Taipei, Taiwan; 23. King Chulalongkorn Memorial Hospital, Bangkok, Thailand; 24. Siriraj Hospital, Mahidol University, Bangkok, Thailand; 25. Heart & Vascular Institute, Cleveland Clinic Abu Dhabi, Abu Dhabi, United Arab Emirates; 26. University of Edinburgh, Edinburgh, UK; 27. Hanoi Medical University, Vietnam National Heart Institute, Hanoi, Vietnam; 28. Liverpool Hospital, Sydney, Australia

Abstract

The unique characteristics of patients with chronic coronary syndrome (CCS) in the Asia-Pacific region, heterogeneous approaches because of differences in accesses and resources and low number of patients from the Asia-Pacific region in pivotal studies, mean that international guidelines cannot be routinely applied to these populations. The Asian Pacific Society of Cardiology developed these consensus recommendations to summarise current evidence on the management of CCS and provide recommendations to assist clinicians treat patients from the region. The consensus recommendations were developed by an expert consensus panel who reviewed and appraised the available literature, with focus on data from patients in Asia-Pacific. Consensus statements were developed then put to an online vote. The resulting recommendations provide guidance on the assessment and management of bleeding and ischaemic risks in Asian CCS patients. Furthermore, the selection of long-term antithrombotic therapy is discussed, including the role of single antiplatelet therapy, dual antiplatelet therapy and dual pathway inhibition therapy.

Keywords

Asia-Pacific, chronic coronary syndrome, ischaemia, antiplatelet, anticoagulant, bleeding, consensus Disclosure: This work was funded through the Asian Pacific Society of Cardiology with unrestricted educational grants from Abbott Vascular, Amgen, AstraZeneca, Bayer and Roche Diagnostics. JWCT reports honoraria from AstraZeneca, Bayer, Amgen, Medtronic, Abbott Vascular, Biosensors, Alvimedica, Boehringer Ingelheim and Pfizer; research and educational grants from Medtronic, Biosensors, Biotronik, Philips, Amgen, AstraZeneca, Roche, Otsuka, Terumo and Abbott Vascular; and consulting fees from Elixir and CSL Behring. DPC reports consulting fees from the Asian Pacific Society of Cardiology (APSC); support for travel to meetings for the study or otherwise from APSC; grants/grants pending from Roche Diagnostics; and payment for development of educational presentations, including service on speakers’ bureaus from AstraZeneca. DB reports honoraria from AstraZeneca, Bristol-Myers Squibb and Pfizer. JA reports honoraria from AstraZeneca, Daiichi Sankyo, Bayer and Sanofi; and grants/grants pending from Daiichi Sankyo. GM reports research grants to the Institution or consulting/lecture fees from Abbott, Amgen, Actelion, American College of Cardiology Foundation, AstraZeneca, Axis-Santé, Bayer, Boston Scientific, Boehringer Ingelheim, Bristol-Myers Squibb, Beth Israel Deaconess Medical, Brigham Women’s Hospital, Idorsia, Elsevier, Fédération Française de Cardiologie, Frequence Medicale, ICAN, Lead-Up, Medtronic, Menarini, MSD, Pfizer, Quantum Genomics, Sanofi, SCOR Global Life, Servier and WebMD. DKQ reports honoraria from Bayer and Pfizer. HFT reports research grants or consulting/lecture fees from Abbott, Amgen, AstraZeneca, Bayer, Boston Scientific, Boehringer Ingelheim, Biosense Webster, Daiichi Sankyo, Pfizer, Sanofi and Servier. KAAF reports research grants from Bayer and AstraZeneca; and consulting/lecture fees from Bayer/Janssen, Sanofi/Regeneron and Verseon. SJA reports honoraria from Bayer. CKC reports speaker or advisory attracting travel expenses or honoraria from Amgen, AstraZeneca and Bayer. SL reports lecture honoraria from Bristol-Myers Squibb, Bayer and Boehringer-Ingelheim; proctorship fees from Abbott, Boston Scientific and Bioexcel; research funding from Abbot; and is an advisory board member for Abbott and Medtronic. HIY has been a speaker for Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Daiichi Sankyo, Lilly, Mitsubishi Tanabe, Novartis, MSD, Orient Europharma, Pfizer and Sanofi. All other authors have no conflicts of interest to declare. Acknowledgement: Medical writing support was provided by Ong Yen May and Ivan Olegario of MIMS Pte Ltd. Received: 24 November 2020 Accepted: 22 March 2021 Citation: European Cardiology Review 2021;16:e26. DOI: https://doi.org/10.15420/ecr.2020.45 Correspondence: Jack Wei Chieh Tan, National Heart Centre, 5 Hospital Dr, Singapore 169609. E: jack.tan.w.c@singhealth.com.sg Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly. © RADCLIFFE CARDIOLOGY 2021 Access at: www.ECRjournal.com

APSC Consensus Recommendations on High-risk Chronic Coronary Syndrome Figure 1: Study Selection

Recommendations Assessment, Development, and Evaluation system, as follows:

Articles identified by searching Medline and Cochrane library from 2010 to January 2020. Search terms: ‘chronic coronary syndrome’ OR ‘chronic stable angina’ AND ‘Asia’ (listed by MeSH headings) (n=244)

Studies after duplicates removed for screening (n=244)

83 Full-text review screened

161 Not relevant after screening

33 studies not relevant to statement development

1. High (authors have high confidence that the true effect is similar to the estimated effect). 2. Moderate (authors believe that the true effect is probably close to the estimated effect). 3. Low (true effect might be markedly different from the estimated effect). 4. Very low (true effect is probably markedly different from the estimated effect).2 The available evidence was then discussed during two consensus meetings. Recommendations were developed during the meetings, which were then put to an online vote. Each statement was voted on by each panel member using a three-point scale (agree, neutral or disagree). Consensus was reached when 80% of votes for a statement were agree or neutral. In the case of non-consensus, the statements were further discussed via email, then revised accordingly until the criteria for consensus was reached.

Chronic Coronary Syndrome Diagnosis and Management Goals

50 Papers used in statement development MeSH = medical subject headings.

How we consider the natural history of coronary artery disease (CAD) was recently revised and updated in the 2019 European Society of Cardiology (ESC) guidelines for the diagnosis and management of chronic coronary syndromes.1 Chronic, progressive accumulation of atherosclerotic coronary artery plaques continues to occur during the seemingly clinically silent and ‘stable’ phases of patients between the index cardiovascular event and recurrent ones. Rather than ‘stable CAD’, this is more accurately defined as chronic coronary syndrome (CCS). This new definition subdivides CAD into acute and chronic phases with the trajectory of disease determined by coronary burden and comorbidities. In the Asia-Pacific region, international guidelines cannot be routinely applied because of the unique characteristics of patients with CCS in this setting. These characteristics include differences in accesses and resources along with the low number of patients from the region in pivotal studies. Thus the Asian Pacific Society of Cardiology (APSC) developed consensus recommendations to provide guidance on the assessment and management of bleeding and ischaemic risks in Asian CCS patients. The selection of long-term antithrombotic treatment is also discussed.

Methods

The APSC assembled an expert consensus panel and convened two meetings (January 2020 and July 2020) to review the available evidence for antithrombotic management of CCS and discuss contemporary issues to provide guidance to clinicians in their local clinical context. The expert consensus panel comprised cardiologists, cardiac and vascular surgeons from Australia, Cambodia, Canada, France, Hong Kong, India, Indonesia, Japan, Korea, Malaysia, Singapore, Taiwan, Thailand, United Arab Emirates, UK and Vietnam. The experts were members of the APSC who were nominated by national societies and endorsed by the APSC consensus board. A comprehensive literature search was performed (Figure 1). Selected applicable articles were reviewed and appraised using the Grading of

Statement 1. Coronary angiography, cardiac CT or other imaging techniques may be used, where available, to confirm CCS diagnosis, estimate the extent of stress-induced ischaemia and evaluate burden of disease. Level of evidence: Low. Level of agreement: Agree 100%, neutral 0%, disagree 0%. In Asia Pacific, CCS is typically diagnosed based on the clinical evaluation of a patient with an accurate medical history and clinical testing. Where available and accessible, non-invasive coronary imaging may be used to detect and confirm a CCS diagnosis, allowing for the assessment of disease burden, visualisation of anatomical characteristics of disease, and determination of the individualised ischaemic risk to inform decision making.3 Patients who experience acute coronary syndrome (ACS) or who undergo percutaneous coronary intervention (PCI) transition to CCS management at the completion of their prescribed period of dual antiplatelet therapy (DAPT). Statement 2. Concomitant patient risk factors should be appropriately managed according to local healthcare standards. Level of evidence: Moderate. Level of agreement: Agree 100%, neutral 0%, disagree 0%. An important aspect of CCS management is to prevent thrombotic events. While antithrombotics include both antiplatelets and oral anticoagulants, antiplatelets, such as aspirin and P2Y12 inhibitors (clopidogrel, ticagrelor and prasugrel), are the most widely used for this purpose. Due to its lower cost and wide availability, aspirin was identified by the consensus panel as the antiplatelet of choice used for long-term antithrombotic management in the Asia-Pacific region. The main concern with the use of antithrombotics is bleeding. Registry data as well as meta-analyses show that, compared with their white counterparts, East Asian patients have lower thrombotic risk, but a higher risk of bleeding, especially for intracranial haemorrhage and gastrointestinal bleeding.4–7 Thus, although international and regional

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APSC Consensus Recommendations on High-risk Chronic Coronary Syndrome guidelines recommend antithrombotics for the secondary prevention of thrombotic events, bleeding concerns have led to consistent underuse of antithrombotics in Asia.8,9 The focus of this document is to provide guidance for clinicians regarding the antithrombotic management and selection of treatments for CCS patients. We recognise that antithrombotic therapy is only one component of a comprehensive approach to management of these patients, which should include lifestyle changes, such as optimal nutrition, exercise and smoking cessation, along with risk factor management including abnormal blood sugar levels, hypertension, dyslipidaemia and obesity.10

Mitigating Thrombotic Risk Following Percutaneous Coronary Intervention Statement 3. Imaging guidance, using intravascular ultrasound (IVUS) or optical coherence tomography (OCT), to optimise stent implantation is encouraged where available. Level of evidence: Low. Level of agreement: Agree 68.0%, neutral 32.0%, disagree 0%. Statement 4: Drug-eluting stents (DES) should be preferred for PCI procedures where available. Level of evidence: Moderate. Level of agreement: Agree 96.0%, neutral 4.0%, disagree 0%. Stent thrombosis is a major concern following PCI, with many patient and procedural factors contributing to the risk of stent thrombosis. While patient factors may be difficult to modify, specific procedural measures may be taken during PCI to mitigate thrombotic and/or bleeding risk and improve patient outcomes. The use of IVUS and OCT has been wellestablished for patient assessment prior to PCI, for lesion assessment, stent selection (diameter and length) and to optimise stent deployment.11 More recently, data have shown that the use of IVUS-guided stent implantation during PCI improves cardiovascular (CV) outcomes following the procedure, compared with angiography-guided stent implantation.11,12 In addition, the use of DES has also been associated with better outcomes and lower risk of stent thrombosis.13 Data from a nationwide study from Taiwan reported that patients receiving DES had better outcomes compared with those who had a bare metal stent implanted.14

Balancing Thrombotic and Bleeding Risk When Selecting Antithrombotic Therapy Statement 5. The bleeding and thrombotic risk of a patient should be assessed before determining which antithrombotic regimen to use. Level of evidence: Moderate. Level of agreement: Agree 100%, neutral 0%, disagree 0%. While minimising bleeding risk is important, so too is ensuring that antithrombotic treatment maximises therapeutic benefits of preventing thrombosis in CCS patients. In this consensus statement, we have developed two treatment algorithms, one for determining excessive bleeding risk and another for high thrombotic risk, to identify CCS patients who may require additional consideration when selecting an antithrombotic treatment strategy. Beyond improving the outcomes of CCS, personalising the intensity of antithrombotic treatment based on

balancing thrombotic and bleeding risks of patients has shown to improve health utility and reduce the cost of CV events.15 Statement 6. Sex alone should not be considered when assessing bleeding and thrombotic risk. Level of evidence: Very low. Level of agreement: Agree 100%, neutral 0%, disagree 0%. In the assessment of thrombotic and bleeding risk of a patient, female sex has been reported to confer both a higher thrombotic and bleeding risk, possibly due to the smaller body habitus of women.16–18 However, the association of thrombotic and bleeding risk with sex has not been confirmed definitively in Asian populations.18 The consensus panel felt that body habitus alone is insufficient to determine thrombotic and bleeding risk and recommended removing sex from consideration when assessing such risks.

Bleeding Risk Assessment Statement 7. The Age–Bleeding–Organ Dysfunction (‘ABO’) algorithm can be used as a binary approach to excessive bleeding risk. Level of evidence: Low. Agree 92.0%, neutral 8.0%, disagree 0%. Statement 8. Advanced age alone is insufficient to confer excessive bleeding risk in CCS patients in Asia Pacific. Level of evidence: Very low. Level of agreement: Agree 76.0%, neutral 24.0%, disagree 0%. Statement 9. Haemoglobin levels <9 g/dl (<5.6 mmol/l) should be used as an indication for anaemia in Asian patients when assessing bleeding risk. Level of evidence: Very low. Level of agreement: Agree 64%, neutral 36%, disagree 0%. Various bleeding risk scores have been proposed for use in the clinic, including the Academic Research Consortium for High Bleeding Risk (ARC-HBR) and the HAS-BLED scores.19,20 These scores have not been validated in Asian populations and are not widely used in clinics in Asia. The consensus panel proposed the use of the ‘ABO’ algorithm as a simple approach to identify patients with excessive bleeding risk, based on ‘Age’, ‘Bleeding’ and ‘Organ dysfunction’ factors (Figure 2). This algorithm employs a binary approach where the presence of any single factor indicates excessive bleeding risk in a patient.

Age

Age is a common risk factor featured across most bleeding risk scores.19,20 Increasing age has been strongly associated with an increase in bleeding risk. In a cohort study of 3,166 patients, the risk of non-major bleeding was unrelated to age.21 On the other hand, major bleeding increased with age ≥75 years in patients with a first transient ischaemic attack, ischaemic stroke or MI treated with antiplatelet drugs (HR 3.10; 95% CI [2.27–4.24]; p<0.0001), particularly for fatal bleeds, and was sustained during long-term follow-up.21 As a result, even with higher risk of death and CV events, the elderly were consistently under-treated with antithrombotics. Such elderly patients could potentially benefit from antithrombotic treatment but miss out on therapeutic benefits due to the fear of major bleeding events.22

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APSC Consensus Recommendations on High-risk Chronic Coronary Syndrome Figure 2: High Bleeding Risk ‘ABO’ Algorithm

mmol/l) were also highlighted by the consensus panel as key risk factors relevant in Asia for predicting bleeding.19,26,27 For anaemia, ethnic differences of mean haemoglobin levels have been reported, suggesting the need to reconsider ethnicity-specific cut-offs when identifying anaemia in Asia.28 With many on the consensus panel reporting the observation of lower mean haemoglobin levels in healthy patients in their clinics, a lower cut-off for haemoglobin levels to 9 g/dl was recommended as an indication of anaemia.

ASSESSMENT OF BLEEDING RISK FACTORS IN PATIENTS • Frail elderly >75 years* • Advanced age >85 years* • Life expectancy <1 year

A AGE

* Must be accompanied by an additional risk factor

BLEEDING

O ORGAN FAILURE

• Spontaneous intracranial haemorrhage • Recurrent gastrointestinal bleeding • Haemoglobin <9 g/dl

• Liver cirrhosis • End-stage renal failure, requiring dialysis • Bone marrow failure, e.g. severe thrombocytopaenia, platelet count < 50,000/μl • Stroke in the last 6 months

The presence of any single factor in a chronic coronary syndrome patient, except where indicated, would identify a patient as having excessive bleeding risk. Presence of multiple factors would indicate even higher risk of bleeding in the patient. *Must be accompanied by an additional risk factor.

Table 1: High Thrombotic Risk Cardiovascular Disease Algorithm Assessment of High-risk Chronic Coronary Syndrome C = CORONARY

V = VASCULAR

• Prior coronary event • High-risk coronary

• Established peripheral • Diabetes on treatment artery disease‡ • eGFR <60 mg/min/1.73 m2 • Cerebrovascular • Micro- and macro-

anatomy* • Documented multi-vessel coronary disease†

disease§

D = DISEASE

albuminuria

• Heart failure due to

coronary artery disease

The presence of any single factor listed would indicate high thrombotic risk in a chronic coronary syndrome patient. Presence of multiple factors would indicate even higher risk of thrombosis in the patient. *Left main PCI, bifurcation PCI, multivessel PCI, more than three stents. †Documented by CT cardiac angiography, severe ischaemia on functional stress test, prior PCI, CABG or bypass. ‡Claudication or prior peripheral intervention, carotid stenosis >50%, mesenteric artery disease, renal artery stenosis. §Ischaemic stroke or transient ischaemic attacks due to atherosclerosis. CABG = coronary artery bypass graft; eGFR = estimated glomerular filtration rate; PCI = percutaneous coronary intervention.

Advanced age is often compounded with other risk factors that similarly confer bleeding risk including prior stroke and gastrointestinal bleeding, hypertension, anaemia, renal insufficiency and presence of cerebrovascular disease.23 In addition, advanced age is associated with frailty, which is thought to be reflective of an individual’s biological age and deemed to be a more accurate predictor for the occurrence of bleeding events compared with chronological age.24 Coupling these with the ARC-HBR considering age as a minor criterion for bleeding risk, the consensus panel suggests that using an age cut-off of ≥75 years on its own would not be a strong enough indicator of excessive bleeding risk for CCS patients in the AsiaPacific region. 25 Rather, CCS patients aged ≥75 years should be identified to have excessive bleeding risk only when accompanied by frailty and another independent risk factor, and for those of advanced age >85 years to be identified as having excessive bleeding risk when accompanied by another independent risk factor. As frailty scores and scales are not commonly used and have not been validated in the Asia-Pacific regions, the determination for frailty should be based on clinical judgement.

Bleeding

Prior serious bleeding events such as intracranial haemorrhage, recurrent gastrointestinal bleeding or anaemia with haemoglobin <9 g/dl (<5.6

Organ Dysfunction

Beyond age and bleeding, organ dysfunction, including liver cirrhosis, end-stage renal failure and severe thrombocytopenia, and prior stroke in the last 6 months have also been implicated as major predictors of bleeding.19,27 With liver cirrhosis, most patients have coagulation abnormalities resulting in higher prothrombin time-derived international normalised ratios, which increases bleeding risk in these patients. Coagulation abnormalities as a result of reduced platelet counts from bone marrow dysfunction also increases bleeding risk. Severe thrombocytopenia as defined by platelet count <50,000/µL has been shown to increase bleeding risk (OR 3.1; 95% CI [2.0–4.8]).29 Chronic kidney disease (CKD) is also associated with increased risk of bleeding. Patients with moderate-to-severe CKD were found to have the highest bleeding risk at a 3.5-fold increase in bleeding risk compared with patients without CKD.30,31

Thrombotic Risk Assessment Statement 10. The Coronary–Vascular–Disease (‘CVD’) algorithm can be used to determine if a CCS patient has high thrombotic risk. Level of evidence: Low. Level of agreement: Agree 92.0%, neutral 8.0%, disagree 0%. Employing a similar binary approach to identify CCS patients at high risk of thrombosis, the ‘CVD’ algorithm (Table 1) was developed to summarise individual patient risk factors that would confer high thrombotic risk to provide guidance on identifying such patients for antithrombotic treatment (Table 1). The risk factors for thrombosis included in the ‘CVD’ algorithm have been classified by ‘Coronary’ factors, ‘Vascular’ factors and ‘Disease’ factors.

Coronary

The ‘coronary’ factors identified to confer high thrombotic risk CCS patients include prior coronary events, documented multi-vessel coronary disease and high-risk coronary anatomy. Prior coronary events, such as MI and/or revascularisation, have been found to increase risk of thrombotic events (HR 1.44; 95% CI [1.40–1.49]), as well as rates of ischaemic events from 4.7% in year 1 to 15.1% in year 4 post-event.32,33 Multi-vessel coronary disease, as documented by CT cardiac angiography, severe ischaemia on functional stress test, prior PCI or coronary artery bypass grafting, has also been shown to increase risk of CV events (HR 4.18; 95% CI [3.66–4.77]) and reduce overall survival by up to fourfold.34,35 Complex coronary anatomical features, such as left main coronary artery stenosis and multi-vessel disease, and procedural factors, such as bifurcation PCI, have been identified by the clinical SYNTAX score as contributors to thrombotic risk.36 These factors have been included in the proposed ‘CVD’ algorithm (Table 1), where presence of any one of these factors would indicate a patient for high thrombotic risk.

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APSC Consensus Recommendations on High-risk Chronic Coronary Syndrome Figure 3: Treatment Algorithm for Antithrombotic Treatment Transitioning from DAPT or considering long-term management for CCS

SAPT • Aspirin • Clopidogrel DAPT • Aspirin + clopidogrel • Aspirin + ticagrelor • Aspirin + prasugrel*

Assess ‘CVD’ risk factors

DPI • Aspirin + rivaroxaban

‘CVD’ risk factors

No ‘CVD’ risk factors

High risk (with ‘ABO’ risk factor)

No excessive bleeding risk

DAPT Complex PCI

Low risk (with ‘ABO’ risk factor)

Excessive bleeding risk

SAPT

DPI

SAPT

Residual multi-vessel coronary disease, poly-vascular bed disease, prior stroke or prior MI

The proposed algorithm takes the thrombotic and bleeding profiles of a chronic coronary syndrome patient into consideration and provides guidance on the selection of the long-term antithrombotic strategy for that patient. ‘ABO’ = Age–Bleeding–Organ Failure algorithm; CCS = chronic coronary syndrome; ‘CVD’ = Coronary–Vascular–Disease algorithm; DAPT = dual antiplatelet therapy; DPI = dual pathway inhibition; SAPT = single antiplatelet therapy. *Only considered following complex percutaneous coronary intervention.

Vascular

Patients with established peripheral artery disease (PAD), as defined by claudication, prior peripheral intervention, carotid stenosis >50%, mesenteric artery disease or renal artery stenosis, had higher rates of adverse CV events compared with patients without disease (5.35% versus 2.15%).5 In patients with CCS, concomitant disease in the vasculature, which includes both PAD and cerebrovascular disease, further increased the risk of thrombosis (HR 1.99; 95% CI [1.78–2.24]).37

Disease

Comorbid conditions included in the ‘CVD’ algorithm that indicate high thrombotic risk in CCS patients include type 2 diabetes with treatment, impaired renal function (estimated glomerular filtration rate [eGFR] <60 ml/min/1.73m2), any degree of micro- and macro-albuminuria and heart failure as a result of CCS. Patients with CCS and type 2 diabetes have a two- to fourfold increase in mortality risk, with CAD being the main cause of death in these patients.38 Renal dysfunction has also been implicated as a risk factor indicating high thrombotic risk. As eGFR decreases below 60 ml/min/1.73m2, mortality risk increases –compared with an eGFR of 95 ml/min/1.73m2, patients with eGFR of 60 ml/min/1.73m2 have an HR of 1.03 while those with an eGFR level of 15 ml/min/1.73m2 have an HR of 3.11.39 In addition, micro- and macro-albuminuria at any level has been reported as an independent predictor of all-cause mortality in CCS patients,39 with HR 2.08 (95% CI [1.30–3.32]) for low-to-medium microalbuminuria and HR 1.99 (95% CI [1.08–3.70]) from high microalbuminuria to macroalbuminuria.40 Finally, patients with heart failure due to CCS have been documented to have poorer prognoses.41 The SOLVD study reported a fourfold increase in mortality risk in patients with CCS and heart failure.42

Selection of Antithrombotic Therapy for Asian Chronic Coronary Syndrome Patients Statement 11. Single antiplatelet therapy (SAPT; aspirin or clopidogrel), rather than DAPT, is recommended for Asian CCS patients with low ischaemic risk or excessive bleeding risk. Level of evidence: High. Level of agreement: Agree 96.0%, neutral 4.0%, disagree 0%. Statement 12. Extended DAPT is recommended for Asian CCS patients without high bleeding risk features, and who have also undergone PCI with complex stent features. Level of evidence: High. Level of agreement: Agree 92.0%, neutral 8.0%, disagree 0%. Statement 13. Dual pathway inhibition therapy (aspirin + rivaroxaban) is recommended for Asian CCS patients with high thrombotic risk and without high bleeding risk, and who also have residual multi-vessel coronary disease, poly-vascular bed disease, prior stroke or prior MI. Level of evidence: Moderate. Level of agreement: Agree 92.0%, neutral 8.0%, disagree 0%. Following assessment of thrombotic and bleeding risk of CCS patients, clinicians are faced with the task of selecting the optimal antithrombotic therapy for their patients. The consensus panel developed a practical algorithm to guide antithrombotic selection for long-term management of CCS patients (Figure 3). This algorithm considers different thrombotic and bleeding risk profiles of CCS patients, as assessed using the ‘ABO’

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APSC Consensus Recommendations on High-risk Chronic Coronary Syndrome Table 2: Summary of Consensus Statements and Related References Statement

Level of Evidence and Agreement

References

Statement 1. Coronary angiography, cardiac CT or other Level of evidence: Low. imaging techniques may be used, where available, to Level of agreement: Agree 100%, neutral 0%, confirm CCS diagnosis, estimate the extent of stress-induced disagree 0%. ischaemia and evaluate burden of disease.

Arasaratnam et al. 20153

Statement 2. Concomitant patient risk factors should be appropriately managed according to local healthcare standards.

Level of evidence: Moderate. Level of agreement: Agree 100%, neutral 0%, disagree 0%.

Levine et al. 2014,4 Steg et al. 2007,5 Bhatt et al. 2006,6 Kang et al. 2018,7 Gao et al. 2010,8 Dalal et al. 20159 and Yang et al. 201210

Statement 3. Imaging guidance, using IVUS or OCT, to optimise stent implantation is encouraged where available.

Level of evidence: Low. Kaul et al. 201811 and Raber et al. 201812 Level of agreement: Agree 68.0%, neutral 32.0%, disagree 0%.

Statement 4. DES should be preferred for PCI procedures where available.

Level of evidence: Moderate. Level of agreement: Agree 96.0%, neutral 4.0%, disagree 0%.

Kereiakes et al. 201513 and Sung et al. 201714

Statement 5. The bleeding and thrombotic risk of a patient Level of evidence: Moderate. should be assessed before determining which antithrombotic Level of agreement: Agree 100%, neutral 0%, regimen to use. disagree 0%.

Baber et al. 201915

Statement 6. Sex alone should not be considered when assessing bleeding and thrombotic risk.

Level of evidence: Very low. Level of agreement: Agree 100%, neutral 0%, disagree 0%.

Singer et al. 2013,16 Lip et al. 201017 and Fukaya et al. 201818

Statement 7. The Age–Bleeding–Organ Dysfunction (‘ABO’) algorithm can be used as a binary approach to excessive bleeding risk.

Level of evidence: Low. Agree 92.0%, neutral 8.0%, disagree 0%.

Urban et al. 2019,19 Pisters et al. 2010,20 Li et al. 2017,21 Xia et al. 2018,22 Marinigh et al. 2010,23 Zathar et al. 2019,24 Urban et al. 2019,25 vam Asch et al. 2010,26 Guo et al. 2016,27 Varghese et al. 2019,28 Uhl et al. 2017,29 Ocak et al. 201830 and Palmer et al. 201331

Statement 8. Advanced age alone is insufficient to confer excessive bleeding risk in CCS patients in Asia Pacific.

Level of evidence: Very low. Urban et al. 2019,19 Pisters et al. 2010,20 Li et al. 2017,21 Xia et Level of agreement: Agree 76.0%, neutral 24.0%, al. 2018,22 Marinigh et al. 2010,23 Zathar et al. 201924 and Urban disagree 0%. et al. 201925

Statement 9. Haemoglobin levels <9 g/dl (<5.6 mmol/l) should be used as an indication for anaemia in Asian patients when assessing bleeding risk.

Level of evidence: Very low. Level of agreement: Agree 64%, neutral 36%, disagree 0%.

Urban et al. 2019,19 vam Asch et al. 2010,26 Guo et al. 201627 and Varghese et al. 201928

Statement 10. The Coronary–Vascular–Disease (‘CVD’) algorithm can be used to determine if a CCS patient has high thrombotic risk.

Level of evidence: Low. Level of agreement: Agree 92.0%, neutral 8.0%, disagree 0%.

Abtan et al. 2016,32 Jernberg et al. 2015,33 Ozcan et al. 2018,34 Emond et al. 1994,35 Garg et al. 2010,36 Bhatt et al. 2010,37 Aronson et al. 2014,38 van der Velde M et al. 2011,39 Solomon et al. 2007,40 Elgendy et al. 201941 and Yusuf et al. 199142

Statement 11. Single antiplatelet therapy (aspirin or clopidogrel), rather than dual antiplatelet therapy, is recommended for Asian CCS patients with low ischaemic risk or excessive bleeding risk.

Level of evidence: High. Level of agreement: Agree 96.0%, neutral 4.0%, disagree 0%.

Baigent et al. 2009,43 CAPRIE Steering Committee et al. 1996,44 Watanabe et al. 201945 and Hahn et al. 201946

Statement 12. Extended DAPT is recommended for Asian CCS patients without high bleeding risk features, and who have also undergone PCI with complex stent features.

Level of evidence: High. Level of agreement: Agree 92.0%, neutral 8.0%, disagree 0%.

Lee et al. 2014,47 Helft et al. 2016,48 Mauri et al. 201449 and Bonaca et al. 201550

Statement 13. Dual pathway inhibition therapy (aspirin + rivaroxaban) is recommended for Asian CCS patients with high thrombotic risk and without high bleeding risk, and who also have residual multi-vessel coronary disease, poly-vascular bed disease, prior stroke or prior MI.

Level of evidence: Moderate. Level of agreement: Agree 92.0%, neutral 8.0%, disagree 0%.

Eikelboom et al. 2018,51 Connolly et al. 201852 and Bonaca et al. 2020.53

CCS = chronic coronary syndrome; DAPT = dual antiplatelet therapy; DES = drug-eluting stent; IVUS = intravascular ultrasound; OCT = optical coherence tomography; PCI = percutaneous coronary intervention.

and ‘CVD’ algorithms, to determine the optimal antithrombotic strategy for each patient profile type.

have a slight benefit over aspirin in reducing thrombotic risk, with similar bleeding rates to that of aspirin.44

Low Thrombotic Risk or Excessive Bleeding Risk

The STOPDAPT-2 and SMART-CHOICE randomised clinical trials investigated the shortening of the DAPT duration from 12 months to 1 or 3 months, respectively, following PCI with the use of clopidogrel monotherapy thereafter. These trials reported potential benefits of switching to SAPT sooner following PCI, with lower or similar rates of CV events (HR 0.64; 95% CI [0.42–0.98]; p=0.04 for superiority in STOPDAPT-2 and 2.9% [SAPT] versus 2.5% [DAPT]; 1-sided 95% CI, [−∞, 1.3%]; p=0.007

The ESC guidelines for CCS recommend for SAPT to be considered in patients without a history of MI or revascularisation, but with evidence of CCS.1 Aspirin may be used for the long-term antithrombotic management of CCS patients with low thrombotic risk or excessive bleeding risk to reduce the risk of future CV events.43 When aspirin is unsuitable, longterm administration of clopidogrel to CCS patients has been shown to

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APSC Consensus Recommendations on High-risk Chronic Coronary Syndrome for noninferiority in SMART-CHOICE) compared with 12-month DAPT duration. Significantly lower rates of bleeding events (HR 0.26; 95% CI [0.11–0.64]; p=0.004 for superiority in STOPDAPT-2 and HR 0.58; 95% CI [0.36–0.92]; p=0.02 in SMART-CHOICE) compared with 12-month DAPT duration were also reported.45,46 This suggests the potential utility of clopidogrel monotherapy for use in Asian CCS patients with excessive bleeding risk. For CCS patients with low thrombotic risk or excessive bleeding risk, who also have a separate indication for oral anticoagulation such as AF, nonvitamin K oral anticoagulants may be considered in place of SAPT.

High Thrombotic Risk and Without Excess Bleeding Risk

Multiple randomised controlled trials have compared the efficacy and safety of extended DAPT duration of >24 months with standard DAPT duration of 12 months. The DES LATE and OPTIDUAL trials investigated the use of aspirin with clopidogrel with an extended DAPT regimen following PCI and reported no differences in both CV outcomes and bleeding events between extended versus standard DAPT duration.47,48 Beyond one year post-PCI, the DAPT trial reported significantly reduced rates of major adverse cardiovascular and cerebrovascular events with aspirin and clopidogrel/prasugrel compared with aspirin alone (4.3% versus 5.9%; HR 0.71; 95% CI [0.59–0.85]; p<0.001) although this was associated with increased moderate or severe bleeding (2.5% versus 1.6%, p=0.001).49 Similarly, the PEGASUS-TIMI 54 trial reported significantly reduced risk of CV mortality, MI or stroke by up to 15% with extended DAPT duration compared with a 12-month DAPT duration, with increased risk of major 1. Knuuti J, Wijns W, Saraste A, et al. 2019 ESC guidelines for the diagnosis and management of chronic coronary syndromes. Eur Heart J 2019;41:407–77. https://doi. org/10.1093/eurheartj/ehz425; PMID: 31504439. 2. Balshem H, Helfand M, Schünemann HJ, et al. GRADE guidelines: 3. Rating the quality of evidence. J Clin Epidemiol 2011;64:401–6. https://doi.org/10.1016/j.jclinepi.2010.07.015; PMID: 21208779. 3. Arasaratnam P, Ruddy TD. Noninvasive imaging for the assessment of coronary artery disease. In: Kirali K, ed. Coronary Artery Disease: Assessment, Surgery, Prevention. London, UK: IntechOpen; 2015. https://doi. org/10.5772/61502. 4. Levine GN, Jeong YH, Goto S, et al. Expert consensus document: World Heart Federation expert consensus statement on antiplatelet therapy in East Asian patients with ACS or undergoing PCI. Nat Rev Cardiol 2014;11:597–606. https://doi.org/10.1038/nrcardio.2014.104; PMID: 25154978. 5. Steg PG, Bhatt DL, Wilson PW, et al. One-year cardiovascular event rates in outpatients with atherothrombosis. JAMA 2007;297:1197–206. https://doi.org/10.1001/jama.297.11.1197; PMID: 17374814. 6. Bhatt DL. International prevalence, recognition, and treatment of cardiovascular risk factors in outpatients with atherothrombosis. JAMA 2006;295:180–9. https://doi. org/10.1001/jama.295.2.180; PMID: 16403930. 7. Kang J, Park K, Palmerini T, et al. Racial differences in ischaemia/bleeding risk trade-off during anti-platelet therapy: individual patient level landmark meta-analysis from seven RCTs. Thromb Haemost 2018;119:149–62. https:// doi.org/10.1055/s-0038-1676545; PMID: 30597509. 8. Gao R, Li X. Risk assessment and aspirin use in Asian and Western populations. Vasc Health Risk Manag 2010;6:943–56. https://doi.org/10.2147/VHRM.S9400; PMID: 21057579. 9. Dalal J, Low LP, Van Phuoc D, et al. The use of medications in the secondary prevention of coronary artery disease in the Asian region. Curr Med Res Opin 2015;31:423–33. https:// doi.org/10.1185/03007995.2015.1010035; PMID: 25629795. 10. Yang Q, Cogswell ME, Flanders WD, et al. Trends in cardiovascular health metrics and associations with allcause and CVD mortality among US adults. JAMA 2012;307:1273–83. https://doi.org/10.1001/jama.2012.339; PMID: 22427615. 11. Kaul P, Kandzari DE. intracoronary imaging and stent implantation technique. Circ Cardiovasc Interv

bleeding (2.60% versus 1.06%; p<0.001).50 Although these trials have indicated mixed results, the use of an extended DAPT regimen as a longterm antithrombotic strategy for CCS patients may provide significant benefit that outweighs the risk of bleeding, especially for patients with high thrombotic risk and without excess bleeding risk. In the COMPASS trial, use of rivaroxaban with or without aspirin was evaluated for use in high-risk CCS patients, including those with PAD, diabetes, heart failure, prior stroke/MI and impaired renal function.51 The COMPASS trial reported that CCS patients with high thrombotic risk and without excess bleeding risk, who received low-dose rivaroxaban plus aspirin had significantly better CV outcomes with 23% relative risk reduction of mortality; although major bleeding events increased.51,52 For patients with polyvascular territory disease (i.e. CCS and PAD), the use of rivaroxaban with aspirin may provide additional benefits of improved peripheral limb outcomes as observed in the VOYAGER PAD randomised clinical trial.53

Conclusions

The consensus statements presented here, summarised in Table 2, aim to serve as a practical guide for clinical practice in the Asia-Pacific region to navigate the complex CCS landscape for antithrombotic management and improve CCS patient outcomes. The topics covered by the statements reflect the issues relevant to contemporary clinical practice in the AsiaPacific region. The algorithms proposed aim to simplify and expedite the identification of CCS patients with excessive bleeding risk and/or high thrombotic risk in the clinic, as well as to guide selection of the optimal antithrombotic strategy and improve patient outcomes.

2018;11:e007453. https://doi.org/10.1161/ CIRCINTERVENTIONS.118.007453; PMID: 30562080. 12. Raber L, Mintz GS, Koskinas KC, et al. Clinical use of intracoronary imaging. Part 1: guidance and optimization of coronary interventions. An expert consensus document of the European Association of Percutaneous Cardiovascular Interventions. Eur Heart J 2018;39:3281–300. https://doi. org/10.1093/eurheartj/ehy285; PMID: 29790954. 13. Kereiakes DJ, Yeh RW, Massaro JM, et al. Stent thrombosis in drug-eluting or bare-metal stents in patients receiving dual antiplatelet therapy. JACC Cardiovasc Interv 2015;8:1552–62. https://doi.org/10.1016/j.jcin.2015.05.026; PMID: 26493248. 14. Sung SH, Chen TC, Cheng HM, et al. Comparison of clinical outcomes in patients undergoing coronary intervention with drug-eluting stents or bare-metal stents: A nationwide population study. Acta Cardiol Sin 2017;33:10–9. https://doi. org/10.6515/acs20160608a; PMID: 28115802. 15. Baber U, Leisman DE, Cohen DJ, et al. Tailoring antiplatelet therapy intensity to ischemic and bleeding risk. Circ Cardiovasc Qual Outcomes 2019;12:e004945. https://doi. org/10.1161/CIRCOUTCOMES.118.004945; PMID: 30606052. 16. Singer DE, Chang Y, Borowsky LH, et al. A new risk scheme to predict ischemic stroke and other thromboembolism in atrial fibrillation: the ATRIA study stroke risk score. J Am Heart Assoc 2013;2:e000250. https://doi.org/10.1161/ JAHA.113.000250; PMID: 23782923. 17. Lip GY, Nieuwlaat R, Pisters R, et al. Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: the euro heart survey on atrial fibrillation. Chest 2010;137:263–72. https://doi.org/10.1378/chest.09-1584; PMID: 19762550. 18. Fukaya H, Ako J. Is female sex always a risk for bleeding? Circ J 2018;82:1743–5. https://doi.org/10.1253/circj.CJ-180402; PMID: 29709995. 19. Urban P, Mehran R, Colleran R, et al. Defining high bleeding risk in patients undergoing percutaneous coronary intervention: a consensus document from the Academic Research Consortium for High Bleeding Risk. Eur Heart J 2019;40:2632–53. https://doi.org/10.1093/eurheartj/ehz372; PMID: 31116395. 20. Pisters R, Lane DA, Nieuwlaat R, et al. A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey. Chest

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2010;138:1093–100. https://doi.org/10.1378/chest.10-0134; PMID: 20299623. 21. Li L, Geraghty OC, Mehta Z, Rothwell PM. Age-specific risks, severity, time course, and outcome of bleeding on longterm antiplatelet treatment after vascular events: a population-based cohort study. Lancet 2017;390:490–9. https://doi.org/10.1016/S0140-6736(17)30770-5; PMID: 28622955. 22. Xia TL, Huang FY, Li YM, et al. The impact of age on the implementation of evidence-based medications in patients with coronary artery disease and its prognostic significance: a retrospective cohort study. BMC Public Health 2018;18:150. https://doi.org/10.1186/s12889-018-5049-x; PMID: 29343223. 23. Marinigh R, Lip GY, Fiotti N, et al. Age as a risk factor for stroke in atrial fibrillation patients: implications for thromboprophylaxis. J Am Coll Cardiol 2010;56:827–37. https://doi.org/10.1016/j.jacc.2010.05.028; PMID: 20813280. 24. Zathar Z, Karunatilleke A, Fawzy AM, et al. Atrial fibrillation in older people: Concepts and controversies. Front Med (Lausanne) 2019;6:175. https://doi.org/10.3389/ fmed.2019.00175; PMID: 31440508. 25. Urban P, Mehran R, Colleran R, et al. Defining high bleeding risk in patients undergoing percutaneous coronary intervention. Circulation 2019;140:240–61. https://doi. org/10.1161/CIRCULATIONAHA.119.040167; PMID: 31116032. 26. van Asch CJ, Luitse MJ, Rinkel GJ, et al. Incidence, case fatality, and functional outcome of intracerebral haemorrhage over time, according to age, sex, and ethnic origin: a systematic review and meta-analysis. Lancet Neurol 2010;9:167–76. https://doi.org/10.1016/S1474-4422(09)703400; PMID: 20056489. 27. Guo YT, Zhang Y, Shi XM, et al. Assessing bleeding risk in 4824 Asian patients with atrial fibrillation: the Beijing PLA Hospital Atrial Fibrillation Project. Sci Rep 2016;6:31755. https://doi.org/10.1038/srep31755; PMID: 27557876. 28. Varghese JS, Thomas T, Kurpad AV. Evaluation of haemoglobin cut-off for mild anaemia in Asians – analysis of multiple rounds of two national nutrition surveys. Indian J Med Res 2019;150:385–9. https://doi.org/10.4103/ijmr. IJMR_334_18; PMID: 31823920. 29. Uhl L, Assmann SF, Hamza TH, et al. Laboratory predictors of bleeding and the effect of platelet and RBC transfusions on bleeding outcomes in the PLADO trial. Blood 2017;130:1247–58. https://doi.org/10.1182/blood-2017-01757930; PMID: 28679741.

APSC Consensus Recommendations on High-risk Chronic Coronary Syndrome 30. Ocak G, Rookmaaker MB, Algra A, et al. Chronic kidney disease and bleeding risk in patients at high cardiovascular risk: a cohort study. J Thromb Haemost 2018;16:65–73. https://doi.org/10.1111/jth.13904; PMID: 29125709. 31. Palmer SC, Di Micco L, Razavian M, et al. Antiplatelet agents for chronic kidney disease. Cochrane Database Syst Rev 2013;(2):CD008834. https://doi.org/10.1002/14651858. CD008834.pub2; PMID: 23450589. 32. Abtan J, Bhatt DL, Elbez Y, et al. Residual ischemic risk and its determinants in patients with previous myocardial infarction and without prior stroke or TIA: insights from the REACH Registry. Clin Cardiol 2016;39:670–7. https://doi. org/10.1002/clc.22583; PMID: 27588731. 33. Jernberg T, Hasvold P, Henriksson M, et al. Cardiovascular risk in post-myocardial infarction patients: nationwide real world data demonstrate the importance of a long-term perspective. Eur Heart J 2015;36:1163–70. https://doi. org/10.1093/eurheartj/ehu505; PMID: 25586123. 34. Ozcan C, Deleskog A, Schjerning Olsen AM, et al. Coronary artery disease severity and long-term cardiovascular risk in patients with myocardial infarction: a Danish nationwide register-based cohort study. Eur Heart J Cardiovasc Pharmacother 2018;4:25–35. https://doi.org/10.1093/ehjcvp/ pvx009; PMID: 28444162. 35. Emond M, Mock MB, Davis KB, et al. Long-term survival of medically treated patients in the Coronary Artery Surgery Study (CASS) registry. Circulation 1994;90:2645–57. https:// doi.org/10.1161/01.cir.90.6.2645; PMID: 7994804. 36. Garg S, Sarno G, Garcia-Garcia HM, et al. A new tool for the risk stratification of patients with complex coronary artery disease: the Clinical SYNTAX Score. Circ Cardiovasc Interv 2010;3:317–26. https://doi.org/10.1161/ CIRCINTERVENTIONS.109.914051; PMID: 20647561. 37. Bhatt DL, Eagle KA, Ohman EM, et al. Comparative determinants of 4-year cardiovascular event rates in stable outpatients at risk of or with atherothrombosis. JAMA 2010;304:1350–7. https://doi.org/10.1001/jama.2010.1322;

PMID: 20805624. 38. Aronson D, Edelman ER. Coronary artery disease and diabetes mellitus. Cardiol Clin 2014;32:439–55. https://doi. org/10.1016/j.ccl.2014.04.001; PMID: 25091969. 39. van der Velde M, Matsushita K, Coresh J, et al. Lower estimated glomerular filtration rate and higher albuminuria are associated with all-cause and cardiovascular mortality. A collaborative meta-analysis of high-risk population cohorts. Kidney Int 2011;79:1341–52. https://doi.org/10.1038/ ki.2010.536; PMID: 21307840. 40. Solomon SD, Lin J, Solomon CG, et al. Influence of albuminuria on cardiovascular risk in patients with stable coronary artery disease. Circulation 2007;116:2687–93. https://doi.org/10.1161/CIRCULATIONAHA.107.723270; PMID: 18025537. 41. Elgendy IY, Mahtta D, Pepine CJ. Medical therapy for heart failure caused by ischemic heart disease. Circ Res 2019;124:1520–35. https://doi.org/10.1161/ CIRCRESAHA.118.313568; PMID: 31120824. 42. Yusuf S, Pitt B, Davis CE, et al. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med 1991;325:293– 302. https://doi.org/10.1056/NEJM199108013250501; PMID: 2057034. 43. Baigent C, Blackwell L, Collins R, et al. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials. Lancet 2009;373:1849–60. https://doi.org/10.1016/ S0140-6736(09)60503-1; PMID: 19482214. 44. CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 1996;348:1329–39. https://doi. org/10.1016/s0140-6736(96)09457-3; PMID: 8918275. 45. Watanabe H, Domei T, Morimoto T, et al. Effect of 1-month dual antiplatelet therapy followed by clopidogrel vs 12-month dual antiplatelet therapy on cardiovascular and bleeding events in patients receiving PCI: the STOPDAPT-2

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randomized clinical trial. JAMA 2019;321:2414–27. https://doi. org/10.1001/jama.2019.8145; PMID: 31237644. 46. Hahn JY, Song YB, Oh JH, et al. Effect of P2Y12 inhibitor monotherapy vs dual antiplatelet therapy on cardiovascular events in patients undergoing percutaneous coronary intervention: the SMART-CHOICE randomized clinical trial. JAMA 2019;321:2428–37. https://doi.org/10.1001/ jama.2019.8146; PMID: 31237645. 47. Lee CW, Ahn JM, Park DW, et al. Optimal duration of dual antiplatelet therapy after drug-eluting stent implantation: a randomized, controlled trial. Circulation 2014;129:304–12. https://doi.org/10.1161/CIRCULATIONAHA.113.003303; PMID: 24097439. 48. Helft G, Steg PG, Le Feuvre C, et al. Stopping or continuing clopidogrel 12 months after drug-eluting stent placement: the OPTIDUAL randomized trial. Eur Heart J 2016;37:365–74. https://doi.org/10.1093/eurheartj/ehv481; PMID: 26364288. 49. Mauri L, Kereiakes DJ, Yeh RW, et al. Twelve or 30 months of dual antiplatelet therapy after drug-eluting stents. N Engl J Med 2014;371:2155–66. https://doi.org/10.1056/ NEJMoa1409312; PMID: 25399658. 50. Bonaca MP, Bhatt DL, Cohen M, et al. Long-term use of ticagrelor in patients with prior myocardial infarction. N Engl J Med 2015;372:1791–800. https://doi.org/10.1056/ NEJMoa1500857; PMID: 25773268. 51. Eikelboom JW, Connolly SJ, Yusuf S. Rivaroxaban in stable cardiovascular disease. N Engl J Med 2018;378:397–8. https://doi.org/10.1056/NEJMc1714934; PMID: 29365302. 52. Connolly SJ, Eikelboom JW, Bosch J, et al. Rivaroxaban with or without aspirin in patients with stable coronary artery disease: an international, randomised, double-blind, placebo-controlled trial. Lancet 2018;391:205–18. https://doi. org/10.1016/S0140-6736(17)32458-3; PMID: 29132879. 53. Bonaca MP, Bauersachs RM, Anand SS, et al. Rivaroxaban in peripheral artery disease after revascularization. N Engl J Med 2020;382:1994–2004. https://doi.org/10.1056/ NEJMoa2000052; PMID: 32222135.

Microvascular Angina

Invasive Diagnosis of Coronary Functional Disorders Causing Angina Pectoris Sascha Beck, Valeria Martínez Pereyra, Andreas Seitz, Johanna McChord, Astrid Hubert, Raffi Bekeredjian, Udo Sechtem and Peter Ong Department of Cardiology and Angiology, Robert-Bosch-Krankenhaus, Stuttgart, Germany

Abstract

Coronary vasomotion disorders represent a frequent cause of angina and/or dyspnoea in patients with non-obstructed coronary arteries. The highly sophisticated interplay of vasodilatation and vasoconstriction can be assessed in an interventional diagnostic procedure. Established parameters characterising adequate vasodilatation are coronary blood flow at rest, and, after drug-induced vasodilation, coronary flow reserve, and microvascular resistance (hyperaemic microvascular resistance, index of microcirculatory resistance). An increased vasoconstrictive potential is diagnosed by provocation testing with acetylcholine or ergonovine. This enables a diagnosis of coronary epicardial and/or microvascular spasm. Ischaemia associated with microvascular spasm can be confirmed by ischaemic ECG changes and the measurement of lactate concentrations in the coronary sinus. Although interventional diagnostic procedures are helpful for determining the mechanism of the angina, which may be the key to successful medical treatment, they are still neither widely accepted nor applied in many medical centres. This article summarises currently well-established invasive methods for the diagnosis of coronary functional disorders causing angina pectoris.

Keywords

Coronary artery spasm, microvascular dysfunction, endothelial dysfunction, ANOCA, interventional diagnostic procedure, coronary blood flow Disclosure: PO is a regional editor on the European Cardiology Review editorial board, which did not affect the peer-review process. All other authors have no conflicts of interest to declare. Received: 15 February 2021 Accepted: 26 April 2021 Citation: European Cardiology Review 2021;16:e27. DOI: https://doi.org/10.15420/ecr.2021.06 Correspondence: Peter Ong, Department of Cardiology and Angiology, Robert-Bosch-Krankenhaus, Auerbachstrasse 110, 70376 Stuttgart, Germany. E: peter.ong@rbk.de Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

The supply of oxygen is an essential requirement for adequate myocardial metabolism, and it is regulated by a continuous adjustment of coronary blood flow according to the actual demand. The processes involved in coronary vasomotion are complex and encompass vasodilative and vasoconstrictive properties. Functional impairments of these mechanisms are possible causes of angina with non-obstructed coronary arteries (ANOCA).1,2 In order to assess coronary vasomotion, non-invasive and invasive techniques have been developed during the last decades. Noninvasive techniques have recently been reviewed.3 They have the advantage of avoiding the small, yet definite, risk associated with an invasive procedure. Non-invasive techniques for testing abnormalities of coronary constriction (spasm testing), however, have several important limitations:

Given that invasive tests can be easily applied to patients undergoing diagnostic coronary angiography, this review shall summarise currently well-established invasive methods for the diagnosis of coronary functional disorders.

• To assess coronary spasm, only ergonovine (ER) can be given IV as a

Assessment of Coronary Vasodilatation

provocation substance due to the short half-life of acetylcholine (ACh). • Given that the vasomotion of a single coronary vessel cannot be tested, IV ER may lead to multivessel spasm. In this case counteracting medications can be given only sublingually or by IV injection, which may be insufficient to resolve prolonged spasm.4 • They do not allow discrimination between focal and diffuse epicardial spasm or between microvascular and epicardial spasm. • Detection of spasm depends on the recognition of regional perfusion defects or wall motion abnormalities by (contrast) echocardiography, which may be difficult in case of suboptimal acoustic windows.5,6

Methods for the Assessment of Coronary Functional Disorders

Coronary vasomotion is the summed effect of a highly sophisticated interplay between vasoconstrictive and vasodilative actions. Several tests addressing different mechanisms of coronary vasomotion need to be applied for a comprehensive assessment. The type and sequence of tests currently differs from centre to centre depending on the equipment and expertise available in the respective medical centre. The main mechanism of increasing coronary blood flow is the dilatation of microvascular resistance vessels, which can be stimulated by an increase in the metabolic activity of the heart. Hence, in the healthy heart, myocardial metabolism (demand) and coronary blood flow (supply) are always matched.7 This vasodilative process (also called coronary autoregulation), however, has been shown to be impaired in various forms of heart disease. Reduced vasodilatation may lead to angina when oxygen demand is increased, for instance during exercise. The effect is very similar to the situation in which an adequate increase in coronary blood flow is restricted by obstructive lesions in epicardial coronary arteries.8 In order to prove that inadequate vasodilatation produces

Invasive Diagnosis of Coronary Functional Disorders Causing Angina Pectoris angina in patients without epicardial obstructive disease, coronary blood flow velocity is measured both at rest and during maximal vasodilatation (hyperaemia). For the latter, IV or intracoronary injections of adenosine are usually used due to its favourable short half-life compared with alternative drugs such as dipyridamole or papaverine.9 Coronary blood flow velocity can be determined by two different techniques.

Direct Measurement of Flow Velocity using the Doppler Shift

The Doppler shift has been used since the 1970s to determine coronary blood flow velocity as the basis for further calculations of coronary flow reserve (CFR) and coronary resistance.10 A Doppler wire is inserted into the coronary artery to be measured. A sonic wave of a defined transmitting frequency is sent from the tip of the Doppler wire, which is then reflected by the erythrocytes, which alter the wave’s frequency depending on the flow velocity of the erythrocytes.11 The main limitation of the technique is that it may be difficult to obtain an optimal Doppler signal.12,13 However, with careful repositioning it is possible to finally receive useful Doppler signals in most patients.14 Sometimes it may be necessary to stabilise the position of the Doppler wire using an intracoronary microcatheter. Despite these challenges and alternative techniques available, intracoronary Doppler measurements are still successfully used in daily clinical practice.3,15

Indirect Measurement of Flow Velocity using the Thermodilution Technique

The principle of the thermodilution technique for the calculation of coronary blood flow velocity was developed by de Bruyne and Pijls in 2001.16,17 A bolus of room-temperature saline is injected into the coronary artery. The distal microsensor can be used to measure both pressure and temperature. The proximal temperature is monitored using the shaft of the wire, which changes its electrical resistance depending on the surrounding temperature.16 Proximal and distal temperature data are used by dedicated software to determine the so-called transit time of the saline moving with the bloodstream. The measurement of three injections at room temperature are averaged to define the mean transit time (Tmn). This parameter has been shown to correlate inversely with the volumetric coronary flow measured in vitro (r=−0.75; p<0.001) and in vivo (R2=0.72).16,18 Intracoronary thermodilution is the most widely used technique to assess coronary flow today.19,20 However, thermodilution-based measurements are usually performed during an extended state of hyperaemia (>30 seconds).17 This steady-state hyperaemia is usually induced by IV adenosine, which is associated with more side-effects and patient discomfort than intracoronary injections.21 However, the intracoronary application of adenosine for thermodilution-based measurement has recently been described.22 Adenosine needs to be given first into the coronary artery and, following a lag time of a few seconds until steadystate hyperaemia has been reached, a bolus of saline is injected.23 Repeated injections of adenosine may be required for the three measurements during hyperaemia, and accurate timing is mandatory.22 Once coronary blood flow velocity has been measured it can be used to quantify the vasodilative potential of the coronary vasculature by the derivation of different parameters.

Coronary Flow Reserve

CFR, which reflects the relative increase of blood flow velocity during hyperaemia, has been the most widely used parameter for assessing the vasodilative potential of the coronary microvasculature. For Dopplerderived measurements, CFR is calculated as the ratio of the average coronary peak flow velocity during hyperaemia to the average flow

velocity at rest. CFR can also be derived from thermodilution measurements. It is calculated inversely as the ratio of Tmn at rest to Tmn at hyperaemia, considering the negative correlation of Tmn and blood flow velocity.16 A reduced CFR is a predictor of major adverse cardiac events such as cardiovascular death, stroke, MI and heart failure hospitalisation.24 According to the current guidelines of the European Society of Cardiology (ESC) for the diagnosis and management of chronic coronary syndromes, an abnormal CFR is defined as <2.0.1 Does one of the techniques of CFR measurement have a clear advantage over the other with respect to the accuracy of the measurements? Doppler-derived CFR (CFRDoppler) and thermodilution-derived CFR (CFRThermo) correlate quite well.13,15–17,25 There are some data favouring CFRThermo over CFRDoppler. Fearon et al. compared both methods with an external flow probe (CFRFlow) and reported a stronger correlation between CFRThermo and CFRFlow (r=0.85; p<0.001) than between CFRDoppler and CFRFlow (r=0.72; p<0.001). Indeed, in that study CFRDoppler was observed to have a greater scattering of values.25 In contrast, Everaars et al. used [15O]H2O PET as the gold standard and found a significantly higher correlation between CFRDoppler and CFRPET (r=0.82; p<0.001) than between CFRThermo and CFRPET (r=0.55; p<0.001).12 In that study the scattering was higher for CFRThermo than for CFRDoppler. Thus, it is currently not clear which of the two measurement techniques is more reliable in determining true CFR. However, CFRThermo tends to provide higher values than CFRDoppler.12,13,16,17,25 Thus, the correct cut-off value may depend on the technique chosen. Hence, it is likely that the absolute cut-off value of <2.0 as recommended by current guidelines is an oversimplification.1 This may result in a significant underestimation of the true prevalence of disease due to a low sensitivity and a low negative predictive value. The true range of normal values is difficult to determine because this would require intracoronary measurements in normal volunteers of different age groups. A study performed in patients shortly after heart transplantation using papaverine for maximal coronary vasodilatation noted mean values for CFRDoppler of 4.5 with a narrow standard deviation of 0.2.26 Hence, in that population of mostly young hearts the lower limit of normal was 4.1. The Coronary Vasomotion Disorders International Study group (COVADIS) acknowledged a range of CFR values of ≤2.0 to ≤2.5, depending on the method chosen, as possible cut-offs, but this is also likely a significant underestimation of the true normal range of reactions to vasodilator stimuli.27 Matters are even more complicated because myocardial perfusion reserve (and hence likely also CFR) is age dependent and decreases with advancing age.28 Moreover, coronary microvascular rarefaction regularly occurs later in life, further limiting the maximum delivery of oxygen to individual myocardial cells.29 Thus, it becomes obvious that the threshold at which symptoms related to myocardial ischaemia occur may vary from patient to patient. The main disadvantage of CFR as a single parameter is that this parameter may reflect two pathophysiologically different conditions. It is commonly accepted and assumed that reduced CFR is indicative of a reduced maximal coronary flow velocity. However, coronary blood flow at rest is another major determinant of CFR. A reduced CFR is also frequently found in patients who have an increased resting flow velocity but who also have a preserved and almost normal maximal flow velocity following pharmacologic vasodilatation.30,31 This condition was also found in a porcine model of microvascular disease introduced by exposure to various coronary risk factors even before the development of atherosclerotic lesions in the epicardial arteries.32 Hence, a reduced CFR may reflect a limited vasodilative potential, despite a near normal maximal

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Invasive Diagnosis of Coronary Functional Disorders Causing Angina Pectoris vasodilatation when the microvasculature is already dilated at rest, in response to conditions that make a higher blood flow at rest necessary.8,30

Therefore one needs to be aware of the limitations of currently available cut-offs for microvascular resistance measurements.

This limitation of CFR might be overcome by evaluating additional parameters.

Thus, both methods of evaluating microvascular resistance correlate only modestly with each other (r=0.39; p=0.0006), probably due to the different approaches for determining blood flow velocity.15

Microvascular Resistance

Microvascular resistance is the ratio of distal coronary pressure to distal coronary flow velocity. If resistance is measured using thermodilution, it is assumed that distal coronary flow velocity is equal to proximal coronary flow velocity. An advantage of measuring microvascular resistance is that its value at maximal hyperaemia is independent of coronary blood flow at rest.33,34 In contrast, the assessment of hyperaemic microvascular resistance (HMR) only will not reflect the limited vasodilative capacity often seen in women with exercise-related symptoms in whom the major abnormality is the increased flow at rest.30 Hyperaemic Microvascular Resistance HMR is determined by dividing distal coronary pressure, Pd, by Dopplerderived average peak flow velocity (APV).35 Pd is measured using the pressure sensor incorporated into the Doppler-equipped guidewire (ComboWire, Philips Volcano). Higher HMR values indicate higher microvascular resistance. There is currently no guideline-recommended threshold of HMR above which it should be considered abnormal.1 Williams et al. report the highest specificity and sensitivity in diagnosing microvascular dysfunction for a threshold of ≥2.5 as compared with the gold standard, a cardiac magnetic resonance imaging-derived myocardial perfusion index.15 This is in accordance with the findings of Van de Hoef et al., who measured HMR values of between 1.5 and 2.5 in a normal reference vessel (<30% obstruction) in patients with obstructive coronary artery disease (CAD) in another vessel.36 Index of Microcirculatory Resistance Alternatively, the index of microcirculatory resistance (IMR), which is based on the thermodilution principle as described above, can be calculated by multiplying Pd by Tmn. IMR shows a good correlation (r=0.54; p<0.0001) with microvascular resistance as measured in a porcine model via an ultrasonic flow probe, using a pressure wire as the reference standard.37 As proposed by COVADIS and successfully applied in the CorMicA trial, a threshold value of ≥25, above which resistance is abnormally high, has made its way into current guideline recommendations.1,27,38,39 The threshold of 25 was derived from the IMR values of only 15 patients who had no clinical evidence of atherosclerosis on angiography.38 These patients underwent cardiac catheterisation for non-coronary reasons (prior to closure of a patent foramen ovale or electrophysiological examination for cardiac arrhythmia). These patients had never reported chest pain and had minimal risk factors for CAD. Mean IMR in the control group was 19 ± 5 with a range of 8–28. Hence, the currently used cut-off for abnormal IMR was derived from this mean value +1 SD. A different approach for defining cut-off values was reported in a recent paper from Japan.20 Suda et al. studied 187 patients who underwent ACh provocation testing and measurement of IMR to evaluate coronary microvascular function.20 All of these patients were followed for a median of 893 days. Major adverse cardiovascular events were defined as the composite of cardiac death, non-fatal MI and hospitalisation due to unstable angina. IMR was correlated with the incidence of cardiac events, and the optimal cut-off value was identified on receiver operating characteristic curve analysis as IMR ≥ 18. Events were more common when IMR was 18 or above, however, only 10 events occurred (cardiovascular death, n=1; hospitalisation for unstable angina, n=9).

Assessment of Endothelial Dysfunction

ACh causes vasodilatation of the epicardial vessels and the microvasculature in normal individuals unless high doses are applied, which may lead to some vasoconstriction but not to coronary spasm.40,41 This is because the vasodilative effect of low doses of ACh mediated by the healthy endothelium is more pronounced than the vasoconstrictive opposing effect of the substance on vascular smooth muscle cells. Dysfunctional endothelium will not be able to release nitric oxide in sufficient amounts and the vasoconstrictive effect caused by the direct action on the vascular smooth muscle cell will become more prominent, resulting in less vasodilatation.42 There are two well-established threshold values for diagnosing endothelial dysfunction. Following intracoronary injection of any dose of ACh, endothelial-dependent microvascular dysfunction is defined as an increase of coronary blood flow ≤50%, whereas a decrease in coronary artery diameter ≥20% indicates epicardial endothelial dysfunction.43 Endothelial dysfunction is associated with cardiac events such as cardiac death or percutaneous coronary revascularisation.44 In order to measure endothelial function, coronary blood flow is calculated by multiplying mean flow velocity (estimated as 0.5 × APV) by vessel cross-sectional area both at baseline and following the injection of ACh.11 Coronary diameters are usually determined 5 mm distal to the tip of the Doppler wire using quantitative coronary angiography.44 Protocols for the assessment of endothelial function vary between centres. In most reports, incremental ACh dosages between 0.4 and 55 µg are used, depending on the concentration of the injectate (0.18– 30 µg/ml), the injection time (2–3 minutes) and the injection rate (unspecified or 0.5–1 ml/min).38,44–47 Ultimately, this form of coronary function testing reflects abnormalities of vasodilatation, although not as a response to adenosine, but to ACh. Thus, the vasodilative capacity of the microvasculature is measured using two different methods: ACh-based endothelial function testing and standard adenosine testing. It is, however, not clear whether these two different ways of assessing the vasodilative capacity of the microvasculature provide additive information to each other. Sara et al. defined coronary microvascular dysfunction either as a reduction in CFR in response to adenosine or as abnormal coronary blood flow in response to low doses of ACh.43 Using this broad definition of a disturbed vasodilative response, two-thirds of all 1,552 patients with chest pain and non-obstructive CAD had microvascular dysfunction. Both tests of coronary microvascular vasodilatation were normal in 520 patients and abnormal in 268 patients. Divergent findings were seen in 651 patients: an abnormality in response to low doses of ACh was more common than an abnormal reaction to adenosine. Thus, the combination of an abnormality in response to ACh and a normal response to adenosine was seen in 478 patients, whereas the contrary was present in only 173 patients. Hence, endothelial function (vasodilatation) testing using ACh produces many more abnormal results than does standard vasodilatation testing using adenosine. In fact, this form of vasodilatation testing is used in very few centres outside the US today, possibly reflecting the absence

EUROPEAN CARDIOLOGY REVIEW Access at: www.ECRjournal.com

Invasive Diagnosis of Coronary Functional Disorders Causing Angina Pectoris of data indicating a better guidance to therapy or a more precise prediction of outcome as compared with adenosine vasodilatation testing. Moreover, the assumption that these two tests measure two different things, namely, predominantly or even exclusively endothelial versus nonendothelial (smooth muscle cell function), may not be correct.48–51

Assessment of Coronary Vasoconstriction or Spasm

Besides the impaired vasodilatation of the coronary vasculature, coronary vasomotion may also be dysfunctional because of an increased vasoconstrictive potential. This abnormality may not only affect the coronary microvasculature but also the epicardial vessels. Vasoconstriction may occur spontaneously and lead to transient subtotal or even total coronary occlusion (spasm). These spasms frequently occur at rest in patients without obstructive CAD. Fortunately, most of these events are self-limiting, which, however, will hamper the diagnosis of spontaneous events. Thus, in order to reproduce spontaneously occurring events, a so-called provocation test is often required. This test permits assessment of coronary vasomotion as an extension to diagnostic coronary angiography. Different vasoconstriction-provoking agents may be applied. This diagnostic tool may be helpful in identifying patients with coronary vasospasms, which are associated with an increased risk of recurrent angina, repeated coronary angiography and MI.52 For the diagnosis of epicardial coronary spasm, the Japanese Circulation Society (JCS), in their guidelines for diagnosis and treatment of patients with vasospastic angina (VSA), have suggested a definition of coronary artery spasm as a >90% reduction of the epicardial vessel diameter. This may occur as a focal spasm (in one isolated segment of the coronary artery) and/or as a diffuse spasm (occurring in ≥2 adjacent segments, usually in the distal portion of the vessel).53 In contrast to epicardial vasospasms, direct visualisation of microvascular spasm (MVS) during spasm testing is not possible due to the limited spatial resolution of coronary angiography. According to the COVADIS definition, a diagnosis of MVS should be made if ACh causes the known angina symptoms accompanied by ischaemic ECG alterations without any demonstrable epicardial spasm (Figure 1).27 Sometimes, MVS will lead to an abrupt increase in microvascular resistance, causing a dramatic decrease in blood flow velocity.54 However, symptoms may be felt differently by the patient in the atmosphere of a busy catheterisation laboratory, and ECG changes may be ambiguous, such as, for instance, the appearance of negative T waves.

Acetylcholine

ACh is also used for assessing the vasoconstrictive tendency of coronary arteries, taking into account that its binding sites are not only on the endothelium but also on the vascular smooth muscle cells.55 For spasm provocation testing, increasing ACh doses of up to 200 µg are injected into the coronary arteries.53,56 However, protocols differ between institutions, and different injection times and different maximal doses of ACh are in use.56,57 Recently, we summarised how we perform ACh testing in our catheterisation laboratory and how we deal with side-effects such as AF and bradycardia.56,58,59 Undoubtedly, higher doses of ACh provoke coronary vasospasm more frequently than lower doses. In the testing of almost 1,400 patients with stable angina and unobstructed coronary arteries we found pathologic ACh tests in almost 60%. More than half of the abnormal tests were positive for MVS. A pathological test was more common in female patients (70% versus 43%). Female patients were more sensitive to ACh and

abnormal tests occurred at lower ACh doses compared with male patients. All of these tests were performed using the slow injection protocol, in which each dose of ACh is given by slow intracoronary injection over 3 minutes.56 Although the criteria for the diagnosis of a pathologic ACh test are commonly accepted, testing may also elicit indeterminate or inconclusive responses.2,27,53 Such responses can be observed in up to one-third of patients.60 This includes reproduction of the usual chest pain without ECG changes or epicardial spasm, the occurrence of epicardial spasm without symptoms, or the observation of ischaemic ST shifts in the ECG without symptoms. All these responses appear to be abnormal but they do not fulfil the criteria for a pathologic test. Some of these patients may have what has been termed ‘the sensitive heart’ by Richard Cannon.61 Hence these indeterminate responses are often grouped together with normal test results. It obviously makes a difference whether a dose of ACh is given over 3 minutes or 20 seconds. The fast approach is favoured by most Asian centres and there are obvious advantages of following such a protocol.53 Provocation testing can be completed in a much shorter time interval3,62 and the proportion of patients with positive tests seems to be higher. Sueda and Kohno examined 30 patients with ischaemic heart disease and administered up to 200 µg of ACh both over 3 minutes and over 20 seconds.63 They found that more patients had spasms during the 20-second injection than during the 3-minute injection (22 versus 10). Moreover, both ischaemic ECG changes and chest symptoms were significantly more frequently seen with short ACh injection. Interestingly only epicardial spasm was considered in that study. Moreover, the 3-minute protocol was carried out only at the highest tolerable dose previously administered during the 20-second protocol. Patients could receive nitrates if spasms following the 20-second protocol did not resolve spontaneously in 3 minutes. The different outcomes of both test protocols in the same patients invite questions about the sensitivity and specificity of ACh testing in patients with ANOCA. There is no gold standard independent test for comparison. Initially, the test was introduced to find a cause for angina in patients with unobstructed coronary arteries. Thus, the gold standard was the reproduction of the usual angina symptoms that had led to the initial investigation. These angina symptoms were more convincing when associated with ischaemic changes in the ECG with or without epicardial spasm. It is ethically very difficult to perform the test in persons who have no symptoms and no coronary plaques. Such persons would form a cohort of normal people in whom the test should be 100% negative. In contrast, there is also the opinion that the test might be positive in every person if the dose of ACh were high enough. Animal models are difficult because the response to ACh differs widely from species to species.64 We are not aware of animal experiments in which very high doses of ACh were applied to determine whether coronary constriction could be elicited in all animals.

Ergonovine

Besides ACh, current guidelines recommend intracoronary injections of ER as an alternative provocation test.1,53 ER binds to serotonin receptors on the smooth muscle cells and therefore involves mediators other than ACh.65 This is the reason why Sueda et al. recommend using both substances for provocation testing.66 Focal epicardial spasms can be detected more often when ER is used as the provocation agent, whereas diffuse distal spasms occur more often when using ACh.60,66 Also, the proportion of patients diagnosed with coronary spasm may increase by using both agents.66 In the early experience with provocation testing

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Invasive Diagnosis of Coronary Functional Disorders Causing Angina Pectoris Figure 1: Flow Chart of Spasm Provocation Testing as Suggested by COVADIS Spasm provocation testing Intracoronary administration of acetylcholine or ergonovine

Reproduction of symptoms?

Ischaemic ECG alterations?

Epicardial vasoconstriction >90%?

Conclusion

Epicardial spasm

Focal

Microvascular spasm

Equivocal

Negative

Diffuse

COVADIS = Coronary Vasomotion Disorders International Study group. Source: Beltrame et al. 20172 and Ong et al. 2018.27

using ER, an IV (and therefore unselective) application was used, which led to a lower frequency of provoked spasms compared with intracoronary application.66 Also, increased complication rates have been described for IV application of ER due to the possibility of prolonged spasm affecting multiple coronary arteries.4 Current guidelines therefore strongly favour intracoronary instead of IV injection of ER.1,53

Lactate Concentration as an Objective Indicator of Microvascular Spasm

Objective detection of the presence of ischaemia during functional testing is important, especially for the diagnosis of MVS. At the moment, one usually relies on whether ischaemic changes can be seen on the ECG because MVS cannot be visualised angiographically. Many patients with MVS report exact reproduction of their usual symptoms and this is associated with horizontal ST segment depression >1 mm. However, despite reproduction of the usual symptoms, some patients show negative T waves and there has been debate on whether this should be interpreted as evidence of MVS. Then there are those whose symptoms are not really the same as in daily life despite horizontal ST-segment depression. Thus, there is a grey zone, and this might affect the reproducibility of test interpretation. Also, the interobserver reproducibility of the diagnosis of MVS has not been reported. An additional and potentially more objective method for proving ischaemia during provocation testing is the measurement of lactate concentration in the coronary sinus, as recommended by the JCS.53 Lactate metabolism by the myocardium encompasses both lactate production and lactate consumption given that lactate is used by the heart as a source of energy. This leads to a net effect of lactate consumption in healthy individuals. During ischaemia, however, the lack of oxygen is associated with an increase in anaerobic glycolysis, resulting in net lactate production.67 Lactate concentration in the coronary sinus will thus increase during ischaemia. The extent of lactate production during MVS can be quantified from paired blood samples taken from the coronary

sinus and the aorta at baseline and following the highest tolerable dose of ACh.68,69 A negative lactate extraction ratio (the ratio of the arteriovenous difference in lactate concentration to arterial lactate concentration, negative values indicating myocardial lactate production with coronary sinus concentration exceeding arterial concentration) can be used as an objective measure of the presence of myocardial ischemia.69,70 Therefore, the lactate extraction ratio may also be helpful for quantifying the severity of ischemia: larger amounts of net lactate production, which are associated with more extensive ischaemia, will result in more negative values of the lactate extraction ratio. The use of lactate to diagnose the presence of myocardial ischaemia has thus been recommended by the current guidelines of the JCS for the diagnosis and treatment of patients with VSA.53 Lactate measurements also permit the objective diagnosis of ischaemia due to MVS occurring before the onset of epicardial spasm at higher doses of ACh.69,71 However, lactate measurements require right heart catheterisation and selective catheterisation of the coronary sinus. Moreover, a dedicated point-of-care measurement device needs to be present in the catheterisation laboratory in order to measure lactate immediately following its procurement.

Sequence of Testing: Vasodilatation or Vasoconstriction Testing First?

Although the aforementioned methods for testing coronary vasomotion are increasingly being applied, there is an ongoing debate about the sequence of testing, which focuses on the use of nitroglycerin and the duration of its vasodilative effects on the coronary vasculature.20,31,72 In patients in whom an interventional diagnostic procedure (IDP) is likely to be performed and who are catheterised via the radial artery, the routine use of intra-arterial spasm prophylactic medications such as nitroglycerin and/or calcium channel blockers should be avoided. The smallest catheter size should be used to avoid spasm in the radial and brachial arteries. Focal epicardial spasm may mimic fixed coronary stenosis, and many centres perform diagnostic coronary angiography only after the application of nitrates, although this practice differs between centres.73,74

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Invasive Diagnosis of Coronary Functional Disorders Causing Angina Pectoris Figure 2: Interventional Diagnostic Procedure Interventional diagnostic procedure 1

Diagnostic angiography 2 Assessment of vasodilatation Flow velocity measurement

Continuous monitoring of 12-lead ECG and symptoms

Doppler

Thermodilution Flow velocity at baseline Adenosine

Flow velocity + pressure at hyperaemia CFR + HMR

FR + IMR

3 Assessment of vasoconstriction Baseline angiogram Provocation testing

Acetylcholine*

Ergonovine** Angiogram Nitroglycerin Angiogram

Final angiogram

In some centres, the order of test is reversed. They begin with acetylcholine testing and add adenosine testing afterwards. *Left coronary artery, 2–200 µg; right coronary artery, 80 µg. **Left coronary artery, 64 µg; right coronary artery, 40 µg. CFR = coronary flow reserve; HMR = hyperaemic microvascular resistance; IMR = index of microcirculatory resistance.

We recommend avoiding nitrates before diagnostic coronary angiography if performing an IDP. The advocates of starting the IDP with vasodilatation testing using adenosine argue that some patients require wire-based measurements (fractional flow reserve [FFR], instantaneous wave-free ratio etc.) to exclude haemodynamically significant epicardial stenoses in the presence of coronary plaques. Thus, a guidewire needs to be placed first and adenosine will be given if FFR is measured. Some centres give intracoronary nitroglycerin (chemical name, glyceryl trinitrate) routinely before the use of adenosine to ascertain maximal vasodilatation. However, this is not a necessary part of the FFR or the CFR procedures.75 Hence, it appears reasonable to perform the vasodilatation testing part (determination of CFR and IMR or HMR) first, keeping in mind that the use of nitroglycerin or calcium channel blockers should be avoided if possible.

However, there are no data on how the prior application of nitroglycerin will affect ACh testing. The two most interesting questions are whether the proportion of pathologic ACh tests will decrease if nitroglycerin has been given before the test, and how long the recommended time delay should be to ensure that prior nitroglycerin does not affect the ACh test results. There is, however, much speculation. The authors of the CorMicA trial argue that at 10 minutes after the application of nitroglycerin, only 3% of the substance will still be present and active due to the short half-life of around 2 minutes of the substance.72 Consequently, they find it unlikely that at 10 minutes after the application of the nitrate the remaining 3% of the compound might lead to false-negative results of ACh testing. In contrast, Morton Kern remarks: “NTG dilates and fixes the diameter of the epicardial vessel for 10–15 minutes after 100–200 mcg i.c.”76 If one suspects a longer duration of the action of nitroglycerin, this would indeed argue against performing the ACh test first. This is because nitroglycerin should be routinely given at the end of the ACh test.53 The reason for giving nitroglycerin at the end of the procedure is that the extent of coronary vasoconstriction with ACh has been quantified, as compared with the relaxed state of the artery following nitroglycerin. In addition, residual spasm may be reversed. Indeed, by injecting nitroglycerin it is more likely that the criterion of a >90% narrowing can be fulfilled and a diagnosis of epicardial spasm made, than if the reference diameter is the arterial diameter at baseline.74 Despite their assumption that nitroglycerin will have little effect 10 minutes after its application, Ford and Berry are reluctant to perform the ACh test first. This is because they feel that AChinduced spasm might lead to false measurements of resting flow and hence CFR.72 They suspect that the provocation of spasm and subsequent ischaemia (which may be prolonged following provocation of MVS) could lead to reflex hyperaemia, which might result in falsely high values of resting blood flow. Thus, CFR would be falsely low. If, in contrast, MVS persists, resting blood flow would be falsely low, resulting in a potentially falsely high CFR. Using Doppler-based flow velocity measurements both before and after provocation testing may solve this dilemma by identifying the right time to proceed, namely after normalisation of coronary blood flow velocity. The opposing view assumed a larger half-life of nitrates in blood77 of up to 6 minutes, leading to >25% remaining in blood 10 minutes after its application. In addition, the vasodilating effects of nitrates on epicardial coronary arteries may last even longer than those on the coronary microvasculature, as demonstrated in a canine model (45 versus 7 minutes).78 This argument (falsely) assumes that intracoronary nitrates are required for the adenosine measurements. Therefore, the best approach for measurements not affected by residual nitroglycerin effects will be to use the smallest possible catheters for coronary angiography and vasomotion testing. This would reduce the prevalence of radial spasm and omit the need for a radial cocktail unless radial spasm occurs.79 Performing adenosine testing first without nitroglycerin is the logical choice. ACh testing can be done afterwards without undue influence of any residual vasoactive substances (Figure 2). This sequence also avoids discussions about persisting MVS. It also has the potential advantage that the delay time between any application of a vasodilating substance in the case of a radial spasm and the ACh test would be maximised.

Endotypes

If the aforementioned assessments of vasodilatation and vasoconstriction are done immediately following clinically indicated coronary angiography, no additional invasive procedure is required for the diagnosis of coronary vasomotion disorders. In the CorMicA trial, Ford et al. used a pathway of testing termed the IDP.38 After diagnostic coronary angiography via the radial artery for exclusion of obstructive CAD, assessment of vasodilatation was performed first, followed by ACh endothelial testing and spasm

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Invasive Diagnosis of Coronary Functional Disorders Causing Angina Pectoris Figure 3: A 53-year-old Patient with Dyspnoea and Angina During Exercise and At Rest Despite Having Non-obstructed Coronary Arteries A

Baseline C

20 µg ACh

2 µg ACh D

100 µg ACh

0.2 mg NTG

Acetylcholine (ACh) provocation testing suggests a common pathomechanism of microvascular and diffuse epicardial spasm. A: Baseline angiogram without relevant stenoses. B,C: Reproduction of the patient’s usual symptoms at low doses of ACh, correlating with ST-segment depressions (black arrows) compared with baseline without relevant narrowing of the epicardial vessels, indicating microvascular spasm. D: Full reproduction of the patient’s symptoms: additional diffuse epicardial spasm of the left anterior descending artery and the first diagonal branch, accompanied by prominent ST-segment depressions (red arrows). E: Relief of symptoms after intracoronary nitroglycerin (NTG), leading to vasodilatation of the epicardial coronary arteries and the returning of ECG alterations back to baseline (green arrows). Source: Martínez Pereyra et al. 2020.80 Reproduced with permission from Wolters Kluwer Health.

provocation testing. Measurement of maximal vasodilatation was achieved by IV infusion of 140 µg/kg/min adenosine. Depending on the results of each assessment, the following endotypes have been classified for patients without obstructive CAD: endotype 1, microvascular angina (MVA; impaired vasodilatation and/or MVS); endotype 2, VSA (epicardial spasm); endotype 3, mixed MVA and VSA (epicardial spasm + impaired vasodilatation); and endotype 4, non-cardiac chest pain. This classification distinguishes between MVS (endotype 1) and epicardial spasm (endotypes 2 and 3), following different therapeutic recommendations. However, sometimes patients may exhibit MVS at lower doses of ACh, followed by (diffuse) epicardial spasm at a higher dose.69,80 Such observations suggest a common pathomechanism of diffuse distal epicardial spasm and MVS (Figure 3). One might therefore adjust the definition of endotypes according to the type of vasomotion that has been found to be impaired when assessing vasodilatation and vasoconstriction: both tests (vasodilatation and vasoconstriction) can be abnormal, one can be normal and the other abnormal, or both can be normal. This new classification has been applied by current ESC guidelines, which recommend the same therapy for both epicardial spasm and MVS. For impairments in vasodilatation, the therapy differs. In the case of both mechanisms being impaired, the medical therapy shall focus on treating the (suspected) dominant mechanism.1 Further variations between centres relate to the type of flow velocity measurement used (Doppler versus thermodilution), the ACh injection speed, the incremental dosages of ACh used or the standardised usage of a pacemaker during provocation testing.19,20,31 As a consequence, the prevalence of the four endotypes might differ between centres due to the different protocols and threshold values applied. Furthermore, some groups prefer other definitions of endotypes that incorporate information

about endothelial function, the type of spasm encountered (focal versus diffuse versus microvascular) and so on.31,43 This not only makes it hard to find a common language for discussion but it also makes it difficult to compare results between centres. The definitions of subgroups, in particular, are inconsistent. For instance, Ford et al. use the term ‘microvascular angina’ to describe a group of patients in whom the vasodilative potential is impaired (reduced CFR and/or increased IMR), or in whom the vasoconstrictive potential of the microvasculature is increased (MVS), or in whom both mechanisms are impaired in parallel.19 Even though this classification makes sense when explaining the microvascular origin of the disease, it does not distinguish between the two pathomechanisms for microvascular dysfunction (i.e. impaired vasodilatation versus enhanced vasoconstriction) and thus cannot be used to select the optimal treatment. Suda et al., in contrast, did not use these classifications, however, they use the term ‘negative test’ in two different ways.20 First, the term ‘negative’ encompasses a group of patients without epicardial spasm and with normal vasodilative properties, even though this subgroup contains patients with and without MVS. In another part of the study, the negative group contained patients without any type of spasm. This may illustrate how terminology makes the comparison of results between different groups very complex. Ideally, the term chosen should be self-explanatory and used in a unique, well-defined sense, thereby reducing the possibility of misunderstandings. If endotypes are defined in the straightforward way as described above (vasodilatation testing and vasoconstriction testing both abnormal, either of them abnormal or both normal) and this is applied to the three studies

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Invasive Diagnosis of Coronary Functional Disorders Causing Angina Pectoris Figure 4: Prevalence of Endotypes A

Table 1: Risks, Costs and Duration of Invasive Tests of Coronary Vasomotion

70% 60%

Method

Risks

Associated Costs

Average Duration in the Catheterisation Laboratory (Present Authors’ Experience)

HMR

Low82

Doppler flow or pressure-wire; adenosine

<10 min

IMR

Low83

Thermodilution flow <10 min or pressure-wire; adenosine

CFR

Low17,82

Dedicated wire; adenosine

No additional time if measured together with HMR or IMR

Assessment of endothelial dysfunction

Low84

Doppler flow or pressure-wire; ACh

<10 min

Provocation test

Low if ACh or ER ACh or ER; nitrates is administered into the coronary arteries60,85

<20 min

50% 40% 30% 20% 10% 0%

CFR normal + no spasm

CFR normal + spasm

Seitz et al.

CFR reduced + CFR reduced + no spasm spasm

Ford et al.

Suda et al.

50% 45% 40% 35% 30%

ACh = acetylcholine; CFR = coronary flow reserve; ER = ergonovine; HMR = hyperaemic microvascular resistance; IMR = index of microcirculatory resistance.

25% 20% 15%

for the multicentre therapeutic and prognostic studies that are urgently needed.

10% 5% 0%

IMR normal + no spasm

IMR normal + spasm

Ford et al.

IMR increased + IMR increased + no spasm spasm Suda et al.

A: Endotypes stratified by coronary flow reserve (CFR). CFR normal = ≥2.0; spasm = epicardial and/ or microvascular spasm.19,20,31 B: Endotypes stratified by index of microcirculatory resistance (IMR).19,20 IMR normal = <25 (Ford et al. 201919); <18 (Suda et al. 201920); spasm = epicardial and/or microvascular spasm.

providing such information, then isolated coronary spasm without accompanying impairment of vasodilatation (Figure 4) is the most prevalent endotype.19,20,31 Interestingly, one encounters only a few patients (around 10%; Figure 4) with an isolated impairment of vasodilatation and without accompanying spasm. These patients have what has been called ‘microvascular angina’, given that this term previously did not include angina secondary to MVS. However, as judged from the available literature, this subgroup of patients would be expected to be the most prevalent one. Finally, the recent expert opinion paper also struggled with the definition of microvascular angina.81 Although in Figure 4 of this expert opinion paper, this group is defined as having an abnormal adenosine test (vasodilatation test) but a normal ACh test, in table 2 of the same publication the patients with microvascular angina are characterised as having an abnormal adenosine test and/or an abnormal ACh test (i.e. they may be positive for MVS).81 Hence, it is mandatory that agreement is reached on the definition of endotypes. Only then will we have the basis 1. Knuuti J, Wijns W, Saraste A, et al. 2019 ESC guidelines for the diagnosis and management of chronic coronary syndromes. Eur Heart J 2020;41:407–77. https://doi. org/10.1093/eurheartj/ehz425; PMID: 31504439. 2. Beltrame JF, Crea F, Kaski JC, et al. International standardization of diagnostic criteria for vasospastic angina. Eur Heart J 2017;38:2565–8. https://doi.org/10.1093/ eurheartj/ehv351; PMID: 26245334. 3. Ong P, Safdar B, Seitz A, et al. Diagnosis of coronary

Conclusion

The methods reviewed in this article can be easily and safely applied by the invasive cardiologist in order to diagnose coronary vasomotion disorders. However, the number of centres routinely implementing coronary vasomotion testing is low, even though neither additional risks nor costs are associated with these tests (Table 1). This is especially true if a wire has already been placed in the coronary artery for another reason, for instance to measure FFR in the presence of coronary plaque. In addition, in Germany the IDP is also reimbursed if performed in smooth coronary arteries in a patient with suspected functional coronary abnormalities, due to separate coding information. Thus, there is no convincing argument for not performing such testing, especially in view of the advantages of clearly identifying the cause of the patient’s symptoms.38 The hesitation prevailing in many catheterisation laboratories with regard to adopting IDPs may be related to the fact that the complexity of coronary function abnormalities is still not fully understood and will require further research and development to improve diagnosis and treatment. Nevertheless, extending intracoronary testing such as the measurement of FFR or of resting flow indices such as instantaneous wave-free ratio or resting full-cycle ratio in the presence of coronary stenoses to the field of coronary function is rather simple. Such testing will expand the scope of the invasive cardiologist and will open a new window onto the fascinating biology and pathophysiology of coronary arteries.

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Inflammation

The Role of C-reactive Protein in Patient Risk Stratification and Treatment Ramón Arroyo-Espliguero ,1 María C Viana-Llamas ,1 Alberto Silva-Obregón

and Pablo Avanzas

3,4,5

1. Department of Cardiology, Hospital Universitario de Guadalajara, Guadalajara, Spain; 2. Department of Intensive Medicine, Hospital Universitario de Guadalajara, Guadalajara, Spain; 3. Department of Cardiology, Hospital Universitario Central de Asturias, Oviedo, Spain; 4. Department of Medicine, Universidad de Oviedo, Oviedo, Spain; 5. Instituto de Investigación Sanitaria del Principado de Asturias, Oviedo, Spain

Abstract

Atherosclerosis is a chronic inflammatory disease. Several circulating inflammatory markers have been proposed for clinical use due to their ability to predict future cardiovascular events and may be useful for identifying people at high risk who might benefit from specific treatment to reduce this risk. Moreover, the identification of new therapeutic targets will allow the development of drugs that can help reduce the high residual risk of recurrence of cardiovascular events in patients with coronary artery disease. The clinical benefits of reducing recurrent major cardiovascular events recently shown by canakinumab and colchicine have renewed the cardiology community’s interest in inflammation as an aetiopathogenic mechanism for atherosclerosis. This review explores the use of C-reactive protein, which is the most frequently studied biomarker in this context; the concept of residual risk in primary and secondary cardiovascular prevention; and the current recommendations in international guidelines regarding the role of this inflammatory biomarker in cardiovascular risk stratification.

Keywords

Inflammation, coronary artery disease, primary prevention, secondary prevention, C-reactive protein Disclosure: PA is an associate editor and RAE is on the European Cardiology Review editorial board, which did not affect the peer-review process. All other authors have no conflicts of interest to declare. Received: 7 December 2020 Accepted: 15 March 2021 Citation: European Cardiology Review 2021;16:e28. DOI: https://doi.org/10.15420/ecr.2020.49 Correspondence: Ramón Arroyo-Espliguero, Department of Cardiology, Hospital Universitario de Guadalajara, 19002 Guadalajara, Spain. E: rarroyo@sescam.jccm.es Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Despite advances in cardiovascular research, coronary artery disease (CAD) remains the leading cause of death and disability in developed nations.1 Atherosclerosis has traditionally been associated with risk factors, such as smoking, dyslipidaemia, arterial hypertension and diabetes.2–4 However, in recent years, inflammation of the arterial wall has emerged as a key mechanism in the development of this condition.5 Given the involvement of inflammatory mechanisms in atherogenesis, attempts have been made to identify circulating inflammatory biomarkers that can predict future cardiovascular events. These biomarkers include C-reactive protein (CRP), serum amyloid A protein, neopterin, lipoproteinassociated phospholipase A2, pro-inflammatory cytokines, matrix metalloproteinases, heat shock proteins and adhesion molecules.6 These biomarkers and the molecular pathways that generate them are the targets in a new field of anti-inflammatory therapeutics for primary and secondary cardiovascular prevention. This review will explore the clinical use of CRP, the most frequently studied biomarker in this context; the concept of residual risk in primary and secondary cardiovascular prevention; and the current recommendations in the main international clinical practice guidelines regarding the role of this inflammatory biomarker in cardiovascular risk stratification.

Inflammatory Markers in Atherosclerosis

Coronary atherosclerosis has been traditionally associated with wellknown cardiovascular risk factors, which form the basis of the current

approach toward controlling the CAD pandemic.2–4 However, it has become apparent that inflammation has a key role in atherogenesis and its complications.5 Atherogenesis represents an inflammatory process with cytokine production and increased blood levels of acute phase reactants similar to that observed in other inflammatory diseases, such as rheumatoid arthritis. Inflammatory cell infiltration is observed in atherosclerotic plaques at all stages of the disease, from the first fatty streak to advanced atheromatous lesions and thrombotic complications. There is a huge amount of evidence implicating inflammation in atherosclerosis and acute coronary syndromes (ACS) and a variety of circulating markers of inflammation have been examined for their ability to predict either the presence of vascular disease or the risk of vascular events in a broad range of clinical settings.7 These markers included CRP, serum amyloid A, fibrinogen, neopterin, lipoprotein-associated phospholipase A2, soluble CD40 ligand, heat shock proteins, matrix metalloproteinases, myeloperoxidase, pro-inflammatory cytokines and many circulating adhesion molecules.6 The identification of vulnerable plaques in vulnerable patients using imaging techniques or inflammatory biomarkers is one of the most promising areas of research in modern cardiology and could revolutionise cardiovascular practice.

C-reactive Protein

Of the various inflammatory biomarkers described to date, CRP has been the most frequently studied.8 CRP is a member of the family of pentraxins, soluble pentameric proteins that recognise microbial structures and play

C-reactive Protein, Patient Risk Stratification and Treatment an essential role in innate immunity. These pentraxins act as pattern recognition receptors capable of recognising pathogen-associated molecular patterns, repetitive structures evolutionarily preserved in microorganisms. CRP binds somatic C-polysaccharide of Streptococcus pneumoniae, a polysaccharide that is rich in lysophosphatidylcholine (LPC), the natural ligand of CRP.9,10 CRP also binds to phosphocholine expressed on the cell membrane of apoptotic cells. CRP has a pentameric structure composed of five identical 23-kDa polypeptide subunits non-covalently associated in a cyclic symmetry.9,10 It is produced primarily in the liver as an acute-phase reactant in response to inflammatory or ischaemic tissue damage following the local or systemic production of pro-inflammatory cytokines, such as interleukin (IL)-1β, IL-6 or tumour necrosis factor-α by the nucleotide-binding and oligomerisation domain-, leucine-rich repeat- and pyrin domain-containing protein 3 (NLRP3) inflammasome. The features that have made CRP an attractive biomarker of chronic inflammation are its long half-life, its stable circulating levels, its minimal circadian variation, and the availability of affordable and validated highsensitivity methods for its determination.8,11 CRP is an independent prognostic marker in patients with atherosclerotic disease and in apparently healthy subjects.12,13

Primary Prevention

Inflammatory markers have a prognostic value for the development of cardiovascular events independent of conventional risk factors and may be useful for identifying people who are at high risk of future cardiovascular events and may benefit from specific treatment to reduce this risk. A meta-analysis that included 160,309 patients without a previous history of cardiovascular disease confirmed that each standard deviation increase in high sensitivity (hs) CRP was associated with increased adjusted relative risk of CAD, ischaemic stroke and cardiovascular death of 37% (95% CI [1.27–1.48]), 27% (95% CI [1.15–1.40]) and 55% (95% CI [1.37–1.76]), respectively.14 This same study showed that the magnitude of such risk was comparable with that associated with traditional cardiovascular risk factors associated with the development of CAD, including total cholesterol (16%), non-HDL cholesterol (28%) and arterial systolic blood pressure (35%). The REGARDS study confirmed the prognostic value of CRP in primary prevention for patients at high risk of cardiovascular disease, defined as Framingham coronary risk score ≥10% or atherosclerotic cardiovascular disease (ASCVD) risk ≥7.5%).15 Of the 6,136 high-risk patients in this study, those with high LDL cholesterol (LDL-C; ≥1.8 mmol/l) and low hs-CRP (<2 mg/l) had a lower risk of incident stroke (HR 0.69; 95% CI [0.47–0.997]), incident CAD (HR 0.71; 95% CI [0.53–0.95]), and cardiovascular death (HR 0.70; 95% CI [0.50–0.99]), whereas low LDL-C (<1.8 mmol/l) was not associated with protective effects. These results support the role of inflammation in atherogenesis and plaque instability. In the PRINCE study, assignment to 40 mg/day of pravastatin reduced CRP concentrations by 16.9% (p<0.001) at 24 weeks, regardless of lipid profile, providing evidence of the anti-inflammatory properties of statins in addition to their lipid-lowering effects.16 However, it is still unknown whether this reduction in CRP levels is associated with a decrease in cardiovascular risk and whether CRP could be used to guide statin therapy. In the AFCAPS/TexCAPS study, baseline CRP concentrations were determined in 5,742 apparently healthy subjects at low or moderate risk for the development of coronary events.17 After a mean follow-up of 5.2

years, 20–40 mg/day lovastatin reduced the occurrence of first acute major coronary event (fatal or non-fatal MI, unstable angina or sudden death from cardiac causes) in subjects with elevated levels of LDL-C (>3.86 mmol/l; RR 0.53; 95% CI [0.37–0.77]), but it also reduced these events in patients with elevated CRP concentrations (>0.16 mg/dl) and normal LDL-C values (RR 0.58; 95% CI [0.34–0.98]). The JUPITER study analysed the effectiveness of rosuvastatin in reducing major cardiovascular events in 17,802 apparently healthy subjects with normal cholesterol levels (<3.4 mmol/l), but with high CRP concentrations (≥2 mg/l).18 The study was prematurely stopped after a median follow-up of 1.9 years. Rosuvastatin significantly reduced the incident of major cardiovascular events (combined endpoint of MI, stroke or death from cardiovascular causes) in these apparently healthy subjects without hyperlipaemia but elevated hs-CRP levels (HR 0.53; 95% CI [0.40–0.69]). These results confirm the usefulness of CRP and lipid profile for the assessment of cardiovascular risk in primary prevention. They demonstrate that achieving both lipid and inflammatory targets significantly improves prognosis compared with the achievement of just one of these therapeutic aims in isolation.8

Secondary Prevention Stable Coronary Artery Disease

CRP has been associated with the development of recurrent cardiovascular events in patients with stable CAD (Table 1), both in prospective cohort studies and in analyses of clinical trials.19–25 These studies demonstrated the association of CRP with the risk of MI, the need for revascularisation, stroke and heart failure, and cardiovascular, cancer-related and total mortality. In a single-centre study of 700 consecutive patients with chronic stable angina (CSA) who underwent scheduled coronary revascularisation, serum hs-CRP levels were significantly associated with the development of the combined endpoint of cardiac death, non-fatal acute MI or hospital admission with unstable angina at 1-year follow-up (OR 1.9; 95% CI [1.1– 3.5]), regardless of age, sex, previous MI, type 2 diabetes and the extent or severity of CAD.20 In the 13,740 patients with CSA and LDL-C ≥1.8 mmol/l on a statin assigned to placebo in the FOURIER study, those with higher baseline hs-CRP categories had significantly higher 3-year Kaplan-Meier rates of the combined endpoint of cardiovascular death, MI, stroke, hospitalisation for unstable angina or coronary revascularisation: 12.0%, 13.7% and 18.1% (ptrend<0.0001) for categories <1, 1–3, and >3 mg/dl, respectively.25 Many of the studies that confirm the predictive capacity of hs-CRP for the development of recurrent events have been carried out in populations treated with pro-protein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, suggesting that hs-CRP can identify residual inflammatory risk even in patients with very low LDL-C levels.24,25 Studies with intravascular ultrasound show that the reduction in hs-CRP is accompanied by a significant decrease in the progression of atherosclerotic plaque, whether or not serum lipid concentrations are modified. In fact, reductions in LDL-C and hs-CRP concentrations are associated with a greater deceleration of atherosclerotic progression than reductions in only one of these markers.26

Acute Coronary Syndromes with or without ST-segment Elevation

Numerous clinical studies have demonstrated the ability of CRP to predict recurrent coronary events in patients with ACS (Table 1).27–39 Liuzzo et al.

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C-reactive Protein, Patient Risk Stratification and Treatment Table 1: Representative Studies Assessing the Relationship Between C-reactive Protein and Recurrent Mayor Cardiovascular Events in Patients with Stable Coronary Artery Disease and Acute Coronary Syndromes Author

Study

CRP (mg/l) Time

Follow-up

Events

Adjusted RR

Significance

Arroyo-Espliguero et al. 200420

Unicentric

790

–

1 year

CV death, MI, UA

1.9 (1.1–3.5)

✓

Sattar et al. 200721

PROSPER

2,515

Tertiles

–

3.2 years

CV death, MI, stroke

1.3 (1.04–1.64)

✓

Held et al. 201723

STABILITY

14,406

Quartiles

–

3.7 years

CV death, MI, stroke

1.36 (1.14–1.63)

✓*

Pradhan et al. 2018 †

SPIRE-1 and -2

9,738

Tertiles

–

14 weeks

CV death, MI, UA, stroke

1.62 (1.14–2.30)

✓

Bohula et al. 2018

FOURIER

27,564

Two-fold increase

–

3 years

CV death, MI, UA, stroke

1.09 (1.07–1.12)

✓

Heeschen et al. 200027

CAPTURE

447

>10

Admission

6 months

Death, MI

1.97 (1.21–3.59)

✓

Lindahl et al. 200028

FRISC

917

2–10

>72 hours

2 years

CV death

2.3 (1.3–4.1)

✓

James et al. 2003

GUSTO-IV

7,108

Quartiles

Admission

30 days

Death

1.31 (0.98–1.74)

Sánchez et al. 200430

Unicentric

5–8

Admission

22 months

CV death

4.5 (1.6–12.5)

✓

Ray et al. 2007

TACTICS-TIMI18

662

≥5.2

24 hours

6 months

Death, MI

1.08 (0.6–2.1)

Scirica et al. 2007

OPUS-TIMI16

1,383

48 hours

30 days

Death

3.6 (1.5–8.3)

✓

Raposeiras-Roubín et al. 201333

Unicentric

Continuous‡

Admission

19.8 months

CV death, MI

1.22 (1.09–1.35)

✓

Sanchís et al. 200434

Unicentric

655

∆5 mg/l

48 hours

6 months

CV death

1.02 (1.01–1.04)

✓

Ridker et al. 200535

PROVE-IT TIMI22

3,745

Quartiles

30 days

2.5 years

CV death, MI

1.7 (1.1–2.5)

✓

EMMACE-2

Stable CAD

ACS NSTEMI

31 32

NSTEMI/STEMI

Kilcullen et al. 2007

1,448

Continuous‡

<24 hours

1 year

Death

1.08 (1.05–1.10)

✓

O´Donoghue et al. 201637 CLARITY-TIMI28

1,140

>2.8

12 hours

30 days

CV death, HF

1.96 (1.17–3.30)

✓

Vanhaverbeke et al. 2018 SAINTEX-CAD

188

Continuous‡

Admission

17 months

Systolic dysfunction

5.1 (1.1–23.6)

✓

Mani et al. 2019

4,257

Continuous‡

96 hours

16 weeks

CV death, MI, UA, stroke

1.36 (1.13–1.63)

✓

VISTA-16

*No longer significant when IL-6 included in the model. †Including high-risk primary prevention. ‡CRP was used as a continuous variable in this study and a cutpoint was not defined. ✓ = significant difference; x = non-significant difference; ACS = acute coronary syndrome; CAD = coronary artery disease; CRP = C-reactive protein; CV = cardiovascular; HF = heart failure; NSTEMI = non-ST segment elevation MI; STEMI = ST-segment elevation MI; UA = unstable angina.

showed that elevation of CRP at hospital admission predicted a poor outcome in patients with unstable angina. Patients who had levels of CRP ≥0.3 mg/dl had more ischaemic episodes (MI, cardiac death and urgent coronary revascularisation) during hospital admission.40 CRP was also predictive of cardiac risk of mortality and MI (18.9% versus 9.5%; p=0.003) at 6-month follow-up in the 447 patients with unstable angina enrolled in the placebo arm of the CAPTURE trial.27 Hs-CRP concentrations increase rapidly after ACS, reaching a peak at 48–96 hours, with a progressive return to baseline levels over the following weeks.41 The measurement of hs-CRP in the acute phase of an ACS may reflect the combination of the low-grade systemic inflammation that triggers the atherosclerotic plaque rupture and the inflammatory response secondary to myocardial ischaemia and necrosis.19 Patients with non-ST segment elevation MI tend to have more stable hs-CRP concentrations in the acute phase of the coronary condition, given the lower degree of inflammation after myocardial necrosis in these patients.42 The origin of the elevated hs-CRP levels in patients with ACS is unknown. In fact, the correlation between markers of myocardial necrosis (troponins) and CRP is weak.43 CRP appears to be a marker of hyperresponsiveness of the inflammatory system to even minimal stimuli. The increases in CRP and IL-6 concentration observed after vascular damage in acute MI or coronary angioplasty correlated with baseline CRP and IL-6 levels, which

suggest that only those patients with high baseline CRP or IL-6 concentrations showed increased CRP values after vascular damage caused by angioplasty.44 This individual difference in response to inflammatory stimuli may have a genetic basis; certain haplotypes in the IL-1/IL-1R gene complex correlate with the sustained inflammatory response and the incidence of CAD.45 However, despite the weak correlation between markers of infarct size and hs-CRP, its predictive value for the development of recurrence is complementary and additive.43 Based on the OPUS TIMI-16 study, the risk of death at 30 days in 450 patients with ACS rose from 1% when CRP, troponin I, and B-type natriuretic peptide were negative to approximately 6% when all markers were positive.46 Hs-CRP concentrations can remain elevated for weeks after an acute coronary event, especially in patients with ST-segment elevation.45,46 Studies such as PROVE IT-TIMI 22 and Aggrastat-to-Zocor (A-to-Z) have shown that hs-CRP measured 30 days after the ACS event is an independent predictor of mortality and recurrent MI.47, 48 Moreover, an analysis of the VISTA-16 trial found that a higher baseline hs-CRP level (HR 1.36; 95% CI [1.13–1.63]) and a higher longitudinal hs-CRP level (HR 1.15; 95% CI [1.09–1.21]) were independently associated with major cardiovascular adverse events (composite of cardiovascular death, MI, non-fatal stroke, or unstable angina with documented ischaemia requiring

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C-reactive Protein, Patient Risk Stratification and Treatment hospitalisation).39 As suggested by this study, serial measurements of hsCRP 16 weeks after an ACS event may help to identify those patients at higher risk of mortality and morbidity.

inflammatory response.57 These studies confirm that pentameric CRP (pCRP) is more of a marker of inflammatory processes than a causative factor for these processes.

Severity, Extent and Activity of Atherosclerosis

However, these studies do not rule out a potential causal pro-inflammatory effect of non-circulating monomeric CRP (mCRP) in atherosclerosis. In fact, CRP monomers may be responsible for enhancing the inflammatory response in tissues after pCRP dissociation on the surface of activated platelets or damaged or apoptotic cells. Modification of the phospholipid composition of the cell membrane mediated by PLA2, released in inflamed or ischaemic tissues, may lead to the exposure of LPC, a natural ligand of pCRP, allowing the release of mCRP. These CRP monomers, predominantly located in tissue, may enhance inflammatory mechanisms, favouring the transendothelial migration of leukocytes, monocyte activation through Fcγ-RI/III receptors and the activation of complement inhibitors factor H and C4b-BP.58

No clear association has been found between CRP concentrations and the severity and extent of coronary atherosclerosis. Zebrack et al. reported that CRP concentration did not correlate with the number of severe (≥70%) or moderate (10–70%) coronary lesions in 2,554 patients with symptomatic ischaemic heart disease who had undergone coronary angiography. In fact, the risk of death or MI at 5 years in patients with high CRP concentrations (>2 mg/dl) and normal coronary arteries (11%) was higher than the risk in patients with low CRP concentrations (<1 mg/dl) and severe coronary disease (8%).49 Other studies have confirmed the independent and complementary predictive value of hs-CRP and the extent of coronary atherosclerosis for the development of cardiovascular events.20,22 Patients with hs-CRP and CAD extension score above the median had a five times higher risk of cardiac death and non-fatal MI at 1-year follow-up than patients with lower than median values (OR 5.0; 95% CI [2.3–10.6]). Therefore, the independent relationship between CRP and cardiovascular adverse events in patients with ischaemic heart disease suggests that clinical stability does not always reflect atherosclerotic plaque stability. Katritsis et al. found that CRP concentrations were correlated with the complex angiographic morphology of the atherosclerotic plaque, specifically with the presence of intracoronary thrombus and eccentric/ irregular discrete morphology.50 Other studies also confirm the correlation of hs-CRP, neutrophil count and neopterin with the number of angiographically complex lesions in patients with ACS.51 These inflammatory markers have also been associated with rapid progression of atherosclerosis. Hs-CRP and intercellular adhesion molecule-1 showed independent associations with rapidly progressive coronary disease, increasing the risk of its development fivefold (15% versus 75%; ptrend<0.001) if both markers are elevated (hs-CRP >3 mg/l and intercellular adhesion molecule-1 >271.4 ng/ml).52 Similar results were obtained in the GENERATION study, where CRP showed an independent association with the progression of CAD in previously untreated lesions at 1-year follow-up.53 These results confirm that endothelial dysfunction of inflammatory origin plays an important pathogenic role in the progression of coronary disease. CRP is a marker of inflamed, vulnerable and unstable atheroma plaque, but not of its severity or extent. The measurement of inflammatory markers can help clinicians to identify patients who are likely to suffer an inflammatory process capable of triggering an acute coronary event or the development of rapidly progressive atherosclerosis.

The Biological Functions of C-reactive Protein Cardiovascular Risk Factor or Marker?

Historically, CRP appeared to be directly involved in the different phases of the atherogenic process, from endothelial activation to the erosion or disruption of the atheroma plaque.54,55 However, the current belief is that all these biological effects of CRP were due to contamination by endotoxins or to the use of recombinant CRP of bacterial origin.56 Studies with highly purified human CRP have not demonstrated any biological effects. In fact, the inhibition of CRP synthesis with an antisense oligonucleotide was accompanied by an endotoxin-mediated decrease in CRP production, but there were no alterations in other components of the

The neutral results with pCRP infusion coincide with the data obtained from Mendelian randomisation studies which confirm that CRP is a predictor of cardiovascular events but is unlikely to play a direct aetiopathogenic role in the inflammatory processes associated with atherosclerosis, in contrast to the powerful evidence for IL-6 or IL-1β, which also seem to have a causative role in the pro-inflammatory process.59,60 Hs-CRP may be the surrogate biomarker for the activation of this pro-inflammatory pathway mediated by IL-1β and IL-6. As a result, translational pharmacological studies are currently focusing on the inhibition of the pathway mediated by the activation of the inflammasome NRLP3/IL-1β and IL-6. CRP appears to be a clinically ideal biomarker for monitoring the inhibition of this pro-inflammatory pathway and the potential reduction of recurrent cardiovascular events associated with its pharmacological inhibition.

Residual Inflammatory Risk

Despite adequate control of risk factors and even achieving the recommended therapeutic goals in secondary prevention, the 10-year risk of recurrence of major cardiovascular events in patients with atherosclerosis is 10–30%.61 There are pathophysiological mechanisms that explain a significant part of this residual risk of recurrence that persists even in patients with adequately controlled LDL-C.19 In the FOURIER study, the median rate of events during the 26 months of follow-up in patients receiving evolocumab, who presented a mean LDL-C of 0.78 mmol/l, was 9.8%.62 In the GLAGOV study, up to one-third of the patients receiving combined treatment of evolocumab and statins presented increased atheroma volume despite reaching a mean LDL-C of 0.95 mmol/l.63 These observations suggest that even with the significant reduction in lipid levels achieved by PCSK9 inhibitors there is a residual risk of atherosclerosis progression and recurrence of major cardiovascular events. Efforts to reduce this residual risk further have focused on enhancing the reduction of LDL-C, lipoprotein-a, triglicerides, prothrombosis, hyperglycaemia, and persistent subclinical arterial inflammation (Figure 1).19 This persistent vascular inflammation is one of the most important pathophysiological mechanisms in the development of recurrent cardiovascular events.

High Potency Statins ± Ezetimibe

The prevalence of this residual inflammatory risk (RIR) in secondary prevention has been analysed in several clinical studies. In the PROVE IT-TIMI 22 study, patients with RIR, defined by an LDL-C <1.8 mmol/l and

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C-reactive Protein, Patient Risk Stratification and Treatment Figure 1: Key Contemporary Residual Risk Pathways in Secondary Prevention Residual cholesterol risk

Residual inflammatory risk

Residual thrombotic risk

Residual triglyceride risk

Residual Lp(a) risk

Residual diabetes risk

Critical biomarker

LDL-C ≥1.42 mmol/l

hs-CRP ≥2 mg/l

No simple biomarker

TG ≥3.89 mmol/l

Lp(a) ≥0.78 mmol/l

Fasting glucose HbA1c

Randomised trial evidence LDL-C

PROVE-IT IMPROVE-IT SPIRE FOURIER ODYSSEY

CANTOS LoDoCo COLCOT

PEGASUS COMPASS THEMIS

REDUCE-IT STRENGTH PROMINENT

Lp(a)HORIZON

EMPA-REG CANVAS DECLARE CREDENCE LEADER SUSTAIN-6 REWIND

Biological issue

hs-CRP = high-sensitivity C-reactive protein; LDL-C = LDL cholesterol; Lp(a) = lipoprotein (a); TG = triglyceride. Source: Lawler et al. 2020.19 Adapted with permission from Oxford University Press.

hs-CRP >2 mg/l (44% of the total), presented an age-adjusted annual event rate of 3.1% compared to 2.4% in patients with hs-CRP <2 mg/l.35 In the IMPROVE-IT study, patients with LDL-C <1.8 mmol/l and hs-CRP> 2 mg/l (33% of all patients) presented a crude event rate of 33.7% at 7-year follow-up (defined as cardiovascular death, heart attack or non-fatal stroke) compared to 28% in patients with a hs-CRP <2 mg/l. In this same study, the combination of simvastatin and ezetimibe achieved the dual objective of controlling LDL-C <1.8 mmol/l and hs-CRP <2 mg/l in 50% of patients, while the use of simvastatin alone achieved this in only 29% of the patients, since ezetimibe produced a significant reduction of 0.3 mg/l in hs-CRP compared to the baseline value.64 These studies confirm that achieving the dual goal of lipid control (LDL-C <1.8 mmol/l) and inflammatory control (hs-CRP <2 mg/l) is accompanied by a significant reduction in the residual risk of cardiovascular events (Figure 2).65

PCSK9 Inhibitors

Large-scale studies with PCSK9 inhibitors have demonstrated this RIR in the development of cardiovascular events. In the SPIRE1 and 2 studies involving bococizumab, hs-CRP also identified patients with a higher risk of events despite adequate lipid control. Patients with hs-CRP >3 mg/l (34.9% of the total) had a cardiovascular event rate of 3.59 per 100 person years, compared to 1.96 in those with hs-CRP <1 mg/l, corresponding to adjusted HR of 1.62 (95% CI [1.14–2.30]) after adjustment for cardiovascular risk factors and on-treatment levels of LDL-C.24 The FOURIER study reported a 59% decrease in LDL-C concentrations using evolocumab, without any change in hs-CRP concentrations.62 Even

so, patients with hs-CRP >3 mg/l presented a greater reduction in events during treatment – absolute risk reduction 2.6% (HR 0.80; 95% CI [0.71– 0.90]), compared to 1.8% (HR 0.93; 95% CI [0.83–1.05]) in patients with hs-CRP 1–3 mg/l and 1.6% (HR 0.82; 95% CI [0.70–0.95]) in those with <1 mg/l.25 Even in patients achieving very low LDL-C levels (<0.52 mmol/l) 1 month after randomisation, those with a hs-CRP >3 mg/l had a 3-year primary event rate of 13.1% (95% CI [10.8–15.3]) compared to those with hs-CRP <1 mg/l (9.0% [95% CI [7.4–10.6]).25 Again, these large-scale studies with PCSK9 inhibitors identify hs-CRP as a predictor of cardiovascular events even in patients with very low LDL-C concentrations. In all these studies, RIR was usually more frequent in women or in patients with metabolic syndrome/diabetes, high blood pressure, heart failure, peripheral arterial disease, chronic kidney disease ≥G3a (eGFR <60 ml/ min/1.73 m2), a TIMI risk score in secondary prevention indicating high risk (≥4), or who were smokers.25

Percutaneous Coronary Intervention

The prognostic value of hs-CRP for predicting the recurrence of cardiovascular events has also been demonstrated after percutaneous coronary intervention (PCI).66 The single-centre study by Guedeney et al. included 3,013 patients undergoing PCI with a baseline LDL-C concentration of ≥1.8 mmol/l. RIR was defined as the persistence of hsCRP concentrations >2 mg/l in the clinical stability phase – at least 4 weeks after an ACS event, the index PCI, or any intercurrent infectious/ inflammatory process. Persistent high RIR (baseline and follow-up hs-CRP >2 mg/l) was recorded in 34.1% of patients and was associated with a

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C-reactive Protein, Patient Risk Stratification and Treatment Figure 2: Recurrent Cardiovascular Event Rates According to Achievement of Both LDL Cholesterol and hs-CRP Reduction Targets in PROVE-IT and IMPROVE-IT Trials PROVE-IT35 p<0.001

IMPROVE-IT64 p<0.001

Event rate (100 patients/year)

RR (% at 7 years)

4.6

0.10

0.4

38.9%

3.1

0.075

3.2

2.4

0.05

Neither target

0.025

0.00 0

Only LDL-C <1.8 mmol/l

0.5

1.0

1.5

Recurrent vascular events (%)

33.7% 33.4% 0.3

28.0%

0.2

Neither target

0.1

Only LDL-C <1.8 mmol/l

Only hs-CRP <2 mg/l

Both targets

2.0

2.5

0 0

Time (years)

Hs-CRP: high-sensitivity C-reactive protein; LDL-C: low-density lipoprotein cholesterol. Adapted from: Ridker et al. 201665 Used with permission from Oxford University Press.

higher risk of serious cardiovascular events (cardiovascular death, heart attack and non-fatal stroke) at 1-year follow-up (adjusted HR 2.10; 95% CI [1.45–3.02]) with an incidence rate of 152.4 (95% CI [126.0–184.4]) per 1,000 person years. In summary, RIR is one of the factors involved in the development of recurrent cardiovascular events. Large-scale studies on secondary prevention confirm that up to one-third of patients with coronary atherosclerosis present RIR, defined as the presence of hs-CRP concentrations >2 mg/l. This RIR is associated with a significantly increased risk of major cardiovascular events, regardless of baseline LDL-C concentrations. Even in patients with extremely low baseline LDL-C concentrations (LDL-C <0.52 mmol/l) undergoing treatment with PCSK9 inhibitors, hs-CRP can identify those with RIR and therefore improve prognostic stratification. The achievement of the dual goal of lipid and inflammatory control is accompanied by a further reduction in major cardiovascular events. Lipidlowering drugs bring down LDL-C levels and significantly reduce the recurrence of major cardiovascular events. Unlike PCSK9 inhibitors, statins and ezetimibe also reduce hs-CRP concentrations but despite their lack of effect on hs-CRP values, PCSK9 inhibitors reduce the recurrence of cardiovascular events in patients with RIR, as borne out by the results obtained with evolocumab in the FOURIER study. Until specific antiinflammatory or immunomodulatory drugs become part of the therapeutic arsenal against atherosclerosis, lipid-lowering drugs can help to reduce lipid and inflammatory residual risks in primary and secondary prevention (Table 2).

Anti-Inflammatory Treatments (Immunomodulators) in Atherosclerosis

The lack of a specific immunomodulatory treatment that interferes with the pro-inflammatory mechanisms involved in atherosclerosis has

restricted the clinical use of inflammatory biomarkers – especially hs-CRP – in risk stratification. Numerous immunomodulatory treatments that interfere with the different pro-inflammatory pathways involved in atherosclerosis, such as the humanised anti-LDL-ox antibody, succinobucol, darapladib, varespladib, losmapimod, methotrexate, anakinra and inclacumab, have been analysed in clinical trials, with negative results.67–75 However, the beneficial clinical effect in reducing recurrent major cardiovascular events with canakinumab and colchicine, which are directed against the pro-inflammatory signalling pathway of the NLRP3/ IL-1b inflammasome, have renewed the interest in inflammation as an aetiopathogenic mechanism of atherosclerosis.

Canakinumab

Canakinumab is a humanised monoclonal antibody directed against IL-1β. It is used to treat rheumatoid arthritis, gout and cryopryrin-associated periodic syndromes. In the CANTOS study, 10,061 patients with stable CAD, previous MI and hs-CRP concentrations of ≥2 mg/l were randomised to receive canakinumab at doses of 50 mg, 150 mg and 300 mg in quarterly subcutaneous injections versus placebo over a mean follow-up period of 3.7 years.76 The primary endpoint of the study was the combination of cardiovascular death, MI or non-fatal stroke. Canakinumab at a dose of 150 mg was associated with a significant reduction of 15% in the risk of the combined primary endpoint (HR 0.85; 95% CI [0.74–0.98]).76 After 48 months of treatment, reductions in hs-CRP of 35–40% were observed without any change in LDL-C concentrations. The patients who benefited from canakinumab treatment were those with reduced hs-CRP concentrations, known as cytokine responders. Patients with hs-CRP <2 mg/l 3 months after treatment had a significant 25% reduction in the risk of developing the combined endpoint (multivariable adjusted HR (HRadj) 0.75; 95 CI [0.66–0.85]).These patients also presented a 31% reduction in the risk of cardiovascular mortality (HRadj 0.69; 95% CI [0.56–0.85]) and

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C-reactive Protein, Patient Risk Stratification and Treatment Table 2: Effects of Lipid-lowering and Anti-inflammatory Drugs on LDL Cholesterol, High-sensitivity C-reactive Protein and Mayor Cardiovascular Events Drug

Study

Target

Event Reduction* Overall/CV Death Adverse Reduction† Events‡

LDL-C Reduction

Hs-CRP Reduction

Statins

PROVE-IT47

HMG-CoA reductase

Yes

Statins+ezetimibe IMPROVE-IT64

Multiple

Yes

Evolocumab

FOURIER

PCSK9

Yes

Alirocumab

ODYSSEY

PCSK9

Yes

Bococizumab

SPIRE 1 and SPIRE 224

PCSK9

Yes

Canakinumab

CANTOS

IL-1β

Yes

Colchicine

COLCOT and LoDoCo/280–82

NLRP3

Yes

Yes¶,**,††

*Reduction of combined primary endpoint. †Reduction of overall or cardiovascular death as endpoints. ‡Severe or fatal adverse events. In cytokine responders: patients with hs-CRP <2 mg/l after 3-month therapy with canakinumab. ||Risk of fatal infection and sepsis (canakinumab [3 groups] versus placebo). ¶No reduction in hs-CRP levels in COLCOT study (sub-analysis limited to 207 patients)82 and no data regarding hs-CRP in LoDoCo study.80 **Relative reduction of 60% in hs-CRP levels with colchicine in CAD patients with baseline hs-CRP ≥2 mg/l.83,84 ††Significant hs-CRP levels reduction with colchicine in LoDoCo2 proteomic substudy.85 CV = cardiovascular; HMG-CoA = 3-hydroxy-3-methyl-glutaryl-CoA; Hs-CRP = high-sensitivity C-reactive protein; LDL-C = LDL cholesterol; NRLP3 = NOD-, LRR- and pyrin domain-containing protein 3; PCSK9 = pro-protein convertase subtilisin/kexin type 9. §

all-cause mortality (HRadj 0.69; 95 CI [0.58–0.81]).77 The decrease in innate immunity recorded with the use of canakinumab was associated with a higher risk of fatal infections and sepsis (0.31 versus 0.18 events in the placebo group per 100 person years), mainly due to Gram-positive microorganisms (Table 2).76 In summary, the results of the CANTOS study demonstrate that inhibition of IL-1β is accompanied by a significant reduction in recurrent cardiovascular events in patients with coronary artery disease and a high RIR (hs-CRP >2 mg/l). The study confirms that the reduction of events runs in parallel to the reduction of inflammatory biomarkers, such as hs-CRP and IL-6 (Figure 3).78 Identifying RIR can help tailor available treatments to the specific risk profile of each patient and personalise cardiovascular therapy based on the predominant residual risk.

Colchicine

Colchicine is an alkaloid that derives from the autumn crocus. Its mechanism of action is not entirely clear, but it is known to bind to tubulins, interfering with mitotic spindles and causing microtubule depolymerisation. Thus, colchicine interferes with processes that depend on the adequate polymerisation of microtubules, such as chemotaxis, phagocytosis and the activation of nuclear factor (NF)-kB or the NLRP3 inflammasome.79 The LoDoCo study included 532 patients with stable coronary artery disease (>6 months) receiving 0.5 mg daily of colchicine versus placebo. After a mean follow-up of 3 years, there was a significant 67% reduction (HR 0.33; 95% CI [0.18–0.59]) in the combined criteria of ACS, out-of-hospital cardiac arrest and non-cardioembolic stroke, mainly caused by the reduction of ACS unrelated to stent disease.80 The recently published follow-up study LoDoCo2 randomised 5,522 patients with stable coronary disease >6 months to colchicine 0.5 mg daily versus placebo. After a mean follow-up period of 28.6 months, there was a 31% reduction in the combined endpoint of cardiovascular death, MI and coronary revascularisation secondary to myocardial ischaemia (HR 0.69; 95 CI [0.57–0.83]).81 The COLCOT study analysed 4,745 patients 30 days after an MI randomised to 0.5 mg daily of colchicine versus placebo with a mean follow-up of 22.6 months.82 The primary endpoint was the combination of cardiovascular death, recovered cardiac arrest, MI or stroke, and unstable angina requiring urgent revascularisation. Colchicine achieved a 23% reduction in the risk of major events (HR 0.77; 95% CI [0.61–0.96]), with an increased

risk of pneumonia (0.9% versus 0.4% of those in the placebo group; p=0.03). The patients had a baseline hs-CRP of 4.28 mg/l. No significant differences were observed in the reduction of hs-CRP at 6 months after the index event between colchicine versus placebo, but data for hs-CRP were only available for 207 patients. However, colchicine was shown to reduce hs-CRP concentrations by up to 60% in patients with atherosclerosis and baseline hs-CRP levels > 2 mg/l, regardless of the use of aspirin and atorvastatin.83,84 A proteomic substudy of LoDoCo2 demonstrated reductions in mean CRP concentrations from 1.52 mg/l to 1.0 mg/l (p<0.001), and in NLRP3 inflammasome-dependent proteins and neutrophil activity, confirming the important and varied anti-inflammatory effect of colchicine in atherosclerosis (Table 2).85

Current Recommendations

The clinical practice guidelines of the main scientific societies state that determining hs-CRP levels is a useful measure for primary cardiovascular prevention. However, the European Society of Cardiology (ESC) guidelines say that the determination of circulating biomarkers did not add relevant prognostic information to the prediction of cardiovascular risk obtained with the SCORE index, and so their measurement was not recommended in primary prevention – class of recommendation (COR): III; level of evidence (LOE): B.3 The 2011 ESC guidelines on the management of dyslipidaemia considered that the determination of hs-CRP could add prognostic information in patients with intermediate risk according to the SCORE index (≥1% and <5%), but the update in 2019 did not establish specific recommendations for its clinical use in primary prevention.86,87 In the 2019 American Heart Association (AHA) guidelines, hs-CRP is considered an enhancer of cardiovascular risk, so its determination is recommended for moderate risk patients (≥7.5% and <20% in the ASCVD risk index) for the initiation or intensification of lipid-lowering treatment with statins (COR: IIa; LOE: B–R).4 The guidelines establish an indication IIa (LOE: B-R) for the determination of hs-CRP. In these cases, the presence of an hs-CRP level of 2 mg/l would warrant the start of lipid-lowering treatment with moderate intensity statins (COR: I; LOE: A) in order to bring LDL-C down to 30–49% (COR: I; LOE: A). Despite the recommendations regarding hs-CRP in primary prevention, there are no specific guidelines for its determination in secondary prevention. The ESC consensus statement on inflammation in atherosclerosis concludes that CRP determination is not advised as it adds little value to the existing methods of cardiovascular risk assessment.88

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C-reactive Protein, Patient Risk Stratification and Treatment Figure 3: Effect of Canakinumab on Cardiovascular Events A

MACE

0.25

Placebo

0.15

0.10

0.05

0.00

Canakinumab 150/300 mg SC/3 months

0.15

0.10

0.05

HR 0.85 95% CI [0.76–0.96] p=0.007 0

Placebo

0.20

Canakinumab 150/300 mg SC/3 months

Cumulative incidence (%)

0.20

MACE-plus

0.25

0.00

HR 0.83 95% CI [0.74–0.92] p=0.0006 0

0.20

0.15

Cumulative incidence (%)

0.20

CV mortality

Placebo

Placebo Canakinumab hs-CRP >2 mg/l Canakinumab hs-CRP <2 mg/l

0.15

Canakinumab hs-CRP <2 mg/l

0.10

0.05

HR 0.69 95% CI [0.58–0.81] p=0.007

HR 0.69 95% CI [0.56–0.85] p=0.0004 0.00

0.00 0

0.25

MACE

Canakinumab Il-6 ≥1.65 ng/l

0.20

Cumulative incidence (%)

Canakinumab Il-6 <1.65 ng/l

0.15

0.10

0.15

0.10

0.05

HR 0.67 95% CI [0.57–0.80] p=0.0001

HR 0.64 95% CI [0.54–0.77] p=0.0001 0.00

Placebo

Canakinumab Il-6 ≥1.65 ng/l Canakinumab Il-6 <1.65 ng/l

Cumulative incidence (%)

MACE-Plus

Placebo 0.20

Time (years)

Time (years) C

Overall mortality

Canakinumab hs-CRP >2 mg/l Cumulative incidence (%)

Time (years)

0.00

Time (years)

Cumulative incidence of cardiovascular events in the placebo group and in the combined canakinumab groups (A)76 and after 3 months of treatment hs-CRP (B)77 or IL-6 (C)78 were above or below the commonly used clinical cut-off point. hs-CRP = high-sensitivity C-reactive protein; IL-6 = interleukin-6. MACE = non-fatal MI, non-fatal stroke, or cardiovascular death. MACE-plus = non-fatal MI, non-fatal stroke, hospitalisation for unstable angina requiring unplanned revascularisation or cardiovascular death. Adapted from: Ridker et al. 2018.78 Used with permission from Elsevier. Adapted from: Ridker et al. 2018.67 Used with permission from Oxford University Press.

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C-reactive Protein, Patient Risk Stratification and Treatment

Persistent elevation of hs-CRP despite adequate control of LDL-C has been shown to indicate the presence of RIR, but the absence of clinical pharmacology studies demonstrating a reduction in events with exclusively anti-inflammatory drugs has restricted the generalisation of the determination of hs-CRP in patients with CAD. However, the CANTOS study showed that the inhibition of IL-1β reduces recurrent cardiovascular events in patients with cardiovascular disease and persistent inflammation (hs-CRP ≥2 mg/l).76 The identification of new therapeutic targets will allow the development of drugs that are likely to help reduce the high residual risk of recurrence of cardiovascular events in patients with CAD.

Conclusion

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for primary and secondary prevention; it identifies a group of patients with residual inflammatory cardiovascular risk despite adequate LDL-C control. Achieving control of both LDL-C and CRP is associated with a greater reduction in the risk of adverse cardiovascular events than adequate control of LDL-C alone. However, despite the evidence of the usefulness of CRP for improving risk stratification in primary and secondary prevention, it remains underused in clinical practice. Advances in research on inflammatory mechanisms in atherosclerosis should provide new insights into the pathophysiology of the disease and help to define the aetiopathogenic factors involved in its development and the occurrence of plaque instability. The clinical studies in progress should allow a definitive assessment of the clinical use of CRP in primary and secondary prevention. The identification of new therapeutic targets in this field of clinical research will also promote the development of new drugs able to reduce the high residual risk of recurrence of major cardiovascular events in patients with coronary artery disease.

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grade natural human C-reactive protein is not proinflammatory in healthy adult human volunteers. Circ Res 2014;114:672–6. https://doi.org/10.1161/ CIRCRESAHA.114.302770; PMID: 24337102. 57. Noveck R, Stroes ES, Flaim JD, et al. Effects of an antisense oligonucleotide inhibitor of C-reactive protein synthesis on the endotoxin challenge response in healthy human male volunteers. J Am Heart Assoc 2014;3:e001084. https://doi. org/10.1161/JAHA.114.001084; PMID: 25012289. 58. Thiele JR, Habersberger J, Braig D, et al. Dissociation of pentameric to monomeric C-reactive protein localizes and aggravates inflammation: in vivo proof of a powerful proinflammatory mechanism and a new anti-inflammatory strategy. Circulation 2014;130:35–50. https://doi.org/10.1161/ CIRCULATIONAHA.113.007124; PMID: 24982116. 59. Lawlor DA, Harbord RM, Timpson NJ, et al. The association of C-reactive protein and CRP genotype with coronary heart disease: findings from five studies with 4,610 cases amongst 18,637 participants. PLoS One 2008;3:e3011. https://doi. org/10.1371/journal.pone.0003011; PMID: 18714384. 60. Interleukin-6 Receptor Mendelian Randomisation Analysis (IL6R MR) Consortium. The interleukin-6 receptor as a target for prevention of coronary heart disease: a mendelian randomisation analysis. Lancet 2012;379:1214–24. https://doi. org/10.1016/S0140-6736(12)60110-X; PMID: 22421340. 61. Kaasenbrood L, Boekholdt SM, van der Graaf Y, et al. Distribution of estimated 10-year risk of recurrent vascular events and residual risk in a secondary prevention population. Circulation 2016;134:1419–29; https://doi. org/10.1161/CIRCULATIONAHA.116.021314; PMID: 27682883. 62. Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med 2017;376:1713–22. https://doi. org/10.1056/NEJMoa1615664; PMID: 28304224. 63. Nicholls SJ, Puri R, Anderson T, et al. Effect of evolocumab on progression of coronary disease in statin-treated patients: the GLAGOV randomized clinical trial. JAMA 2016;316:2373–84. https://doi.org/10.1001/jama.2016.16951; PMID: 27846344. 64. Bohula EA, Giugliano RP, Cannon CP, et al. Achievement of dual low-density lipoprotein cholesterol and high-sensitivity C-reactive protein targets more frequent with the addition of ezetimibe to simvastatin and associated with better outcomes in IMPROVE-IT. Circulation 2015;132:1224–33. https://doi.org/10.1161/CIRCULATIONAHA.115.018381; PMID: 26330412. 65. Ridker PM. Residual inflammatory risk: addressing the obverse side of the atherosclerosis prevention coin. Eur Heart J 2016;37:1720–2. https://doi.org/10.1093/eurheartj/ ehw024; PMID: 26908943. 66. Guedeney P, Claessen BE, Kalkman DN, et al. Residual inflammatory risk in patients with low ldl cholesterol levels undergoing percutaneous coronary intervention. J Am Coll Cardiol 2019;73:2401–9. https://doi.org/10.1016/j. jacc.2019.01.077; PMID: 31097159. 67. Lehrer-Graiwer J, Singh P, Abdelbaky A, et al. FDG-PET imaging for oxidized LDL in stable atherosclerotic disease: a phase II study of safety, tolerability, and anti-inflammatory activity. JACC Cardiovasc Imaging 2015;8:493–4. https://doi. org/10.1016/j.jcmg.2014.06.021; PMID: 25457756. 68. Tardif JC, McMurray JJ, Klug E, et al. Effects of succinobucol (AGI-1067) after an acute coronary syndrome: a randomised, double-blind, placebo-controlled trial. Lancet 2008;371:1761– 8. https://doi.org/10.1016/S0140-6736(08)60763-1; PMID: 18502300. 69. STABILITY Investigators, White HD, Held C, et al. Darapladib for preventing ischemic events in stable coronary heart disease. N Engl J Med 2014; 370:1702–11. https://doi. org/10.1056/NEJMoa1315878; PMID: 24678955. 70. O’Donoghue ML, Braunwald E, White HD, et al. Effect of darapladib on major coronary events after an acute coronary syndrome: the SOLID-TIMI 52 randomized clinical trial. JAMA 2014;312:1006–15. https://doi.org/10.1001/ jama.2014.11061; PMID: 25173516. 71. Nicholls SJ, Kastelein JJP, Schwartz GG, et al. Varespladib and cardiovascular events in patients with an acute coronary syndrome: the VISTA-16 randomized clinical trial. JAMA 2014;311:252–62. https://doi.org/10.1001/ jama.2013.282836; PMID: 24247616. 72. O’Donoghue ML, Glaser R, Cavender MA, et al. Effect of losmapimod on cardiovascular outcomes in patients hospitalized with acute myocardial infarction: a randomized clinical trial. JAMA 2016;315:1591–9. https://doi.org/10.1001/

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jama.2016.3609; PMID: 27043082. 73. Ridker PM, Everett BM, Pradhan A, et al. Low-dose methotrexate for the prevention of atherosclerotic events. N Engl J Med 2019;380:752–62. https://doi.org/10.1056/ NEJMoa1809798; PMID: 30415610. 74. Morton AC, Rothman AMK, Greenwood JP, et al. The effect of interleukin-1 receptor antagonist therapy on markers of inflammation in non-ST elevation acute coronary syndromes: the MRC-ILA Heart Study. Eur Heart J 2015;36:377–84. https://doi.org/10.1093/eurheartj/ehu272; PMID: 25079365. 75. Stähli BE, Tardif JC, Carrier M, et al. Effects of P-selectin antagonist inclacumab in patients undergoing coronary artery bypass graft surgery: SELECT-CABG trial. J Am Coll Cardiol 2016;67:344–6. https://doi.org/10.1016/j. jacc.2015.10.071; PMID: 26796402. 76. Ridker PM, Everett BM, Thuren T, et al. Antiinflammatory therapy with canakinumab for atherosclerosis disease. N Eng J Med 2017;377:1119–31. https://doi.org/10.1056/ NEJMoa1707914; PMID: 28845751. 77. Ridker PM, MacFadyen JG, Everett BM, et al. Relationship of C-reactive protein reduction to cardiovascular event reduction following treatment with canakinumab: a secondary analysis from the CANTOS randomized controlled trial. Lancet 2018;391:319–28. https://doi.org/10.1016/S01406736(17)32814-3; PMID: 29146124. 78. Ridker PM, Libby P, MacFadyen JG, et al. Modulation of the interleukin-6 signalling pathway and incidence rates of atherosclerotic events and all-cause mortality: analyses from the Canakinumab Anti-inflammatory thrombosis Outcomes Study (CANTOS). Eur Heart J 2018;39:3499–507. https://doi.org/10.1093/eurheartj/ehy310; PMID: 30165610. 79. Li X, Thome S, Ma X, et al. MARK4 regulates NLRP3 positioning and inflammasome activation through a microtubule-dependent mechanism. Nat Commun 2017;8:15986. https://doi.org/10.1038/ncomms15986; PMID: 28656979. 80. Nidorf SM, Eikelboom JW, Budgeon CA, Thompson PL. Lowdose colchicine for secondary prevention of cardiovascular disease. J Am Coll Cardiol 2013;61:404–10. https://doi. org/10.1016/j.jacc.2012.10.027; PMID: 23265346. 81. Nidorf SM, Fiolet ATL, Mosterd A, et al. Colchicine in patients with chronic coronary disease. N Engl J Med 2020;383:1838–47. https://doi.org/10.1056/NEJMoa2021372; PMID: 32865380. 82. Tardif JC, Kouz S, Waters DD, et al. Efficacy and safety of low-dose colchicine after myocardial infarction. N Engl J Med 2019;381:2497–505. https://doi.org/10.1056/NEJMoa1912388; PMID: 31733140. 83. Vaidya K, Arnott C, Martínez GJ, et al. Colchicine therapy and plaque stabilization in patients with acute coronary syndrome. JACC Cardiovasc Imaging 2018;11:305–16. https:// doi.org/10.1016/j.jcmg.2017.08.013; PMID: 29055633. 84. Nidorf M, Thompson PL. Effect of colchicine (0.5mg twice daily) on high-sensitivity C-reactive protein independent of aspirin and atorvastatin in patients with stable coronary artery disease. Am J Cardiol 2007;99:805–7. https://doi. org/10.1016/j.amjcard.2006.10.039; PMID: 17350370. 85. Opstal TSJ, Hoogeveen RM, Fiolet ATL, et al. Colchicine attenuates inflammation beyond the inflammasome in chronic coronary artery disease: a LoDoCo2 proteomic substudy. Circulation 2020;142:1996–8. https://doi.org/10.1161/ CIRCULATIONAHA.120.050560; PMID: 32864998. 86. Reiner Z, Catapano AL, De Backer G, et al. ESC/EAS guidelines for the management of dyslipidaemias. Eur Heart J 2011;32:1769–818. https://doi.org/10.1093/eurheartj/ehr158; PMID: 21712404. 87. Mach F, Baigent C, Catapano AL, et al. 2019 ESC/EAS guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J 2019;41:111–88. https://doi.org/10.1093/eurheartj/ehz455; PMID: 31504418. 88. Tuñón J, Badimón L, Bochaton-Piallat ML, et al. Identifying the anti-inflammatory response to lipid lowering therapy: a position paper from the working group on atherosclerosis and vascular biology of the European Society of Cardiology. Cardiovasc Res 2019;115:10–9. https://doi.org/10.1093/cvr/ cvy293; PMID: 30534957. 89. Schwartz GG, Steg PG, Szarek M, et al. Alirocumab and cardiovascular outcomes after acute coronary syndrome. N Engl J Med 2018;379:2097–107. https://doi.org/10.1056/ NEJMoa1801174; PMID: 30403574.

Aortic Valve Stenosis

New Challenging Scenarios in Transcatheter Aortic Valve Implantation: Valve-in-valve, Bicuspid and Native Aortic Regurgitation Sandra Santos-Martínez

and Ignacio J Amat-Santos

CIBERCV, Cardiology Department, University Clinic Hospital of Valladolid, Valladolid, Spain

Abstract

Transcatheter aortic valve implantation (TAVI) is the most frequently performed structural technique in the field of interventional cardiology. Initially, this procedure was only used in patients with severe symptomatic aortic stenosis and prohibitive risk. Now, barely one decade after its introduction, TAVI indications extend to low- and intermediate-risk patients. Despite these advances, several challenging scenarios are still on the periphery of the evidence base for TAVI. These include valve-in-valve procedures, lower-risk patients with bicuspid aortic valve and the treatment of pure aortic regurgitation. Whereas the valve-in-valve indication has expanded rapidly, evidence for the use of TAVI compared with conventional surgery for bicuspid aortic valve is limited, including the best choice of device should TAVI be used. Evidence for TAVI in pure aortic regurgitation is still anecdotal because of suboptimal outcomes. Operators worldwide have described variations in the TAVI procedural technique to achieve commissural alignment and to minimise the rate of pacemaker use through cusp overlap implantation. In light of the potential clinical benefits, this may also be an area of further development. This review aims to discuss the current evidence available supporting the use of TAVI for these new indications.

Keywords

Transcatheter aortic valve implantation, interventional cardiology, aortic stenosis, valve-in-valve, devices. Disclosure: IJAS is on the European Cardiology Review editorial board; this did not influence peer review. SSM has no conflicts of interest to declare. Received: 21 May 2021 Accepted: 14 June 2021 Citation: European Cardiology Review 2021;16:e29. DOI: https://doi.org/10.15420/ecr.2021.12 Correspondence: Ignacio J Amat-Santos, Instituto de Ciencias del Corazón (ICICOR), Hospital Clínico Universitario de Valladolid, Ramón y Cajal 3, 47005 Valladolid, Spain. E: ijamat@gmail.com Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

The growing incidence of aortic stenosis (AS) in line with the increasingly elderly population has led to the aortic valve being the most commonly treated valve in Europe and North America, via both surgery and through percutaneous approaches.1 Since the first transcatheter aortic valve implantation (TAVI) procedure in 2002, application of this technique to all risk settings has rapidly advanced.2,3 In parallel, there has been an increase in off-label indications for this technology. Such indications have spearheaded the more frequent recommendation for TAVI in clinical practice guidelines in some scenarios. Nevertheless, in other scenarios, the current technology has not yet reached the point of being a better option than the classical alternative – surgical aortic valve replacement (SAVR). New indications – as well as alternative approaches for TAVI – have progressively expanded, preceded by application in compassionate-use settings. In this review, we aim to explore in detail the current boundaries of these indications by examining the main off-label uses of TAVI and the reported outcomes in such challenging scenarios.

Special Scenarios for TAVI

Several controversial indications currently exist for the TAVI procedure. In this review, we focus on the following scenarios: TAVI for valve-in-valve (ViV) procedures, TAVI for bicuspid AS and TAVI for pure aortic regurgitation (AR). Finally, recently developed implantation strategies are described in a dedicated section.

TAVI for Valve-in-valve Procedures

Structural Valve Deterioration of Bioprostheses

Compared with mechanical valves, bio-prostheses have limited durability, eventually failing within 5–20 years of the intervention. However, in these circumstances, treatment with ViV procedures can be used, as opposed to mechanical valves. Furthermore, bio-prostheses do not require the use of anticoagulation, minimising the associated risks.4 These factors have led to a significant increase in their use in the last two decades. Structural valve deterioration (SVD) is an acquired intrinsic bioprosthetic valve abnormality defined as deterioration of the leaflets or supporting structures resulting in thickening, calcification, tearing, or disruption of the prosthetic valve materials with eventual associated valve haemodynamic dysfunction. Mechanical stress, collagen fibre disruption and tissue calcification are the main elements involved in this process. Although there is not a standard definition for SVD, Dvir et al. proposed a practical definition of SVD in the Valve-in-Valve International Data registry and provided recommendations for the timing of clinical and imaging follow-up assessment.5 This definition describes SVD as a continuum instead of a binary categorical variable. Stage 1 correlates with early morphological leaflet changes, without haemodynamic sequelae. Stage 2 refers to morphological abnormalities of valve leaflets associated with haemodynamic dysfunction. This stage is divided according to the type of dysfunction – either stenosis (Stage 2S) or

TAVI in Challenging Scenarios Table 1: Larger Studies on Aortic Valve-in-valve Procedures Study

THV

Age (years) STS score Logistic Procedural Mean AR >2 PPI (%) THV 30-day 1-year (%) Euroscore Success (%) Gradient (%) Malposition Mortality Mortality (%) Post-ViV (%) (%) (%) (mmHg)

Eggebrecht et al. 20116

79.8 ± 7.1

11.6 ± 8.5

35.0 ± 18.5

100

17.0 ± 10

Bedogni et al. 25 20117

82.4 ± 3.2

8.2 ± 4.2

31.5 ± 14.8

100

13.8

Bapat et al. 20128

76.9 (43–92)

7.6 ± 3.8

31.8 ± 15.3

100

9.1

4.3

12.5

Linke et al. 20129

74.8 ± 8

31.3 ± 17

100

18 ± 8

7.4

3.7

7.4

12.5

Dvir et al. 201210

202

CV/ES

77.7 ± 10.4

11.8 ± 9.9

31.1 ± 16.4

93.1

15.9 ± 8.6

5.0

7.4

15.3

8.4

14.2

Dvir et al. 201411

459

CV/ES

77.6 ± 9.8

9.8 (6.2–16.1) 29 (19.1–42.3) 93.1

15.8 ± 8.9

5.4

8.3

15.3

7.6

16.8

Ihlberg et al. 45 201312

CV/ES

80.6 (61–91)

15.0 ± 10.8

35.4 ± 16.1

95.6

16.4 ± 8.7

2.2

4.4

11.9

Camboni et al. 201513

CV/ES/ ME/SY

77.8 ± 6.3

20.9 ± 8.8

16.1 ± 7.2

22.5

Webb et al. 201714

365

78.9 ± 10.2

9.1 ± 4.7

12.3 ± 9.8

97.5*

17.6 (16.2–19.1)

1.9

2.7

12.4

Zenses et al. 79 201815

CV/ES/P 74.5 ± 11.0

10.2 ± 2.7

78.5

22.2 ± 9.3

3.9

3.8

de Freitas Campos Guimaraes et al. 201816

116

CV/ES

76 ± 11

8.0 ± 5.1

94.8

18.5 ± 10.5

4.3

5.2

6.9

25.9 (3 years)

Tuzcu EM et al. 201817

1,150 CV/ES

79 (74–85)

6.9 (4.5–10.8) NA

96.9*

16.0 3.5 (10.0–22.0)

3.0

<1%

2.9

11.7

Holzamer et al. 201918

77 ± 8

6.8 ± 6.0

16 ± 8

11.4 ± 7.9

Values are mean ± SD or median (interquartile range). *Not explicit in text. Procedural success according to Valve Academic Research Consortium criteria. AR = aortic regurgitation; AN = ACURATE neo; CV = CoreValve; ES = Edwards SAPIEN; ME = Medtronic Engager; NA = Not available; P = Portico; PPI = permanent pacemaker implantation; SA = Symetis ACURATE; STS score = Society of Thoracic Surgeons predicted risk of mortality; THV = transcatheter heart valve.

regurgitation (Stage 2R) – because the clinical implications and speed of deterioration are likely to differ between these two failure modes. Investigators categorised a mixed moderate stenosis/regurgitation condition as Stage 2RS. Some patients in this Stage 2 SVD with symptoms could be considered for re-intervention. The most severe stage of SVD, classified as Stage 3, is the development of severe stenosis and/or regurgitation.

developing to help operators. These include fracturing the ring during post-dilation to improve the transvalvular gradients in patients with prior small bioprosthesis and a certain degree of miss-match, along with the BASILICA technique (bioprosthetic or native aortic scallop intentional laceration to prevent coronary artery obstruction).20,21 These procedures are based on short series of cases but are rapidly extending in light of the promising results (Figure 1).

Indications for the Valve-in-valve Procedure

A relatively new scenario – likely to soon become more common – is the TAVI-in-TAVI procedure. Little is known about the mid- and long-term durability of transcatheter aortic valves beyond the first decade of implantation.22 Although the transcatheter ViV procedure is now recognised as a good alternative to redo surgery in high-risk patients with failed surgical bioprostheses, there are specific risks of TAVI-in-TAVI that differ across each device. On the one hand, supra-annular self-expandable valves might present an increased risk of coronary occlusion if treated with the current devices and render the challenging access to the coronary ostia afterwards even more difficult. This is discussed in more detail in the ‘New Implantation Strategies for TAVI’ section, below. On the other hand, intra-annular devices might obtain worse residual gradients after ViV or have an increased risk of annular rupture if post-dilation is performed. Globally, the available data on this very new scenario – albeit scarce – appear favourable.

Until last decade, the standard of care for degenerated bioprosthesis (SVD Stage 3) was redo valve replacement. Due to its less invasive and appealing nature to both patients and physicians compared with redo open-heart surgery, ViV procedure rates continue to grow rapidly, even without CE mark approval for some of the current devices.5 Relatively small series and certain long registries of use of the device have been published and the findings of those with larger populations are summarised in Table 1.6–18

Tips and Tricks for Valve-in-valve Procedures

Positioning during ViV procedures can be very challenging as it is predicting the risk of coronary obstruction, more likely when the leaflets are sutured outside the sewing ring or in stentless valves.19 To facilitate better outcomes, better devices and dedicated techniques are rapidly

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TAVI in Challenging Scenarios Figure 1: Tips and Tricks for Valve-in-valve Procedures: Valve Fracturing and BASILICA A

13.1 mm

15.0 mm Leaflet wire puncture and snaring

Leaflet slicing

Valve-in-valve

A: Micro-CT analysis of ACURATE neo device (Boston Scientific) used for the valve-in-valve procedure showing difference of expansion before (13.1 mm) and after (15.0 mm) valve fracturing; B: Schematic explanation of the BASILICA technique. BASILICA = bioprosthetic aortic scallop intentional laceration to prevent iatrogenic coronary artery obstruction.

TAVI for Bicuspid Aortic Stenosis

Figure 2: Example of TAVI Using the Myval Device

Incidence and Specific Challenges of Bicuspid Aortic Stenosis

Bicuspid aortic valve (BAV) is the most common congenital valvular defect, occurring in 1–2% of the general population.23 BAV stenosis has been considered an anatomical challenge for TAVI for several reasons. First, there is often an extreme elliptical shape of the annulus and trend to aortic dilation – as opposed to the characteristic oval shape of the annulus in calcified tricuspid aortic valve (TAV) – that might be associated with greater leakage. Second, BAVs usually have higher point of coaptation of the cusps (Figure 2) that can result confounding during the procedure and increase the risk of valve embolisation. Finally, asymmetric distribution of calcium with a trend to bulky formations increases the risk of paravalvular leak and annulus rupture.24 All these elements have to be taken into account when TAVI is considered for a patient with BAV. Misdeployment is more frequent in patients with these abnormalities and might be associated with a higher rate of paravalvular regurgitation, prosthesis dysfunction or early degeneration of the implanted valve.25

Current Evidence

BAV patients have not been included in landmark trials of TAVI devices. To date, all specific studies analysing the different outcomes of TAVI in BAV and TAV patients are retrospective. Studies demonstrating the feasibility and safety of TAVI in BAV stenosis along with main baseline characteristics and procedural outcomes are summarised in Tables 2 and 3.26–37 Quintana et al. conducted a meta-analysis of studies mainly focused on earlygeneration devices.38 The analysis demonstrated that TAVI therapy was feasible and safe in BAV disease. The primary endpoint of 1-year all-cause mortality revealed 11.8% mortality in BAV compared with 15.06% in TAV patients, with no differences between groups (RR 1.03; 95% CI [0.70– 1.51]). However, the BAV group was associated with a decrease in device success and an increase in significant prosthetic valve regurgitation after TAVI compared to patients with TAV. Yoon et al. compared procedural and clinical outcomes in patients with BAV versus TAV including newer generation devices.39 Within the group receiving early-generation devices, BAV patients had more frequent

A and B: CT showing bicuspid aortic valve and suggested incidence for implantation; C and D: Valve implantation of Myval device (Meril Life), showing that virtual annulus is higher (white arrows) than for tricommisural aortic valve stenosis. CAU = caudal; CRA = cranial; LAO = left anterior oblique; RAO = right anterior oblique.

aortic root injury (4.5% versus 0.0%; p=0.015) when receiving the balloonexpanding device and moderate-to-severe paravalvular leak (19.4% versus 10.5%; p=0.02) when receiving the self-expanding devices. However, among patients with newer generation devices, procedural results were comparable across different prostheses. Cumulative allcause mortality rates at 2 years were comparable between bicuspid and tricuspid AS (17.2% versus 19.4%; p=0.28). Takagi et al. performed the latest meta-analysis available to date and demonstrated lack of statistical difference in pacemaker implantation rate and in early- and mid-term mortality (RR 1.35; 95% CI [0.94–1.93] and RR 1.00; 95 [CI 0.77–1.31], respectively).40 However, the BAV group presented a significant increase in prosthetic AR compared to TAV (RR 1.42; 95% CI [1.11–1.82]). This issue was less frequent with the use of balloon-expandable devices compared to self-expandable ones. Likely for this reason, the balloon-expandable prosthesis was the preferred option in the most recent studies (Table 2).

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TAVI in Challenging Scenarios Table 2: Characteristics and Baseline Data of Studies of TAVI in Bicuspid and Tricuspid Aortic Stenosis Study

Age (years)

Logistic Euroscore (%)

STS Score (%)

TF Approach Balloon(%) expandable (%)

BAV

TAV BAV

TAV

BAV

TAV

BAV TAV

Hayashida et al. 201325

208

82.0 ± 7.0

83.2 ± 6.5

19.9 ± 11.9

20.1 ± 11.4

61.9

50.5

52.4

83.7

Bauer et al. 201426

1357

80.7 ± 6.6

81.8 ± 6.2

18.0 ± 10.0 20.0 ± 13.0 81.6

88.0

31.6

18.0

Costopoulos et al. 201427 21

447

76.7 ± 7.1

79.8 ± 7.4

7.6 ± 4.2

7.8 ± 7.3

23.9 ± 12.0 24.4 ± 17.3 71.4

83.9

38.1

58.6

Kochman et al. 201428

77.6 ± 5.5

79.1 ± 6.8

19.2 ± 9.0

18.8 ± 8.7

78.6

77.4

17.9

Liu et al. 201529

75.4 ± 5.7

75.8 ± 5.5

5.6 ± 4.1

7.5 ± 5.9

16.1 ± 11.1

21.8 ± 14.7

86.7

92.0

0.0

Sannino et al. 201730

735

80.2 ± 8.4

81.8 ± 7.9

7.4 ± 3.9

7.6 ± 3.9

88.6

87.1

52.3

59.7

Yoon et al. 201731

546

77.2 ± 8.2

77.2 ± 8.8

4.6 ± 4.6

4.3 ± 3.0

16.1 ± 12.0

16.9 ± 13.9 79.1

78.8

57.7

57.1

Arai et al. 201732

143

81.3 ± 5.1

82.6 ± 6.2

19.0 ± 12.5 18.1 ± 11.0

70.0

87.4

100.0 100.0

Liao et al. 201733

80.2 ± 8.4

81.8 ± 7.9

7.9 ± 4.0

8.6 ± 4.4

100.0 100.0

0.0

De Biase et al. 201834

166

81.4 ± 7.6

82.9 ± 5.7

5.1 ± 3.3

5.1 ± 2.9

98.8

60.2

36.7

Xiong et al. 201835

74.0 (68.0–77.0) 75.0 (68.0–79.0)

6.5 (4.4–9.3) 8.3 (5.2–9.5) NA

98.5

100.0

0.0

Kawamori et al. 201836

239

80 (70.5–83.0)

97.6

98.7

100.0 100.0

Makkar et al. 201937

2,691

2,691 74.0 (66.0–81.0) 74.0 (66.0–81.0)

4.9 ± 4.0

5.1 ± 4.2

93.6

93.9

100.0 100.0

83 (78.0–87.0)

Values are mean ± SD or median (interquartile range). BAV = bicuspid aortic valve; NA = not available; STS score = Society of Thoracic Surgeons predicted risk of mortality; TAV = tricuspid aortic valve; TAVI = transcatheter aortic valve implantation; TF = transfemoral.

Table 3: Outcomes of Studies of TAVI in Bicuspid and Tricuspid Aortic Stenosis Study

Permanent Pacemaker (%)

Mean Prosthetic Gradient (mmHg) Prosthetic AR >2 (%)

30-day mortality

BAV

TAV

BAV

TAV

BAV

TAV

BAV

TAV

Hayashida et al. 2013

10.0 ± 3.4

9.7 ± 4.1

19.0

14.9

14.3

7.2

1 (4.8)

17 (8.2)

Bauer et al. 201426

5.5 ± 7.1

5.9 ± 6.8

23.7

15.0

15.8

35.0

4 (10.5)

5 (11.0)

Costopoulos et al. 2014

10.3 ± 5.7

10.5 ± 4.7

23.8

21.7

14.3

15.0

3 (14.3)

3.6 (3.6)

Kochman et al. 2014

11.5 ± 6.4

10.4 ± 4.5

32.1

22.6

28.6

33.3

1 (3.6)

6 (7.1)

Liu et al. 201529

9.6 ± 3.1

11.0 ± 4.2

0.0

4.0

13.3

12.0

1 (6.7)

2 (8.0)

Sannino et al. 2017

7.96 ± 4.15

8.5 ± 4.2

5.3

5.0

22.7

18.1

3 (3.4)

23 (3.1)

Yoon et al. 201731

10.8 ± 6.7

10.2 ± 4.4

10.4

6.8

15.4

20 (3.7)

18 (3.3)

Arai et al. 2017

0.0

6.0

0.0

8.4

0 (0.0)

1 (0.7)

Liao et al. 2017

13.7 ± 8.4

13.0 ± 7.5

1.2

0.0

24.1

28.6

8 (9.2)

3 (4.3)

De Biase et al. 201834

10.0 ± 4.0

9.8 ± 4.5

3.6

2.4

14.5

10.2

4 (4.8)

5 (3.0)

Xiong et al. 2018

13.5 (10.0–17.0)

13.0 (10.0–18.0)

25.4

22.4

6 (9.0)

2 (4.1)

Kawamori et al. 201836

11.9 ± 4.2

10.8 ± 4.0

2.4

1.3

22.0

9.6

0 (0.0)

1 (0.4)

Makkar et al. 2019

9.1

7.5

66 (2.6)

63 (2.5)

32 33

Values are mean ± SD, median (interquartile range) or n (%). AR = aortic regurgitation; BAV = bicuspid aortic valve, NA = not available; TAV: tricuspid aortic valve; TAVI = transcatheter aortic valve implantation.

Is TAVI the Future Gold Standard for BAV Treatment?

In agreement with the gathered data, TAVI has been demonstrated to be an excellent option for selected BAV cases. In order to extend indications, Elbadawi et al. compared TAVI and SAVR, demonstrating similar inhospital mortality (3.1% versus 3.1%; OR 1.00; 95% CI [0.60–1.67]).41 There were no differences between TAVI and SAVR in the rates of procedural complications and early outcomes such as cardiac arrest, cardiogenic

shock, acute kidney injury, cardiac tamponade or acute stroke. TAVI was associated with lower rates of acute MI, post-operative bleeding complications and a shorter length of hospital stay. Conversely, TAVI was also associated with a higher incidence of complete heart block and permanent pacemaker insertion (13.8% versus 4.6%; OR 3.32; 95% CI [2.34–4.71]; p<0.001). However, no randomised study has yet been conducted to compare these two alternatives.

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TAVI in Challenging Scenarios Table 4: Larger Series and Registries on TAVI for Pure Aortic Regurgitation

Study

THV

Conversion Procedural to Open THV-in- Annulus ReSuccess (%) Surgery THV (%) Rupture intervention

PPI (%)

>/= 30-day Moderate Mortality PAR (%)

Roy et al. 201346

74.4

2.3

18.6

16.3

4.7

9.3

Seiffert et al. 2014

96.8

0.0

6.5

0.0

12.9

Testa et al. 2014

76.9

0.0

19.2

7.7

23.1

Frerker et al. 201549

CV/ES

81.8

27.3

22.7

Zhu et al. 2016

93.9

3.0

6.1

3.0

Yoon et al. 2017 (EGD)45

119

CV/ES

61.3

3.4

24.4

1.7

5.0

17.5

18.8

13.4

Yoon et al. 2017 (NGD)45

212

CV/ES/JE/JV/SA/ DF/ME/LO/P

81.1

3.8

12.7

1.4

3.8

18.6

4.2

9.4

Sawaya et al. 2017

CV/ES/JE/DF/LO

70.5

16.7

2.6

18.5

13.4

14.3

Liu et al. 2018

97.7

2.3

0.0

4.7

2.3

2.4

2.3

De Backer et al. 2018 (EGD)53

109

CV/ES

46.5

3.7

25.5

17.1

De Backer et al. 2018 (NGD)53

145

CV/ES/JE/SA/DF/ ME/LO/P 82.5

4.4

4.7

7.7

Silaschi et al. 201854

3.7

0.0

3.3

3.8

0.0

10.0

88.9

AR = aortic regurgitation; CV = CoreValve; DF = Direct Flow; EGD = early-generation device; ES = Edwards SAPIEN; JV = J-Valve; JE = JenaValve; LO = Lotus; ME = Medtronic Engager; NA = not available; NGD = new-generation device; P = Portico; PAR = paravalvular aortic regurgitation; PPI = permanent pacemaker implantation; SA = Symetis ACURATE; THV = transcatheter heart valve.

TAVI for Pure Aortic Regurgitation

Clinical Course and Current Management

AR is characterised by a prolonged silent clinical course. When patients with severe AR become symptomatic, they present with congestive heart failure owing to volume overload, increased wall stress and left ventricular dysfunction.1 The anatomy in patients with native valve AR is often challenging, with dilated aortic root, dilated ascending aorta and – often – an elliptical annulus.42 Finally, patients with AR are usually referred for valve replacement at a younger age. For these reasons, SAVR is the standard therapy.1

Mechanisms of Aortic Regurgitation

Different aetiologies for AR have been described, with degenerative, congenital and rheumatic causes the more frequent. Less often, radiotherapy or healed infective endocarditis (IE) can be responsible for this condition. Patients who have recovered after IE but with significant valve damage represent a small but challenging population, frequently with comorbidities that increase operative risk. In recent research, TAVI in this scenario was demonstrated feasible with low risk of IE relapse at 1-year follow-up, and comparable mortality rates to the TAVI procedure in alternative settings.43 However, one-quarter of the cases presented residual significant AR.

The Role of TAVI

As a result of a clinical need, inoperable or high-risk patients with AR have been treated with TAVI worldwide.44 Scarce valve calcification is considered a contraindication for TAVI since it increases risks because of poor anchoring of the device.45 Since Roy et al. published the first case series of TAVI for pure native AR, other retrospective studies have tried to increase the evidence supporting the feasibility of the procedure for this indication.46–54 As in other TAVI scenarios, pre-procedure echocardiography and multislice 3D CT should be considered mandatory. Careful examination of the annulus, sinus of Valsalva diameters, and ascending aortic diameter

measurement are essential. Valve sizing should be according to perimeter and area, but frequently adequately contrasting the annulus during CT is more difficult and the dimensions of the annulus can quickly change if the procedure is not performed shortly after the imaging evaluation. Moreover, greater oversizing might be needed. Table 4 summarises the main registries on this topic.46–54 TAVI in pure native AR with early-generation devices was associated with relatively high rates of procedural complications. Development of new-generation devices improved procedural outcomes with lower rates of need for second valve implantation or significant post-procedural AR (≥grade 2). However, recent studies suggest that a significant reduction in the degree of AR is not sufficient because post-procedural AR ≥2 remains associated with higher rates of re-hospitalisation and all-cause mortality suggesting the need for dedicated devices.

TAVI Devices for the Treatment of Aortic Regurgitation

The Medtronic CoreValve (Medtronic) was preferentially chosen in early reports of TAVI for treating native pure AR. Its self-expandable properties were considered to offer stability during the implantation and ensure anchoring. However, the frequent need for a second valve and the high rates of significant post-procedural AR resulted in modest device success, as defined by the Valve Academic Research Consortium, point to the limitations of this device for the use in this setting.55 Other self-expanding transcatheter valves as ACURATE neo (Boston Scientific), Lotus (Boston Scientific), Portico (Abbott) and the balloon-expandable Edwards SAPIEN XT/S3 (Edwards Lifesciences) have been used for AR treatment (Table 4 and Figure 3) with variable outcomes but – in all cases – poorer than their results in AS patients. Novel devices have been developed for treating patients with severe pure AR, such as the JenaValve (JenaValve Technology), the J-Valve (JieCheng Medical Technology; not available in Europe) and the Direct Flow Valve System (Direct Flow Medical), but there is still a lack of evidence to extend use for this indication.

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TAVI in Challenging Scenarios Figure 3: Case Example of Aortic Regurgitation

Figure 4: Commissural Alignment

A and B: Pure aortic regurgitation without calcification of the leaflets; C and D: Echocardiographically guided implantation of the SAPIEN 3 device (Edwards Lifesciences).

New Implantation Strategies for TAVI Commissural Alignment

Final position of the neo-commissures is uncontrolled during transcatheter aortic valve implantation (TAVI), potentially hindering coronary access in future procedures, but also increasing the risk of coronary obstruction if a TAVI-in-TAVI procedure is eventually required due to valve degeneration. This risk is usually prevented by BASILICA technique for ViV interventions, but surgical bioprostheses are well aligned with the coronary ostia and therefore tearing the prosthesis leaflet is enough to avoid its occlusion since the tear is always in front of the ostium. On the contrary, until recently, TAVI devices were not aligned, which means that, even after BASILICA, if a new TAVI is implanted within a former degenerated one with the coronary ostia close to the commissural posts, the risk of coronary obstruction is still high after leaflet tearing. Such positioning might can make engaging the coronaries with a catheter particularly challenging, especially if a TAVI device extending into the ascending aorta has been implanted. Different strategies have been developed to optimise coronary alignment, the great majority of them focused on rotation of the delivery system inside the vascular anatomy, which might lack of accuracy and is not riskfree due to intravascular manipulation of the device.56,57 More recently, a new strategy for self-expandable devices based on the estimation of a patient-specific rotation of the delivery system before introducing it into the patient has been described.58 This strategy is based on CT analysis with a specific software and can be complemented by the use of a dedicated tool designed for precise measurement of the exact number of degrees that the delivery system is rotated (Figures 4A and 4B). Furthermore, the concept can be applied to

A: Simulated implant of ACURATE neo valve (Boston Scientific) with coronary overlap; B: after predicted commissural alignment. The required degree of rotation of the delivery system before accessing the vascular anatomy is precisely obtained by a dedicated device. C: After analysis with dedicated software, the correct position of the commissures during crimping of a balloonexpandable device is obtained. The intended result is shown in a 3D printing model.

Figure 5: Coplanar and Cusp Overlap Views with Simulated ACURATE Neo Valve Coplanar

Cusp overlap

Coplanar and cusp overlap views with simulated ACURATE Neo Valve (Boston Scientific), as seen angiographically with successful commissural alignment.

balloon-expandable devices by crimping the valve with the commissure in a specific position and advancing the delivery system as recommended by the manufacturer (Figure 4C).

Optimal Valve Implantation Depth

Since description of the technique, the vast majority of operators have used the three-cusp coplanar view, where the three aortic cusps are angiographically aligned, having the right coronary cusp (RCC) between

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TAVI in Challenging Scenarios the noncoronary cusp (NCC) and the left coronary cusp (LCC). However, description of cusp-overlap view, comprising overlapping the RCC and LCC (Figure 5) has been associated with a significant reduction in pacemaker rates with self-expanding prostheses. First, this projection eliminates parallax of the delivery catheter and presents the delivery catheter more centred across the aortic valve. Second, and most important, the en-face view of NCC allows higher deployment – reducing conduction disturbances – and simultaneously minimising the risk of device aortic displacement, especially in large annuli with minimal oversizing.59 Recently, Ben-Shoshan et al. compared the double S-Curve technique versus cusp-overlap view.60 This method is based in automated software calculations of optimal projection, which is an S-shaped curve of continuous pairs of C-arm angulations orthogonal to the axial plane of the aortic valve annulus. The second S-curve is the delivery catheter calculation. At the intersection point of these two curves, both delivery catheter and aortic annulus are perpendicular amongst them without foreshortening. Both cusp-overlap and double S-curve models provide right and caudal projections in most cases (Figure 5). 1. Baumgartner H, Falk V, Bax JJ, et al. 2017 ESC/EACTS guidelines for the management of valvular heart disease. Eur Heart J 2017;38:2739–91. https://doi.org/10.1093/ eurheartj/ehx391; PMID: 28886619. 2. Leon MB, Smith CR, Mack MJ, et al. Transcatheter or surgical aortic-valve replacement in intermediate-risk patients. N Engl J Med 2016;374:1609–220. https://doi. org/10.1056/NEJMoa1514616; PMID: 27040324. 3. Mack MJ, Leon MB, Thourani VH, et al. Transcatheter aorticvalve replacement with a balloon-expandable valve in lowrisk patients. N Eng J Med 2019;380:1695–705. https://doi. org/10.1056/NEJMoa1814052; PMID: 30883058. 4. Paradis JM, Del Trigo M, Puri R, et al. Transcatheter valve-invalve and valve-in-ring for treating aortic and mitral surgical prosthetic dysfunction. J Am Coll Cardiol 2015;66:2019–37. https://doi.org/10.1016/j.jacc.2015.09.015; PMID: 26516006. 5. Dvir D, Bourguignon T, Otto CM, et al. Standardized definition of structural valve degeneration for surgical and transcatheter bioprosthetic aortic valves. Circulation 2018;137:388–99. https://doi.org/10.1161/ CIRCULATIONAHA.117.030729; PMID: 29358344. 6. Eggebrecht H, Schäfer U, Treede H, et al. Valve-in-valve transcatheter aortic valve implantation for degenerated bioprosthetic heart valves. J Am Coll Cardiol Intv 2011;4:1218– 27. https://doi.org/10.1016/j.jcin.2011.07.015; PMID: 22115663. 7. Bedogni F, Laudisa ML, Pizzocri S, et al. Transcatheter valvein-valve implantation using Corevalve Revalving System for failed surgical aortic bioprostheses. J Am Coll Cardiol Intv 2011;4:1228–34. https://doi.org/10.1016/j.jcin.2011.10.002; PMID: 22115664. 8. Bapat V, Attia R, Redwood S, et al. Use of transcatheter heart valves for a valve-in-valve implantation in patients with degenerated aortic bioprosthesis: technical considerations and results. J Thorac Cardiovasc Surg 2012;144:1372–9. https://doi.org/10.1016/j.jtcvs.2012.07.104; PMID: 23140962. 9. Linke A, Woitek F, Merx MW, et al. Valve- in-valve implantation of Medtronic CoreValve prosthesis in patients with failing bioprosthetic aortic valves. Circ Cardiovasc Interv 2012;5:689–97. https://doi.org/10.1161/ CIRCINTERVENTIONS.112.972331; PMID: 23048050. 10. Dvir D, Webb JG, Brecker, et al. Transcatheter aortic valve replacement for degenerative bioprosthetic surgical valves: Results from the Global Valve-in-Valve Registry. Circulation 2012;126:2335–44. https://doi.org/10.1161/ CIRCULATIONAHA.112.104505; PMID: 23052028. 11. Dvir D, Webb JG, Bleiziffer S, et al. Transcatheter aortic valve implantation in failed bioprosthetic surgical valves. JAMA 2014;312:162–70. https://doi.org/10.1001/ jama.2014.7246; PMID: 25005653. 12. Ihlberg L, Nissen H, Nielsen NE, et al. Early clinical outcome of aortic transcatheter valve- in-valve implantation in the Nordic countries. J Thorac Cardiovasc Surg 2013;146:1047–54. https://doi.org/10.1016/j.jtcvs.2013.06.045; PMID: 23998786. 13. Camboni D, Holzamer A, Flörchinger B, et al. Single institution experience with transcatheter valve-in-valve implantation emphasizing strategies for coronary protection.

Conclusion

The TAVI procedure is rapidly expanding in use, but limited evidence exists for certain challenging indications. The ViV procedure is still not fully established, although it has become the preferred alternative for failing bio-prostheses. In order to obtain optimal outcomes, operators need to master several complex techniques such as valve fracturing and BASILICA. TAVI for BAV stenosis might be a good alternative in terms of mortality and major complications but has not been demonstrated superior to surgery. If TAVI is decided, the best device to use remains unclear since balloon-expandable prosthesis might have slightly higher rate of annular rupture and self-expanding devices a greater rate of pacemaker and paravalvular leak. Finally, there is a clear need for new devices to improve the results of TAVI for the treatment of AR. Until then, TAVI should be considered only in prohibitive risk patients and after careful imaging evaluation. Novel devices along with optimised implantation strategies will increase success rates with the TAVI procedure, reducing complications such as valve embolisation and conduction disturbances and simplifying future interventions in patients harbouring percutaneous valves.

Ann Thorac Surg 2015;99:1532–8. https://doi.org/10.1016/j. athoracsur.2014.11.047; PMID: 25661576. 14. Webb JG, Mack MJ, White JM, et al. Transcatheter aortic valve implantation within degenerated aortic surgical bioprostheses: PARTNER 2 valve-in-valve registry. J Am Coll Cardiol 2017;69:2253–62. https://doi.org/10.1016/j. jacc.2017.02.057; PMID: 28473128. 15. Zenses AS, Dahou A, Salaun E, et al. Haemodynamic outcomes following aortic valve-in-valve procedure. Open Heart 2018;5:e000854. https://doi.org/10.1136/ openhrt-2018-000854; PMID: 30018783. 16. de Freitas Campos Guimaraes, Urena M, Wijeysundera HC, et al. Long-term outcomes after transcatheter aortic valvein-valve replacement. Circ Cardiovasc Interv 2018;11:e007038. https://doi.org/10.1161/CIRCINTERVENTIONS.118.007038; PMID: 30354588. 17. Tuzcu EM, Kapadia SR, Vemulapalli S, et al. Transcatheter aortic valve replacement of failed surgically implanted bioprostheses: The STS/ACC registry. J Am Coll Cardiol 2018;72:370–82. https://doi.org/10.1016/j.jacc.2018.04.074; PMID: 30025572. 18. Holzamer A, Kim WK, Andreas Rück, et al. Valve-in-valve implantation using the ACURATE Neo in degenerated aortic bioprostheses: an international multicenter analysis. J Am Coll Cardiol Intv 2019;12:2309–16. https://doi.org/10.1016/j. jcin.2019.07.042; PMID: 31753302. 19. Amat-Santos IJ, Gutiérrez H, Sathananthan J, et al. Fracture of small Mitroflow aortic bioprosthesis following valve-invalve transcatheter aortic valve replacement with ACURATE neo valve valve – From bench testing to clinical practice. Catheter Cardiovasc Interv 2019;10:e005216. https://doi. org/10.1002/ccd.28347; PMID: 31140682. 20. Khan JM, Dvir D, Greenbaum AB, et al. Transcatheter laceration of aortic leaflets to prevent coronary obstruction during transcatheter aortic valve replacement: concept to first-in-human. J Am Coll Cardiol Intv 2018;11:677–89. https://doi.org/10.1016/j.jcin.2018.01.247; PMID: 29622147. 21. Salaun E, Zenses AS, Clavel MA, et al. Valve-in-valve procedure in failed transcatheter aortic valves. JACC Cardiovasc Imaging 2019;12:198–202. https://doi.org/10.1016/j. jcmg.2018.03.011; PMID: 29778868. 22. Michelena HI, Desjardins VA, Avierinos JF, et al. Natural history of asymptomatic patients with normally functioning or minimally dysfunctional bicuspid aortic valve in the community. Circulation 2008;117:2776–84. https://doi. org/10.1161/CIRCULATIONAHA.107.740878; PMID: 18506017. 23. Watkins C, Gupta A, Griffith BP. Preoperative imaging. Transcatheter Aortic Valve Replacement: A How-to Guide for Cardiologists and Cardiac Surgeons. 1st ed. Cham, Switzerland: Springer International Publishing AG, 2018;40–1. https://doi. org/10.1007/978-3-319-93396-2_5. 24. Buellesfeld L, Stortecky S, Kalesan B, et al. Aortic root dimensions among patients with severe aortic stenosis undergoing transcatheter aortic valve replacement. JACC Cardiovasc Interv 2013;1:72–83. https://doi.org/10.1016/j. jcin.2012.09.007; PMID: 23347864. 25. Hayashida K, Bouvier E, Lefèvre T, et al. Transcatheter aortic valve implantation for patients with severe bicuspid aortic

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valve stenosis. Circ Cardiovasc Interv 2013;6:284–91. https:// doi.org/10.1161/CIRCINTERVENTIONS.112.000084; PMID: 23756698. 26. Bauer T, Linke A, Sievert H, et al. Comparison of the effectiveness of transcatheter aortic valve implantation in patients with stenotic bicuspid versus tricuspid aortic valves (from the German TAVI Registry). Am J Cardiol 2014;113:518– 21. https://doi.org/10.1016/j.amjcard.2013.10.023; PMID: 24342758. 27. Costopoulos C, Latib A, Maisano F, et al. Comparison of results of transcatheter aortic valve implantation in patients with severely stenotic bicuspid versus tricuspid or nonbicuspid valves. Am J Cardiol 2014;113:1390–3. https:// doi.org/10.1016/j.amjcard.2014.01.412; PMID: 24581922. 28. Kochman J, Huczek Z, Scisło P, et al. Comparison of oneand 12-month outcomes of transcatheter aortic valve replacement in patients with severely stenotic bicuspid versus tricuspid aortic valves (results from a multicenter registry). Am J Cardiol 2014;114:757–62. https://doi. org/10.1016/j.amjcard.2014.05.063; PMID: 25037674. 29. Liu XB, Jiang JB, Zhou QJ, et al. Evaluation of the safety and efficacy of transcatheter aortic valve implantation in patients with a severe stenotic bicuspid aortic valve in a Chinese population. J Zhejiang Univ Sci B 2015;16:208–14. https://doi. org/10.1631/jzus.B1500017; PMID: 25743122. 30. Sannino A, Cedars A, Stoler RC, et al. Comparison of efficacy and safety of transcatheter aortic valve implantation in patients with bicuspid versus tricuspid aortic valves. Am J Cardiol 2017;120:1601–6. https://doi.org/10.1016/j. amjcard.2017.07.053; PMID: 28886853. 31. Yoon SH, Bleiziffer S, De Backer ,O et al. Outcomes in transcatheter aortic valve replacement for bicuspid versus tricuspid aortic valve stenosis. J Am Coll Cardiol 2017;69:2579–89. https://doi.org/10.1016/j.jacc.2017.03.017; PMID: 28330793. 32. Arai T, Lefèvre T, Hovasse T, et al. The feasibility of transcatheter aortic valve implantation using the Edwards SAPIEN 3 for patients with severe bicuspid aortic stenosis. J Cardiol 2017;70:220–24. https://doi.org/10.1016/j. jjcc.2016.12.009; PMID: 28209261. 33. Liao YB, Li YJ, Xiong TY, et al. Comparison of procedural, clinical and valve performance results of transcatheter aortic valve replacement in patients with bicuspid versus tricuspid aortic stenosis. Int J Cardiol 2018;254:69–74. https://doi.org/10.1016/j.ijcard.2017.12.013; PMID: 29246428. 34. De Biase C, Mastrokostopoulos A, Philippart R, et al. Aortic valve anatomy and outcomes after transcatheter aortic valve implantation in bicuspid aortic valves. Int J Cardiol 2018;266:56–60. https://doi.org/10.1016/j.ijcard.2018.01.018; PMID: 29887473. 35. Xiong TY, Wang X, Li YJ, et al. Less pronounced reverse left ventricular remodeling in patients with bicuspid aortic stenosis treated with transcatheter aortic valve replacement compared to tricuspid aortic stenosis. Int J Cardiovasc Imaging 2018;34:1761–67. https://doi.org/10.1007/s10554-0181401-6; PMID: 29915878. 36. Kawamori H, Yoon SH, Chakravarty T, et al. Computed tomography characteristics of the aortic valve and the

TAVI in Challenging Scenarios geometry of SAPIEN 3 transcatheter heart valve in patients with bicuspid aortic valve disease. Eur Heart J Cardiovasc Imaging 2018;19:1408–18. https://doi.org/10.1093/ehjci/ jex333; PMID: 29315371. 37. Makkar RR, Yoon SH, Leon MB, et al. Association between transcatheter aortic valve replacement for bicuspid vs tricuspid aortic stenosis and mortality or stroke. JAMA 2019;321:2193–202. https://doi.org/10.1001/jama.2019.7108; PMID: 31184741. 38. Quintana RA, Monlezun DJ, DaSilva-DeAbreu A, et al. Oneyear mortality in patients undergoing transcatheter aortic valve replacement for stenotic bicuspid versus tricuspid aortic valves: a meta-analysis and meta-regression. J Interv Cardiol 2019;2019:8947204. https://doi. org/10.1155/2019/8947204; PMID: 31772549. 39. Yoon SH, Bleiziffer S, De Backer O et al. Outcomes in transcatheter aortic valve replacement for bicuspid versus tricuspid aortic valve stenosis. J Am Coll Cardiol 2017;69:2579–89. https://doi.org/10.1016/j.jacc.2017.03.017; PMID: 28330793. 40. Takagi H, Hari Y, Kawai N, et al. Meta-analysis of transcatheter aortic valve implantation for bicuspid versus tricuspid aortic valves. J Cardiovasc Med 2019;20:237–44. https://doi.org/10.2459/JCM.0000000000000777; PMID: 30762660. 41. Elbadawi A, Saad M, Elgendy IY, et al. Temporal trends and outcomes of transcatheter versus surgical aortic valve replacement for bicuspid aortic valve stenosis. JACC Cardiovasc Interv 2019;12:1811–22. https://doi.org/10.1016/j. jcin.2019.06.037; PMID: 31537280. 42. Franzone A, Piccolo R, Siontis GCM, et al. Transcatheter aortic valve replacement for the treatment of pure native aortic valve regurgitation: a systematic review. JACC Cardiovasc Interv 2016;9:2308–17. https://doi.org/10.1016/j. jcin.2016.08.049; PMID: 28026742. 43. Santos-Martínez S, Alkhodair A, Nombela-Franco L. Transcatheter aortic valve replacement for residual lesion of the aortic valve following “healed” infective endocarditis. JACC Cardiovasc Interv 2020;13:1983–96. https://doi. org/10.1016/j.jcin.2020.05.033; PMID: 32912458. 44. Hira RS, Vemulapalli S, Li Z, et al. Trends and outcomes of off-label use of transcatheter aortic valve replacement:

insights from the NCDR STS/ACC TVT registry. JAMA Cardiol 2017;2:846–54. https://doi.org/10.1001/jamacardio.2017.1685; PMID: 28636718. 45. Yoon SH, Schmidt T, Bleiziffer S, et al. Transcatheter aortic valve replacement in pure native aortic valve regurgitation. J Am Coll Cardiol 2017;70:2752–63. https://doi.org/10.1016/j. jacc.2017.10.006; PMID: 29191323. 46. Roy DA, Schaefer U, Guetta V, et al. Transcatheter aortic valve implantation for pure severe native aortic valve regurgitation. J Am Coll Cardiol 2013;61:1577–84. https://doi. org/10.1016/j.jacc.2013.01.018; PMID: 23433565. 47. Seiffert M, Bader R, Kappert U, et al. Initial German experience with transapical implantation of a secondgeneration transcatheter heart valve for the treatment of aortic regurgitation. JACC Cardiovasc Interv 2014;7:1168–74. https://doi.org/10.1016/j.jcin.2014.05.014; PMID: 25129672. 48. Testa L, Latib A, Rossi ML, et al. CoreValve implantation for severe aortic regurgitation: a multicentre registry. EuroIntervention 2014;10:739–45. https://doi.org/10.4244/ EIJV10I6A127; PMID: 25330506. 49. Frerker C, Schewe lJ, Schewel D, et al. Expansion of the indication of transcatheter aortic valve implantation — feasibility and outcome in ‘‘off-label” patients compared with ‘‘on-label” patients. J Invasive Cardiol 2015;27:229–36; PMID: 25929299. 50. Zhu D, Wei L, Cheung A, et al. Treatment of pure aortic regurgitation using a second-generation transcatheter aortic valve implantation system. J Am Coll Cardiol 2016;67:2803– 05. https://doi.org/10.1016/j.jacc.2016.03.568; PMID: 27282902. 51. Sawaya FJ, Deutsch MA, Seiffert M, et al. Safety and efficacy of transcatheter aortic valve replacement in the treatment of pure aortic regurgitation in native valves and failing surgical bioprostheses: results from an international registry study. J Am Coll Cardiol Intv 2017;10:1048–56. https://doi. org/10.1016/j.jcin.2017.03.004; PMID: 28521923. 52. Liu H, Yang Y, Wang W, et al. Transapical transcatheter aortic valve replacement for aortic regurgitation with a second-generation heart valve. J Thorac Cardiovasc Surg 2018;156:106–16. https://doi.org/10.1016/j.jtcvs.2017.12.150; PMID: 29525255. 53. De Backer O, Pilgrim T, Simonato M, et al. Usefulness of

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transcatheter aortic valve implantation for treatment of pure native aortic valve regurgitation. Am J Cardiol 2018;122:1028–35. https://doi.org/10.1016/j. amjcard.2018.05.044; PMID: 30072124. 54. Silaschi M, Conradi L, Wendler O, et al. The JUPITER registry: one-year outcomes of transapical aortic valve implantation using a second generation transcatheter heart valve for aortic regurgitation. Catheter Cardiovasc Interv 2018;91:1345–51. https://doi.org/10.1002/ccd.27370; PMID: 29171730. 55. Kappetein AJ, Head SJ, Généreux P, et al. Updated standardized endpoint definitions for transcatheter aortic valve implantation: The Valve Academic Research Consortium-2 consensus document. J Thorac Cardiovasc Surg 2013;145:6–23. https://doi.org/10.1016/j.jtcvs.2012.09.002; PMID: 23084102. 56. Fuchs A, Kofoed KF, Yoon SH, et al . Commissural alignment of bioprosthetic aortic valve and native aortic valve following surgical and transcatheter aortic valve replacement and its impact on valvular function and coronary filling. JACC Cardiovasc Interv 2018;11:1733–43. https://doi.org/10.1016/j.jcin.2018.05.043; PMID: 30121280. 57. Tang GHL, Zaid S, Fuchs A, et al. Alignment of transcatheter aortic-valve neo-commissures (ALIGN TAVR): Impact on final valve orientation and coronary artery overlap. JACC Cardiovasc Interv 202011;13:1030–42. https://doi.org/10.1016/j. jcin.2020.02.005; PMID: 32192985. 58. Redondo A, Valencia-Serrano F, Santos-Martínez S, et al. Accurate commissural alignment during ACURATE neo TAVI procedure. Proof of concept. Rev Esp Cardiol (Engl Ed) 2021. https://doi.org/10.1016/j.rec.2021.02.004; PMID: 33781722; epub ahead of press. 59. Tang GHL, Zaid S, Michev I, et al. “Cusp-overlap” view simplifies fluoroscopy-guided implantation of self-expanding valve in transcatheter aortic valve replacement. JACC Cardiovasc Interv 2018;11:1663–5. https://doi.org/10.1016/j. jcin.2018.03.018; PMID: 30139479. 60. Ben-Shoshan J, Alosaimi H, Lauzier PT, et al. Double s-curve versus cusp-overlap technique: defining the optimal fluoroscopic projection for TAVR with a self-expanding device. JACC Cardiovasc Interv 2021;14:185–94. https://doi. org/10.1016/j.jcin.2020.10.033; PMID: 33478635.

Coronary Functional Abnormalities

Pathophysiology and Diagnosis of Coronary Functional Abnormalities Jun Takahashi, Akira Suda, Kensuke Nishimiya, Shigeo Godo , Satoshi Yasuda

and Hiroaki Shimokawa

Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan

Abstract

Approximately one-half of patients undergoing diagnostic coronary angiography for angina have no significant coronary atherosclerotic stenosis. This clinical condition has recently been described as ischaemia with non-obstructive coronary arteries (INOCA). Coronary functional abnormalities are central to the pathogenesis of INOCA, including epicardial coronary spasm and coronary microvascular dysfunction composed of a variable combination of increased vasoconstrictive reactivity and/or reduced vasodilator function. During the last decade – in INOCA patients in particular – evidence for the prognostic impact of coronary functional abnormalities has accumulated and various non-invasive and invasive diagnostic techniques have enabled the evaluation of coronary vasomotor function in a comprehensive manner. In this review, the authors briefly summarise the recent advances in the understanding of pathophysiology and diagnosis of epicardial coronary artery spasm and coronary microvascular dysfunction.

Keywords

Epicardial coronary spasm, coronary microvascular dysfunction, coronary vasoreactivity testing, coronary flow reserve, biomarker, Rho-kinase Disclosure: HS is an international advisor on the European Cardiology Review editorial board; this did not affect peer review. All other authors have no conflicts of interest to declare. Support: This work was supported in part by the Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology, Tokyo, Japan (16K09413, 17K15983) and the Agency for Medical Research and Development (21gk0210030h0001). Received: 15 May 2021 Accepted: 7 July 2021 Citation: European Cardiology Review 2021;16:e30. DOI: https://doi.org/10.15420/ecr.2021.23 Correspondence: Hiroaki Shimokawa, Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan. E: shimo@cardio.med.tohoku.ac.jp Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Ischaemic heart disease (IHD) is primarily caused by various combinations of three mechanisms – epicardial organic coronary stenosis attributable to atherosclerosis, epicardial coronary artery spasm and coronary microvascular dysfunction (CMD).1–3 The representative clinical manifestations of these three mechanisms are effort angina, vasospastic angina (VSA) and microvascular angina (MVA), respectively. To date, much attention has been paid to the first mechanism, epicardial organic coronary stenosis, leading to the successful developments of percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG). However, approximately 40% of patients with obstructive coronary artery disease (CAD) still suffer from persistent/recurrent angina even after complete revascularisation with PCI and/or CABG.4 In fact, numerous patients with symptoms and evidence of myocardial ischaemia have no significant epicardial organic coronary stenosis (>50%).

coronary functional abnormalities in the pathogenesis and prognosis of chronic coronary syndrome, which has been described in the excellent European Association of Percutaneous Cardiovascular Interventions expert consensus document.8

Epicardial spasm and CMD, which represent typical manifestations of coronary functional abnormalities, account for the condition recently termed as ischaemia with non-obstructive coronary arteries (INOCA).5 Importantly, the prevalence of INOCA has rapidly increased, reported as reaching approximately 70% in women and 50% in men undergoing coronary angiography.6 Furthermore, to the surprise of the cardiology community, the ISCHEMIA trial convincingly demonstrated that a revascularisation strategy with PCI or CABG has no significant prognostic benefit in patients with stable CAD and proven moderate to severe myocardial ischaemia.7 These lines of evidence indicate the importance of

Pathophysiology of Coronary Functional Abnormalities Endothelial Dysfunction

Although aetiologies of impaired coronary vasomotion appear to be complex and heterogeneous, they always encompass vasodilator and vasoconstrictive properties in various combinations, where endothelial dysfunction and hypercontraction of vascular smooth muscle cells (VSMC) are substantially involved.3,9,10 Various non-invasive and invasive techniques have been developed to evaluate coronary vasomotion during the last decade.11,12 The aim of this review is to briefly summarise the current knowledge on the pathophysiology and diagnosis of coronary functional abnormalities.

Endothelial dysfunction has been shown to be a key mediator in the pathogenesis of coronary functional abnormalities.3,13,14 The endothelium plays pivotal roles in modulating the tone of underlying VSMC by synthesising and releasing endothelium-derived relaxing factors (EDRFs), including vasodilator prostaglandins, nitric oxide (NO), and endotheliumdependent hyperpolarisation (EDH) factors, as well as endotheliumderived contracting factors (Figure 1).15–17 Endothelial dysfunction is

Coronary Functional Abnormalities: Pathophysiology and Diagnosis Figure 1: Vessel-size-dependent Contribution of Endothelium-derived Relaxing Factors and Rho-kinase-mediated Vascular Smooth Muscle Hypercontraction Agonist

Shear stress

Receptor Endothelium Endothelium-derived relaxing factors Vasodilator prostaglandins

NO EDH factors

Conduit artery

Resistance artery

Agonist

Receptor Vascular smooth muscle Rho/Rho-kinase cGMP

cAMP

Hyperpolarisation Inhibition of MLCPh

Relaxation

Hypercontraction

Vasodilatation

Coronary spasm

MLC phosphorylation

Endothelium-derived NO mainly causes vasodilation of large conduit vessels (e.g. epicardial coronary arteries), while EDH factors including H2O2 predominantly dilate resistance arteries (e.g. coronary microvessels). Rho-kinase plays a central role in the molecular mechanism of vascular smooth muscle hypercontraction caused by enhanced MLC phosphorylation through MLCPh inhibition. cAMP = cyclic adenosine monophosphate; cGMP = cyclic guanosine monophosphate; EDH = endothelium-dependent hyperpolarisation; NO = nitric oxide; MLC = myosin light chain; MLCPh = myosin light chain phosphatase.

characterised by reduced production and/or action of EDRFs, serving as the hallmark of atherosclerotic cardiovascular diseases as well as one of the major pathogenetic mechanisms of CMD. It is important to note that these EDRFs regulate vascular tone in a distinct vessel size-dependent manner (Figure 1). Endothelium-derived NO mainly mediates vasodilatation of relatively large, conduit vessels (e.g. epicardial coronary arteries), while EDH factors-mediated responses are the predominant mechanisms of endothelium-dependent vasodilatation of resistance arteries (e.g. coronary microvessels).16,17 Experimental studies have demonstrated that inhibition of endothelial NO production can aggravate myocardial hypoperfusion distal to an epicardial organic stenosis and that reduced NO bioavailability results in attenuation of endothelium-dependent vasodilatation.16 On the other hand, endothelium-derived H2O2, which exerts various cardioprotective effects, such as metabolic coronary dilatation, coronary autoregulation, and myocardial protection against reperfusion injury, is a major EDH factor in various vascular beds including human coronary arteries.3,17–19 Thus, it is conceivable that impaired H2O2/ EDH factor-mediated vasodilatation is involved in the pathogenesis of CMD.1,17 Indeed, our recent study revealed that both NO- and EDH-derived vasodilatations are prominently impaired in patients with MVA.14

Rho-kinase as a Key Molecule of Coronary Artery Spasm

Coronary artery spasm causes a primary reduction in coronary blood flow (CBF), resulting in the abrupt development of myocardial ischaemia. It can develop in both epicardial coronary arteries and coronary microvessels. Since coronary spasm can be induced by a variety of stimuli with different mechanisms of action (even in the same patient), it is not caused by abnormalities of specific agonist–receptor interaction but an enhanced reactivity (hyperreactivity) of the vessel to a generalised stimulus.20 Reduced availability of endogenous vasodilator substances and VSMC hypersensitivity may contribute to vascular hyperreactivity leading to the onset of coronary spasm, whereas the role of endothelial dysfunction may be minimal.3 Evidence for the primary role of VSMC hypercontraction but not endothelial dysfunction in the pathogenesis of coronary artery spasm is summarised in Table 1.3 Accumulated evidence proves that a major mechanism of VSMC hypersensitivity is caused by enhanced Rho-kinase activity, an enzyme that controls contraction and relaxation of VSMC independently of intracellular Ca2+ concentration (Figure 1).21 Activated Rho-kinase enhances myosin light chain phosphorylation through inhibition of the myosinbinding subunit of myosin phosphatase, leading to VSMC hypercontraction.

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Coronary Functional Abnormalities: Pathophysiology and Diagnosis Table 1: Primary Role of Vascular Smooth Muscle Hypercontraction in the Pathogenesis of Coronary Artery Spasm Coronary Artery Spasm (VSMC Hypercontraction)

Endothelial Dysfunction

Local

Systemic

Evidence of coronary VSMC hypercontraction

Preserved endothelium-dependent response to BK and SP Failure of EPA with improved endothelial function to suppress coronary spasm

Racial difference

No racial difference

Marked diurnal change

Less diurnal change

Fluctuation and spontaneous remission

No fluctuation and spontaneous remission

Acute effects of vasodilators

No acute effects of vasodilators

BK = bradykinin; EPA = eicosapentaenoic acid; SP = substance P; VSMC = vascular smooth muscle cells. Source: Shimokawa et al. 2014.3 Reproduced with permission from Oxford University Press.

Importantly, the Rho-kinase inhibitor fasudil has been shown to prevent acetylcholine (ACh)-induced coronary artery spasm in patients with VSA, confirming that Rho/Rho-kinase pathway plays a central role in the pathophysiology of coronary spasm.22 It is known that various inflammatory stimuli, including angiotensin II and interleukin-1β, upregulate the expression and activity of Rho-kinase in VSMCs.3 Intriguingly, oestrogen has an inhibitory effect on inflammation-induced Rho-kinase upregulation, which may partly account for the increased incidence of atherosclerotic and vasospastic disorders in postmenopausal women.5,23

Table 2: The Japanese Coronary Spasm Association Risk Score

Diagnosis of Coronary Functional Abnormalities Clinical Importance of the Evaluation of Epicardial Coronary Vasoreactivity

Coronary artery spasm plays an important role in the pathogenesis of a wide variety of IHD, including VSA, variant angina, acute MI, sudden cardiac death and intractable angina after successful coronary stent implantation.24–26 In particular, VSA is the centre of entity among disorders that represent hyperreactivity of epicardial coronary arteries to vasoconstrictor stimuli. Thus, it is important to make a correct diagnosis of VSA and evaluate epicardial coronary vasoreactivity.

Clinical Definition and Diagnostic Criteria of Vasospastic Angina

Definite VSA is diagnosed when ischaemic ECG changes – defined as a transient ST-segment elevation or depression of >0.1 mV, or new appearance of negative U waves in at least two contiguous leads – are documented during spontaneous angina attack.27 In cases without such diagnostic ECG ischaemic changes, definite VSA is angiographically diagnosed when transient, total, or subtotal (>90% stenosis) of a coronary artery accompanied by angina pain and ischaemic ECG changes during spasm provocation testing with ACh, ergonovine, or hyperventilation.27 The position paper from the Coronary Artery Vasomotion Disorders International Study group also refers to typical symptoms for VSA as follows: subjective symptoms often appear at rest, especially between night and early morning; exercise tolerance is markedly reduced in the morning; hyperventilation relates to the symptoms; and calcium-channel blockers (CCBs) are effective to suppress the symptoms.28

Clinical Significance of Pharmacological Spasm Provocation Testing

Intracoronary pharmacological spasm provocation testing is highly recommended for patients with suspected coronary artery spasm.27,28 In particular, high diagnostic accuracy of ACh testing for coronary spasm (90% sensitivity, 99% specificity) is universally recognised.29 Thus, invasive ACh provocation testing remains the gold standard of diagnostic approach of coronary spasm at present, although non-invasive spasm provocation testing including transthoracic echocardiography with IV ergonovine has

Predictive Factor

Score

History of out-of-hospital cardiac arrest

Smoking

Angina at rest alone

Significant organic stenosis

Multivessel spasm

ST-segment elevation

β-blocker use

Possible range

0–14

Developed by Takagi et al. 2013.

also been proposed.30 Recent studies from Europe also revealed that pharmacological spasm provocation testing with ACh is safe and that coronary spasm plays a key role in development of a broad range of IHD in white patients as it does in Asian patients.31,32 Importantly, Japanese and German patients with VSA have similar results of ACh provocation testing in terms of distribution of spasm type and frequency of multivessel spasm.33 Moreover, risk stratification for VSA patients can be done using the findings of ACh testing. Indeed, studies have demonstrated that a mixture of focal and diffuse spasm provoked in multivessel coronary arteries strongly correlated with the occurrence of adverse events during the follow-up period, while coronary spasm induced at the site of significant organic stenosis was also associated with poor prognosis of VSA patients.34,35 The Japanese Coronary Spasm Association (JCSA) risk score could provide comprehensive risk assessment and prognostic stratification for VSA patients, which consists of seven variables, including history of outof-hospital cardiac arrest (OHCA; 4 points), smoking, rest angina alone, organic coronary stenosis, multivessel spasm during spasm provocation testing (2 points each), ST-segment elevation during angina and β-blocker use (1 point each; Table 2).36 Among those seven variables, organic coronary stenosis and multivessel spasm could be identified by angiography and pharmacological spasm provocation testing.

Diagnostic Approaches to Sudden Cardiac Death Related to Coronary Spasm

Syncope, which is caused by ventricular tachyarrhythmias or bradycardia due to transient conduction disturbances, is an important manifestation of VSA. It is commonly preceded by anginal pain, although not in all cases. In a subgroup of survivors with OHCA, coronary spasm and silent myocardial ischaemia were identified as a likely cause of their fatal arrhythmias.37

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Coronary Functional Abnormalities: Pathophysiology and Diagnosis Since VSA patients who survived OHCA are a particularly high-risk population, even in the current era with established effective therapies such as long-acting CCBs, implantation of an ICD with optimal medications may be appropriate for them.38,39 We have previously reported that the dual induction tests for coronary artery spasm and lethal ventricular arrhythmias could stratify high-risk OHCA patients and evaluate the necessity of ICD by underlying mechanisms involved.40 Among OHCA survivors without structural heart disease, provokable coronary spasm and ventricular arrhythmias were common and could also be seen in Brugada syndrome.40 Thus, patients with coronary spasm alone but not Brugada syndrome who are treated with CCBs could be regarded as a low-risk group, indicating that ICD may not be essential for them.

Diagnostic Imaging for Coronary Spasm

Cardiovascular imaging could provide additional information at cellular and molecular levels in patients with VSA. An intravascular imaging study showed that atherosclerotic changes are more common in the segment of focal spasm site as compared with diffuse spasm.41 In particular, optical coherence tomography (OCT), which is a high-resolution imaging modality, is capable of visualising not only morphological features of coronary vascular wall but also adventitial vasa vasorum formation at the spasm site.42,43 Chronic inflammatory changes in the coronary adventitia play important roles in the pathogenesis of coronary spasm through Rhokinase activation and resultant VSMC hypercontraction.44 Indeed, OCTdelineated adventitial vasa vasorum formation was significantly enhanced at the spastic segments of VSA patients compared with those of control subjects.43,45 Coronary perivascular adipose tissue volume measured by CT coronary angiography is also increased at the spastic segment of VSA patients.46 Intriguingly, coronary perivascular adipose tissue inflammatory changes evaluated by 18F-fluorodeoxyglucose PET imaging were more extensive at the spastic coronary segments of VSA patients as compared with control subjects, and the inflammatory changes were significantly suppressed after medical treatment with CCBs.46 These imaging approaches may serve as a promising avenue for elucidation of the pathogenesis of coronary spasm in patients with VSA.

Advances in Diagnostic Approaches to Coronary Microvascular Dysfunction

CMD has emerged as a third potential mechanism of myocardial ischaemia in addition to atherosclerotic stenosis and spasm of epicardial coronary arteries.2,3 Since the presence of CMD appears to be associated with increased risk of cardiovascular events, it is important to make a correct diagnosis of CMD based on objective and functional assessments of coronary microcirculation.47 From a pathophysiological point of view, CMD represents the impairment in inherent regulatory mechanisms of coronary microvasculature for myocardial blood flow to adapt to changes in myocardial oxygen demand.48 More specifically, CMD is originated by a variable combination of impaired vasodilatation and increased vasoconstriction of coronary microvessels.48 However, in contrast with epicardial coronary arteries, coronary microvessels cannot be directly visualised in vivo with coronary angiography or intracoronary imaging devices. Thus, in the clinical setting, microvascular function must be assessed indirectly, generally through measurements of coronary blood flow regulated mainly by coronary arteriolar tone, or detection of propensity to coronary vasoconstriction.

Clinical Characteristics of Microvascular Angina Due to Coronary Microvascular Dysfunction

Patients with MVA due to CMD often have chest pain that can persist even after cessation of the activity. They have no rapid or sufficient symptom

relief in response to sublingual nitroglycerin, which selectively dilates larger arteries but not arterioles or microvessels.49 Based on these clinical features of MVA, the Coronary Vasomotor Disorders International Study group has proposed diagnostic criteria for MVA (Table 3).50 Angina occurs in approximately 30–70% of patients with CMD, whereas other cardiac manifestations of CMD include exertional dyspnoea and possibly heart failure.51–53 CMD may represent an ischaemic equivalent caused by left ventricle (LV) diastolic dysfunction with an excessive rise in end-diastolic pressure leading to cardiopulmonary congestion. Indeed, coexistence of CMD and LV diastolic dysfunction is associated with a remarkably increased risk of heart failure with preserved ejection fraction (HFpEF) hospitalisation.53 Particularly in patients with hypertension and preserved systolic function, CMD as well as subclinical myocardial mechanical dysfunction predicted HF hospitalisation independently of LV remodelling severity.54

Assessment for Vasodilator Function of Coronary Microvessels

Coronary microvascular vasodilator function is usually assessed by measurement of coronary microvascular response to vasodilator stimuli. In many cases, the vasodilator capacity is often evaluated by coronary flow reserve (CFR) calculated as the ratio of CBF during maximal vasodilatation over basal CBF.11,12 CFR reflects an integrated measurement of flow throughout both large epicardial artery and coronary microvessels. Thus, without obstructive stenosis of epicardial coronary arteries, reduced CFR indicates the entity of CMD.11,12 Depending on the methodology, CFR cut-off values between ≤2.0 and ≤2.5 are indicative for impaired coronary microvascular function.55 The most widely used agent to assess coronary microvascular dilator function is adenosine. Adenosine is intravenously administered at 140 μg/ kg/min, as this dose has been found to achieve maximal coronary microvascular dilatation.56 Adenosine has possible adverse effects, including bradycardia due to atrioventricular or sino-atrial node blockade and bronchoconstriction, both of which are mediated by purinergic A1 receptors. However, a relevant advantage of adenosine is its very short half-life (10 seconds) that enables rapid regression of side-effects and repetition of the test during the same session, if necessary.56 ACh is also used as a coronary microvascular vasodilator.52 However, ACh is not an ideal substance to assess endothelium-dependent vasodilator function, since it also acts directly on VSMCs, leading to vasoconstriction (Table 1).3 There is a range of non-invasive approaches for evaluation of coronary vasodilator responses, but all of them have several limitations.11 Transthoracic Doppler echocardiography (TTDE) enables us to measure coronary blood flow velocity of the distal left anterior descending artery as a surrogate for CBF with advantages of low cost and high feasibility. A reduced coronary blood flow velocity reserve index obtained by TTDE helps to identify patients with CMD and enables the risk stratification for them.57 On the other hand, considerable intra- and inter-observer variabilities (~10%) need to be taken into account when examining serial recordings obtained for assessing the effects of therapy.58 PET is a well-validated technique that can provide non-invasive, accurate, and reproducible quantification of myocardial blood flow and CFR in humans, and thus has been used for the assessment of coronary vasomotor function.48 PET also has the advantage of assessing all three coronary distributions, allowing a more accurate assessment of microvascular dysfunction, where CMD has been shown to have a heterogenous distribution over the three coronary arteries.48 Recent PET

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Coronary Functional Abnormalities: Pathophysiology and Diagnosis Table 3: Clinical Criteria for Suspecting Microvascular Angina 1. Symptoms of myocardial ischaemia a. Effort and/or rest angina b. Angina equivalents (e.g. shortness of breath) 2. Absence of obstructive CAD (<50% diameter reduction or FFR >0.80) by a. Coronary CTA b. Invasive coronary angiography 3. Objective evidence of myocardial ischaemia a. Ischaemic ECG changes during an episode of chest pain b. Stress-induced chest pain and /or ischaemic ECG changes in the presence or absence of transient/reversible abnormal myocardial perfusion and/or wall motion abnormality 4. Evidence of impaired coronary microvascular function a. Impaired coronary flow reserve (cut-off values depending on methodology use between ≤2.0 and ≤2.5) b. Coronary microvascular spasm, defined as reproduction of symptoms, ischaemic ECG shifts but no epicardial spasm during acetylcholine testing c. Abnormal coronary microvascular resistance indices (e.g. IMR >25) d. Coronary slow flow phenomenon, defined as TIMI frame count >25 Definite MVA is only diagnosed if all four criteria are present. Suspected MVA is diagnosed if symptoms of ischaemia are present with non-obstructive CAD but only objective evidence of myocardial ischaemia, or evidence of impaired coronary microvascular function alone. CAD = coronary artery disease; CTA = computed tomographic angiography; FFR = fractional flow reserve; IMR = index of microcirculatory resistance; TIMI = thrombolysis in myocardial infarction. Source: Ong et al. 2018.50 Used with permission from Elsevier.

studies demonstrated that coronary vasodilator dysfunction, as defined by reduced CFR, is highly prevalent among patients with CAD, increases the severity of inducible myocardial ischaemia and subclinical myocardial injury, and identifies patients at high risk for future cardiac events.59,60 Cardiac magnetic resonance (CMR) has also been used to quantify myocardial perfusion following the injection of a gadolinium-based contrast agent. Advantages of CMR include high spatial resolution that allows transmural characterisation of myocardial blood flow, the lack of ionising radiation, and the ability to perform a comprehensive assessment of cardiovascular structure and function. In particular, CMR-derived myocardial perfusion reserve index (MPRI) is a robust semi-quantitative imaging surrogate that reflects vasodilator capacity of coronary microvessels.61 Recent studies demonstrated that a MPRI threshold of ≤1.84 has a diagnostic predictive value for CMD and that of ≤1.47 is associated with the occurrence of major adverse cardiac events.62,63 Coronary angiography combined with complementary catheter-based devices is a useful approach to examine coronary vasodilator capacity of patients with CMD.11,12 It often involves an interventional procedure where a guidewire-based assessment of CBF is performed at rest and at hyperaemia induced by pharmacological agents (e.g. adenosine).32,52,64 Although the procedure is invasive by nature and can be time-consuming, it has been shown to be safe and effective when performed by experienced interventional operators as discussed in detail later.65

Objective Documentation of Coronary Microvascular Spasm

In a sizable number of patients with angina, pressure-rate product (an index of myocardial oxygen demand) is usually comparable between at rest and at onset of attack, indicating that the decrease in CBF rather than increased myocardial oxygen consumption is a likely explanation for myocardial ischaemia.48 Primary reduction in CBF caused by coronary spasm at not only epicardial conduit arteries but also myocardial microvasculature could be attributable to angina at rest.66 Since a visualisation of coronary microvascular spasm (MVS) is still difficult due to the limited spatial resolution of existing intracoronary imaging devices, the development of MVS is generally identified by the reproduction of chest discomfort suggestive of angina with ischaemic ECG changes, in the absence of ≥90% epicardial stenosis during intracoronary ACh administration (Table 3).50

Almost a quarter of a century has passed since Mohri et al. originally described the incidence of MVS in a subset of patients with rest angina and normal epicardial coronary arteries.67 Indeed, it has been recently reported that the vast majority (97%) of INOCA patients with coronary functional abnormalities have epicardial or microvascular vasospasm in approximately equal proportions.68 Furthermore, in INOCA patients, MVS is sometimes provoked at lower doses of intracoronary ACh, followed by diffuse epicardial spasm at higher doses, indicating that a common mechanism is involved in both epicardial and microvascular spasms such as Rho-kinase activation.69 Meanwhile, for corroborating the entity of MVS, monitoring of myocardial lactate production throughout ACh provocation testing as an objective marker of myocardial ischaemia is recommended.27 Negative myocardial lactate extraction ratio, which is calculated as the ratio of the coronary arterial–venous difference in lactate concentration to the arterial concentration, is considered to be highly sensitive for myocardial ischaemia.69 Inevitably, MVS is defined as having a negative myocardial lactate extraction ratio despite the absence of angiographically demonstrable epicardial spasm throughout ACh provocation testing or prior to the occurrence of epicardial coronary spasm following intracoronary injection of ACh.67,69

Comprehensive Evaluation of Coronary Functional Abnormalities by Interventional Procedures

Recently, the combined invasive assessment of coronary vasoconstrictor and vasodilator abnormalities has been titled as an interventional diagnostic procedure (IDP), which typically consist of vasoreactivity testing with ACh and measurement of CFR and IMR with adenosine (Figure 2).12,70 Although there has been a critical missing link between IDP for assessment of coronary vasomotor function and health outcomes of INOCA patients, this gap has recently been addressed in the CorMicA randomised controlled trial.32,71 In this landmark study, Ford et al. demonstrated that an IDP linked to the stratified medication could ameliorate health status of patients with INOCA and that better quality of life was maintained among patients undergoing an IDP over 1 year.71 The IDP also allows us to acknowledge that several vascular dysfunction mechanisms may co-exist and overlap in a patient with INOCA.64,72 Furthermore, clarifying INOCA endotypes enable us to predict the clinical course of INOCA patients. The entity of impaired coronary microvascular dilator function predicts adverse cardiovascular outcomes, including death and non-fatal MI, in female

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Coronary Functional Abnormalities: Pathophysiology and Diagnosis Figure 2: Protocol for the Invasive Diagnostic Procedure Step 1: Coronary anatomical evaluation (Coronary angiography)

(–) Organic stenosis

(+) Organic stenosis

FFR measurement

Step 2: Coronary vasoreactivity evaluation (ACh provocation testing) Baseline

ACh 100 µg

A case with MVS

Increasing dosage of ACh IC No epicardial coronary spasm

(+) Ischaemic ECG change Nitroglycerin

(+) Myocardial lactate production

Step 3: Coronary vasodilator capacity evaluation (Diagnostic guidewire and adenosine test)

CFR

= resting Tmn/hyperaemic Tmn

Pressure–temperature sensor guidewire

Adenosine IV or IC

IMR

= Pd × hyperaemic Tmn

Injection of saline Mean transit time (Tmn) Epicardial

Microvascular

The first step is the identification of coronary organic stenosis by diagnostic coronary angiography. In patients with significant organic coronary stenosis (>50% luminal narrowing), measurement of FFR should be considered. The second step is ACh provocation testing for coronary spasm. Additional evaluation for myocardial lactate production is useful to confirm the emergence of MVS without or prior to the development of epicardial coronary spasm. A case diagnosed with MVS is demonstrated. The third step is to perform wire-based assessment of CFR and IMR for evaluation of vasodilator microvascular capacity in response to adenosine. ACh = acetylcholine; CFR = coronary flow reserve; FFR = fractional flow reserve; IC = intracoronary; IMR = index of microcirculatory resistance; MVS = microvascular spasm; Pa = mean proximal coronary pressure; Pd = mean distal coronary pressure; Tmn = mean transit time.

INOCA patients, whereas enhanced epicardial coronary vasoconstrictive reactivity was related to angina hospitalisation.47 Additionally, in INOCA patients, coexistence of epicardial coronary spasm and increased microvascular resistance was associated with worse prognosis, for which Rho-kinase activation appears to be involved.64 Taken together, comprehensive assessment of coronary functional abnormalities with the IDP could be useful to develop a strategic and distinct outlook for managements of INOCA patients. This is the reason why the IDP is highly recommended for patients with chest pain and no obstructive CAD in the recent consensus documents on INOCA by the European Society of Cardiology.8 Meanwhile, CMD diagnosed based on the results of IDP may be associated with the presence of virtual histology intravascular-ultrasound-derived thin-cap fibroatheroma.73 Also, in our recent work, the prognostic links between coronary morphologies evaluated by optical coherence tomography and coronary vasomotor were noted in INOCA patients.74 These findings indicate that a combination

of intracoronary imaging device-derived morphometric assessment and coronary functional assessment with IDP could greatly improve the prognostic prediction of INOCA patients.

Biomarkers of Coronary Functional Abnormalities

We have previously demonstrated that Rho-kinase activity in circulating neutrophils is a useful surrogate biomarker for coronary spasm, not only for the diagnosis of the disorder but also for the assessment of disease activity and efficacy of medical treatment.75 Furthermore, there is a circadian variation of Rho-kinase activity in circulating neutrophils with a peak noted in the early morning, associated with alterations in coronary basal tone and vasomotor reactivity.76 A previous experimental study showed that sustained elevation of serum cortisol level sensitises coronary VSMC to serotonin to cause coronary vasoconstrictive responses in pigs in vivo, suggesting the cross-link between stress and coronary artery spasm.77 In fact, Rho-kinase activity in

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Coronary Functional Abnormalities: Pathophysiology and Diagnosis circulating neutrophils in VSA patients was temporarily enhanced immediately after the Great East Japan Earthquake associated with disaster-related mental stress.78 Finally, Rho-kinase activity in circulating leucocytes is also useful for prognostic stratification of VSA patients.79 The combination of the JCSA risk score and Rho-kinase activity substantially improved risk stratification of VSA patients as compared with either alone.79 Taking these issues into consideration, Rho-kinase activity in circulating leucocytes appears to be a useful biomarker for coronary spasm with a broad versatility, comparing favourably with B-type natriuretic peptide in patients with heart failure and high-sensitivity cardiac troponin T or I in those with acute coronary syndrome.

INOCA patients.81 Although several clinical studies previously addressed the relationship between systemic serotonin concentrations and coronary vasomotor abnormalities, we have recently demonstrated that plasma concentration of serotonin was significantly higher in patients with microvascular spasm as compared with controls.82 Importantly, in patients with INOCA, there was a positive correlation between plasma serotonin concentration and baseline thrombolysis in myocardial infarction frame count, a marker of coronary vascular resistance.11,82 These findings suggest that plasma concentration of serotonin may be a novel biomarker to predict latent microvascular spasm and enable us to dissect it from epicardial coronary artery spasm.

Although the importance of CMD has been emerging, reliable biomarkers for CMD remain to be developed. Low-grade inflammation attracts much attention in the pathogenesis of CMD, since elevated C-reactive protein levels correlated with reduced CFR in patients with cardiac syndrome X, which is indicative of CMD.80 A recent study also demonstrated that cardiovascular protein biomarkers of inflammatory status and coagulation changes are associated with endothelium-independent CMD in female

Conclusion

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In summary, it is important to evaluate coronary vasomotor function comprehensively and diagnose coronary functional abnormalities including VSA and CMD precisely, particularly in INOCA patients. Further studies are needed to better understand the pathophysiology of coronary vasomotor dysfunction and to develop new effective therapeutic strategies for patients with coronary functional abnormalities.

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microvascular dysfunction: a subclinical marker of end organ damage and heart failure. Eur Heart J 2020;41:2366– 75. https://doi.org/10.1093/eurheartj/ehaa191; PMID: 32221588. 55. Löffler AI, Bourque JM. Coronary microvascular dysfunction, microvascular angina, and management. Curr Cardiol Rep 2016;18:1. https://doi.org/10.1007/s11886-015-0682-9; PMID: 26694723. 56. Layland J, Carrick D, Lee M, et al. Adenosine: physiology, pharmacology, and clinical applications. JACC Cardiovasc Interv 2014;7:581–91. https://doi.org/10.1016/j. jcin.2014.02.009; PMID: 24835328. 57. Gan LM, Svedlund S, Wittfeldt A, et al. Incremental value of transthoracic Doppler echocardiography-Assessed coronary flow reserve in patients with suspected myocardial ischemia undergoing myocardial perfusion scintigraphy. J Am Heart Assoc 2017;6. https://doi.org/10.1161/JAHA.116.004875; PMID: 28420647. 58. Rigo F, Richieri M, Pasanisi E, et al. Usefulness of coronary flow reserve over regional wall motion when added to dualimaging dipyridamole echocardiography. Am J Cardiol 2003;91:269–73. https://doi.org/10.1016/s00029149(02)03153-3; PMID: 12565081. 59. Taqueti VR, Everett BM, Murthy VL, et al. Interaction of impaired coronary flow reserve and cardiomyocyte injury on adverse cardiovascular outcomes in patients without overt coronary artery disease. Circulation 2015;131:528–35. https:// doi.org/10.1161/CIRCULATIONAHA.114.009716; PMID: 25480813. 60. Gupta A, Taqueti VR, van de Hoef TP, et al. Integrated noninvasive physiological assessment of coronary circulatory function and impact on cardiovascular mortality in patients with stable coronary artery disease. Circulation 2017;136:2325–36. https://doi.org/10.1161/ CIRCULATIONAHA.117.029992; PMID: 28864442. 61. Wöhrle J, Nusser T, Merkle N, et al. Myocardial perfusion reserve in cardiovascular magnetic resonance: correlation to coronary microvascular dysfunction. J Cardiovasc Magn Reson 2006;8:781–7. https://doi.org/10.1080/ 10976640600737649; PMID: 17060099. 62. Thomson LE, Wei J, Agarwal M, et al. Cardiac magnetic resonance myocardial perfusion reserve index is reduced in women with coronary microvascular dysfunction. A National Heart, Lung, and Blood Institute-sponsored study from the Women’s Ischemia Syndrome Evaluation. Circ Cardiovasc Imaging 2015;8. https://doi.org/10.1161/ CIRCIMAGING.114.002481; PMID: 25801710. 63. Zhou W, Lee JCY, Leung ST, et al. Long-term prognosis of patients with coronary microvascular disease using stress perfusion cardiac magnetic resonance. JACC Cardiovasc Imaging 2021;14:602–11. https://doi.org/10.1016/j. jcmg.2020.09.034; PMID: 33248966. 64. Suda A, Takahashi J, Hao K, et al. Coronary functional abnormalities in patients with angina and nonobstructive coronary artery disease. J Am Coll Cardiol 2019;74:2350–60. https://doi.org/10.1016/j.jacc.2019.08.1056; PMID: 31699275. 65. Wei J, Mehta PK, Johnson BD, et al. Safety of coronary reactivity testing in women with no obstructive coronary artery disease: results from the NHLBI-sponsored WISE (Women’s Ischemia Syndrome Evaluation) study. JACC Cardiovasc Interv 2012;5:646–53. https://doi.org/10.1016/j. jcin.2012.01.023; PMID: 22721660. 66. Pereyra VM, Seitz A, Hubert A, et al. Coronary microvascular spasm as the underlying cause of the angiographic slow flow phenomenon. JACC Case Rep 2020;2:35–39. https://doi. org/10.1016/j.jaccas.2019.11.059. 67. Mohri M, Koyanagi M, Egashira K, et al. Angina pectoris caused by coronary microvascular spasm. Lancet 1998;351:1165–9. https://doi.org/10.1016/S01406736(97)07329-7; PMID: 9643687. 68. Konst RE, Damman P, Pellegrini D, et al. Vasomotor dysfunction in patients with angina and nonobstructive coronary artery disease is dominated by vasospasm. Int J

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Cardiol 2021;333:14–20. https://doi.org/10.1016/j. ijcard.2021.02.079; PMID: 33711394. 69. Sun H, Mohri M, Shimokawa H, et al. Coronary microvascular spasm causes myocardial ischemia in patients with vasospastic angina. J Am Coll Cardiol 2002;39:847–51. https://doi.org/10.1016/s07351097(02)01690-x; PMID: 11869851. 70. Ford TJ, Berry C. How to diagnose and manage angina without obstructive coronary artery disease: Lessons from the British Heart Foundation CorMicA Trial. Interv Cardiol 2019;14:76–82. https://doi.org/10.15420/icr.2019.04.R1; PMID: 31178933. 71. Ford TJ, Stanley B, Sidik N, et al. 1-year outcomes of angina management guided by invasive coronary function testing (CorMicA). JACC Cardiovasc Interv 2020;13:33–45. https://doi. org/10.1016/j.jcin.2019.11.001; PMID: 31709984. 72. Ford TJ, Yii E, Sidik N, et al. Ischemia and no obstructive coronary artery disease: Prevalence and correlates of coronary vasomotion disorders. Circ Cardiovasc Interv 2019;12:e008126. https://doi.org/10.1161/ CIRCINTERVENTIONS.119.008126; PMID: 31833416. 73. Godo S, Corban MT, Toya T, et al. Association of coronary microvascular endothelial dysfunction with vulnerable plaque characteristics in early coronary atherosclerosis. EuroIntervention 2020;16:387–94. https://doi.org/10.4244/EIJD-19-00265; PMID: 31403459. 74. Nishimiya K, Suda A, Fukui K, et al. Prognostic links between OCT-delineated coronary morphologies and coronary functional abnormalities in patients with INOCA. JACC Cardiovasc Interv 2021;14:606–18. https://doi. org/10.1016/j.jcin.2020.12.025; PMID: 33736768. 75. Kikuchi Y, Yasuda S, Aizawa K, et al. Enhanced Rhokinase activity in circulating neutrophils of patients with vasospastic angina: a possible biomarker for diagnosis and disease activity assessment. J Am Coll Cardiol 2011;58:1231–7. https://doi.org/10.1016/j.jacc.2011.05.046; PMID: 21903056. 76. Nihei T, Takahashi J, Tsuburaya R, et al. Circadian variation of Rho-kinase activity in circulating leukocytes of patients with vasospastic angina. Circ J 2014;78:1183–90. https://doi. org/10.1253/circj.cj-13-1458; PMID: 24670923. 77. Hizume T, Morikawa K, Takaki A, et al. Sustained elevation of serum cortisol level causes sensitization of coronary vasoconstricting responses in pigs in vivo: a possible link between stress and coronary vasospasm. Circ Res 2006;99:767–75. https://doi.org/10.1161/01. RES.0000244093.69985.2f; PMID: 16960099. 78. Nihei T, Takahashi J, Kikuchi Y, et al. Enhanced Rho-kinase activity in patients with vasospastic angina after the Great East Japan Earthquake. Circ J 2012;76:2892–4. https://doi. org/10.1253/circj.cj-12-1238; PMID: 23131720. 79. Nihei T, Takahashi J, Hao K, et al. Prognostic impacts of Rho-kinase activity in circulating leucocytes in patients with vasospastic angina. Eur Heart J 2018;39:952–9. https://doi. org/10.1093/eurheartj/ehx657; PMID: 29165549. 80. Recio-Mayoral A, Rimoldi OE, Camici PG, Kaski JC. Inflammation and microvascular dysfunction in cardiac syndrome X patients without conventional risk factors for coronary artery disease. JACC Cardiovasc Imaging 2013;6:660–7. https://doi.org/10.1016/j.jcmg.2012.12.011; PMID: 23643286. 81. Schroder J, Zethner-Moller R, Bove KB, et al. Protein biomarkers and coronary microvascular dilatation assessed by rubidium-82 PET in women with angina pectoris and no obstructive coronary artery disease. Atherosclerosis 2018;275:319–27. https://doi.org/10.1016/j. atherosclerosis.2018.06.864; PMID: 29981522. 82. Odaka Y, Takahashi J, Tsuburaya R, et al. Plasma concentration of serotonin is a novel biomarker for coronary microvascular dysfunction in patients with suspected angina and unobstructive coronary arteries. Eur Heart J 2017;38:489–96. https://doi.org/10.1093/eurheartj/ehw448; PMID: 27694191.

Women and Heart Disease

The Fourth Trimester: Pregnancy as a Predictor of Cardiovascular Disease Pensée Wu ,1 Ki Park

and Martha Gulati

1. School of Medicine, Keele University, Staffordshire, UK; 2. University of Florida, Gainesville, FL, US; 3. University of Arizona, Phoenix, AZ, US

Abstract

Pregnancy identifies women who may be at a greater risk of cardiovascular disease (CVD), based on the development of adverse pregnancy outcomes (APOs), and may identify women who may benefit from atherosclerotic CVD (ASCVD) risk reduction efforts. APOs are common and although they are separate diagnoses, all these disorders seem to share an underlying pathogenesis. What is not clear is whether the APO itself initiates a pathway that results in CVD or whether the APO uncovers a woman’s predisposition to CVD. Regardless, APOs have immediate risks to maternal and foetal health, in addition to longer-term CVD consequences. CVD risk assessment and stratification in women remains complex and, historically, has underestimated risk, especially in young women. Further research is needed into the role of ASCVD risk assessment and the effect of aggressive ASCVD risk modification on CVD outcomes in women with a history of APOs.

Keywords

Hypertensive disorders of pregnancy, pre-eclampsia, preterm delivery, cardiovascular disease, cardiovascular risk Disclosure: PW is funded by a National Institute for Health Research (NIHR) Transitional Research Fellowship (TRF-2017-10-005). All other authors have no conflicts of interest to declare. Received: 3 May 2021 Accepted: 10 July 2021 Citation: European Cardiology Review 2021;16:e31. DOI: https://doi.org/10.15420/ecr.2021.18 Correspondence: Pensée Wu, School of Medicine, David Weatherall Building, Keele University, University Road, Staffordshire ST5 5BG, UK. E: p.wu@keele.ac.uk Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

In women, cardiovascular disease (CVD) is the leading cause of death and, despite great strides in reducing mortality from CVD, the number of women dying because of CVD has increased recently.1 The increase in mortality has been attributed, in part, to the risk of death in younger women with CVD due to a lack of recognition and undertreatment of young women with CVD.2 CVD is also the leading cause of maternal mortality, accounting for one in three maternal deaths.3 The peripartum and postpartum risk of CVD mortality is only one part of the risk to a young woman’s health. Pregnancy also identifies women who may be at a greater risk of CVD, based on the development of adverse pregnancy outcomes (APOs), and, in essence, may identify women who could benefit from atherosclerotic CVD (ASCVD) risk reduction efforts. As such, APOs are considered as risk enhancers of ASCVD by the 2018 American College of Cardiology (ACC)/American Heart Association (AHA) guideline on the management of blood cholesterol and the 2019 ACC/AHA guideline on the primary prevention of CVD.4,5 Identifying women with such risk enhancers and addressing ASCVD risk has been identified as an important component of care in the ‘fouth trimester’, which should involve comprehensive care and risk assessment within the 12-week postpartum period.6 The risk of APOs is not rare, with approximately 30% of women experiencing an APO. This includes gestational hypertension (3–14% of births), pre-eclampsia (2–5% of births), gestational diabetes (5%), preterm delivery (6–12%) and the delivery of a small-for-gestational-age (SGA) infant (prevalence varies by country; Table 1).7 APOs occur more frequently in black and Asian women, who often present with more severe clinical presentations and have poorer outcomes.8–10 There are numerous observational studies showing a strong association between these APOs and CVD, including premature CVD.7,11–15 Identifying women with a history

of APOs provides a unique opportunity to identify women at risk for CVD and initiate early primary prevention efforts in a higher-risk group before the onset of adverse cardiovascular events. The American College of Obstetrics and Gynecology and the AHA have proposed a new paradigm for postpartum care to identify women at risk for future CVD, aptly named the ‘fourth trimester’.6,16 The purpose of this paper is to discuss the effects of pregnancy and APOs on the risk of CVD.

Pregnancy as a Stress Test

Pregnancy is a physiological stress test to the heart. During pregnancy, there is an increase in circulating blood volume. This occurs in the setting of a reduction in systemic vascular resistance, lower blood pressure and increased cardiac output, which is essential for the optimal growth of the developing foetus.17 These adaptive changes are designed to provide adequate uteroplacental circulation, given the increased metabolic demands during the gravid state. Insufficient haemodynamic changes can result in significant maternal and fetal morbidity and mortality. In addition, even after these acute issues resolve, some studies have shown an association between APOs and hypertension, left ventricular changes, vascular dysfunction, chronic kidney disease and CVD after the reproductive years.12,18–23

Adverse Pregnancy Outcomes and Associated Adverse Cardiovascular Outcomes

Gestational hypertension and pre-eclampsia have been associated with a 2- to 4-fold increased risk of CHD, heart failure and stroke, with recurrent pre-eclampsia having the highest risk.24–26 Although the relative risk is highest within the first year postpartum, the risks persist decades after the pregnancy, when the absolute risks are greater than those immediately

The Fourth Trimester: Pregnancy as a Predictor of CVD Table 1: Definitions of Adverse Pregnancy Outcomes Adverse Pregnancy Outcome

Definition

Gestational diabetes

Any degree of glucose intolerance with its onset or first recognition during pregnancy

Gestational hypertension

New hypertension that develops after week 20 of pregnancy without proteinuria

Pre-eclampsia

New hypertension that develops after week 20 of pregnancy, with proteinuria or evidence of end-organ dysfunction

Preterm delivery

Delivery before 37 weeks gestational age (regardless of cause)

Small-for-gestational age

Birthweight in the 10th percentile or less for gestational age

postpartum.25,26 Hypertensive disorders of pregnancy (HDP) are associated with accelerated cardiovascular aging, with a greater prevalence of subclinical atherosclerosis and arterial stiffness index among women aged >40 years.26,27 In addition, HDP have been associated with aortic stenosis and mitral regurgitation, as demonstrated by the UK Biobank cohort, showing that the CVD risk goes beyond the impact of just the development of chronic hypertension.26 Women who had gestational diabetes have up to seven- and twofold increased risks of developing type 2 diabetes and major cardiovascular events (independent of type 2 diabetes), respectively, than those without gestational diabetes.28,29 Studies have shown a 16–29% cumulative incidence of diabetes after 10–20 years of follow-up in women with gestational diabetes.30,31 Preterm delivery has been associated with a 1.4- to 2-fold risk of CVD, CHD and stroke.12,32 The highest risks occurred when the deliveries occurred before 32 weeks gestation or in medically indicated preterm deliveries.12 A recent study showed that at 5 years postpartum, the incidence of MI increased more rapidly in preterm than term deliveries, whereas for ischaemic stroke this occurred after 10 years.33 A recent meta-analysis did not pool studies on women with delivery of a SGA infant due to variations in the definition of SGA between the studies.34 However, the authors of that analysis noted a consistent trend of increased CVD risk in these women across all 10 studies included, with an effect estimate ranging between 1.09 and 3.50 and a follow-up period of up to 21 years.34

Mechanisms Driving the Association Between Adverse Pregnancy Outcomes and Cardiovascular Disease

APOs are common and, although they are separate diagnoses, all these disorders seem to share an underlying pathogenesis, including placental ischaemia, maternal inflammation and vascular dysfunction.35–39 What is not clear is whether the APO itself initiates a pathway that results in CVD or whether the APO uncovers a woman’s predisposition to CVD (Figure 1). Regardless, APOs have immediate risks to maternal and fetal health, in addition to longer-term CVD consequences.7,12,40,41 As such, the occurrence of APOs provides an insight into a woman’s future cardiovascular health.

Systemic Endothelial/Microvascular Dysfunction

APOs appear to share similar metabolic and/or vascular abnormalities, which are reflected within the placenta. In a pregnancy without any APOs, the maternal spiral arteries widen after a trophoblast invasion, resulting in low-resistance blood flow in the uteroplacental unit.37 In contrast, in a

pregnancy affected by pre-eclampsia, the trophoblast invasion is shallow, with inadequate spiral artery remodelling that results in poor perfusion of the placenta, placental ischaemia and oxidative stress. There is also evidence of inflammatory markers within the maternal blood in those with APOs, which are not seen in those with an uncomplicated pregnancy.37,42–44 Theoretically, the inflammatory state and the anti-angiogenic state could be the shared mechanisms by which APOs increase underlying CVD risk.45 Placental lesions have also been associated with cardiovascular risk factors.46–48 Increased soluble fms-like tyrosine kinase-1 has been associated with atherosclerosis.49 Furthermore, women exposed to pre-eclampsia may also have arterial stiffness or endothelial damage, which, in turn, are related to their increased long-term CVD risk.50,51 Women with spontaneous preterm delivery have been observed to have a proinflammatory phenotype, with higher C-reactive protein levels during pregnancy.52,53 It may be that the inflammatory processes associated with preterm delivery increase the risk of endothelial dysfunction and subclinical vascular disease, and consequently increase CVD risk in the future.52,54 In addition, because placental dysfunction may be due to vascular and endothelial cell dysfunction, women who have subclinical CVD phenotypes may not be able to mount an appropriate haemodynamic response in pregnancy. For example, placental growth factor, a hormone that promotes angiogenesis, is significantly reduced in pregnancies with pre-eclampsia, with or without SGA infants.55,56 The shared placental and maternal vascular characteristics in those with APOs support an overlapping pathophysiology for future CVD, regardless of how different the APOs appear in their presentation.

Cardiac and Coronary Changes

Structural changes in the myocardium can occur in women with APOs. In pre-eclampsia specifically, afterload-dependent cardiac remodelling can be seen that is similar to the remodelling of the myocardium seen in hypertension. Specifically, an increase in left ventricular wall thickness, particularly concentric left ventricular hypertrophy, has been seen even in those with mild gestational hypertension.57,58 Diastolic dysfunction and impaired left ventricular relaxation have been documented in patients with pre-eclampsia.58 Left atrial remodelling may also develop, most noted in preterm pre-eclampsia.59 These changes can also persist many years after the incident pregnancy.22,23 Furthermore, women with previous pre-eclampsia had higher carotid intima–media thickness, lower coronary flow reserve and higher highsensitivity C-reactive protein values than those without pre-eclampsia.60 In addition, both pre-eclampsia and high parity number have been linked with accelerated atherosclerosis.27,61 Women with previous preterm births also have higher atherogenic lipids and carotid arterial wall thickening in the decade after delivery than women who had term births.62 For women with ischaemia without obstructive coronary artery disease, a history of APO is associated with lower coronary flow reserve suggestive of coronary microvascular dysfunction.63

Role of Cardiovascular Disease Risk Factors

APOs and CVD share ASCVD risk factors, and women with APOs have been shown to have a higher CVD risk factor burden, with a greater prevalence of hypertension, hyperlipidaemia, diabetes, kidney disease, obesity and tobacco use, in addition to a greater risk of developing these risk factors several years after the pregnancy.7,64–66 Except for tobacco use, which is inversely associated with pre-eclampsia, the other

EUROPEAN CARDIOLOGY REVIEW Access at: www.ECRjournal.com

The Fourth Trimester: Pregnancy as a Predictor of CVD Figure 1: Impact of Adverse Pregnancy Outcomes on the Cardiovascular System

Pre-existing CVD risk factors

Left ventricular hypertrophy/diastolic dysfunction

Shared genetic risk between APOs and CVD

Cardiac adaptations to APOs

Decreased arterial compliance CVD consequences Endothelial dysfunction Vascular dysfunction

Maternal inflammation

Premature IHD/CAC/stroke

Placental ischaemia

APOs = adverse pregnancy outcomes; CAC = coronary artery calcium; CVD = cardiovascular disease; IHD = ischaemic heart disease.

biochemical risk factors have been shown to persist in women years after HDP.67 Therefore, pre-eclampsia and gestational hypertension may be independent risk factors for future CVD because the post-pregnancy body may not fully recover from the damage to the vascular, endothelial and metabolic systems during pregnancy. With further insults to the body over time, the damage sustained during pregnancy may manifest in later life as cardiovascular events.68 Women with pre-existing cardiovascular risk factors, such as an adverse lipid profile and glucose status, are also at increased risk of preterm delivery.69 Similarly, delivery of SGA infants is linked to the development of maternal hyperlipidaemia, hypertension and increased calculated 10-year CVD risk prior to the onset of CVD.70,71 Nonetheless, the excess risk based on risk factors does not fully account for the amount of CVD seen women with APOs.72 Therefore, other mechanisms are likely to be involved in the association between APOs and CVD.

Other Mechanisms

Families of women with an APO also have increased risks of APOs and CVD, suggesting that underlying genetic factors may also contribute to the association.73,74 Women at risk of APOs and CVD may also have genetic mutations that are involved in the disease process. For example, there are maternal sequence variants associated with both pre-eclampsia and hypertension.75 Similarly, genetic predisposition to hypertension has been associated with HDP.76 Furthermore, an association was found between single nucleotide polymorphism variations in genes for cholesterol metabolism and preterm delivery.77 Conversely, multifactorial mechanisms may explain the association of APO with CVD, and socioeconomic factors have also been considered. For example, CVD and high parity number are both more frequently observed in low socioeconomic classes.78 High parity number is also associated with a small increased future paternal CVD risk.79–81 Because the observed

associations in both mothers and fathers attenuated following adjustment for lifestyle factors, there may be residual confounding by socioeconomic class and/or lifestyle.80

Evolving Role of Adverse Pregnancy Outcomes in the Prediction of Cardiovascular Disease Risk

CVD risk assessment and stratification in women remain complex and, historically, have underestimated risk, especially in young women.82 Not only do traditional CVD risk factors such as hypertension, hyperlipidaemia and tobacco use, among others, need to be considered, but additional sex-specific factors, such as APOs, should also be included. However, existing risk stratification schemes, such as the ASCVD Pooled Cohort Equations model, do not include pregnancy or other gynaecological history.82 Whether routine incorporation of pregnancy complications improves the ability to risk stratify women for CVD is unknown and has more recently been investigated. The HUNT study by Markovitz et al. assessed the long-term risk of CVD, including MI, CHD and stroke, in women without prior CVD history in approximately 18,000 subjects with a prevalence of APOs of 39%.11 In that study, of all APOs, only pre-eclampsia was associated with increased CVD risk. The inclusion of pregnancy complications only led to the reclassification of 0.4% of women without events into lower-risk categories and 2% of women with events were correctly reclassified into higher-risk categories.11 A similar study by Timpka et al. assessed HDP and low birth weight in subjects aged ≥50 years and found that the inclusion of these APOs did not significantly improve CVD risk prediction.83 In the US, Stuart et al. studied the role of HDP and parity in a cohort of women aged ≥40 years without CVD risk factors or history of CVD.24 HDP and parity were added to the ASCVD Pooled Cohort Equations model, and these variables were associated with elevated ASCVD risk independent of established CVD risk factors; however, the risk reclassification across risk groups or age stratification did not change: 0.6% of previously low-risk women who developed CVD

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The Fourth Trimester: Pregnancy as a Predictor of CVD Figure 2: Incorporation of Adverse Pregnancy Outcomes into the Atherosclerotic Cardiovascular Disease Risk Assessment of Women

Traditional CVD risk factors Hyperlipidaemia Hypertension Diabetes Tobacco use Physical inactivity

History/examination/risk assessment Assess for APOs

Laboratory/imaging studies

Assess for other ASCVD risk enhancers

Lipids

Calculation of ASCVD risk

HbA1c

Blood pressure

Consider coronary artery

Waist circumference

calcium score

The incorporation of APOs involves traditional ASCVD risk factors, other risk enhancers, blood pressure and waist circumference on examination, as well as the assessment of lipids, HbA1c and consideration of coronary CT angiography. APOs = adverse pregnancy outcomes; ASCVD = atherosclerotic cardiovascular disease.

were reclassified into a higher-risk group, but 8.3% of women previously classified as being of intermediate risk were incorrectly reclassified as low risk.24 Dam et al. compared CVD risk prediction in women with and without a history of HDP among the Framingham Risk Score, the Pooled Cohort Equations model and the Systematic Coronary Risk Evaluation (SCORE) model, and similarly found that none of the models was more predictive in women with than without a history of HDP.84 Although these studies do not demonstrate improved discrimination of risk with the inclusion of APOs, this may be explained by underlying embedded association of APO risk with traditional CVD risk factors such as hypertension and diabetes. APOs serve as a ‘window’ into future CVD risk, either through development of traditional CVD risk factors and/or an independent association with underlying vascular dysfunction. As such, it is important to screen for APOs as risk markers to guide potential risk mitigation strategies. In 2018, the ACC/AHA cholesterol guidelines for the first time acknowledged APOs as CVD ‘risk enhancers’ for consideration of statin use in women with borderline to intermediate risk, as calculated by the Pooled Cohort Equation.4 The inclusion of APOs among other risk enhancers allows clinicians to personalise decision making regarding statin therapy beyond just generalised risk assessment. The ACC/AHA cholesterol guidelines also recommend the consideration of coronary artery calcium (CAC) assessment to help further guide decisions regarding statin therapy.4 The use of CAC to guide prevention therapies, such as statins, is particularly intriguing in women with a history of APOs. 1. Virani SS, Alonso A, Aparicio HJ, et al. Heart disease and stroke statistics – 2021 update: a report from the American Heart Association. Circulation 2021;143:e254–743. https://doi. org/10.1161/CIR.0000000000000950; PMID: 33501848. 2. Khan SU, Yedlapati SH, Lone AN, et al. A comparative analysis of premature heart disease- and cancer-related mortality in women in the USA, 1999–2018. Eur Heart J Qual Care Clin Outcomes 2021:qcaa099. https://doi.org/10.1093/ ehjqcco/qcaa099; PMID: 33555018. 3. Petersen EE, Davis NL, Goodman D, et al. Vital signs: pregnancy-related deaths, United States, 2011–2015, and strategies for prevention, 13 states, 2013–2017. MMWR Morb Mortal Wkly Rep 2019;68:423–9. https://doi.org/10.15585/ mmwr.mm6818e1; PMID: 31071074. 4. Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/ AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: a report of the American College of Cardiology/American Heart

Several studies have noted an association between coronary CT angiography (CTA)/calcium scoring in young women and a history of APOs (Figure 2). Benschop et al. found that, compared with women without a history of pre-eclampsia, pre-eclampsia is independently associated with CAC even when accounting for traditional CVD risk factors.85 Another study assessed a broader set of APOs in Black women, including preterm delivery, pre-eclampsia and gestational diabetes, against matched controls without APOs with regard to coronary CTA findings.86 In that study, any APO was associated with higher rates of atherosclerotic coronary disease, defined as ≥20% luminal narrowing disease and obstructive ≥50% luminal narrowing disease. That study was particular important because research in this area in Black women, who have high rates of pregnancy complications, is lacking. Whether coronary CTA should play a more routine role in assessing CVD risk in women with APOs is unknown and an area in need of further study.

Conclusion

Associations of APOs with future CVD have been reported in the literature. However, the underlying causal mechanisms remain unknown. It is important to raise awareness of the importance of these associations and the current recommendations among healthcare professionals, as well as among the women themselves. Further research is needed to elucidate the pathophysiology behind these associations. This, in turn, will inform future research in the role of ASCVD risk assessment and the effect of aggressive ASCVD risk modification on CVD outcomes in women with a history of APOs.

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of cardiovascular disease. N Engl J Med 1993;329:1893–4; https://doi.org/10.1056/NEJM199312163292515; PMID: 8247047. 82. Goff DC Jr, Lloyd-Jones DM, Bennett G, et al. 2013 ACC/AHA guideline on the assessment of cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2014;63:2935–59. https://doi.org/10.1161/01. cir.0000437741.48606.98; PMID: 24222018. 83. Timpka S, Fraser A, Schyman T, et al. The value of pregnancy complication history for 10-year cardiovascular disease risk prediction in middle-aged women. Eur J Epidemiol 2018;33:1003–10. https://doi.org/10.1007/s10654018-0429-1; PMID: 30062549. 84. Dam V, Onland-Moret NC, Verschuren WMM, et al. Cardiovascular risk model performance in women with and without hypertensive disorders of pregnancy. Heart 2019;105:330–6. https://doi.org/10.1136/ heartjnl-2018-313439; PMID: 30209122. 85. Benschop L, Brouwers L, Zoet GA, et al. Early onset of coronary artery calcification in women with previous preeclampsia. Circ Cardiovasc Imaging 2020;13:e010340. https://doi.org/10.1161/CIRCIMAGING.119.010340; PMID: 33190533. 86. Wichmann JL, Takx RAP, Nunez JH, et al. Relationship between pregnancy complications and subsequent coronary artery disease assessed by coronary computed tomographic angiography in black women. Circ Cardiovasc Imaging. 2019;12:e008754. https://doi.org/10.1161/ CIRCIMAGING.118.008754; PMID: 31303028.

Aortic Valve Stenosis

Timing of Intervention in Asymptomatic Patients with Aortic Stenosis Teresa Sevilla ,1,2 Ana Revilla-Orodea

1,2

and J Alberto San Román

1,2

1. Department of Cardiology, Hospital Clínico Universitario de Valladolid, Valladolid, Spain; 2. Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares, Madrid, Spain

Abstract

Aortic stenosis is a very common disease. Current guidelines recommend intervention mainly in symptomatic patients; aortic valve replacement can be considered in asymptomatic patients under specific conditions, but the evidence supporting these indications is poor. Continuous advances in both surgical and percutaneous techniques have substantially decreased rates of perioperative complications and mortality; with this in mind, many authors suggest that earlier intervention in patients with severe aortic stenosis, when they are still asymptomatic, may be indicated. This paper summarises what is known about the natural history of severe aortic stenosis and the scientific evidence available about the optimal timing for aortic valve replacement.

Keywords

Aortic stenosis, high-risk markers, prognosis, aortic valve replacement Disclosure: The authors have no conflicts of interest to disclose. Received: 7 April 2021 Accepted: 25 June 2021 Citation: European Cardiology Review 2021;16:e32. DOI: https://doi.org/10.15420/ecr.2021.11 Correspondence: Teresa Sevilla, Department of Cardiology, Hospital Clínico Universitario de Valladolid, Ramón y Cajal 3, 47003 Valladolid, Spain. E: tereseru@gmail.com Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Aortic stenosis (AS) is one of the most common valvular diseases in Western countries. AS is a degenerative disease and is therefore linked to age. The prevalence of severe AS is >7% among those aged >80 years,1 and the number of patients with AS will probably increase in coming decades due to the aging of the population.2 Progressive valve obstruction occurs during a long latent phase, with the patient remaining asymptomatic until the severity of the obstruction results in an inadequate heart function leading to symptom onset. Once symptomatic, severe AS has a poor prognosis, with a 12-month survival rate of approximately 65% among unoperated symptomatic patients.3,4 To date, there are no medical therapies that have been proven to delay the progression of AS or to correct valve degeneration. Aortic valve replacement (AVR; either surgical or percutaneous) remains the only treatment that has been demonstrated to improve survival.5–7 Current clinical guidelines recommend AVR when symptoms appear or left ventricular (LV) dysfunction occurs.8,9 However, management of asymptomatic severe AS remains a matter of controversy, and earlier AVR in certain scenarios is being increasingly supported by some groups. The aim of this review is to summarise the current evidence regarding the management of patients with asymptomatic AS.

Current Guideline Recommendations

European and US guidelines present similar recommendations about AVR is indicated in asymptomatic patients that are based on three scenarios:8,9

• abnormal LV ejection fraction (LVEF); • abnormal exercise test (with symptom development or a fall in blood pressure below baseline); and • low surgical risk and the presence of high-risk criteria, namely very

severe AS (defined as aortic peak velocity >5.5 m/s by the European guidelines and >5.0 m/s by the more recent US guidelines), a rate of peak transvalvular velocity progression >0.3 m/s per year or repeated and markedly elevated B-type natriuretic peptide (BNP).8,9 The European Society of Cardiology (ESC) guidelines also acknowledge severe pulmonary hypertension (systolic pulmonary artery pressure >60 mmHg confirmed by invasive measurement) with no evident explanation, whereas the US guidelines grant a 2b recommendation to progressive decreases in LVEF to <60% on three or more serial imaging studies.8,9 The ESC guidelines emphasise that all the recommendations regarding early intervention in asymptomatic AS relate to surgical aortic valve replacement (SAVR), but the US guidelines consider both SAVR and transcatheter aortic valve replacement (TAVR) in the case of systolic dysfunction, but only SAVR in the other indications (Table 1).8,9 It is important to note that there are low levels of evidence for all these recommendations. The recommendations are based on small, singlecentre, retrospective, observational studies or expert opinions. Most of the situations identified as high-risk criteria are based on studies in which the primary end-point usually included the development of symptoms or undergoing AVR. It is crucial to understand that the evidence shows that all these factors are markers of the progression of the disease, but it is not clear whether early AVR in these scenarios will improve patients’ prognosis.

Natural History of Patients with Aortic Stenosis

Ross and Braunwald published a review of AS in 1968 that has traditionally been accepted as the natural evolution of AS: survival was excellent during a latent period when increasing obstruction and myocardial

Timing of Intervention in Asymptomatic Patients with Aortic Stenosis Table 1: Current Guideline Recommendations for Aortic Valve Replacement in Asymptomatic Aortic Stenosis Indications for AVR in Asymptomatic AS

2017 ESC/EACTS Guidelines8

2020 AHA/ACC Guidelines9

Class

LOE

Intervention Class

LOE

Intervention

LVEF <50%

SAVR

B-NR

SAVR, TAVI

Undergoing other cardiac surgery

SAVR

B-NR

SAVR, TAVI

Symptoms on exercise test clearly related to AS

SAVR

Considered as symptomatic

Exercise-induced fall in blood pressure

IIa

SAVR

IIa

B-NR

SAVR

Aortic velocity >5.5 m/s (ESC/EACTS); aortic velocity >5.0 m/s (AHA/ACC) and low surgical risk

IIa

SAVR

IIa

B-NR

SAVR

Rate of peak transvalvular velocity progression >0.3 m/s per year and low IIa surgical risk

SAVR

IIa

B-NR

SAVR

Repeated elevated (×3) BNP and low surgical risk

IIa

SAVR

IIa

B-NR

SAVR

Severe pulmonary hypertension without explanation

IIa

SAVR

–

Progressive decrease in LVEF <60% on ≥3 serial studies

–

B-NR

SAVR

IIb

ACC = American College of Cardiology; AHA = American Heart Association; AS = aortic stenosis; AVR = aortic valve replacement; EACTS = European Association for Cardio-Thoracic Surgery; ESC = European Society of Cardiology; LOE = Level of Evidence; LVEF = left ventricular ejection fraction; SAVR = surgical aortic valve replacement; TAVI = transcatheter aortic valve implantation.

overload were occurring.10 Then, when symptoms appeared (angina, syncope and/or heart failure), survival rapidly decreased. This scheme represented the evolution of AS that was predominantly rheumatic in origin, with the age at the time of symptom onset being <60 years and the average age at the time of death being 63 years.10 Therefore, it does not necessarily represent the natural history of AS nowadays. Currently, most AS patients in the Western countries are older, usually have degenerative aortic disease and often present with significant comorbidities.11 Despite the extensive research on the field, the current natural evolution of AS is difficult to evaluate. Many groups have published observational studies about the natural history of AS, but most have combined death and AVR as an event. The approaches to symptom evaluation and patient follow-up differ widely among the studies, as does the way to report death, so it is difficult to reach solid conclusions based on these studies. The main results of these studies are summarised in Table 2.12–21 Most of the events reported in these studies are the development of symptoms or AVR. Approximately half the patients required intervention, with total and cardiovascular mortality approximately 5% and 3.5% per year, respectively. The rate of sudden cardiac death is approximately 0.95% per year, as described previously.13,18,19 A recently published metaanalysis on the natural history of AS reported similar results: a rate of allcause death of 4.8 per 100 patients per year and a rate of cardiovascular death of 3.0 per 100 patients per year, with sudden death occurring at a rate of 1.1 per 100 patients per year.22 Some studies have reported on the symptom status of patients who died and the reasons for not performing AVR.12,15,17,19,20 There is considerable disparity here, with the rate of patients who remained asymptomatic until the fatal event ranging between 0% and 75% (Table 3). However, because some patients developed symptoms before death, these figures cannot be interpreted as mortality in asymptomatic patients with AS. Only a few studies have reported deaths after AVR: the mortality rate within the perioperative period was reported to be 4.9%, increasing to 15.4% during the entire follow-up period.12,14,17,20,21 Of these studies, that of Rosenhek et al. in 2010 included only patients with very severe AS (peak velocity >5 m/s), although the results are similar to those reported by the other studies.17

In their study, Zilberszac et al. only included patients >70 years of age.20 As a result, mortality in that study is notably higher in both patients under clinical vigilance and after intervention.20 The effect of age on the natural history of AS and on the results of interventions performed in AS patients must be addressed because, as Table 2 clearly shows, the mean age of these patients is increasing. The rate of progression of the disease is highly variable among subjects and difficult to predict.23 On average, aortic peak velocity is estimated to increase 0.2–0.3 m/s and aortic area to decrease 0.1 cm2.24,25 Symptom onset in patients with severe AS is likely to occur within 2–5 years.9 In the meta-analysis of Gahl et al., the yearly rate of patients who developed symptoms was 18.5%.22 As soon as symptoms appear, the prognosis of severe AS is very poor, with survival rates of only 15–50% at 5 years.8 Until now, symptom onset had been considered as the essential moment in the evolution of AS. We know that prognosis significantly worsens at this point, and we wait for it to occur before intervening in patients. However, as the complication rates of both SAVR and TAVR have decreased with time, there has been increasing concern about the development of irreversible cardiac damage that would not be corrected or reduced by later AVR and that may precede symptoms. Symptoms are subjective in nature and, so, basing treatment decisions on what the patient reports can be deleterious. Assessing the symptomatic status of a patient with AS is complex: on the one hand the disease progresses slowly and patients may adjust their activity gradually and unconsciously. On the other hand, symptoms may be non-specific: these patients are typically old, deconditioned and often present with comorbidities, such as pulmonary disease or obesity. Attributing the dyspnoea to AS can be challenging in many cases. In addition to the symptom status of a patient, given the increasing age of the AS patient population, comorbidities play a very important role in the clinical evaluation of and decision-making for these patients. Guidelines recommend against performing AVR in patients with severe comorbidities if it is unlikely that the patient’s quality of life or survival will improve. A multicentre prospective registry of patients with AS has documented the effects of comorbidities on the presentation and management of patients.26 In that study, 50% of patients with severe AS had any kind of comorbidity, and the presence of comorbidities was associated with a greater likelihood of being symptomatic. The authors also reported that

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Timing of Intervention in Asymptomatic Patients with Aortic Stenosis Table 2: Summary of Prospective Observational Studies Reporting Outcomes in Asymptomatic Severe Aortic Stenosis in the Past 20 Years Study

Age (years)

FollowAVR up (Months)

Deaths

CV Deaths

n (%)

Yearly n (%)

22 ± 18

3.5

SCD

Yearly n (%)

Rosenhek et al. 2000

126

60 ± 18

59 (46.8)

8 (6.3)

Amato et al. 200113

44.2 ± 13.7 15 ± 12

–

Lancellotti et al. 2005

66 ± 12

15 ± 7

12 (17.3)

2 (2.8)

Avakian et al. 200815

133

66.2 ± 13.6

40 ± 22

–

– 2 (3.3)

3.3

–

8 (6.8)

1 (0.8)

Lafitte et al. 200916

2.2

POP Deaths Yearly

n (%)

Yearly

1+5‡ (4.7) 2.6

1 (0.8)

4 (6.7)

5 (8.4%) 4.6

–

4 (6.06) 1.2

–

2 (2.8)

2.2

1 (8.3)

4+3A (5.2)

1.5

–

0.2

1 (1.2)

8 (10.1)

2 (2.8)

2.2

0.4

Death After AVR

6.6

70 ± 12

42 (70)

–

116

67 ± 15

41 [26–63]

80 (68.9)

11 (9.4)

Lancellotti et al. 2012

105

71 ± 9

19 ± 11

49 (46)

–

7(6.6)

4.17

3 (2.8)

1.7

–

Yingchoncharoen et al. 201219

77 ± 12

49 (62)

5 (6.3)

4.7

3A (3.7)

2.7

1A (1.2)

0.9

–

Zilberszac et al. 201720

103

77 ± 5

19 [9–36]

71 (68.9)

15+8A (22.3)

14.1

9+7A (15.5)

9.8

1 (0.9)

0.5

5 (7)

21 (29.5)

18.6

Lancellotti et al. 201821

861

72 ± 12

27 ± 24

388

64 (7.4)

3.2

32 (3.7)

1.6

4 (0.4)

0.2

–

59 (15)

6.6

Total

1,718

750 (49)

174 (10.1) 5

116 (6.7)

3.5

36 (2)

0.95

25(4.9)

94 (15.4)

Rosenhek et al. 2010

2.7

2.9

Unless indicated otherwise, data are given as the mean ± SD, median [interquartile range] or n (%). APatients with an indication for aortic valve replacement (AVR), but no intervention. CV = cardiovascular deaths; POP deaths = deaths in the perioperative period; SCD = sudden cardiac death.

Table 3: Summary of Studies Reporting the Symptom Status of Patients Who Died Author

Patients (n) Age (years)

Follow-up (months)

Cardiac Deaths (n)

Symptom Status AVR Before the Fatal Event

Rosenhek et al. 200012

126

60 ± 18

22 ± 18

1 asymptomatic (SCD), 5 symptomatic

3 refused, 1 high risk, 1 4 HF, 1 endocarditis, 1 waiting list SCD

Avakian et al. 200815

133

66.2 ± 13.6

40 ± 22

4 asymptomatic, 3 symptomatic

–

7 SCD

Rosenhek et al. 201017

116

67 ± 15

41 [26–63]

6 asymptomatic (1 SCD), 2 symptomatic (1 SCD)

2 refused

2 SCD, 5 HF, 1 infarction

Yingchoncharoen et al. 201219 79

77 ± 12

3 symptomatic

2 refused, 1 high risk

2 HF, 1 SCD

Zilberszac et al. 2017

77 ± 5

19 [9–36]

9 asymptomatic, 8 symptomatic (1 SCD)

8 refused

10 HF, 3 MI, 2 multiorgan failure, 1 SCD

103

Causes of Death

Unless indicated otherwise, data are given as the mean ± SD or median [interquartile range]. AVR = aortic valve replacement; HF = heart failure; SCD = sudden cardiac death.

certain comorbidities, such as chronic kidney disease, appear to act as deterrents for indications for surgery, whereas the presence of ventricular dysfunction seems to be an incentive. TAVR is more frequently indicated in comorbid patients, and an active decision not to treat was more frequently chosen in the subgroup of patients with a higher comorbidity burden.26 Sudden cardiac death (SCD) can occur in asymptomatic patients with severe AS; in fact, SCD can be the first clinical manifestation of the disease.12–15,17,19,20,27,28 The estimated annual risk of SCD in clinically asymptomatic patients with severe AS is around 1%. Similar results are presented in Table 2 for data from prospective observational studies. Whether this low rate of sudden death would be reduced with early AVR is unknown. Although traditionally SCD has been linked to the severity of the stenosis, the exact mechanism that ultimately leads to SCD is unknown; patients with AS often have associated coronary artery disease. Moreover, hypertrophy and myocardial fibrosis are common in these patients and are known causes of tachyarrhythmias. In fact, it has been reported that SCD also occurs in patients with mild and moderate AS with

an annual incidence of 0.39%/year.29 In these patients, sudden death has been related to LV hypertrophy, but not to stenosis severity.29 Moreover, the risk of SCD does not completely disappear after AVR, and SCD has been described as the second cause of cardiac death after both SAVR and TAVR.30 In a large contemporary register of 3,726 TAVR patients investigating cardiac death after the intervention, SCD occurred in 57 patients after a mean follow-up of 22 ± 18 months (5.6% of deaths, 16.9% of cardiac deaths).31 In that study, LVEF ≤40% and new-onset persistent left bundle branch block were identified as independent predictors of SCD, especially if the QRS duration was >160 ms.31 Unfortunately, no significant differences were observed in survival rate among patients who did and did not receive a prophylactic pacemaker, although this could be related to the small number of patients in this subgroup with new-onset persistent left bundle branch block who received a pacemaker.31

High-risk Markers in Asymptomatic Aortic Stenosis

The uncertainty about the best management in asymptomatic AS has led researchers towards the identification of patients at high risk of developing

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Timing of Intervention in Asymptomatic Patients with Aortic Stenosis complications. These factors can be considered to be predictors of eventfree survival, but, again, it must be pointed out that in most cases the predominant event analysed in the studies was the development of symptoms requiring intervention. Therefore, currently there is no evidence that AVR in these scenarios will improve outcomes in asymptomatic patients.

Echocardiographic High-risk Markers

Very severe AS, defined as aortic peak velocity >5 or >5.5 m/s depending on the study, has been defined as a high-risk marker in many studies. At aortic peak velocity above 5 m/s, the rate of symptoms onset is 50% at 2 years.9 Peak velocity is one of the strongest independent echocardiographic predictors of adverse cardiovascular events in patients with AS.12,19,25,27,32–35 In a recent prospective cohort of 1,375 patients with asymptomatic AS, among patients with a peak velocity >5 m/s, the risk of cardiovascular mortality was sixfold higher and the risk of postprocedural mortality was higher for those patients who underwent AVR.21 The very first published randomised control trial (RCT) comparing early surgery or conservative care in asymptomatic AS was performed in patients with very severe AS (defined as an aortic valve area of ≤0.75 cm2 with either peak velocity >4.5 m/s or mean gradient >50 mmHg).36 Although that study has several limitations that are addressed below, the authors reported a better prognosis in the early surgery group (death for any cause 7% in early surgery versus 15% in conservative care; HR 0.33; 95% CI [0.12–0.90]). In some studies, a reduction in LVEF was an independent predictor of events.15,37–39 Current clinical guidelines recommend surgery when LVEF is <50%.8,9 However, patients with AS often have concentric hypertrophy and, in these cases, LVEF may substantially underestimate the degree of LV systolic dysfunction. In a large register of more than 900 subjects, LVEF <50%, as well as LVEF between 50% and 59%, was independently associated with poorer outcomes compared with LVEF ≥70%.40 Another retrospective study found that mortality was higher for patients with LVEF 50–59% than >60% after AVR.41 In addition, up to one-third of patients with AS and LVEF >50% had subclinical ventricular dysfunction, identified by speckle tracking echocardiography.42 All these data suggest that a cutoff of LVEF <50% lacks sensitivity to identify subclinical ventricular systolic dysfunction and that patients with an LVEF between 50% and 59% should be monitored closely. The rate of progression in peak velocity is individual and difficult to predict. The normal rate is estimated to be around 0.3 m/s per year. Some studies have reported that a higher rate of progression is associated with a higher risk of events.12,24,32 Rapid progression (≥0.3 m/s per year) predicted excess mortality (versus a slow progression rate) after adjustment for other important risk factors, such as LVEF or peak aortic velocity, in a recent retrospective study.43 Global longitudinal strain (GLS) is an early marker of abnormal contractility and is more sensitive than LVEF in identifying subtle abnormalities in myocardial function; in addition, GLS abnormalities are related to myocardial fibrosis.44 Although the optimal scenario for GLS analysis and cut-off values are still under investigation, there is growing evidence of the added value of GLS in patients with severe AS and a normal LVEF.27,45,46

Exercise Stress Test

The incidence of an abnormal exercise stress test in patients with asymptomatic AS is approximately 50%.23 Developing clearly valverelated symptoms during the stress test is considered a Class I indication for AVR in both European and US guidelines, and an abnormal pressure

response is a Class IIa indication for AVR. Studies investigating exercise tests in asymptomatic AS are very heterogeneous regarding the exercise protocols and the criteria to be considered abnormal. Most studies have shown that an abnormal test is an excellent predictor of developing spontaneous symptoms in the future, but there has been no clear relationship shown with mortality.14,16,33 A classic study reported that the stress test may identify patients at risk of SCD,13 but these results have not been confirmed in other studies. Exercise stress testing may help uncover symptoms, revealing them in up to 38% of patients with asymptomatic AS.47 However, it has to be noted that the positive predictive accuracy for exercise-induced symptoms is limited in patients aged >70 years.33

Biomarkers

Serum BNP concentrations are predictive of symptom onset during followup, but also of persistent symptoms after AVR.48 A recent observational study demonstrated that elevated BNP levels were associated with an increased risk of death or hospitalisation for heart failure.49 Based on this evidence, the new US guidelines have changed and now recommend AVR (Class IIa indication) with a BNP level >300 pg/ml (threefold normal). Remarkably, asymptomatic patients with BNP concentrations <100 pg/ml had an event rate of only 2.1% at 1 year.9,49 Although the true value of BNP has to be tested in an RCT, it seems reasonable to integrate BNP concentrations in the clinical assessment of patients with asymptomatic AS, particularly for the identification of lower-risk patients who can be followed periodically. The BNP ratio is calculated as measured BNP/maximal normal BNP value for age and sex, and represents BNP activation.50 In a large cohort of 1,953 consecutive patients with at least moderate AS, the BNP ratio was an independent predictor of mortality.50 In the subgroup of patients with severe asymptomatic AS and a normal LVEF, a BNP ratio >1 independently predicted survival.50

Cardiovascular MRI

In AS, progressive narrowing of the valve causes chronic pressure overload of the LV. This triggers a hypertrophic response able to maintain myocardial performance for a long time. This ventricular remodelling is also accompanied by the development of myocardial fibrosis, myocyte injury and adverse remodelling of the extracellular matrix.51 Histological studies have shown that higher degrees of myocardial fibrosis at the time of AVR are associated with worse long-term survival after the intervention.52 Advances in cardiac imaging allow a precise non-invasive quantification of myocardial fibrosis with cardiac magnetic resonance (CMR). Two different patterns of myocardial fibrosis can be identified by CMR, namely diffuse interstitial fibrosis and replacement fibrosis. Diffuse interstitial fibrosis is a reactive and at least partially reversible process. It is assessed by novel CMR T1 mapping approaches and it has been demonstrated to improve after AVR.53,54 High native T1 values on non-contrast T1 mapping have been shown to be an independent predictor of mortality and hospitalisation for heart failure in patients with significant AS.55 Replacement fibrosis is a later phenomenon and is irreversible. Replacement fibrosis is assessed by late gadolinium enhancement techniques and is relatively common in patients with AS (found in 20–66% of patients undergoing CMR).51 Late gadolinium enhancement does not regress after AVR, decreases the chances of improvement of LVEF and has been found to be an independent predictor of all-cause mortality after the intervention.52,56

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Timing of Intervention in Asymptomatic Patients with Aortic Stenosis It seems clear that myocardial fibrosis detected by CMR is frequent in patients with severe AS and is an adverse prognostic indicator. These findings raise the question of whether long-term outcomes would be improved if AVR is performed before adverse LV remodelling has occurred.

Table 4: Meta-analyses Comparing Early Aortic Valve Replacement with Conservative Management Study

Year

95% CI

Généreux at al.2

2016

0.29

0.17–0.51

–

Lim et al.62

2017

0.54

0.26–1.12

–

Gahl et al.22

2020

0.38

0.25–0.58

–

Yokohama et al.

2020

0.49

0.36–0.68

0.42

0.22–0.82

Ullah et al.

2020

0.24

0.13–0.45

0.21

0.06–0.70

Kumer et al.65

2021

0.36

0.24–0.53

0.36

0.27–0.48

Cardiac CT

Multislice cardiac CT allows the severity of aortic valve calcification to be quantified with high accuracy. In asymptomatic AS, the calcium score of the aortic valve correlates strongly with clinical outcomes, such as symptom development, death or AVR.57,58 Recent research has demonstrated that the extracellular volume, a parameter of diffuse myocardial fibrosis, can be assessed by cardiac CT, with a good correlation with histology and CMR measurements in patients with AS.59 Furthermore, in patients with severe AS undergoing CT before AVR, quantification of extracellular volume fraction was correlated with functional status and predicted a composite of adverse clinical outcomes after the intervention.60,61 Although its value in patients with asymptomatic AS has to be proven, cardiac CT is worthy of further investigation given the need for cardiac CT imaging prior to TAVR and the utility of calcium scoring as a marker of stenosis severity in cases of doubt.

Early Aortic Valve Intervention Versus Watchful Waiting

Determining the optimal timing of AVR in patients with AS depends not only on the severity of the valvular lesion, but also on the safety, efficacy and long-term results of the procedure to be applied. An early intervention while the patient is asymptomatic exposes the patient to both procedural complications (which can be fatal, but also create disabilities) and longterm complications (bleeding, embolism, paravalvular leak, endocarditis). In addition, the earlier the intervention, the higher the probability of a reintervention in the future due to prosthesis degeneration. Conversely, postponing AVR confers a low but real risk of suffering a life-threatening event and a risk of developing irreversible structural damage in the heart that would worsen the prognosis after the intervention. In addition, the risk of the intervention itself will be higher if the patient gets older. In the quest to determine whether early AVR benefits patients with asymptomatic severe AS compared with the current recommendations (clinical vigilance and AVR if the patient becomes symptomatic or the LVEF decreases below 50%), an RCT and several meta-analyses have been published recently. The RECOVERY trial randomised 145 patients with asymptomatic very severe AS to early surgery or to conservative care.36 The cardiovascular mortality rate after a median follow-up period of 6 years was 1% in the early surgery group and 15% in the conservative care group. Several aspects regarding that study deserve to be mentioned. Patients >80 years of age were excluded, the mean (±SD) age was 64±9 years and more than half the patients had a bicuspid aortic valve, so this population differs considerably from what a real clinical scenario of severe AS represents nowadays.36 Probably due to this selected population, operative mortality was zero and the mortality in the follow-up period was also strikingly low (7% of all-cause mortality). These figures are far from the 5% and 15%, respectively, reported in the observational studies (Table 2). The small number of deaths represents a statistical limitation of the RECOVERY trial. The surgical outcomes reflect the surgical excellence of the participant centres, but the results may not be extrapolated to less-experienced centres. It is also surprising that 22% of patients in the conservative arm never underwent surgery despite the long follow-up period.36 This reflects that patients with asymptomatic

All-cause Mortality Cardiovascular (AVR versus Mortality Conservative) (AVR versus Conservative) 95% CI

AVR = aortic valve replacement.

AS are a heterogeneous population in whom a one-size-fits-all strategy may not be the best approach. Six meta-analyses have been published in recent years.2,22,62–65 All have included a variable combination of the same 12 studies: one RCT and some prospective and most retrospective observational studies. The meta-analysis published by Lim et al. showed a trend towards a reduction in mortality with early AVR, but no significant difference in cardiac mortality.62 The remaining studies found a significant benefit for AVR compared with conservative management, with lower all-cause and cardiovascular mortality rates.2,22,63–65 The results of all six meta-analyses are summarised in Table 4. Although all these studies point the same direction, their results must be analysed with caution. All showed a significant heterogeneity between studies; the meta-analyses are, of course, exposed to publication bias, but their main limitation is that their quality depends on the quality of the studies they included, many of which were retrospective studies. In addition, the stress test was not universally performed in the studies included, so there is no way to determine whether all patients were truly asymptomatic, and the follow-up of patients in the conservative group was not protocolised. In fact, in one of the studies included in all six meta-analysis, up to 30% of the patients developing symptoms in the conservative group during the follow-up did not undergo AVR.28 Thus, although the conservative strategy is often known as ‘watchful waiting’, we have no evidence that, in these cases, the waiting was watchful. There are currently five ongoing RCTs (AVATAR [NCT02436655]; EARLY TAVR [NCT03042104]; EVoLVeD [NCT03094143]; DANAVR [NCT03972644]; EASY-AS [NCT04204915]) comparing the ‘wait for symptoms strategy’ with surgical or percutaneous AVR.66 Although all these RCTs will help us to better understand the role of AVR in asymptomatic AS, the most promising seems to be the DANAVR trial (NCT03972644). This trial is designed to evaluate patients with high-risk features: left atrium dilatation, diastolic dysfunction, abnormal GLS or elevated N-terminal pro BNP (NT-proBNP); the primary end-point is death and the estimated follow-up period is 60 months. We believe that, to adequately address early aortic valve intervention versus watchful waiting, a controlled trial should not include AVR or symptoms in the medical group as an outcome and that follow-up must be long enough to include both perioperative deaths and long-term deaths in the conservative arm. Disability and quality of life parameters should also be considered because they are a significant event in aged patients. Due to the specific features of patients with asymptomatic severe AS, individual life expectancy in good health should be the focus

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Timing of Intervention in Asymptomatic Patients with Aortic Stenosis Figure 1: Extravalvular Staging in Aortic Stenosis With Echocardiographic Parameters and Other Risk Factors, and Its Relationship With the Timing of Intervention Stage 0

Stage 1

Stage 2

Stage 3

Normal

LVH Increased EVC in CMR

LA enlargement

LGE in CMR

Normal Abnormal relaxation

Elevated LVFP

sPAP >60 mmHg

Normal

LVEF <60% GLS <15%

Moderate to severe MR

Stage 4 Yes

Structural

Haemodynamics

Functional

Stroke volume index <30 ml/m2

<17 mm Moderate to severe TR TAPSE S <9.5 cm/s BNP ×3 LVE <50% Benefit of AVR

Asymptomatic

Symptoms

Symptomatic

Guidelines Ideal Early AVR

No Time

The actual guideline recommendations (symptomatic patients or left ventricular ejection fraction (LVEF) <50%, positive stress test, certain high-risk parameters) lead to advanced stages in many patients. Patients undergoing aortic valve replacement (AVR) in Stages 3 and 4 have a worse prognosis after the intervention.68,71 An ideal strategy would integrate a personalised risk assessment based on multiparametric evaluation of disease severity and progression to formulate a follow-up and management plan that allows intervention before irreversible damage occurs. Under an indiscriminate early AVR strategy in all patients with severe aortic stenosis (AS), many patients would probably undergo intervention without benefit. AF = atrial fibrillation; BNP = B-type natriuretic peptide; CMR = cardiac magnetic resonance; ECV = extracellular volume; GLS = global longitudinal strain; LA = left atrium; LGE = late gadolinium enhancement; LVFP = left ventricular filling pressure; LVH = left ventricular hypertrophy; MR = mitral regurgitation; sPAP = systolic pulmonary artery pressure; TAPSE = tricuspid annular plane systolic excursion. Data sources: Généreux et al.68; Tastet et al.69 (echocardiographic parameters); Fukui et al.71; Lancellotti and Vannan (other risk factors).72

of the comparison between the different strategies rather than overall survival.

Role of Transcatheter Aortic Valve Replacement in Asymptomatic Patients

Current European guidelines do not recommend TAVR in asymptomatic patients, whereas US guidelines only recommend TAVR in the case of LV dysfunction.8,9 Although it stands to reason that TAVR is an interchangeable treatment choice to SAVR in asymptomatic patients, there is scarce scientific evidence in this scenario. Until comparable long-term durability is demonstrated, SAVR remains the first choice for lower-risk younger patients, at least from an academic point of view. However, real-world data show that with the emergence of percutaneous techniques in the treatment of AS, an increasing number of patients are undergoing TAVR while asymptomatic.67 A recent prospective multinational registry of patients with severe AS across Europe reported that, in the subgroup of 392 asymptomatic patients who were clinically evaluated to decide on treatment, AVR was decided on for 153 patients and, in 58% of cases, was performed percutaneously.67 In that registry, up to 66 patients underwent TAVR while asymptomatic and having no formal indication according to current clinical guidelines. As the technique improves and the complications of the procedure decrease, the indications for TAVR are expanding. TAVR will definitely play an important role in the shift towards earlier intervention in AS patients in the future, but, while we wait for scientific support for earlier indications, we should be cautious and try to avoid overusing percutaneous interventions, as has occurred with percutaneous coronary interventions over the past three decades.

Beyond the Aortic Valve: Role of Extravalvular Cardiac Damage Staging

A novel staging classification for patients with AS has recently been proposed.68 This staging system is based on the extent of the extravalvular

cardiac damage caused by the aortic stenosis as determined using echocardiography: Stage 0, no extravalvular cardiac damage; Stage 1, LV damage that includes significant hypertrophy or diastolic dysfunction and subclinical systolic dysfunction; Stage 2, left atrial or mitral valve damage; Stage 3, pulmonary vasculature or tricuspid valve damage; and Stage 4, right ventricular damage. This classification was predictive of 1 year mortality in patients undergoing AVR.68 The model was refined and validated in a cohort of patients with asymptomatic severe AS.69 In these patients, Stage ≥2 was an independent predictor of mortality. Notably, up to 60% of patients were in these advanced stages despite being asymptomatic. This classification has also been validated by other investigators.70,71 Because this staging system is based only on echocardiography, a variation to the system to include other markers of heart damage with prognostic association in AS, such as fibrosis in CMR or biomarkers, has been proposed.72 Figure 1 illustrates this way of staging and its relationship with the timing for surgery This constitutes a promising approach to the problem of asymptomatic AS: an individualised strategy focused on the repercussions of the disease in the heart, looking to intervene before there is irreversible damage to the structure and function, which may have an effect on patients’ prognosis not only before, but also after the intervention.

Conclusion

Patients with asymptomatic AS are a heterogeneous population in whom early AVR will surely have a role, but to date there is no evidence supporting changing the usual ‘wait for symptoms’ practice. However, this waiting must be active: close monitoring of patients is warranted and symptoms should be evaluated carefully, performing stress tests in case of equivocal or non-specific symptoms. It has been proven that symptoms are not a good marker of the status of the patient with severe AS; to

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Timing of Intervention in Asymptomatic Patients with Aortic Stenosis improve patient assessment, many high-risk markers are being identified and will be tested in RCTs. While we wait for the results of RCTs to set the appropriate indications for early AVR, a shift in the paradigm from focusing 1. Danielsen R, Aspelund T, Harris TB , Gudnason V. The prevalence of aortic stenosis in the elderly in Iceland and predictions for the coming decades: the AGES-Reykjavík study. Int J Cardiol 2014;176:916–22. https://doi.org/10.1016/j. ijcard.2014.08.053; PMID: 25171970. 2. Généreux P, Stone GW, O’Gara PT, et al. Natural history, diagnostic approaches, and therapeutic strategies for patients with asymptomatic severe aortic stenosis. J Am Coll Cardiol 2016;67:2263–88. https://doi.org/10.1016/j. jacc.2016.02.057; PMID: 27049682. 3. Varadarajan P, Kapoor N, Bansal RC, Pai RG. Clinical profile and natural history of 453 nonsurgically managed patients with severe aortic stenosis. Ann Thorac Surg 2006;82:2111–5. https://doi.org/10.1016/j.athoracsur.2006.07.048; PMID: 17126120. 4. Bach DS, Siao D, Girard SE, et al. Evaluation of patients with severe symptomatic aortic stenosis who do not undergo aortic valve replacement: the potential role of subjectively overestimated operative risk. Circ Cardiovasc Qual Outcomes 2009;2:533–9. https://doi.org/10.1161/ CIRCOUTCOMES.109.848259; PMID: 20031890. 5. Schwarz F, Baumann P, Manthey J, et al. The effect of aortic valve replacement on survival. Circulation 1982;66:1105–10. https://doi.org/10.1161/01.CIR.66.5.1105; PMID: 7127696. 6. Thourani VH, Suri RM, Gunter RL, et al. Contemporary realworld outcomes of surgical aortic valve replacement in 141,905 low-risk, intermediate-risk, and high-risk patients. Ann Thorac Surg 2015;99:55–61. https://doi.org/10.1016/j. athoracsur.2014.06.050; PMID: 25442986. 7. Leon MB, Smith CR, Mack M, et al. Transcatheter aorticvalve implantation for aortic stenosis in patients who cannot undergo surgery. N Engl J Med 2010;363:1597–607. https:// doi.org/10.1056/NEJMoa1008232; PMID: 20961243. 8. Baumgartner H, Falk V, Bax JJ, et al. 2017 ESC/EACTS guidelines for the management of valvular heart disease. Eur Heart J 2017;38:2739–91. https://doi.org/10.1093/ eurheartj/ehx391; PMID: 28886619. 9. Otto CM, Nishimura RA, Bonow RO, et al. 2020 ACC/AHA guideline for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. J Am Coll Cardiol 2021;77:e25– 197. https://doi.org/10.1161/CIR.0000000000000923; PMID: 33342586. 10. Ross J, Braunwald E. Aortic stenosis. Circulation 1968;38:61– 7. https://doi.org/10.1161/01.CIR.38.1S5.V-61; PMID: 4894151. 11. Braunwald E. Aortic stenosis: then and now. Circulation 2018;137:2099–100. https://doi.org/10.1161/ CIRCULATIONAHA.118.033408; PMID: 29650546. 12. Rosenhek R, Binder T, Porenta G, et al. Predictors of outcome in severe, asymptomatic aortic stenosis. N Engl J Med 2000;343:611–7. https://doi.org/10.1056/ NEJM200008313430903; PMID: 10965007. 13. Amato MC, Moffa PJ, Werner KE, Ramires JA. Treatment decision in asymptomatic aortic valve stenosis: role of exercise testing. Heart 2001;86:381–6. https://doi. org/10.1136/heart.86.4.381; PMID: 11559673. 14. Lancellotti P, Lebois F, Simon M, et al. Prognostic importance of quantitative exercise Doppler echocardiography in asymptomatic valvular aortic stenosis. Circulation 2005;112:I377–82. https://doi.org/10.1161/ CIRCULATIONAHA.104.523274; PMID: 16159850. 15. Avakian SD, Grinberg M, Ramires JAF, Mansur AP. Outcome of adults with asymptomatic severe aortic stenosis. Int J Cardiol 2008;123:322–7. https://doi.org/10.1016/j. ijcard.2006.12.019; PMID: 17395323. 16. Lafitte S, Perlant M, Reant P, et al. Impact of impaired myocardial deformations on exercise tolerance and prognosis in patients with asymptomatic aortic stenosis. Eur J Echocardiogr 2009;10:414–9. https://doi.org/10.1093/ ejechocard/jen299; PMID: 18996958. 17. Rosenhek R, Zilberszac R, Schemper M, et al. Natural history of very severe aortic stenosis. Circulation 2010;121:151–6. https://doi.org/10.1161/CIRCULATIONAHA.109.894170; PMID: 20026771. 18. Lancellotti P, Magne J, Donal E, et al. Determinants and prognostic significance of exercise pulmonary hypertension in asymptomatic severe aortic stenosis. Circulation 2012;126:851–9. https://doi.org/10.1161/ CIRCULATIONAHA.111.088427; PMID: 22832784. 19. Yingchoncharoen T, Gibby C, Rodriguez L, et al. Association of myocardial deformation with outcome in asymptomatic aortic stenosis with normal ejection fraction. Circ Cardiovasc

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COVID-19

Coronavirus Disease 2019: Psychological Stress and Cardiovascular Diseases Maki Komiyama

and Koji Hasegawa

Division of Translational Research, National Hospital Organization Kyoto Medical Center, Kyoto, Japan

Abstract

Minimising deaths due to coronavirus disease 2019 (COVID-19) is a global priority. However, the harmful effects are not limited to those directly related to the infection. The COVID-19 pandemic has also had a serious impact on the mental health of the general population. An increasing number of people are exhibiting signs of depression and an increase in suicides has also been noted around the world. Mental health issues may be linked to starting or increasing the use of addictive substances, such as tobacco, alcohol and drugs, along with increased overweight and obesity resulting from changes in eating habits. These issues can impact cardiovascular diseases because of worsened risk factor control. This review discusses the impact of the COVID-19 pandemic on mental health and cardiovascular risk factors. It will also summarise the measures that can be taken to maintain good mental health and their importance in mitigating cardiovascular disease.

Keywords

COVID-19, psychological stress, depression, mental health, smoking, obesity, cardiovascular disease Disclosure: KH is on the European Cardiology Review editorial board; this did not influence peer review. MK has no conflicts of interest to declare. Received: 23 March 2021 Accepted: 4 May 2021 Citation: European Cardiology Review 2021;16:e33. DOI: https://doi.org/10.15420/ecr.2021.10 Correspondence: Maki Komiyama, Clinical Research Institute, National Hospital Organization Kyoto Medical Center, 1-1 Mukaihata-cho, Fukakusa, Fushimi-ku, Kyoto 612-8555, Japan. E: nikonikomakirin@yahoo.co.jp Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

The coronavirus disease 2019 (COVID-19) pandemic is ongoing and has had a severe impact around the world. The pandemic has been classified as a public health problem that needs to be dealt with urgently, and minimising deaths due to the virus is an international priority. However, the harmful effects reach beyond those caused by the infection itself. COVID-19 has also had a serious impact on the mental health of the general population. An increasing number of people are exhibiting signs of depression globally, and an increase in suicides has been noted. Mental health issues may be associated with starting or increasing the use of addictive substances, such as tobacco, alcohol or drugs, along with changes in eating habits. These factors may in turn exacerbate cardiovascular risk.

COVID-19-related Depression

Various countries have been forced to implement strict systems of hygiene and social distancing because of the COVID-19 pandemic leading to their populations dealing with stressful events. The pandemic has caused a mental health crisis, as evidenced by the appearance of the new term ‘COVID-19-related depression’.1 The WHO has highlighted prolonged physical and social isolation due to lockdowns, fear of infection and losing cherished family and friends, an economic crisis, an increase in domestic violence and abuse primarily of women and children along with anxiety about young persons’ futures following disruption of their education as factors contributing to this crisis. Furthermore extensive misinformation about the virus and preventive measures and repeated images in the media of seriously ill people can intensify fear.1 Typically, mental health issues exist on a continuum from a minor issue lasting a certain period of time to more serious issues.2 The COVID-19

pandemic has affected everyone’s mental health and the state of people with prior mental health issues has worsened, leading to dysfunction.2 Citing the Lancet Commission on Global Mental Health and Sustainable Development, the UN warned: “Many people who previously coped well, are now less able to cope because of the multiple stressors generated by the pandemic.”3 In fact, symptoms of depression or anxiety are reported to be at higher levels than normal in various countries. According to the UN, surveys after the start of the pandemic indicated that 35% of people in China, 45% of people in the US, and 60% of people in Iran had their mental health troubled by the COVID-19 pandemic.3 The US Centers for Disease Control and Prevention conducted an online survey of 5,412 American adults in June 2020 to assess their mental health, substance use and suicidal ideation during the pandemic.4 Of those respondents, 40.9% indicated that they had some form of a psychiatric disorder, including an anxiety disorder or symptoms of a depressive disorder, and 10.7% indicated that they had seriously considered suicide in the past 30 days.4 This was a substantial increase compared to the same period in 2019. A large-scale study was conducted in the Amhara region of Ethiopia in April 2020, finding that the estimated prevalence of symptoms matching a depressive disorder was 33%.5 This was a threefold increase compared to the level before the outbreak. A study in adults in the US reported that symptoms of depression posed a bigger burden on subjects with lower income or few savings and on subjects who were often exposed to stressors, such as loss of a job.6 The negative mental health impacts associated with the COVID-19 pandemic have also been reported to be more pronounced for women than men among people living in rural areas

COVID-19: Psychological Effects and CVD Figure 1: The Relationship Between COVID-19-related Stress and Smoking

frequency) and resumption of smoking.15 When a state of emergency is declared, time spent at home increases as a result of self-isolation and smoking habits change as a result.15–17 Various studies to examine this are being conducted in different countries. Numerous studies have reported an increase in the number of cigarettes smoked, but conversely, other studies have also reported no change in the total number of cigarettes smoked since some people smoke more while others smoke less.15–17 A study in the UK found that 25.2% of current smokers (n=329) smoked more than usual, 50.9% smoked the same amount and 20.2% smoked less.17

Smokers: Increase or decrease their tobacco use

Need to take care of psychological stress

• Anxiety, psychosocial stress and depressive mood

• Information that smoking leads to severe symptoms in COVID-19

Need to increase dissemination of information on smoking and COVID-19 severity

COVID-19 = coronavirus disease 2019.

because of increased care responsibilities and loss of income.7 In Japan, suicides increased for 4 months consecutively after July 2020, and overall suicides in October 2020 increased 39.9% compared to the same period the previous year. Of note, suicides in women increased by 82.6% in October 2020 compared to October 2019.8

Stress and Dependence as a Result of COVID-19

Prolonged confinement following a large-scale natural disaster is known to greatly affect people mentally, as exemplified by an increased incidence of psychiatric disorders following the imposed lockdown measures.9 Being subjected to stress in conditions with no known time limit, such as when a state of emergency is declared, can lead to an inability to control one’s decision-making.10 To cope with stress, people tend to rely on negative coping strategies, such as the use of addictive drugs, alcohol or tobacco, or spending excessive time engaging in potentially addictive behaviours, such as online gaming. Stress is a well-known risk factor for the development and worsening of dependence and vulnerability to its recurrence. The underlying pathophysiology is the effects of those changes (i.e. substance use or addictive behaviour) on corticostriatal-limbic systems of motivation, learning and adaptation, including the mesolimbic dopamine, glutamate and γ-aminobutyric acid pathways.11 There are global concerns about an increase in the use of addictive substances, such as alcohol, to cope with stress associated with self-isolation amidst the COVID-19 pandemic.12 According to Canadian statistics, alcohol consumption among people aged 15–49 years increased 20% during the pandemic.13 A study in the US reported that 13.3% of adults aged 18 or over had started or increased the use of drugs.4 Worsening health behaviour change has also been reported to be associated with being younger, female and having a higher BMI.14

The Relationship Between Stress and Smoking as a Result of COVID-19

COVID-19 has had a similar impact on smoking. Stress and worsening mental health are known to be predisposing factors for increased nicotine dependence among smokers, increased smoking (both in quantity and

At present, no studies have examined which factors predict smoking behaviour – either an increase or decrease in the number of cigarettes – during the COVID-19 pandemic. However, it has been reported that high depressive tendency is closely related to the failure to quit smoking.18 Consequently, smokers with existing depressive tendencies or with worsened signs of depression due to the pandemic may be causing an increase in the number of smokers.15,17 In fact, that study noted a significant worsening of mental health (p<0.001), anxiety (p<0.001), stress (p<0.001) and a depressed mood (p=0.012) in smokers who smoked more.17 It also revealed that worsening mental health and psychosocial wellbeing due to the pandemic was associated with increased smoking. Figure 1 shows suggested relationships between COVID-19-related stress and smoking. For tobacco companies, this represents a golden business opportunity, and their promotional campaigns in the media are not stopping.19,20 Caution is warranted, since tobacco use may increase and the number of people who resume smoking may also increase. Caution is also warranted since having fewer social ties is associated with starting to smoke.21 That said, the fact that some people are smoking less warrants attention. The threat of contracting COVID-19 and developing severe symptoms has motivated people to improve their health.22 Moreover, greater awareness of health risks, reduced availability and socialising could reduce consumption.23 Smoking is a key factor for developing more severe symptoms of COVID-19 and is a serious threat to smokers.24 Given the demonstrated harm of smoking and exposure to second-hand smoke, the WHO recommends that people quit smoking.25 Smoking less is ineffective, but quitting can lead to restoration of immune functions and reduced susceptibility to infection in as little as a month. Providing smokers with this information could further encourage them to quit smoking.

Mental Health Improves as a Result of Quitting Smoking

The reduction in stress that smokers view as a benefit of smoking is ultimately nothing more than the alleviation of the symptoms of nicotine withdrawal. In sharp contrast, quitting smoking is known to eliminate symptoms of withdrawal, decrease stress and alleviate psychiatric disorders, such as anxiety neurosis and depression, over the long term.26 A Japanese study reported that depressive symptoms were significantly alleviated in a brief period of just 12 weeks after the start of smoking cessation treatment.27 The extent to which depression is alleviated by quitting smoking is equivalent to or greater than the extent to which mood or anxiety disorder is alleviated by drug therapy (antidepressants).26 Now that the COVID-19 pandemic has brought serious mental health issues to light, quitting smoking will be increasingly important.

Methods of Quitting Smoking During the COVID-19 Pandemic

Numerous reviews have assessed interventions to help people quit smoking. A combination of smoking cessation aids and behavioural

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COVID-19: Psychological Effects and CVD support should be used to maximise the percentage of individuals who successfully quit smoking.28 A study in a smoking cessation clinic in Japan reported that a high percentage of individuals successfully quit smoking at the end of five visits; 82% were using nicotine patches and 83% were taking varenicline.29 Therefore, an important duty for medical personnel is to encourage smokers who are hesitant about quitting smoking to visit a smoking cessation clinic. It is also necessary to be aware that the increased psychological stress may diminish smokers’ recognition of the extensive established benefits of smoking cessation. Although there are debates regarding the infection rates in smokers and non-smokers, smoking has been established as a risk factor for disease severity.24,25 Furthermore, it is well known that quitting smoking restores immunity in a few weeks. Therefore, it is important for healthcare professionals to continue providing smokers information that smoking is a factor for the development of more severe symptoms of COVID-19. When seeing patients, medical personnel should also ask about and record smoking status. Mental healthcare may be even more important when providing smoking cessation support amidst the pandemic. Additionally, behavioural support provided via printed materials from reliable services, online programmes and mobile phone text messaging apps is considered to be effective. In many countries, smokers can also receive advice on quitting smoking via a quit line. In an age of reduced travel outside the home, services that can be provided remotely are increasingly important.30 Public education about quitting smoking should be highly encouraged as part of public health efforts to reduce the spread of COVID-19.

Quarantine and Weight Gain

Lifestyles have significantly changed in light of the COVID-19 pandemic. People have gained weight during the pandemic due to lack of exercise and increased calorie intake as a result of self-quarantine and stress. Additionally, an increase in sedentary behaviour has a negative influence on mental health.31 Stress is known to cause weight gain. Appetite is greatly affected by internal factors, such as an empty stomach, as well as external factors, such as dietary preferences and environmental stimuli. When the body is subjected to stress, cortisol is secreted by the adrenal glands, which stimulates appetite. Not only can this lead to overeating, but also excess energy as a result of the action of cortisol is stored as fat. A cross-sectional online survey of 1,097 people examined the effects of the COVID-19 pandemic on diet and weight changes and found that more than 43.0% of the respondents ate more and that close to 52% snacked more.32 Those trends were even more evident in overweight and obese respondents. Moreover, 30% of the respondents reported weight gain (3.0 ± 1.6 kg). Weight gain was associated with reduced consumption of fresh foods and legumes and increased consumption of processed foods with high fat, sugar or salt content due to restrictions and lockdowns. Conversely, over 18% of the respondents reported weight loss (−2.9 ± 1.5 kg), and underweight subjects reported further weight loss, prompting concerns about conditions, such as sarcopenia. Overeating and smoking are closely linked to psychological stress. Salivary cortisol levels – a marker of psychological stress – have been reported to be high in obese patients who have difficulty losing weight.33 During the COVID-19 pandemic, people who were originally overweight and obese have experienced greater weight gain.32 Therefore, it is considered that people who have greater psychological stress and tend to be obese are gaining weight due to further increased stress.

Figure 2: The Effects of Psychological Stress on Cardiovascular Diseases During the COVID-19 Pandemic Fear of infection and anxiety Staying home Decreased opportunities for meeting and communication Economic collapse

Psychological stress Depressive state

Lack of exercise, smoking, overeating, excessive alcohol consumption

Cardiovascular diseases: Stroke, MI COVID-19 = coronavirus disease 2019.

Incidentally, 14.6% of the respondents in this study reported increased alcohol consumption, and in particular people with alcoholism reported increased alcohol consumption.32 Overweight and obesity are largely preventable by making the choice of healthier foods, limiting energy intake from fats and sugars and increasing consumption of fruit and vegetables, along with legumes, whole grains and nuts.34 In addition to these dietary instructions, engagement in regular physical activity will increase effectiveness, as it not only improves overweight but also reduces psychological stress. Worldwide, 3 million deaths every year result from harmful use of alcohol, accounting for 5.3 % of all deaths.35 The WHO advocates strategies for reducing harmful alcohol use.36 There are also epidemiological data that low-volume drinkers have less cardiovascular disease than non-drinkers.37 At present, international measures regarding alcohol control measures are not as thorough as tobacco control measures. While excessive alcohol consumption clearly contributes to an increase in diseases including cancer, liver disease and cardiovascular disease, there remain many people with potential alcoholism. An increase in drinking volume during the COVID-19 pandemic may be the result of psychological stress along with overeating and smoking. In patients with cardiovascular disease, it is important to check drinking levels and carefully observe the possibility of alcohol addiction. Lockdowns imposed to contain an infectious pathogen have multiple effects on lifestyles throughout the population. Restrictions and lockdowns lead to decreased physical activity, unhealthy diets due to restricted access to healthy and fresh food, restricted access to health promotion services, worsening mental health and misuse of tobacco and alcohol leading to secondary health hazards (Figure 2). There is mounting evidence that obesity is a risk factor for cardiovascular diseases, and for developing severe pneumonia due to COVID-19.38 Obesity inhibits breathing, weakens immunity and enhances the inflammatory response. Although there are no guidelines advocating weight loss as a way to deal with COVID-19, prevention of obesity is recommended.

Effects of the Pandemic on Cardiovascular Diseases

The COVID-19 pandemic may trigger the onset of or exacerbate cardiovascular diseases and caution is warranted. Moreover, the COVID-19

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COVID-19: Psychological Effects and CVD pandemic is causing serious mental health issues, and the association between depression and cardiovascular disease has long been reported. In specific terms, approximately 20% of patients with coronary artery disease or heart failure also have depression. The presence of depression increases the relative risk of coronary artery disease by 2.69-fold.39 Even mild depression, such as a depressed mood, can increase the relative risk of coronary artery disease by 1.49-fold. Among patients with coronary heart disease, unmarried people have been shown to have higher depression levels compared with the married people and patients with comorbid diseases showed a high level of depression.40 Having depression increases the relative risk of heart failure by 2.1-fold. Depression affects at least one-fifth of heart failure patients and worsens New York Heart Association classes.41 Various studies have examined the mechanisms by which depression increases the risk of coronary artery disease and heart failure. These mechanisms can be divided into the direct effect on cardiovascular systems by stress and indirect effects via lifestyle changes. Direct effects include increased serum cortisol and catecholamine levels, increases in inflammatory cytokines, platelet aggregation and oxidative stress along with endothelial dysfunction and autonomic neuropathy. It has also been suggested that the neural government of the diaphragm adversely affect emotional factors, such as psychological stress, as well as respiratory rhythms, leading to worsening of heart failure.41 Indirect mechanisms include obesity and smoking due to changes in lifestyle, failure to adhere to medication and failure to maintain adequate exercise habits.42 While restrictive measures are taken during the COVID-19 pandemic, it is important to conduct regular assessments of anxiety and depression as a component of the comprehensive management of coronary artery disease and heart failure patients, in order to detect depression tendencies. Depression needs to be identified early and appropriate treatment provided. Additionally, quitting smoking, maintaining an appropriate level of physical activity, eating a healthy diet and managing stress may be crucial in the care of patients with cardiovascular diseases. It has been suggested that anxiety about pandemic-derived infections may delay acute coronary syndrome patients seeking help.43 It has also been reported that remote monitoring of vital signs and physical activity levels in patients with heart failure can lead to prevention of worsening heart failure and encouragement of patients for medical check-up.44 As stay-at-home requests are enforced to control infection, telemedicine applications are important measures to prevent the development of cardiovascular diseases. 1. WHO. Mental health preparedness and response for the COVID-19 pandemic Report by the Director-General. Geneva: WHO, 8 January 2021. https://apps.who.int/gb/ ebwha/pdf_files/EB148/B148_20-en.pdf (accessed 11 May 2021). 2. Jenkins R. Global mental health and sustainable development 2018. BJPsych Int 2019;16:34–7. https://doi. org/10.1192/bji.2019.5; PMID: 31144683. 3. UN leads call to protect most vulnerable from mental health crisis during and after COVID-19. UN, 14 May 2020. https:// news.un.org/en/story/2020/05/1063882 (accessed 9 September 2021). 4. Czeisler MÉ, Lane RI, Petrosky E, et al. Mental health, substance use, and suicidal ideation during the COVID-19 Pandemic — United States, June 24–30, 2020. MMWR Morb Mortal Wkly Rep 2020;69:1049–57. https://doi.org/10.15585/ mmwr.mm6932a1; PMID: 32790653. 5. UN. Policy Brief: COVID-19 and the need for action on mental health. New York: UN, 2020. https://unsdg.un.org/sites/ default/files/2020-05/UN-Policy-Brief-COVID-19-and-mentalhealth.pdf (accessed 11 May 2021).

Recommended Actions

Following a healthy lifestyle is crucial to managing mental health in response to the COVID-19 outbreak. This includes staying in touch with family and friends, getting adequate rest, deep breathing, following a healthy diet and getting an adequate amount of physical activity and sleep, as advocated by the WHO.45 Moreover, people should obtain information from reliable sources and spend less time exposed to anxietyinducing reports in the media. Not turning to addictive substances, such as alcohol and tobacco, to relieve anxiety and stress is also important. People need to draw on skills that previously helped them overcome adversity, and they need to consult medical personnel or a counsellor when necessary.46 A healthy diet, an adequate amount of exercise and sleep and quitting smoking to improve one’s immunity to maintain a healthy lifestyle is an important part of the response to COVID-19.47 In specific terms, a diet of fruits, vegetables and whole-grain foods should be consumed to optimise one’s immune system and prevent obesity, and overconsumption of salt, fat and sugar should be avoided.48 Exercise is also effective in reducing the risk of cardiovascular diseases and conditions, such as locomotive syndrome, depression and dementia, and it is crucial during this pandemic. People should engage in an exercise of adequate intensity while taking steps to protect themselves from infection by walking in places with few people or doing yoga or strength training at home. People attempting to quit smoking should receive a combination of drug and behavioural therapy at a smoking cessation clinic. Moreover, smoking cessation support needs to be available remotely through the receipt of advice using tools, such as a smoking cessation app, email, telephone or the internet.15 Typically, people temporarily gain weight after quitting smoking, and apprehensions about weight gain and worsening glucose tolerance can lead to failure to quit smoking.49 Even if such temporary weight gain is noted, it is outweighed by the reduced cardiovascular risk as a result of quitting smoking, so continuous abstinence from smoking is recommended.50 A study has reported that smokers who are highly dependent on nicotine are particularly likely to gain weight after quitting smoking.49 An intervention to deal with weight gain should be provided at the same time as smoking cessation support. A combination of nicotine replacement therapy and diet and exercise will help to prevent weight gain after quitting smoking and also increase the likelihood that one successfully quits smoking.49 Furthermore, effective measures are required to mitigate negative impacts on health. This may be a way to sustain care for people living during the COVID-19 pandemic.

6. Ettman CK, Abdalla SM, Cohen GH, et al. Prevalence of depression symptoms in US adults before and during the COVID-19 pandemic. JAMA Netw Open 2020;3:e2019686. https://doi.org/10.1001/jamanetworkopen.2020.19686; PMID: 32876685. 7. Glenister KM, Ervin K, Podubinski T. Detrimental health behaviour changes among females living in rural areas during the COVID-19 pandemic. Int J Environ Res Public Health 2021;18:722. https://doi.org/10.3390/ijerph18020722; PMID: 33467693. 8. Japan Broadcasting Corporation. Suicide last month increased by 40% from last year. Women increased significantly. Corona’s impact. 2020 [in Japanese]. 9. Fergusson DM, Horwood LJ, Boden JM, et al. Impact of a major disaster on the mental health of a well-studied cohort. JAMA Psychiatry 2014;71:1025–31. https://doi. org/10.1001/jamapsychiatry.2014.652; PMID: 25028897. 10. Starcke K, Brand M. Decision making under stress: a selective review. Neurosci Biobehav Rev 2012;36:1228–48. https://doi.org/10.1016/j.neubiorev.2012.02.003; PMID: 22342781.

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11. Sinha R. Chronic stress, drug use, and vulnerability to addiction. Ann N Y Acad Sci 2008;1141:105–30. https://doi. org/10.1196/annals.1441.030; PMID: 18991954. 12. Clay JM, Parker MO. Alcohol use and misuse during the COVID-19 pandemic: a potential public health crisis? Lancet Public Health 2020;5:e259. https://doi.org/10.1016/S24682667(20)30088-8; PMID: 32277874. 13. Statistics Canada. How are Canadians coping with the COVID-19 situation? 8 April 2020. https://www150.statcan. gc.ca/n1/pub/11-627-m/11-627-m2020029-eng.htm (accessed 11 May 2021). 14. Naughton F, Ward E, Khondoker M, et al. Health behaviour change during the UK COVID-19 lockdown: findings from the first wave of the C-19 health behaviour and well-being daily tracker study. Br J Health Psychol 2021;26:624–43. https:// doi.org/10.1111/bjhp.12500; PMID: 33410229. 15. Patwardhan P. COVID-19: Risk of increase in smoking rates among England’s 6 million smokers and relapse among England’s 11 million ex-smokers. BJGP Open 2020;4:bjgpopen20X101067. https://doi.org/10.3399/ bjgpopen20X101067; PMID: 32265183.

COVID-19: Psychological Effects and CVD 16. Bommele J, Hopman P, Walters BH, et al. The double-edged relationship between COVID-19 stress and smoking: implications for smoking cessation. Tob Induc Dis 2020;18:63. https://doi.org/10.18332/tid/125580; PMID: 32733178. 17. Chen DTS. The psychosocial impact of the COVID-19 pandemic on changes in smoking behavior: evidence from a nationwide survey in the UK. Tob Prev Cessat 2020;6:59. https://doi.org/10.18332/tpc/126976; PMID: 33163705. 18. Komiyama M, Ozaki Y, Miyazaki Y, et al. Short-term changes in self-rating depression scale scores after smoking cessation in neurotic patients. Intern Med 2021;60:1175–81. https://doi.org/10.2169/internalmedicine.4868-20; PMID: 33055476. 19. Tobacco Free Kids. Big tobacco is exploiting COVID-19 to market its harmful products. https://www.tobaccofreekids. org/media/2020/2020_05_covid-marketing (accessed 4 June 2021). 20. Rowell A. Coronavirus: big tobacco sees an opportunity in the pandemic. The Conversation 14 May 2020. https:// theconversation.com/coronavirus-big-tobacco-sees-anopportunity-in-the-pandemic-138188 (accessed 4 June 2021). 21. Giordano GN, Lindstrom M, The impact of social capital on changes in smoking behaviour: a longitudinal cohort study. Eur J Public Health 2011;21:347–54. https://doi.org/10.1093/ eurpub/ckq048; PMID: 20570962. 22. López-Bueno R, Calatayud J, Casaña J, et al. COVID-19 confinement and health risk behaviors in Spain. Front Psychol 2020;11:1426. https://doi.org/10.3389/fpsyg.2020.01426; PMID: 32581985. 23. Niedzwiedz CL, Green MJ, Benzeval M, et al. Mental health and health behaviors before and during the initial phase of the COVID-19 lockdown: longitudinal analyses of the UK Household Longitudinal Study. J Epidemiol Community Health 2021;75:224–31. https://doi.org/10.1136/jech-2020-215060; PMID: 32978210. 24. Komiyama M, Hasegawa K. Smoking cessation as a public health measure to limit the coronavirus disease 2019 pandemic. Eur Cardiol 2020;15:e16. https://doi.org/10.15420/ ecr.2020.11; PMID: 32373189. 25. WHO. Tobacco use and COVID-19. 11 May 2020. https:// www.who.int/news-room/detail/11-05-2020-who-statementtobacco-use-and-covid-19 (accessed 11 May 2021). 26. Taylor G, McNeill A, Girling A, et al. Change in mental health after smoking cessation: systematic review and metaanalysis. BMJ 2014;348:g1151. https://doi.org/10.1136/bmj. g1151; PMID: 24524926. 27. Komiyama M, Yamakage H, Satoh-Asahara N, et al. Sex

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39. Rugulies R. Depression as a predictor for coronary heart disease: a review and meta-analysis. Am J Prev Med 2002;23:51–61. https://doi.org/10.1016/S07493797(02)00439-7; PMID: 12093424. 40. Eng HS, Yean LC, Das S, et al. Anxiety and depression in patients with coronary heart disease: a study in a tertiary hospital. Iran J Med Sci 2011;36:201–6. PMID: 23358115. 41. Bordoni B, Marelli F, Morabito B, et al. Depression and anxiety in patients with chronic heart failure. Future Cardiol 2018;14:115–9. https://doi.org/10.2217/fca-2017-0073; PMID: 29355040. 42. Gehi A, Haas D, Pipkin S, Whooley M. Depression and medication adherence in outpatients with coronary heart disease: findings from the Heart and Soul Study. Arch Intern Med 2005;165:2508–13. https://doi.org/10.1001/ archinte.165.21.2508; PMID: 16314548. 43. Greco A, Spagnolo M, Capodanno D. Unmasking psychological reasons of delay in acute coronary syndromes presentation during the COVID-19 pandemic. Catheter Cardiovasc Interv 2021;98:407–8. https://doi.org/10.1002/ ccd.29103; PMID: 32583925. 44. Bertagnin E, Greco A, Bottaro G, et al. Remote monitoring for heart failure management during COVID-19 pandemic. Int J Cardiol Heart Vasc 2021;32:100724. https://doi.org/10.1016/j. ijcha.2021.100724; PMID: 33532544. 45. UN News. COVID-19: Mental health in the age of coronavirus. 16 March 2020. https://news.un.org/en/ story/2020/03/1059542 (accessed 11 May 2021). 46. WHO. Coping with stress during the 2019-nCoV outbreak. https://www.who.int/docs/default-source/coronaviruse/ coping-with-stress.pdf?sfvrsn=9845bc3a_2 (accessed 11 May 2021). 47. Kluge HHP, Wickramasinghe K, Rippin HL, et al. Prevention and control of non-communicable diseases in the COVID-19 response. Lancet 2020;395:1678–80. https://doi.org/10.1016/ S0140-6736(20)31067-9; PMID: 32401713. 48. Coelho-Ravagnani CF, Corgosinho FC, Sanches FFZ, et al. Dietary recommendations during the COVID-19 pandemic. Nutr Rev 2021;79:382–93. https://doi.org/10.1093/nutrit/ nuaa067; PMID: 32653930. 49. Komiyama M, Wada H, Ura S, et al. Analysis of factors that determine weight gain during smoking cessation therapy. PLoS One 2013;8:e72010. https://doi.org/10.1371/journal. pone.0072010; PMID: 23991026. 50. Komiyama M, Wada H, Ura S, et al. The effects of weight gain after smoking cessation on atherogenic α1-antitrypsinlow-density lipoprotein. Heart Vessels 2015;30:734–9. https:// doi.org/10.1007/s00380-014-0549-9; PMID: 25086816.

ISCHEMIA Trial

ISCHEMIA Trial: Key Questions and Answers Jose Lopez-Sendon ,1 Raúl Moreno

and Juan Tamargo

1. IdiPaz Research Institute, Hospital Universitario La Paz, Universidad Autonoma de Madrid, Madrid, Spain; 2. Interventional Cardiology Unit, Hospital Universitario La Paz, IdiPaz, Madrid, Spain; 3. Pharmacology Department, Universidad Complutense de Madrid, Madrid, Spain

Abstract

A healthy lifestyle, myocardial revascularisation and medical therapy constitute the three pillars for the treatment of ischaemic heart disease. Lifestyle and optimal medical therapy should be used in all cases. However, the selection of cases for revascularisation among stable patients remains controversial. The ISCHEMIA trial compared an early invasive strategy with revascularisation plus optimal medical therapy against initial optimal medical therapy alone with revascularisation reserved for cases in which symptom control was insufficient. The study included over 5,000 patients with stable coronary artery disease and moderate to severe myocardial ischaemia. No differences were found in relevant clinical outcomes, including all-cause mortality, cardiovascular death, MI, heart failure and stroke, over a follow-up of 3.2 years. Conversely, angina control was better in patients with severe symptomatic angina. Following the tradition of all trials comparing medical therapy alone with revascularisation, the ISCHEMIA trial results are controversial, but an analysis of the design and results of the trial offers important information to better understand, evaluate and treat the growing number of patients with stable chronic ischaemic heart disease and moderate to severe myocardial ischaemia.

Keywords

Myocardial ischaemia, stable angina, stable coronary artery disease; optimal medical therapy; myocardial revascularisation; percutaneous coronary intervention; coronary artery bypass grafting Disclosure: JT is a Section Editor for European Cardiology Review; this did not affect peer review. All other authors have no conflicts of interest to declare. Received: 28 April 2021 Accepted: 26 July 2021 Citation: European Cardiology Review 2021;16:e34. DOI: https://doi.org/10.15420/ecr.2021.16 Correspondence: Jose Lopez-Sendon, IdiPaz Research Institute, Hospital Universitario La Paz, Universidad Autonoma de Madrid, Paseo de la Castellana 261, Madrid 28046, Spain. E: jlopezsendon@gmail.com Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Intensive basic and clinical research over the past 50 years resulted in a progressively better understanding of ischaemic heart disease, its diagnosis and treatment, with a sustained reduction in mortality in both acute coronary syndromes and during the chronic phase of the disease.1,2 However, better long-term prognosis and aging of the population are responsible for a continuous worldwide increase in the prevalence of cardiovascular disease, particularly chronic ischaemic heart disease, with stable angina being the most frequent complaint in clinical practice.3 Modern treatment of myocardial ischaemia is based on three main pillars: lifestyle, medical therapy and myocardial revascularisation (Figure 1). All are equally important and none of them can be ignored. The quick evolution of knowledge in the field underlines the paramount importance of guidelines and patient education. The benefit of prompt myocardial revascularisation has been well established in acute coronary syndromes, particularly in patients presenting with chest pain and ST-elevation MI (STEMI). However, despite the ever-increasing number of revascularisation procedures, the potential benefit of coronary angiography and revascularisation in chronic stable patients remain controversial.4–6 Thus, the International Study of Comparative Health Effectiveness with Medical and Invasive Approaches (ISCHEMIA) trial was designed to determine the effect of adding cardiac catheterisation (hereafter ‘angiography’) and revascularisation, when

feasible, to medical therapy in patients with stable coronary disease and moderate or severe ischaemia.7

What is the ISCHEMIA Trial?

The ISCHEMIA trial was a prospective multicentre randomised study supported by the US National Heart, Lung, and Blood Institute. The study compared two initial treatment strategies in chronic stable patients with moderate to severe myocardial ischaemia identified during stress testing, namely an initially invasive strategy (INV) with cardiac catheterisation and revascularisation in addition to optimal medical therapy (OMT) and an initially conservative strategy (CON; i.e. OMT), with coronary angiography and revascularisation reserved for patients with angina incompatible with normal life or acute coronary syndrome episodes.7 The main objective of the ISCHEMIA trial was to demonstrate that initial INV was superior to CON in improving relevant clinical outcomes, including cardiovascular death, MI, hospital admission for unstable angina, heart failure or resuscitated cardiac arrest (Figure 2). The design of the ISCHEMIA trial followed the contemporary standards used in multicentre clinical trials.7 Patients with moderate to severe myocardial ischaemia (>10% of the left ventricle) were selected for screening. Blinded coronary CT angiography (CCTA) identified patients with significant coronary stenosis in at least one epicardial vessel as candidates for the trial, excluding cases with nonprotected left main stem stenosis (>50%) and patients without significant

ISCHEMIA Trial: Key Questions and Answers Figure 1: Treatment Components for Chronic Stable Coronary Artery Disease Non-smoking habits

Exercise

Participating hospitals were required to demonstrate experience with both percutaneous and revascularisation procedures. The use of pressure guidewires and fractional flow reserve (FFR) measurement in borderline lesions, third-generation drug-eluting stents (DES) and complete revascularisation were strongly recommended. Decisions regarding surgical or percutaneous revascularisation were made for each patient individually according to coronary anatomy and heart team discussion. Frequent quality controls benchmarked the use of medications and target levels of blood pressure, non-smoking status, LDL and glycaemic levels according to guideline recommendations.7

Diet

Lifestyle

Chronic ischaemic disease treatment

Was the ISCHEMIA Trial Needed?

Medical therapy

Anti-ischaemic drugs*

Revascularisation

Secondary prevention drugs†

CABG

PCI

*Anti-ischaemic drugs include combinations of drugs with a direct anti-ischaemic action that are used with the target of controlling angina and myocardial ischaemia. Heart rate, blood pressure and comorbidities determine the preferred drug combination following guidelines. †Secondary prevention includes antiplatelet drugs, anticoagulants, lipid-lowering drugs (mainly statins) and renin–angiotensin–aldosterone inhibitors. CABG = coronary artery bypass grafting; PCI = percutaneous coronary intervention.

Figure 2: ISCHEMIA Trial Design Stable patients Moderate to severe ischaemia* Blinded CCTA* Core laboratory anatomy eligible* Randomised

Initial invasive strategy (OMT + cath + optimal revascularisation)

Initial conservative strategy (OMT alone; cath reserved for OMT failure)

Follow-up 3.2 years *Central laboratory evaluation. Cath = catheterisation; CCTA = coronary CT angiography; OMT = optimal medical therapy.

stenosis in the epicardial coronary arteries.7 Patients with a recent episode of acute coronary syndromes, New York Heart Association Class III–IV heart failure, left ventricular ejection fraction (LVEF) <35%, unacceptable angina according to patients preferences to perform a desired life activity and previously determined non-revascularisable coronary anatomy were also excluded.7 Patients with advanced kidney disease (estimated glomerular filtration rate <30 ml/min/1.73 m2 or on dialysis) were included in a parallel randomised trial (ISCHEMIA-CKD) that had the same design except that no CCTA was use to select eligible cases.8 Patients were randomly assigned to INV or CON (Figure 2). The primary outcome of the ISCHEMIA trial was a composite outcome of cardiovascular death, MI, hospitalisation for unstable angina, heart failure or resuscitated cardiac arrest. The mean follow-up period was 3.2 years.7

The clear answer is yes. Clinical guidelines recommend revascularisation in stable high-risk patients, particularly if the myocardium at risk is >10%.9,10 These recommendations are based primarily on evidence from classic clinical trials, including Veterans Administration Cooperative Revascularisation Study, ECSS and CASS, with less evidence of benefit in more recent trials, such as COURAGE, BARI 2D and FAME 2.11–16 In all trials, revascularisation improved angina symptoms, but better clinical outcomes were never demonstrated with the exception of the early trials, particularly in the presence of heart failure or if the myocardium at risk was >10% and a reduced need for revascularisation procedures during follow-up in the FAME 2 trial (Table 1).9,14 In addition, an ischaemia severity threshold was not defined, a fact that may have led to the selection of patients in whom revascularisation was unlikely to be of benefit.17 In addition, in all previous trials, patients were selected according to coronary artery anatomy, with the opportunity of selecting the best suitable cases for revascularisation and thus imposing a bias to generalise recommendations in broad populations. Table 2 summarises the evolution of optimal revascularisation and medical treatment, including the contemporary state of the art, still in constant evolution. Certainly, there has been considerable progress in medical treatments and interventions, somehow making the results of trials conducted many years ago obsolete. For these reasons, a trial comparing an invasive to a conservative strategy was clearly needed. The ISCHEMIA trial avoided some of the design deficiencies of previous trials and represents the largest trial using contemporary revascularisation procedures and OMT to test the hypothesis that early initial INV plus OMT is better than OMT alone.

Neutral Results

The median age of participants in the ISCHEMIA trial was 64 years; 41% had diabetes, 19% had prior MI and 90% had prior angina.18 Stress imaging was the qualifying test for 75% of participants (86% with moderate or severe ischaemia); of those in whom CCTA was performed, 79% had multivessel disease, 87% had left anterior descending coronary artery disease and 47% had proximal left anterior descending coronary artery disease. There were no differences between the INV and CON groups.18 Therefore, although the study population could not be considered as low risk, certainly the highest-risk population (low LVEF, unstable angina and unprotected left main disease) was excluded. The results of the ISCHEMIA trial, in which participants were followed for a median of 3.2 years, summarised in Table 3.19 There were no differences between the INV and CON groups for the primary endpoint (a composite of death from cardiovascular causes, MI or hospitalisation for unstable angina, heart failure or resuscitated cardiac arrest), and similar results were found in the ISCHEMIA-CKD trial.8 The rate of hospitalisations for unstable angina was lower, but that for heart failure was higher, in the INV group, but the differences did not reach statistical significance.19 Subgroup

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ISCHEMIA Trial: Key Questions and Answers Table 1: Main Trials Comparing Revascularisation with Optimal Medical Therapy in Chronic Stable Coronary Artery Disease VA Cooperative ECSS12 Revascularisation Study11

CASS13

COURAGE14

BARI 2D15

FAME 216

ISCHEMIA18

Publication year

1977

1979

1983

2007

2009

2014

2020

No. patients

568

767

780

2,287

2,368

1,220

5,279

Inclusion before cardiac catheterisation?

Yes

Severity of ischaemia No required?

>10%

Contemporary medical treatment?

OMT 2000

Yes, without emphasis on OMT

Emphasis on OMT

Contemporary revascularisation?

No, only CABG

No, only PCI; no DES 35% DES, 10% no stent

Yes, complete revascularisation, FFR, DES

Follow-up (years)

1–5

4.6

3.2

Neutral Less angina in revascularisation group

Neutral Fewer CV events in CABG group

Neutral Less need for urgent revascularisation

Neutral QOL improvement in patients with severe angina

Outcomes and results Neutral Survival benefit in subgroup of patient with left main disease

Neutral Neutral Survival benefit in Survival benefit in subgroup of patients subgroups of multivessel disease and LV dysfunction

CABG = coronary artery bypass grafting; CV = cardiovascular; DES = drug eluting stents; FFR = fractional flow reserve; OMT = optimal medical therapy; PCI = percutaneous coronary intervention; QOL = quality of life.

Table 2: Evolution of Optimal Revascularisation and Medical Therapies Optimal Surgical Revascularisation 1970 ↓ ↓ ↓ ↓ ↓ ↓ ↓ ↓ ↓ ↓ ↓ 2020

Optimal Percutaneous Coronary Revascularisation

Venous CABG

Optimal Medical Therapy Anticoagulants, nitrates, empirical treatments

Internal mammary CABG

Balloon coronary angioplasty

Beta-blockers

Myocardial protection

Bare metal stents

Aspirin

Antiplatelet therapy

Statins, ACEI

Complete revascularisation

Drug-eluting stents

Strong rehabilitation, lifestyle interventions

Radial approach

Stronger lipid-lowering therapies

FFR

Targeted LDL, blood pressure, smoking, exercise, diabetes, ischaemia control

Complete revascularisation

Dual antiplatelet therapy

SYNTAX score to select CABG or PCI

Benchmarking targets

Heart team decisions

Newer secondary prevention drugs/strategies

Use of OMT in all cases Coming soon

Genotyping for precision medicine

ACEI = angiotensin-converting enzyme inhibitors; CABG = coronary artery bypass grafting; FFR = fractional flow reserve; OMT = optimal medical therapy; PCI = percutaneous coronary intervention.

analysis also failed to demonstrate differences between INV and CON in patients with prior MI or previous revascularisation or according to LVEF, the severity of myocardial ischaemia or coronary artery anatomy, adding consistency to the main results of the trial.19 Overall, the superiority of an initial INV could not be demonstrated. However, there was a benefit favouring INV: an improvement in angina control and quality of life metrics in patients who had severe angina (daily/ weekly), with no improvement in patients with less frequent or no angina.20

What Are Optimal Revascularisation and OMT?

Standards for both revascularisation procedures, anti-ischaemic therapy and secondary prevention strategies have evolved considerably (Table 2). Contemporary optimal medical revascularisation includes the selection of

surgical revascularisation or percutaneous coronary intervention (PCI) according to complexity scores (the SYNTAX score being the most commonly recommended) and heart team decisions, large use internal mammary artery, the use of FFR for better evaluation of epicardial stenosis, complete revascularisation of significant coronary artery stenosis, the use of radial artery and DES during PCI and, most importantly, concomitant OMT in all cases.10 Today, OMT includes strong lifestyle programs for non-smoking, exercise and healthy diet; the routine use of antiplatelet agents and lipid-lowering drugs (mainly statins), as well as target-oriented therapies to control myocardial ischaemia using a combination of anti-ischaemic drugs; controlling LDL to levels that were unthinkable only a few years ago; controlling blood pressure; and the use of new therapies, such as newer

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ISCHEMIA Trial: Key Questions and Answers Table 3: Main Results of the ISCHEMIA Trial INV (n=2,588)

CON (n=2,591)

HR [95% CI]

MACE

318

352

0.93 [0.80–1.08]

All-cause death

145

144

1.05 [0.83–1.32]

CV mortality or AMI

276

314

1.9 [0.9–3.0]

AMI

210

233

1.8 [0.8–2.8]

CV mortality

~1%/year

0.87 [0.66–1.15]

AMI = acute MI; CON = conventional strategy; CV = cardiovascular; INV = invasive strategy; MACE = major adverse cardiac events. Source: Bangalore et al.8

antidiabetic agents.9,10,21,22 This approach was simply non-existent even a few years ago. Continuous improvements should be added to OMT, and older therapies discarded when they become obsolete. The ISCHEMIA trial recommended both optimal revascularisation and OMT, which was somehow achieved in a significantly higher proportion of patient than in previous trials. In the INV group, coronary angiography was performed in 96% of patients and revascularisation was performed in 70% (74% PCI, 24% coronary artery bypass grafting).19 No revascularisation was justified by the presence of no significant stenosis using FFR or was considered not technically feasible. Surgery was selected in 26% of patients, with 93% undergoing arterial grafting and DES being used in 98% of PCI procedures. During follow-up, 5,337 and 1,706 revascularisation procedures were performed in the INV and CON groups, respectively. One in four patients in the CON group needed revascularisation during the follow-up period.19 These findings are similar to those reported in the more recent previous trials in which patients were selected according to angiographic coronary anatomy. OMT was monitored at each visit, with bench marking between countries and sites participating in the trial. The control of risk factors and the use of secondary prevention medication increased throughout the follow-up period to levels higher than in contemporary registries. Furthermore, 90% of patients stopped smoking, blood pressure was controlled in 77% of patients and LDL <1.81 mmol/l was achieved in 59% of patients. High levels of optimisation of medical therapy (defined as meeting all the following criteria: LDL <1.81 mmol/l, the use of antiplatelet drugs, no smoking, systolic blood pressure <140 mmHg) increased from 20% at baseline to 40% through the trial.7,23 Of note, the level of OMT achieved in the INV and CON groups was similar.

Other Findings of Clinical Interest Low Event Rates

Cardiovascular and all-cause deaths were very low (<2%/year).7 A low number of clinically relevant events has been reported in most contemporary trials in stable chronic heart disease patients.24,25 This may be related to extensive exclusion criteria, in particular heart failure and major comorbidities, but optimisation of contemporary medical therapy following secondary prevention guideline recommendations for the control of risk factors, rehabilitation, anti-ischaemic therapy and the routine use of drugs with evidence-based benefits, as in the ISCHEMIA trial, may have had a large impact on outcomes. The need for revascularisation during long-term follow-up has been the leading event in some secondary prevention trials. However, it is difficult to standardise indications for revascularisation in multicentre trials, and revascularisation was deliberately not included as a primary endpoint in

the ISCHEMIA trial. In the FAME 2 trial, recurrent events were not detailed, but excluding revascularisation, death or MI at 2 years, the rate of recurrence was 7.3%, without differences between groups, and the rate of death from cardiac causes was 0.7%.16,26

High Proportion of Normal Coronary Arteries

Screening of patients with moderate to severe myocardial ischaemia revealed a high proportion of patients with normal epicardial coronary arteries (21%).18 This population, recently defined as ischaemia with normal coronary arteries (INOCA), remains a challenge to our understanding the mechanisms responsible for myocardial ischaemia, and it is essential that diagnostic and treatment strategies are defined for this population.27

Coronary CT Angiography

In total, 7% of screened cases showed a significant (>50%) left main stem stenosis, and these patients were still considered a priority for myocardial revascularisation in contemporary guidelines. Non-invasive coronary angiography using CCTA was proved to be effective and may become a good strategy for the selection of patients for invasive coronary angiography and revascularisation in the presence of moderate to severe myocardial ischaemia.

Trial Limitations

Due to the nature of the study, the ISCHEMIA trial was not blinded, although the investigators were not aware of the coronary anatomy in the CCTA. The planned number of subjects to be enrolled in the study was decreased from 8,000 to 5,000 (8,518 patients were screened, but only 5,179 were randomised), and the initial composite endpoint was extended due to low recruitment throughout the study, <14% of patients having less than moderate to severe myocardial ischaemia, event rates that were lower than expected and follow-up that was shorter than originally planned.28 Nevertheless, this has been the largest trial conducted so far, and there was a consistency of results in predefined subgroups. Other strengths of the trial were that patients were selected according to an ischaemia threshold and that state-of-the-art contemporary revascularisation procedures and OMT were used. The neutral results regarding clinical outcomes should be interpreted in the context of quality of life, with a reduction in angina in the subgroup of patients with more frequent and severe symptoms.

Change in Guidelines?

Current European guidelines for myocardial revascularisation recommend revascularisation on top of medical therapy in stable patients with large areas of ischaemia (≥10%) in the left ventricle or if patients have a high-risk clinical profile (Class IB).9,10 The American Heart Association guidelines also recommend revascularisation in patients with severe ischaemia according to clinical characteristics and stress testing.29 In clinical practice, the indications for cardiac catheterisation go beyond these recommendations: revascularisation is performed in some patients without evaluating the severity of the myocardial ischaemia, as well as in patients with mild or no angina. The results of the large multicentre ISCHEMIA trial challenging current clinical practice cannot be ignored, and new guidelines will most probably modify the recommendation for revascularisation in stable ischaemic heart disease.

Future Research Needed to Complement the ISCHEMIA Trial

The large ISCHEMIA database will provide additional data to better understand the results and refine practical conclusions. The limitations of

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ISCHEMIA Trial: Key Questions and Answers the trial support new research in the clinical setting of stable coronary artery disease, including investigations of the following. The potential benefit of early INV over the long term; this is currently being explored in the ongoing ISCHEMIA-EXTEND trial (NCT04894877). The constant evolution of OMT will improve the medical management of stable coronary artery disease. Of particular interest is the concept of precision medicine, with the identification of patients more likely to benefit with less secondary effect from a particular therapy. The main challenge will be adherence to long-term medical therapies recommended in guidelines by patients, physicians and healthcare providers. Stable coronary artery disease in patients with heart failure remains a challenging field. A single study, the STICH trial, had initially neutral results and a significant reduction in mortality during an extended 10 years of follow-up.30,31 Left main disease is considered a clear indication for revascularisation.9,10 However, the benefit may be different in distinct clinical settings (nonprotected stenosis, SYNTAX score, severity of myocardial ischaemia, collateral circulation, progression of atherosclerosis over time, comorbidities). Even if a controlled trial may not be possible, more information is needed and real-life registries and data analysis may provide relevant insights. Myocardial ischaemia with normal epicardial coronary arteries remains a challenge, with a better understanding of its physiopathology, diagnosis and treatment still needed.27

Conclusion

Revascularisation remains an important component of treatment in patients with chronic ischaemic disease. The results of the ISCHEMIA trial can only be applied to stable patients without angina or those with mild, acceptable angina during normal life. Revascularisation indications for patients excluded from the trial, namely unstable angina, unacceptable 1. Gonzalez-Juanatey JR, Agra Bermejo R, Lopez-Sendon J. A brief history. Impact of the advances in ischaemic heart disease. Rev Esp Cardiol Supl 2017;17(Suppl A):2–6. https:// doi.org/10.1016/S1131-3587(19)30009-3. 2. Guzman Castillo M, Gillespie DOS, Allen K, et al. Future declines of coronary heart disease mortality in England and Wales could counter the burden of population ageing. PLoS One 2014;9:e99482. https://doi.org/10.1371/journal. pone.0099482; PMID: 24918442. 3. Steg PG, Greenlaw N, Tendera M, et al. Prevalence of anginal symptoms and myocardial ischemia and their effect on clinical outcomes in outpatients with stable coronary artery disease: data from the International Observational CLARIFY registry. JAMA Internal Med 2014;174:1651–9. https:// doi.org/10.1001/jamainternmed.2014.3773; PMID: 25110899. 4. Barbato E, Dudek D, Baumbach A, et al. Current trends in coronary interventions: an overview from the EAPCI registries. EuroIntervention 2017;13:Z8–10. https://doi. org/10.4244/EIJV13IZA2; PMID: 28504221. 5. Stergiopolus Boden WE, Hartigan P, Möbius-Kathleen S, et al. Percutaneous coronary intervention outcomes in patients with stable obstructive coronary artery disease and myocardial ischemia: a collaborative meta-analysis of contemporary randomized clinical trials. JAMA Intern Med 2014;174:232–40. https://doi.org/10.1001/ jamainternmed.2013.12855; PMID: 24296791. 6. Gersh BJ, Boden WE, Bhatt DL, et al. To stent or not to stent? Treating angina after ISCHEMIA: introduction. Eur Heart J 2021;42:1387–8. https://doi.org/10.1093/eurheartj/ ehab069; PMID: 33827136. 7. ISCHEMIA Trial Research Group, Maron DJ, Hochman JS, et al. International Study of Comparative Health Effectiveness with Medical and Invasive Approaches (ISCHEMIA) trial:

10.

11.

12.

13.

14.

15.

Figure 3: Algorithm for Optimal Medical Therapy and Revascularisation Strategy in Patients with Stable Angina/Myocardial Ischaemia Based on ISCHEMIA Trial Results

Angina Stable

–

Ischaemia stress test moderate to severe ischaemia

Unstable Rest angina Recent onset Progressive Early post-ACS Heart failure III–IV LVEF ≤35% Other high risk*

Initiate OMT No coronary stenosis

Consider CCTA

Left main stem stenosis

Patient unsatisfied with angina control

Consider cardiac cath and revascularisation

*Other high-risk groups (e.g. valvular repair required). ACS = acute coronary syndrome; cath = catheterisation; CCTA = coronary CT angiography; OMT = optimal medical therapy.

stable angina, low LVEF and episodes of acute coronary syndromes, remain unchanged. The evaluation of a patient with chest pain should include an ischaemia test and, if mild or severe ischaemia is identified, CCTA could be the preferred strategy to exclude left main disease, as well as patients without epicardial coronary stenosis who do not require invasive cardiac catheterisation. In stable patients, OMT is a priority and revascularisation should be considered only in patients with uncontrolled, unacceptable angina with medical treatment alone (Figure 3).

rationale and design. Am Heart J 2018;201:124–35. https:// doi.org/10.1016/j.ahj.2018.04.011; PMID: 29778671. Bangalore S, Maron DJ, O’Brien SM, et al. Management of coronary disease in patients with advanced kidney disease. N Engl J Med 2020;382:1608–18. https://doi.org/10.1056/ NEJMoa1915925; PMID: 32227756. Knuuti J, Wijns W, Saraste A, et al. 2019 ESC guidelines for the diagnosis and management of chronic coronary syndromes. Eur Heart J 2020;41:407–77. https://doi. org/10.1093/eurheartj/ehz425; PMID: 31504439. Neumann FJ, Sousa-Uva M, Ahlsson A, et al. 2018 ESC/ EACTS guidelines on myocardial revascularization. Eur Heart J 2019;40:87–165. https://doi.org/10.1093/eurheartj/ehy394; PMID: 30165437. Murphy ML, Hultgree HN, Detre K, et al. Treatment of chronic stable angina. A preliminary report of survival data of the randomized Veterans Administration Cooperative Study. N Engl J Med 1977;297:621–7. https://doi.org/10.1056/ NEJM197709222971201; PMID: 331107. European Coronary Surgery Study Group. Coronary-artery bypass surgery in stable angina pectoris: survival at two years. Lancet 1979;1:889–93. https://doi.org/10.1016/S01406736(79)91372-2; PMID: 86665. CASS Principal investigators and their Associates. Coronary Artery Surgery Study (CASS): a randomized study of coronary artery bypass surgery. Survival data. Circulation 1983;68:939–50. https://doi.org/10.1161/01.CIR.68.5.939; PMID: 6137292. Boden WE, O’Rourke RA, Teo KK, et al. Optimal medical therapy with or without PCI for stable coronary disease. N Engl J Med 2007;356:1503–16. https://doi.org/10.1056/ NEJMoa070829; PMID: 17387127. Frye RL, August P, Brooks MM, et al. A randomized trial of

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therapies for type 2 diabetes and coronary artery disease. N Engl J Med 2009;360:2503–15. https://doi.org/10.1056/ NEJMoa0805796; PMID: 19502645. 16. De Bruyne B, Pijls NH, Kalesan B, et al. Fractional flow reserve-guided PCI versus medical therapy in stable coronary disease. N Engl J Med 2012;367:991–1001. https:// doi.org/10.1056/NEJMoa1205361; PMID: 22924638. 17. Hachamovitch R, Hayes SW, Friedman JD, et al. Comparison of the short-term survival benefit associated with revascularization compared with medical therapy in patients with no prior coronary artery disease undergoing stress myocardial perfusion single photon emission computed tomography. Circulation 2003;107:2900–7. https://doi. org/10.1161/01.CIR.0000072790.23090.41; PMID: 12771008. 18. Hochman J, Reynolds H, Bangalore S, et al. Baseline characteristics and risk profiles of participants in the ISCHEMIA randomized clinical trial. JAMA Cardiol 2019;4:273–86. https://doi.org/10.1001/ jamacardio.2019.0014; PMID: 30810700. 19. Maron DJ, Hochman JS, Reynolds HR, et al. Initial invasive or conservative strategy for stable coronary disease. N Engl J Med 2020; 382:1395–407. https://doi.org/10.1056/ NEJMoa1915922; PMID: 32227755. 20. Spertus JA, Jones PG, Maron DJ, et al. Health-status outcomes with invasive or conservative care in coronary disease. N Engl J Med 2020;382:1408–19. https://doi. org/10.1056/NEJMoa1916370; PMID: 32227753. 21. Ferrari R, Camici P, Crea F, et al. A ‘diamond’ approach to personalized treatment of angina. Expert consensus statement. Nat Rev Cardiol 2018;15:120–32. https://doi. org/10.1038/nrcardio.2017.131; PMID: 28880025. 22. Ferrari R, Pavasini R, Camici PG, et al. Anti-anginal drugs – beliefs and evidence: systematic review covering 50 years

ISCHEMIA Trial: Key Questions and Answers of medical treatment. Eur Heart J 2019;40:190–4. https://doi. org/10.1093/eurheartj/ehy504; PMID: 30165445. 23. Newman JD, Alexander KP, Gu X, et al. Baseline predictors of low-density lipoprotein cholesterol and systolic blood pressure goal attainment after 1 year in the ISCHEMIA trial. Circ Cardiovasc Qual Outcomes 2019;12:e006002. https://doi. org/10.1161/CIRCOUTCOMES.119.006002; PMID: 31718297. 24. Tijssen JGP, Sharif F, Onuma Y, et al. Comparative methodological assessment of the randomized GLOBAL LEADERS trial using total ischemic and bleeding events. Circ Cardiovasc Qual Outcomes 2020;13:e006660. https://doi. org/10.1161/CIRCOUTCOMES.120.006660; PMID: 32762446. 25. Ferrari R, Ford I, Fox K, et al. Efficacy and safety of trimetazidine after percutaneous coronary intervention (ATPCI): a randomised, double-blind, placebo-controlled trial. Lancet 2020;396:830–8. https://doi.org/10.1016/S01406736(20)31790-6; PMID: 32877651.

26. De Bruyne B, Fearon WF, Pijls NH, et al. Fractional flow reserve-guided PCI for stable coronary artery disease. N Engl J Med 2014; 371:1208–17. https://doi.org/10.1056/ NEJMoa1408758; PMID: 25176289. 27. Berry C. Stable coronary syndromes: the case for consolidating the nomenclature of stable ischemic heart disease. Circulation 2017;136:437–9. https://doi.org/10.1161/ CIRCULATIONAHA.117.028991; PMID: 28760869. 28. Maron DJ, Harrington RA, Hochman JS. Planning and conducting the ISCHEMIA trial. Circulation 2018;138:1384–6. https://doi.org/10.1161/CIRCULATIONAHA.118.036904; PMID: 30354348. 29. Fihn SD, Blankenship JC, Alexander KP, et al. 2014 ACC/ AHA/AATS/PCNA/SCAI/STS focused update of the guideline for the diagnosis and management of patients with stable ischemic heart disease: a report of the American College of Cardiology/American Heart Association Task Force on

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Practice Guidelines, and the American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. J Am Coll Cardiol 2014;64:1929–49. https://doi.org/10.1161/ CIR.0000000000000095; PMID: 25077860. 30. Velazquez EJ, Lee KL, Deja MA, et al. Coronary-artery bypass surgery in patients with left ventricular dysfunction. N Engl J Med 2011;364:1607–16. https://doi.org/10.1056/ NEJMoa1100356; PMID: 21463150. 31. Petrie MC, Jhund PS, She L, et al. Ten-year outcomes after coronary artery bypass grafting according to age in patients with heart failure and left ventricular systolic dysfunction: an analysis of the extended follow-up of the STICH trial (Surgical Treatment for Ischemic Heart Failure). Circulation 2016;134:1314–24. https://doi.org/10.1161/ CIRCULATIONAHA.116.024800; PMID: 27573034.

Aortic Valve Stenosis

Transcatheter Aortic Valve Implantation and Subclinical and Clinical Leaflet Thrombosis: Multimodality Imaging for Diagnosis and Risk Stratification María Martín ,1 Javier Cuevas ,1 Helena Cigarrán ,2 Juan Calvo

and César Morís

1. Cardiology Department, University Hospital of Asturias, Oviedo, Asturias, Spain; 2. Radiology Department, University Hospital of Asturias, Oviedo, Asturias, Spain

Abstract

In recent years, the phenomenon of subclinical leaflet thrombosis (SLT) in patients who have undergone transcatheter aortic valve implantation has become increasingly relevant. Hypo-attenuating leaflet thickening and hypo-attenuation affecting motion diagnosed by CT are the hallmarks of SLT, and their incidence varies depending on the intensity of screening. Whether these phenomena are a surrogate for leaflet thrombosis reducing valve durability and increasing the risk of stroke is still a matter of debate. Uncertainty remains over the optimal antithrombotic therapy after TAVI and the best treatment strategy is still not confirmed. Ongoing and future trials will provide more evidence about the best strategy for the prevention and treatment of SLT.

Keywords

Transcatheter aortic valve implantation, subclinical thrombosis, cardiac CT, hypo-attenuating leaflet thickening, hypo-attenuation affecting motion Disclosure: CM is a proctor for Medtronic. All other authors have no conflict of interests to declare. Received: 21 March 2021 Accepted: 9 July 2021 Citation: European Cardiology Review 2021;16:e35. DOI: https://doi.org/10.15420/ecr.2021.09 Correspondence: María Martín, Cardiology Department, University Hospital of Asturias, Avda de Roma s/n 33011 Oviedo, Asturias, Spain. E: mmartinf7@hotmail.com Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Aortic stenosis is the most frequent primary heart valve disease leading to surgery or catheter intervention in the Western world, with a growing prevalence due to the ageing population. No medical treatment can improve outcome above its natural history; the only treatments are surgical aortic valve replacement (SAVR) or transcatheter aortic valve implantation (TAVI). The decision over type of intervention should take into account the patient’s cardiac and extra-cardiac features, their individual risk of surgery, which is assessed by the heart team using criteria including scores, the feasibility of TAVI and local experience. According to current clinical practice guidelines in elderly patients at high surgical risk, TAVI is superior in terms of mortality to medical therapy in patients at extreme risk; non-inferior or superior to surgery in high-risk patients; and non-inferior to surgery and even superior when transfemoral access is feasible in intermediate-risk patients.1–7 The positive outcomes of TAVI have been demonstrated in several largescale, nationwide registries, sustaining the generalisation of results in randomised controlled trials. This supports the use of TAVI over surgery in elderly patients at high surgical risk. Nevertheless, the choice between SAVR and TAVI (including the decision of access route) must be made by the heart team after careful individual evaluation. Initial studies regarding subclinical leaflet thrombosis (SLT) began in 2015 and its natural history as well as its management and prognosis are still not well known. After cardiac CT first showed hypo-attenuated leaflet thickening (HALT) as the hallmark of SLT in a SAPIEN XT transcatheter aortic valve, Pache et al. evaluated the frequency of this phenomenon

in 156 consecutive patients by dual-source CT angiography. They found that, irrespective of antiplatelet regimen, early HALT occurred in 10% of patients undergoing TAVI. Early HALT was clinically inapparent and reversible by full anticoagulation.8 Since this study, similar ones using cardiac CT (such as those of Makkar et al. and Chakravarty et al.) and even meta-analyses like the one by Rheude et al. have concluded in general that SLT occurs frequently in bioprosthetic aortic valves, and more commonly in transcatheter than in surgical valves.9–11 Although SLT is considered subclinical because it is fundamentally an imaging finding, there are discrepancies regarding its clinical relevance in the literature. There have been hypotheses suggesting that SLT may have clinical consequences, such as increasing the transvalvular gradient, being a precursor of thrombosis, reducing the durability of the prosthesis and increasing the likelihood of cerebrovascular events. However, these concerns are still a matter of debate and further studies are needed to clarify them. On the other hand, from a therapeutic point of view, anticoagulation with new oral anticoagulants and warfarin, but not dual antiplatelet therapy (DAPT), has been shown to be effective in preventing and treating SLT. As a result, SLT is now recognised as a complication that follows TAVI. Its incidence varies, according to different studies, depending on whether cardiac CT is performed, so clearly it may be underdiagnosed. However, it is not a problem only for TAVI; it has also been described in surgical bioprostheses.9–11

Imaging in Clinical and Subclinical Leaflet Thrombosis in TAVI Box 1: Predictors of Leaflet Thrombosis after Transcatheter Aortic Valve Replacement

movement of leaflets, is in a wide range (7–35%) with regard to transcatheter valves.9,10 There are few studies reporting its incidence in surgical aortic bioprosthesis. In the SAVORY/RESOLVE registry mentioned above, the incidence in surgical valves was lower than in transcatheter valves. Of course, surgical patients were significantly younger and had fewer comorbidities.15,19 Finally, in a prospective study of an aortic sutureless bioprosthesis, a higher incidence was found, with up to 38% of patients having HALT and 28% showing HAM in CT.10

Valve-in–valve procedure Large sinus of Valsalva Large size of transcatheter aortic valve Greater BMI Bicuspid aortic valve Male sex

CT is now considered the standard method for diagnosis of SLT and its incidence depends mainly on the intensity of cardiac CT screening.

No anticoagulation therapy at discharge

Many gaps therefore still exist regarding this condition, despite growing interest and the numerous published studies. The time SLT appears after TAVI, its short- and long- term consequences and, of course, the best strategies for prevention and treatment are some examples of topics that are not completely known and need further analysis.9–11 In this article, we review aspects of subclinical and clinical thrombosis with special mention to the role of imaging tests.

Definition of Clinical and Subclinical Valve Thrombosis

Prosthetic valve thrombosis is a well-known consequence regarding mechanical valves and anticoagulation is required for life after implantation. However, it is seen much less observed in biological valves, including those implanted using TAVI, where patients receive antiplatelet therapy. Nevertheless, as previously mentioned, during recent years, studies have reported thrombosis in these patients and, furthermore, two conditions are now are well recognised: clinical valve thrombosis and SLT.12,13 Clinical valvular thrombosis is identified as a clinical apparent prosthetic valve dysfunction with the characteristic finding of a mobile mass/ thrombus in the prosthetic valve; it is diagnosed by either echocardiography or CT. It is due to a thrombus causing increased aortic gradients due to impaired leaflet coaptation or reduced leaflet motion. Differential diagnosis includes valvular degeneration, the most frequent being pannus or endocarditis. Symptoms, as described below, include heart failure or systemic embolic events.9,14,15 On the other hand, as Pache et al. first said using CT, SLT can be described as a hypo-attenuating defect at the aortic side of the leaflets, also called HALT, but with a normal transvalvular pressure gradient on echocardiography. If more than 50% of leaflet motion is affected, this phenomenon is defined as hypo-attenuation affecting motion (HAM). Because this is frequently an incidental finding with no clinically apparent valvular dysfunction, it is known as subclinical leaflet thrombosis.8,9

Magnitude: Incidence of Clinical and Subclinical Valve Thrombosis

After SAVR with a bioprosthesis, the incidence of clinical valve thrombosis has been reported at 0.3–6% depending on the series.12,16 This condition was later identified also after TAVI. Based on retrospective observational records, the incidence in these patients is estimated to range between 0.6% and 2.8%.17,18 However, the reported incidence of SLT depends on the strength of screening, the diagnostic criteria applied, and the imaging technique used. The incidence of this condition, both with and without reduced

Pathophysiology and Predisposing Factors

Numerous physiopathological mechanisms have been proposed for the development of bioprosthetic valve thrombosis. Rashid et al. referred to Virchow’s triad to explain the potential mechanisms underlying thrombosis. First is surface damage related to native aortic valves which are present in transcatheter aortic valve replacement: they are pushed aside in the sinus of Valsalva, which not only cause changes in valve geometry and haemodynamics but also can induce thrombosis due to exposure of tissue factor. Second are haemodynamic flow alterations and finally is a hypercoagulable state related to some host variables.20 Jaffer et al. reviewed the pathogenesis of clotting on blood contacting medical devices.21 Artificial surfaces promote clotting through complex processes including initial protein adsorption, which induces platelet adhesion, activation and aggregation; thrombin generation; and complement activation. Several factors have been associated with an increased risk of thrombus formation in the prosthetic surface, including mechanical factors during the implantation such as crimping and postdilatation, and the nature of the tissue valves, with porcine valves having a higher risk than bovine ones.14,21,22 Furthermore, haemodynamic flow alterations across the prosthesis with turbulence at the leaflet surface level can contribute also to thrombus formation. Factors, such as underexpansion, malapposition, postdilatation or native calcification, may also stimulate thrombosis. Intraannular valves in which larger neo sinuses (between the prosthesis frame and the prosthesis leaflets) are created are also at increased risk of thrombosis due to the flow stagnation. Other scenarios such as low cardiac output with blood stasis also promotes hypercoagulability.20 Moreover, some patient comorbidities and characteristics are associated with a pro-thrombotic and hypercoagulable state, such as an advanced age, diabetes, chronic kidney disease, heart failure, AF, chronic anaemia, cancer and smoking. All of them can both increase circulating thrombogenic factors and reduce their clearance.23 There are also procedural characteristics that predispose the patient to leaflet thrombosis after TAVI: valve-in-valve procedure, large diameter prosthesis, balloonexpandable prosthesis, underexpansion of the device, asymmetrical implantation and supra-annular implantation.24 Factors associated with an increased risk of thrombosis after TAVI are summarised in Box 1.14,20,25

Clinical Implications of Clinical and Subclinical Leaflet Thrombosis

The consequences of clinical valve thrombosis are secondary to valve stenosis or regurgitation and range from progressive dyspnoea to heart failure in a more acute form and depend on the degree of valve

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Imaging in Clinical and Subclinical Leaflet Thrombosis in TAVI Table 1: Clinical and Subclinical Bioprosthetic Valve Thrombosis: Presentation and Diagnosis Clinical Manifestation Diagnosis Clinical thrombosis

Symptomatic: Valve stenosis/regurgitation, dyspnoea, heart failure, thromboembolic events

Transthoracic echocardiogram/transesophageal echocardiogram, increased gradients. Cardiac CT if necessary

Subclinical thrombosis

Asymptomatic but could progress to: thrombosis, increased risk of neurological events and related to less durability of the aortic bioprosthesis

Transesophageal echocardiogram/cardiac CT if necessary: hypo-attenuated leaflet thickening and hypo-attenuation affecting motion as hallmarks

obstruction. Another possible manifestation is through a cardioembolic event such as a transient ischaemic attack, stroke or peripheral embolism. Thrombosis of a bioprosthetic valve is rare and is usually diagnosed in the early postoperative period.26 In subclinical leaflet thrombosis, patients are often asymptomatic but an increased risk of neurological events has been reported. It has been suggested that subclinical leaflet thrombosis has a possible negative effect on long-term valve durability and, of course, an increased risk of valve thrombosis and obstruction. For all of these, early detection should be essential.14,23 However, the suggested relationship between SLT in TAVI and neurological events is controversial at the moment because there is a discrepancy between the 10–15% prevalence of thrombosis in CT studies and 3–4% proportion of patients with stroke in large clinical trials.23,26 As Roseel et al. recently reported, although HAM was associated with an increased risk of transient ischaemic attack in the SAVOR/RESOLVE registry, this finding must be interpreted with caution because there was a longer time between the neurological event and the CT scan.14 At shortand mid-term follow-up, cerebrovascular events are similar following TAVI and SAVR.14,27 The hypothesis that subclinical thrombosis can affect long-term durability is a crucial issue; however, mid-term studies have demonstrated that TAVI durability is not inferior to surgical implantation of bioprosthetic valves.28 Finally, whether subclinical thrombosis is a substrate or precursor of valve thrombosis is not clear and needs further studies and follow-up.23,29 Table 1 summarises the main differences between clinical and subclinical valve thrombosis.

Diagnosis of Clinical and Subclinical Thrombosis Echocardiographic Assessment after TAVI

As with for valvular heart disease and prosthesis, echocardiography is the main diagnostic tool for the assessment of TAVI. The American and European societies of echocardiography have published a consensus document with recommendations for the use of echocardiography in TAVI. The Valve Academic Research Consortium has also elaborated a consensus document for systematic echocardiographic surveillance after TAVI. Furthermore, Pislaru et al. established the imaging approach for a proper assessment of TAVI to detect early and late complications.30 Transthoracic echocardiography (TTE) examination after implantation must be performed before discharge, at 6 and 12 months following implantation and every year thereafter.13,31,32 These consensus documents and recommendations established a detailed echocardiography assessment for prosthetic valve function. The first step is a visual inspection of the valve by 2D echocardiography and Doppler colour to evaluate the correct stent position and cusp mobility. It

Figure 1: Periprosthetic Aortic Regurgitation

Transoesophageal echocardiogram showing periprosthetic aortic regurgitation, the most frequent complication after transcatheter aortic valve implantation.

is essential to know the correct position of each prosthesis as both transcatheter aortic valve migration or malposition due to poor initial deployment or acute embolisation are early complications that must be prevented. Next is haemodynamic analysis of traditional parameters by continuous wave Doppler: mean gradient; peak velocity; Doppler velocity index (DVI); and effective orifice area (EOA). Also, using Doppler colour, prosthetic and peri-prosthetic regurgitation have to be carefully evaluated. Complications such as TAVI thrombosis, obstruction, patient-prosthesis mismatch and regurgitation can be present and must be properly evaluated. Aortic regurgitation is, without any doubt, the most frequent and reported complication due to it causing excess of mortality and morbidity, and because measuring it is complex (Figure 1). Other matters that have to be comprehensively analysed during echo assessment include mitral valve impingement, left and right ventricular size and function, and coronary artery obstruction. During patient follow-up, comparative analysis with the basal study will be fundamental to determining valve function and complications. Suggested normal values for TAVI valves are gradient <20 mmHg, EOA 1.1 cm2 and DVI >0.35. Differential diagnosis of high gradients is similar to that for a surgical prosthesis.32

Clinical and Subclinical Thrombosis: from Transthoracic Echocardiogram to CT

Clinical thrombosis can have dramatic consequences and must be suspected by TTE if elevated transprosthetic gradients are present with reduce mobility of the cusps and increased leaflet thickness. However, TTE sensitivity for visualising thrombus formation is limited, and TEE and cardiac CT should be than the next diagnostic step.33

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Imaging in Clinical and Subclinical Leaflet Thrombosis in TAVI Figure 2: Leaflets after Transcatheter Aortic Valve Implantation A

catheter, at a rate of 4–5 ml/s and the scan is initiated by bolus tracking on the ascending aorta. The volume of contrast material is variable; 60– 80 ml can be used with the intention of achieving opacification of only the left-sided cardiac chambers and aorta.34,35

A: Cardiac CT showing transcatheter aortic valve implantation with normal leaflets. B: Cardiac CT showing transcatheter aortic valve implantation with hypo-attenuation affecting motion.

In subclinical leaflet thrombosis, patients are asymptomatic with transvalvular gradient measurements within the normal range. HALT and HAM are the CT diagnostic hallmarks. HALT (Supplementary Video) appears as a wedge shape or semilunar opacities of the leaflets that can be seen both in systole and diastole by 3D volume – rendered views. It can lead to reduced mobility of the leaflets (RELM), assessed in 4D volume-rendered CT. HAM is related to the presence of HALT and RELM at the same time with reduce leaflet excursion by more than 50% (Figures 2 and 3).35 The natural history of SLT is not known. The period during which it may start to develop is not restricted to a brief window after valve implantation but may develop over a prolonged period of time.

Figure 3: Complications after Transcatheter Aortic Valve Implantation

As Jose et al. describe, the development of obstructive TAVI thrombosis depends on the amount of thrombus, the number of leaflets involved and the duration of the phenomenon.36 They speculated it could be a progressive disease with an early phase where the predominant finding is just an imaging and subclinical abnormality and a late phase with an extensive thrombus, and a resultant gradients elevation of and manifestation of symptoms.36,37 HALT and HAM would be the earliest signs on imaging before clinical thrombosis with elevated transvalvular gradients.35,38 In addition, although SLT seems to be merely an imaging finding, NT-proBNP and D-dimer levels can be elevated. The relationship between SLT and clinical thrombosis is still controversial but, without a doubt, the detection of SLT clearly changes patient follow-up and treatment.14

From Prevention to Treatment: Gaps in Evidence

Uncertainty about optimal antithrombotic therapy after TAVI remains and the best treatment strategy for prevention and treatment of SLT is still not established.

Hypo-attenuating leaflet thickening and mitral valve impingement after transcatheter aortic valve implantation.

Cardiac CT is the gold standard diagnostic tool to assess the mobility and thickness of the leaflets. Jilaihawi et al. perfectly described the systematic methodology for the evaluation of leaflet thrombosis by CT.34 Their acquisition protocol used a contrast-enhanced, ECG-gated cardiac CT scan with full cardiac-cycle coverage with retrospective gating, which is necessary to assess leaflet motion. Retrospective imaging acquires continuous data through the cardiac cycle allowing the assessment of valvular motion in cine mode. Scan slice thickness should be submillimetre and heart rate controlled (below 70 BPM) to avoid artifacts is necessary. For most scanners, the pitch varies according to the patient’s heart rate, and the tube current–time product may vary with the patient’s body surface, whereas the voltage is usual near 120 kV. Contrast material is usually administrated as a bolus through an antecubital intravenous

Recently published American College of Cardiology and American Heart Association guidelines established that for patients with a bioprosthetic TAVI who are at low risk of bleeding, DAPT with aspirin 75–100 mg and clopidogrel 75 mg may be reasonable for 3–6 months after valve implantation, and that for patients with TAVI who are at low risk of bleeding, anticoagulation with a vitamin K antagonist (VKA) to achieve an INR of 2.5 may be reasonable for at least 3 months after valve implantation.39 European guidelines (published in 2017) recommend DAPT for 3–6 months followed by single antiplatelet therapy in all patients who do not require anticoagulation therapy.40 Otherwise, oral anticoagulant (OAC) therapy seems to prevent the development of both SLT and clinical thrombosis; at the same time, OAC restores leaflet motion in case of HAM.14 Sondergaard et al. suggested that patients on OAC were less likely to show progression than those on antiplatelet therapy or no antithrombotic therapy.37 In case of clinical valve thrombosis, treatment with VKA should be started and continued until valve function is restored. Different antithrombotic strategies have been studied in several trials (the AUREA (NCT01642134), ATLANTIS (NCT02664649) and AVATAR

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Imaging in Clinical and Subclinical Leaflet Thrombosis in TAVI [NCT02735902]), which will provide further evidence about the optimal antithrombotic treatment after TAVI. At the moment, there is no evidence to support OAC therapy for all patients after TAVI given the increased bleeding risk in this elderly group of patients.14 In the randomised ARTE trial, which compared aspirin plus clopidogrel with aspirin alone, patients in the single antiplatelet therapy arm experienced fewer major and life-threatening bleeding events without increasing risk of stroke.41 The GALILEO trial, which compare rivaroxaban plus aspirin with standard antiplatelet therapy was stopped prematurely due to higher risk of bleeding in the rivaroxaban group.14 Furthermore, GALILEO-4D, a substudy of the main GALILEO trial, aimed to evaluate the effect of a rivaroxaban-based strategy compared with an antiplateletbased antithrombotic strategy on leaflet thickening and leaflet-motion abnormalities in patients with transcatheter aortic bioprostheses. In patients with no indication for long-term anticoagulation after successful TAVI, a treatment strategy that included anticoagulation with rivaroxaban 10 mg once daily was more effective than an antiplatelet-based strategy in preventing subclinical reduced leaflet motion at 90 days. However, given the unfavourable clinical outcomes with rivaroxaban in the main GALILEO trial, the authors concluded that they could not recommend routine imaging for the detection of reduced leaflet motion or the routine 1. Leon MB, Smith CR, Mack M, et al. Transcatheter aorticvalve implantation for aortic stenosis in patients who cannot undergo surgery. N Engl J Med 2010; 363:1597–607. https:// doi.org/10.1056/NEJMoa1008232; PMID: 20961243. 2. Deeb GM, Reardon MJ, Chetcuti S, et al. 3-year outcomes in high-risk patients who underwent surgical or transcatheter aortic valve replacement. J Am Coll Cardiol 2016;67:2565–74. https://doi.org/10.1016/j.jacc.2016.03.506; PMID: 27050187. 3. Adams DH, Popma JJ, Reardon MJ, et al. Transcatheter aortic-valve replacement with a self-expanding prosthesis. N Engl J Med 2014;370:1790–8. https://doi.org/10.1056/ NEJMoa1400590; PMID: 24678937. 4. Thyregod HG, Steinbruchel DA, Ihlemann N, et al. Transcatheter versus surgical aortic valve replacement in patients with severe aortic valve stenosis: 1-year results from the all-comers NOTION randomized clinical trial. J Am Coll Cardiol 2015;65:2184–94. https://doi.org/10.1016/j. jacc.2015.03.014; PMID: 25787196. 5. Thourani VH, Kodali S, Makkar RR, et al. Transcatheter aortic valve replacement versus surgical valve replacement in intermediate-risk patients: a propensity score analysis. Lancet 2016; 387:2218–25. https://doi.org/10.1016/S01406736(16)30073-3; PMID: 27053442. 6. Siontis GC, Praz F, Pilgrim T, et al. Transcatheter aortic valve implantation vs surgical aortic valve replacement for treatment of severe aortic stenosis: a meta-analysis of randomized trials. Eur Heart J 2016;37:3503–12. https://doi. org/10.1093/eurheartj/ehw225; PMID: 27389906. 7. Reardon MJ, Van Mieghem NM, Popma JJ, et al. Surgical or transcatheter aortic-valve replacement in intermediate-risk patients. N Engl J Med 2017;376:1321–31. https://doi. org/10.1056/NEJMoa1700456; PMID: 28304219. 8. Pache G, Schoechlin S, Blanke P, et al. Early hypoattenuated leaflet thickening in balloon-expandable transcatheter aortic heart valves. Eur Heart J 2016;37:2263– 71. https://doi.org/10.1093/eurheartj/ehv526; PMID: 26446193. 9. Makkar RR, Fontana G, Jilaihawi H, et al. Possible subclinical leaflet thrombosis in bioprosthetic aortic valves. N Engl J Med 2015;373(21):2015–24. https://doi.org/10.1093/ eurheartj/ehv526; PMID: 26446193. 10. Chakravarty T, Søndergaard L, Friedman J, et al. Subclinical leaflet thrombosis in surgical and transcatheter bioprosthetic aortic valves: an observational study Lancet 2017;389:2383–92. https://doi.org/10.1016/S01406736(17)30757-2; PMID: 28330690. 11. Rheude T, Pellegrini C, Stortecky S, et al. Meta-analysis of bioprosthetic valve thrombosis after transcatheter aortic valve implantation. Am J Cardiol2021;138:92–99. https://doi. org/10.1016/j.amjcard.2020.10.018; PMID: 33065085. 12. Puri, V Auffret, J Rodés-Cabau. Bioprosthetic valve thrombosis. J Am Coll Cardiol 2017;69:2193–211. https://doi. org/10.1016/j.jacc.2017.02.051; PMID: 28449781.

use of anticoagulation after TAVI with the aim of preventing leaflet-motion abnormalities.42 A recent meta-analysis including the POPular TAVI trial, the ARTE trial, and the Dual Antiplatelet Therapy Versus Aspirin Alone in Patients Undergoing Transcatheter Aortic Valve Implantation trial concluded that, in patients without an indication for oral anticoagulation undergoing TAVI, aspirin alone significantly reduce the composite of thromboembolic and bleeding events, and do not increase the composite of thromboembolic events after transcatheter aortic valve implantation compared with DAPT.43 Questions about optimal strategies for prevention and treatment still exist and ongoing and future studies will probably help to solve them.

Conclusion

Many questions remain over SLT. HALT and HAM diagnosed by CT are the hallmarks of this condition, the incidence of which depends on the intensity of screening. Whether these phenomena are a surrogate for leaflet thrombosis reducing valve durability and increasing the risk of stroke is still controversial. More studies are needed to understand not only the natural history of HALT but also its clinical and prognostic implications and, what is more, whether screening and preventive strategies are needed. Further evidence is also needed about the most appropriate antithrombotic therapy after TAVI.

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24. Pieniak K, Jędrzejczyk S, Domaszk O, et al. Predictors And biomarkers of subclinical leaflet thrombosis after transcatheter aortic valve implantation. J Clin Med 2020;9:3742. https://doi.org/10.3390/jcm9113742; PMID: 33233321. 25. Del Trigo M, Muñoz-Garcia AJ, Wijeysundera HC, et al. Incidence, timing, and predictors of valve hemodynamic deterioration after transcatheter aortic valve replacement: multicenter registry. J Am Coll Cardiol 2016;67:644–55. https://doi.org/10.1016/j.jacc.2015.10.097; PMID: 27978952. 26. Dangas GD, Weitz JI, Giustino G, et al. Prosthetic heart valve thrombosis. J Am Coll Cardiol 2016;68:2670–89. https://doi. org/10.1016/j.jacc.2016.09.958; PMID: 27978952. 27. Kapadia SR, Huded CP, Kodali SK, et al. Stroke after surgical versus transfemoral transcatheter aortic valve replacement in the PARTNER Trial. J Am Coll Cardiol 2018;72:2415–26. https://doi.org/10.1016/j.jacc.2018.08.2172; PMID: 30442284. 28. Eltchaninoff H, Durand, Cribier A. TAVI durability beyond five years: no alarms but stay alert. Eurointervention 2018;14:e380–2. https://doi.org/10.4244/EIJV14I4A67; PMID: 30028301. 29. Ruile P, Minners J, Breitbart P, et al. Medium-term follow-up of early leaflet thrombosis after transcatheter aortic valve replacement. JACC Cardiovasc Interv 2018;11:1164–71. https:// doi.org/10.1016/j.jcin.2018.04.006; PMID: 29929639. 30. Pislaru SV, Nkomo VT, Sandhu GS. Assessment of prosthetic valve function after TAVR. JACC Cardiovasc Imaging 2016;9(2):193–206. https://doi.org/10.1016/j.jcmg.2015.11.010; PMID: 26846938. 31. Zamorano JL, Badano LP, Bruce C, et al. EAE/ASE recommendations for the use of echocardiography in new transcatheter interventions for valvular heart disease. Eur Heart J 2011;32:2189–214. https://doi.org/10.1093/eurheartj/ ehr259; PMID: 21885465. 32. Kappetein AP, Head SJ, Généreux P, et al. Updated standardized endpoint definitions for transcatheter aortic valve implantation: the Valve Academic Research Consortium-2 consensus document. J Am Coll Cardiol 2012; 60:1438–54. https://doi.org/10.1016/j.jacc.2012.09.001 PMID: 23036636. 33. Pislaru SV, Pellikka PA, Schaff HV, et al. Bioprosthetic valve thrombosis: the eyes will not see what the mind does not know. J Thorac Cardiovasc Surg 2015;149:e86–7. https://doi. org/10.1016/j.jtcvs.2015.03.012; PMID: 25862603. 34. Jilaihawi H, Asch FM, Manasse E, et al. Systematic CT methodology for evaluation of subclinical leaflet thrombosis. JACC Cardiovasc Imaging 2017 10:461–70. https://doi. org/10.1016/j.jcmg.2017.02.005; PMID: 28385256. 35. Kanjanauthai S, Pirelli L, Nalluri N, et al .Subclinical leaflet thrombosis following transcatheter aortic valve replacement. J Interv Cardiol 2018; 31:640–7. https://doi. org/10.1111/joic.12521; PMID: 29790209. 36. Jose J, Sulimov D, El-Mawardy M, et al. Clinical

Imaging in Clinical and Subclinical Leaflet Thrombosis in TAVI bioprosthetic heart valve thrombosis after transcatheter aortic valve replacement: incidence, characteristics, and treatment outcomes. JACC Cardiovasc Interv 2017;10:686–97. https://doi.org/10.1016/j.jcin.2017.01.045; PMID: 28385406. 37. Sondergaard L, De Backer O, Kofoed KF, et al. Natural history of subclinical leaflet thrombosis affecting motion in bioprosthetic aortic valves. Eur Heart J 2017;38:2201–7. https://doi.org/10.1093/eurheartj/ehx369; PMID: 28838044. 38. Oliveira DC, Okutucu S, Russo G, et al. The issue of subclinical leaflet thrombosis after transcatheter aortic valve implantation. Cardiol Res 2020;11:269–73. https://doi. org/10.14740/cr1108; PMID: 32849960. 39. Otto CM, Nishimura RA, Bonow RO, et al 2020. ACC/AHA guideline for the management of patients with valvular

heart disease: executive summary: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. J Am Coll Cardiol 2021;77:450–500 https://doi.org/10.1016/j.jacc.2020.11.035; PMID: 33342587. 40. Baumgartner H, Falk V, Bax JJ, et al. 2017 ESC/EACTS guidelines for the management of valvular heart disease. Eur Heart J 2017;38:2739–91. https://doi.org/10.1093/ eurheartj/ehx391; PMID: 28886619. 41. Rodés Cabau J, Masson JB, Welsh RC, et al. Aspirin versus aspirin plus clopidogrel as antithrombotic treatment following transcatheter aortic valve replacement with a balloon-expandable valve: the ARTE (Aspirin Versus Aspirin + Clopidogrel Following Transcatheter Aortic Valve

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Implantation) randomized clinical trial JACC Cardiovasc Interv 2017;10:1357–65. https://doi.org/10.1016/j.jcin.2017.04.014; PMID: 28527771. 42. De Backer O, Dangas GD, Jilaihawi H, et al. Reduced leaflet motion after transcatheter aortic-valve replacement. N Engl J Med 2020;382:130–9. https://doi.org/10.1056/ NEJMoa1911426; PMID: 31733182. 43. Brouwer J, Nijenhuis VJ, Rodés-Cabau J, et al. Aspirin alone versus dual antiplatelet therapy after transcatheter aortic valve implantation: a systematic review and patient-level meta-analysis. J Am Heart Assoc 2021;16:e019604. https://doi. org/10.1161/JAHA.120.019604; PMID: 33860685.

Women and Heart Disease

Novel Cardiovascular Biomarkers Associated with Increased Cardiovascular Risk in Women With Prior Preeclampsia/HELLP Syndrome: A Narrative Review Esmee ME Bovee ,1 Martha Gulati

and Angela HEM Maas

1. Radboud University, Nijmegen, the Netherlands; 2. University of Arizona, Phoenix, Arizona, US; 3. Department of Cardiology, Radboud University Medical Center, Nijmegen, the Netherlands

Abstract

Evidence has shown that women with a history of preeclampsia or haemolysis, elevated liver enzymes and low platelets (HELLP) syndrome have an increased risk of cardiovascular disease later in life. Recommendations for screening, prevention and management after such pregnancies are not yet defined. The identification of promising non-traditional cardiovascular biomarkers might be useful to predict which women are at greatest risk. Many studies are inconsistent and an overview of the most promising biomarkers is currently lacking. This narrative review provides an update of the current literature on circulating cardiovascular biomarkers that may be associated with an increased cardiovascular disease risk in women after previous preeclampsia/HELLP syndrome. Fifty-six studies on 53 biomarkers were included. From the summary of evidence, soluble fms-like tyrosine kinase-1, placental growth factor, interleukin (IL)-6, IL-6/IL-10 ratio, high-sensitivity cardiac troponin I, activin A, soluble human leukocyte antigen G, pregnancy-associated plasma protein A and norepinephrine show potential and are interesting candidate biomarkers to further explore. These biomarkers might be potentially eligible for cardiovascular risk stratification after preeclampsia/HELLP syndrome and may contribute to the development of adequate strategies for prevention of hypertension and adverse events in this population.

Keywords

Hypertensive disorders of pregnancy, preeclampsia, cardiovascular disease, cardiovascular risk, biomarkers, review Disclosure: AM is a section editor on the European Cardiology Review editorial board; this did not influence peer review. All other authors have no conflicts of interest to declare. Received: 9 June 2021 Accepted: 11 August 2021 Citation: European Cardiology Review 2021;16:e36. DOI: https://doi.org/10.15420/ecr.2021.21 Correspondence: Angela HEM Maas, Department of Cardiology, Radboud University Medical Center, Geert Grooteplein-Zuid 10, 6525GA Nijmegen, the Netherlands. E: angela.maas@radboudumc.nl Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Hypertensive disorders of pregnancy (HDP) are a group of four disorders, whose definition depends on how far along in the pregnancy the hypertension occurs and the presence of maternal organ dysfunction: chronic hypertension (CH), gestational hypertension (GH), preeclampsia (PE) and superimposed preeclampsia (SPE). HDP is a complication seen in approximately 5–15% of all pregnancies.1–4 In previous years, evidence has shown that PE and its severe variant termed haemolysis, elevated liver enzymes and low platelets (HELLP) syndrome are associated with a significant increased risk of maternal cardiovascular diseases (CVD) later in life including hypertension, coronary artery disease, heart failure, MI and stroke.5–11 PE/HELLP syndrome and CVD share common pathophysiological pathways and markers such as endothelial dysfunction, inflammation and angiogenic factors, which may explain this association.12 These findings have led to the acknowledgement of PE/HELLP syndrome as an important female-specific risk factor for CVD later in life by the American Heart Association (AHA), American Stroke Association and the European Society of Cardiology (ESC).13–15 As yet there is no consensus regarding clinical guidelines on how to optimally screen, prevent and manage CVD risk after pregnancies complicated in this way.16,17 The AHA recommends that healthcare professionals obtain pregnancy history in risk assessment for CVD, but

this is infrequently implemented.13,17 Despite PE being listed as a risk enhancer of CVD by the AHA/ESC, women with a history of PE/HELLP syndrome and their doctors are often not aware of the increased risk. This may result in undetected hypertension and lack of adequate treatment and further cardiovascular risk assessment.18–20 Nonetheless, not all women who experienced PE/HELLP syndrome develop CVD later in life, indicating the existence of different levels of future risk. Currently, risk counselling for CVD is mainly based on traditional risk factors and biochemical markers (e.g. LDL and HDL cholesterol, triglycerides, glucose), only partially explaining the increased prevalence of CVD in these women.11,21,22 The identification of circulating non-traditional cardiovascular biomarkers of relevance for myocardial and coronary artery function may therefore be of additional value to determine which women are at greatest risk and to better understand the pathophysiological mechanism of CVD. Our understanding of these cardiovascular biomarkers in women has grown over the years. However, study designs vary widely and their findings have not been consistent. To date, a clear overview of the most promising biomarkers associated with CVD risk is lacking.23 The aim of this narrative review is to provide an update of the current literature on circulating non-traditional cardiovascular biomarkers in blood that may be associated with an increased cardiovascular risk in women after a previous PE/HELLP syndrome.

CV Risk Biomarkers in Women with Prior Preeclampsia/HELLP Syndrome Figure 1: Flow Diagram of Study Selection Process Search Biomarker CVD + history of PE/ HELLP syndrome

Add filter English language

PubMed n=843 results 34 excluded based on study language n=809 results

Title/keyword screening Abstract screening

725 excluded based on title n=84 results 26 excluded based on abstract n=58 results

Full text assessment

11 studies added from reference lists

n=45 results

Exclusion after full text assessment: • Investigated only traditional biomarkers* n=7 • Not the correct target population n=3 • Focus on cardiovascular changes/markers during PE n=3

Studies included in review n=56

*Lipids, lipoproteins, markers of glucose metabolism and C-reactive protein. CVD = cardiovascular disease; HELLP = haemolysis, elevated liver enzymes and low platelets; PE = preeclampsia.

Review Methods Classification and Definitions of Hypertensive Disorders of Pregnancy

PE and HELLP syndrome are characterised by hypertension developing after 20 weeks of gestation in combination with maternal organ dysfunction. In older definitions, proteinuria was mandatory, but this has been deleted in the latest guidelines.24,25 PE can be divided into early onset (e-PE) occurring before 34 weeks of gestation and late onset if it develops at 34 weeks of gestation or later (l-PE). The precise definitions of hypertension in pregnancy, PE, HELLP syndrome, GH, CH and SPE are presented in Supplementary Material Table 1.24–26

Source and Search Strategy

To find corresponding cardiovascular biomarkers, a literature search was performed in the PubMed database from inception to February 2021. The search was specified on cardiovascular biomarkers that may be associated with future CVD risk in women with a previous hypertensive disorder of pregnancy. Supplementary Material Table 2 presents the synonyms used to build a comprehensive search strategy. Further relevant studies were identified by examining the reference lists of the selected studies.

Study Selection

Observational studies, (systematic) reviews and meta-analyses were eligible for inclusion if written in English. First, titles and keywords were screened for containing terms for both PE/HELLP syndrome or HDP, as well as CVD or associated biomarkers. In addition, attention was paid to whether it concerns the risk of developing CVD in the future, not the risk of developing PE/HELLP syndrome. CVDs of interest were all pathological conditions involving the cardiovascular system including the heart, the blood vessels or the pericardium. In case there was doubt whether the study should be selected based on its title, the abstract was reviewed. Thereafter, the abstracts were screened for mentioning biomarkers in blood samples of women with (previous) PE/HELLP syndrome, linking this with CVD. Potential eligible studies were subsequently assessed by reading the full text, after which a final selection of publications was

made. Studies comparing biomarker levels between women with a previous PE/HELLP syndrome and women who experienced uncomplicated, normotensive pregnancies were eligible for inclusion. Furthermore, studies investigating overlapping biomarkers between PE and any kind of CVD or studies evaluating the correlation between biomarkers and cardiovascular risk factors in women with (previous) PE/ HELLP syndrome were eligible for inclusion. Biomarkers of interest were circulating non-traditional cardiovascular markers of relevance for myocardial and coronary artery function. Studies investigating only traditional markers were excluded (lipids, lipoproteins, markers of glucose metabolism, C-reactive protein). In order to gain information about women after a previous PE/HELLP syndrome, studies including only a case/group of women with GH, CH or SPE were excluded. Moreover, there was a preference for studies using a PE cohort or studies separately analysing the results of the different disorders of HDP in order to comment on PE/ HELLP syndrome.

Outcomes of Interest

The primary outcome of interest is non-traditional cardiovascular biomarkers in blood that differentiate whether women with a history of PE/HELLP syndrome may have an elevated risk to develop any kind of CVD in the future or not. Another outcome measure of interest is cardiovascular biomarkers shown to be significantly different in women after previous PE/HELLP syndrome compared to controls or biomarkers correlated with cardiovascular risk factors in women with a history of PE/ HELLP syndrome.

Results Literature Identification

The process of study inclusion and exclusion is depicted in Figure 1. The initial search in PubMed yielded 843 articles. After removing non-English studies, 809 studies were screened for retrieval and finally 45 studies were included and 11 studies were added from the reference lists of selected studies. The total of 56 studies included 53 different nontraditional cardiovascular biomarkers.

Study Characteristics

Study characteristics of included studies are shown in the Supplementary Material Table S3. Included studies were published from 2001 to 2021. Most studies assessed PE/HELLP syndrome separately from other HDP; four studies used a combined group of GH and PE or other pregnancy complications. As the definition of PE has changed over the years, there is a slight difference in study population between studies. The follow-up period varied from 3–6 days to decades after pregnancy. The 53 identified biomarkers were grouped according to their biochemical function (Table 1): angiogenesis, endothelial function, inflammation, cardiac, thrombotic, micro-RNA (miRNA) and a remaining group of biomarkers that do not fit well in one of these categories and/or have only been assessed in a single study. For the following parts of the review, women with a history of PE/HELLP syndrome are referred to as cases and women with a history of uncomplicated normotensive pregnancy as controls. If another case and/ or control-group is used in the included study, this will be described.

Biomarkers of Angiogenesis

Soluble fms-like Tyrosine Kinase-1 and Placental Growth Factor

Benschop et al. associated lower mid-pregnancy placental growth factor (PlGF) concentrations with worse cardiac structure and systolic

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CV Risk Biomarkers in Women with Prior Preeclampsia/HELLP Syndrome blood pressure at 6–9 years postpartum in a mixed cohort of complicated and uncomplicated pregnancies. These associations persisted after exclusion of women with complicated pregnancies.27 Another study associated increased soluble fms-like tyrosine kinase-1 (sFlt-1) and decreased PlGF values in third trimester of PE with cardiovascular risk factors at 12 years postpartum, such as increased carotid intima media thickness (cIMT) measurements and worse lipid profiles.28 Neuman et al. found lower third trimester PlGF levels in women with PE with subsequent hypertension 1-year postpartum compared to women with PE without subsequent hypertension. However, third trimester PlGF and sFlt-1 values did not show significant value to predict hypertension at one year postpartum.29 In the first 10 years after delivery, several studies found some differences in biomarker levels between cases and controls. Kvehaugen et al. reported increased sFlt-1 values, but not PlGF, in cases both at delivery and 5–8 years postpartum.30 Three other studies reported significantly higher sFlt-1 levels in cases as well at 1, 1.5 and 4.5 years postpartum.31–33 Akhter et al. additionally observed a correlation between angiogenic factors and signs of arterial aging, measured by intima thickness and intima/media thickness ratio (I/M ratio).32 In contrast, Noori et al. and Yinon et al. found comparable sFlt-1 levels in cases and controls at 12 weeks and 6–24 months postpartum. However, they used smaller subject sample sizes compared to the above mentioned studies.34,35 Noori et al. did find higher PlGF levels 12 weeks postpartum in cases, whereas Escouto et al. found comparable levels in cases and controls at 6 weeks postpartum in a larger cohort of 288 cases.34,36 After a decade postpartum, four studies reported comparable sFlt-1 and PlGF levels in cases and controls.28,37–39 Finally, a meta-analysis found modestly higher sFlt-1 levels in women with previous HDP in a pooled analysis of 704 women (359 prior HDP and 345 controls). This difference was more pronounced when the sFlt-1 level was measured closer to the pregnancy (before 94 months postpartum).40

Soluble Endoglin and Vascular Endothelial Growth Factor

Four studies found comparable soluble endoglin (sEng) levels, and six studies mentioned comparable vascular endothelial growth factor (VEGF) levels in cases and controls in the postpartum period, ranging from weeks to 12 years postpartum.28,30,31,34,35,37,39,40

Biomarkers of Endothelial Function

Soluble Intercellular Adhesion Molecule-1 and Soluble Vascular Cell Adhesion Molecule-1

Table 1: Biomarkers and Categories Category

Biomarkers

Angiogenesis

sFlt-1 VEGF

PlGF sEng

Endothelial function

sICAM-1 sVCAM-1 sE-selectin

sP-selectin VE-cadherin

Inflammation

Interleukins TNF-α TNF-α receptor 1 IFN-γ PTX3 NGAL

Calprotectin Myeloperoxidase MIP-1α Fractalkine GM-CSF

Cardiac

BNP NT-proBNP MR-proANP

hs-cTnI Troponin T

Thrombotic

Fibrinogen VWF Hcy PAI-1

tPA D-dimer Endothelin Thrombomodulin

miRNA

Remaining

Activin A sHLA-G PAPPA Norepinephrine pro-NT pro-RLX2 CA-125 ADMA SDMA l-arginine

Homoarginine Neopterin Cathepsin B Cathepsin S Superoxide dismutase Neutrophil count and (re)activity MRproADM ADM Cystatin C

ADM = adrenomedullin; ADMA = asymmetric dimethylarginine; BNP = brain natriuretic peptide; CA-125 = cancer antigen 125; GM-CSF = granulocyte-macrophage colony-stimulating factor; Hcy = homocysteine; hs-cTnI = high-sensitivity cardiac troponin I; IFN = interferon; MIP = macrophage inflammatory protein; miRNA = micro RNA; MR-proANP = midregional pro-atrial natriuretic peptide; MRproADM = midregional pro adrenomedullin; NGAL = neutrophil gelatinase-associated lipocalin; NT-proBNP = n-terminal prohormone brain natriuretic peptide; PAI-1 = plasminogen activator inhibitor-1; PAPPA = pregnancy-associated plasma protein A; PlGF = placental growth factor; pro-NT = pro neurotensin; pro-RLX2 = prorelaxin 2; PTX3 = pentraxin 3; SDMA = symmetric dimethylarginine; sE-selectin = soluble E-selectin; sEng = soluble endoglin; sFlt-1 = soluble fms-like tyrosine kinase-1; sHLA-G = soluble human leukocyte antigen G; sICAM-1 = soluble intercellular adhesion molecule-1; sP-selectin = soluble P-selectin; sVCAM-1 = soluble vascular cell adhesion molecule-1; TNF = tumour necrosis factor; tPA = tissue plasminogen activator; VE-cadherin = vascular endothelial cadherin; VEGF = vascular endothelial growth factor; VWF = von Willebrand factor.

Soluble E-selectin

In the first decade after PE, seven studies reported no difference between cases and controls for soluble intercellular adhesion molecule-1 (sICAM-1) levels.23,33,41–45 Of note, one study even described lower levels 0.7 years postpartum in women with prior e-PE.46 Between 10–20 years postpartum, three studies described higher levels in cases and one study additionally related these high levels of sICAM-1 to features of the metabolic syndrome (MetS).38,47,48 In contrast, Tanz et al. reported comparable sICAM-1 levels 17 years postpartum in cases and controls.49 However, the use of a combined case group of PE and GH, and being based on women self-reporting makes the study less reliable.49 Studies including soluble vascular cell adhesion molecule-1 (sVCAM-1) levels, ranging from 1 to 20 years postpartum, have demonstrated no difference in cases and controls.23,28,33,38,39,43,45,48 Additionally, two meta-analyses found comparable sICAM-1 and sVCAM-1 levels in cases and controls.40,50

In a small study of 12 women with severe PE, there was a significant increase in soluble E-selectin (sE-selectin) in cases compared to controls at 3–6 days and then 12–15 weeks postpartum.51 Similarly, Chambers et al. reported higher levels in cases 3 years postpartum.42 Nonetheless, other studies have demonstrated no difference in sE-selectin at 1 and 2.5 years postpartum when comparing cases and controls.41,43 Four studies found comparable sE-selectin values 4.5–20 years postpartum in cases and controls, while Drost et al. described higher levels 10 years postpartum in a large cohort of 339 women with a history of e-PE.23,33,37,47,48

Soluble P-selectin, Soluble Intercellular Adhesion Molecule-3 and Vascular Endothelial-Cadherin

Soluble P-selectin, sICAM-3 and vascular endothelial-cadherin were mentioned in a single study, reporting no difference between cases and controls.37,51

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CV Risk Biomarkers in Women with Prior Preeclampsia/HELLP Syndrome Biomarkers of Inflammation

Interleukin 6 and Interleukin 10

Two studies reported higher interleukin (IL)-6 levels 12–14 weeks and 0.7 year postpartum in cases compared to controls.46,52 In contrast, three studies found comparable levels in cases and controls at 6 months, 1 and 2.5 years postpartum, with one of these studies examining a combined cohort of PE and GH.53–55 At 8, 9–16 and 17 years postpartum, three studies found higher levels of IL-6 in cases.47,49,56 One study observed a trend towards increased IL-6 levels and decreased IL-10 levels resulting in a higher IL-6/IL-10 ratio 20 years postpartum in cases compared to controls.57

Tumour Necrosis Factor α and Tumour Necrosis Factor Receptor 1

Vitoratos et al. found higher tumour necrosis factor (TNF)-α levels 12–14 weeks postpartum in a case-group of 17 women and Ehrenthal et al. showed higher values one year postpartum in a combined PE and GH group.52,54 However, six studies described comparable TNF-α levels in cases and controls, ranging from 6 months to 20 years postpartum, and one study even reported lower levels in cases 8 years postpartum.39,47,53,55–58 Östlund et al. found higher levels of TNF receptor 1 at 12 years postpartum in cases compared to controls.38

Other Markers of Inflammation

Two studies reported on interleukins other than IL-6 and IL-10, interferon-γ and macrophage inflammatory protein-1α at 6 months and 1.5–3.5 years postpartum. Both found comparable baseline levels but one study observed associations between inflammatory markers and multiple MetS parameters in cases and not controls and the other study showed alterations in the innate and adaptive immune response after a preeclamptic pregnancy.53,55 Finally, pentraxin-3, neutrophil gelatinaseassociated lipocalin, granulocyte-macrophage colony-stimulating factor, fractalkine, calprotectin and myeloperoxidase showed no distinctive results.30,36,38,53,55,59

Biomarkers of Cardiac Function

Studies assessing postpartum levels of brain natriuretic peptide (BNP) and N-terminal prohormone BNP (NT-proBNP) described comparable levels in cases and controls.28,36,38,60 However, Alma et al. concluded that NTproBNP and BNP differentiate both women with diastolic dysfunction from controls as well as women with preeclampsia from controls, implying common pathophysiology.61 Muijsers et al. found a strong association between high-sensitivity cardiac Troponin I (hs-cTnI) and blood pressure. Among formerly preeclamptic women, hs-cTnI levels were higher in currently hypertensive women compared to their normotensive counterparts.62 Levels of Troponin T and mid-regional pro atrial natriuretic peptide were comparable in cases and controls 12 and 5–8 years postpartum respectively.28,63

Biomarkers of Thrombosis

Fibrinogen and von Willebrand Factor

whereas Blaauw et al. reported higher VWF levels 4.5 years postpartum in 17 women with prior e-PE.43,44,46,65 Furthermore, a meta-analysis showed no differences in cases and controls for these markers.50

Homocysteine

Five studies, of which three used a sample size of <20 cases, described comparable homocysteine (Hcy) levels in cases and controls at 3, 4.5, 5.5, 3-11 and 11 years postpartum.38,42,44,66,67 Three studies found higher levels in cases at 2.5, 8 years and decade(s) postpartum, although one study used a combined cohort of GH and PE, in which women self-reported making it less reliable.56,68,69 Wu et al. showed that cases with high Hcy levels have an increased arterial stiffness compared to cases with normal Hcy levels.70 Finally, a meta-analysis pooling 390 cases and 342 controls showed higher Hcy levels in cases.50

Plasminogen Activator Inhibitor-1, Tissue Plasminogen Activator, Endothelin-1, Thrombomodulin and D-dimer

Included studies described no significant difference in the postpartum levels of plasminogen activator inhibitor-1, tissue plasminogen activator, endothelin-1 and thrombomodulin in cases compared with controls.23,37,43,56,64,71 One study evaluated D-dimer levels 6 years postpartum and found higher levels in cases compared to controls.64

miRNA

Five studies were identified that assessed miRNA levels, all investigating different sets of miRNAs and therefore without confirmation in another study.72–76 Results of these studies are shown in Supplementary Material Table S4.

Other Biomarkers

Fifteen biomarkers examined to date show little potential: asymmetric dimethylarginine, symmetric dimethylarginine, l-arginine, homoarginine, neopterin, midregional pro adrenomedullin, adrenomedullin, cancer antigen 125, superoxide dismutase, cathepsin B, cathepsin S, cystatin C, pro neurotensin and prorelaxin 2 and neutrophil count and (re) activity.38,39,44,61,77,78 On the other hand, activin A, soluble human leukocyte antigen G (sHLA-G), pregnancy-associated plasma protein A (PAPPA) and norepinephrine did show interesting results. Shahul et al. showed that third trimester activin A levels in women with PE correlated positively with abnormal global longitudinal strain one year postpartum and that postpartum activin A level are associated with increased left ventricular mass index and worse diastolic function.79 Jacobsen et al. described that women with previous e-PE have higher levels of sHLA-G compared to controls at 1 and 3 years postpartum. This difference was not observed in the previous l-PE group.80 Drost et al. reported higher levels of PAPPA 10 years postpartum in women with a history of e-PE compared to controls after adjustment for traditional cardiovascular risk factors.23 Lampinen et al. found higher plasma norepinephrine levels 6 years postpartum in the resting lying supine position in cases compared to controls.71

Discussion Main Findings

Six studies described comparable fibrinogen levels in cases and controls, ranging from 1 year to decade(s) after pregnancy.11,39,43,55,64,65 One study found increased fibrinogen levels 0.7 years postpartum in women with a previous e-PE compared to controls.46

This narrative review presents an updated overview of the evidence available on non-traditional cardiovascular biomarkers in women with a previous PE/HELLP syndrome. After a complete review of the literature, nine biomarkers stand out as potential markers: sFlt-1, PlGF, IL-6, IL-6/IL10 ratio, hs-cTnI, activin A, sHLA-G, PAPPA and norepinephrine.

Three studies found no difference in von Willebrand factor (VWF) values between cases and controls at 0.7-year, 1 year and decade(s) postpartum,

The angiogenic marker sFlt-1 shows potential until 8 years after the index pregnancy as multiple studies show differences between cases and

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CV Risk Biomarkers in Women with Prior Preeclampsia/HELLP Syndrome controls (not after 10 years postpartum). In addition, the association between the angiogenic markers sFlt-1 and PlGF and later CVD risk may be even stronger when these markers are determined during pregnancy (mid-pregnancy or third trimester). sFlt-1 is a soluble form of the VEGF receptor and neutralises both proangiogenic factors VEGF and PlGF by binding. An anti-angiogenic environment created by an increase in sFlt-1 (and sEng), and thereby decrease in PlGF and VEGF, plays a major role in the development of PE.81–84 Angiogenic factors are also associated with the development and progression of CVD. sFlt-1 levels are elevated in patients with heart failure and high levels are associated with adverse cardiovascular outcomes such as ischaemic heart disease.85–88 PlGF levels are also elevated in heart failure and are associated with intima thickening, pathophysiology of atherosclerosis, coronary heart disease and adverse cardiovascular events.89–93 Altered sFlt-1 and PlGF levels during pregnancy and the first few years postpartum may predispose these women for future CVD. Markers of endothelial function examined to date show little potential. From the few studies that do find a difference and take time of biomarker determination into consideration, there seems to be some small trend towards increased sICAM-1 levels in cases more than 10 years postpartum, when compared with controls. However, the evidence remains too uncertain to conclude usability. In addition, results on sE-selectin are highly variable, making it unlikely to be meaningful for CVD risk stratification. For the inflammatory biomarkers, IL-6 and the IL-6/IL-10 ratio appear to be the most promising. Years after PE, studies demonstrate a tendency towards increased proinflammatory IL-6 and decreased anti-inflammatory IL-10 levels, therefore the ratio could increase the sensitivity for detecting (subclinical) inflammation. Studies on other inflammatory biomarkers mainly showed comparable levels in cases and controls. However, two studies showed no baseline differences but alterations in inflammatory response and unique correlations between inflammatory markers and MetS in women with previous PE. Together this might hint that the alteration in baseline levels after PE is very small, or not measurable, and that an enhanced inflammatory response or unique associations explain the increased CVD risk. Inflammation plays a major role in the pathogenesis of PE, but also in atherosclerosis and coronary artery disease.94–100 Small changes in inflammatory baseline levels or response after a pregnancy with PE may explain the link with CVD. The cardiac biomarker hs-cTnI appears to be promising as it is significantly higher in hypertensive women with a history of PE compared to their normotensive counterparts. Hs-cTnI is a widely used marker for cardiac tissue damage, such as MI, coronary heart disease, heart failure and is also associated with hypertension.101–106 Elevated levels in formerly preeclamptic women with hypertension may indicate some ongoing myocardial cell injury. BNP, NT-proBNP and MR-proANP show comparable postpartum levels in cases and controls, but these markers are increased during a preeclamptic pregnancy and are predictive for PE.61,63,107 Further research is suggested to investigate whether BNP, NT-proBNP and MRproANP levels in pregnancy are associated with CVD risk later in life as these are known markers of heart failure.108,109 As for the thrombotic markers, only studies on Hcy show some diversity. However, no obvious trend is manifest and other thrombotic markers show comparable postpartum levels in cases and controls. miRNA is a relatively new category of biomarker and a wide variety of miRNAs are associated with cardiovascular diseases. However, there are

just a few studies linking PE and future CVD using miRNAs. These studies mainly investigate different miRNAs and lack the ability to conclude causality. At this point it is thought to be too early to make a statement on the utility of miRNAs in CVD risk stratification after PE/HELLP syndrome and studies express the need for further research.72–76 Four biomarkers were noteworthy in the remaining category: activin A, sHLA-G, PAPPA and norepinephrine. Activin A is a member of the transforming growth factor-ß family and associated with myocardial remodelling, cardiac fibrosis and involved in the pathogenesis of heart failure.110–112 sHLA-G has immunosuppressive effects and high levels indicate low-grade proinflammatory state and have been linked to negative cardiovascular health outcomes, such as decreased ejection fraction and heart failure.113–116 PAPPA is a metalloproteinase and increased levels are associated with atherosclerotic plaques, acute coronary syndrome and cardiovascular death.117–119 Finally, elevated norepinephrine levels increase arterial pressure and promote atherosclerosis and insulin resistance.120–122 The most interesting non-traditional cardiovascular biomarkers, including notification of the time period in which the biomarker level differs between cases and controls, are presented in the timeline of Figure 2. These biomarkers suggest alterations in different pathways which together might contribute to the increased cardiovascular risk seen in these women postpartum.

Strengths and Limitations

In this review we assessed differences in non-traditional cardiovascular biomarker levels between women with a previous PE/HELLP syndrome and women with a prior uncomplicated pregnancy, taking the timepoint of biomarker measurement into account. Among the included studies were also two meta-analyses. These contain pooled studies with different points in time at follow-up, ranging from weeks to decades. However, it cannot be ruled out that there might be an (optimal) point in time when the biomarker levels between cases and controls do differ from each other. This is where the present review provides new insights: by separately analysing the different studies while taking the timepoint of biomarker analyses into account. It should be noted that apart from biomarkers, there are studies investigating the potential role of imaging techniques (e.g. measuring cIMT, I/M ratio) and vascular functional testing (e.g. pulse wave velocity, augmentation index, flow mediated dilation) to screen these women postpartum.32,35,39,43,44 The predictive value of imaging and functional testing was out-of-scope for this review. The focus was on biomarkers as these are considered to be more favourable because they are easier, faster and cheaper to measure. However, the combination of most potential circulating biomarkers and functional tests could be of significance in the whole process of biomarker validation. This review has some limitations. First, some articles may have been missed by the search strategy because they do not use the keyword ‘biomarker’, or a synonym, but the name of the biomarker itself. However, the reference lists of included studies have been scanned, so it is highly likely that these initially missed articles have nevertheless been included in the review. Overall, studies on cardiovascular biomarkers in women after PE/HELLP syndrome are quite inconsistent. This is probably due to a variety of reasons: heterogeneity of included patients (early, late, severe or mild PE, combined cohort of PE and GH), difference in the definition of PE (in older studies proteinuria was required), dissimilarities in recognition of confounders (e.g. known risk factors such as smoking and obesity) and the subsequent statistical models to adjust for it, and finally the difference in time interval between pregnancy and biomarker assessment. Besides

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CV Risk Biomarkers in Women with Prior Preeclampsia/HELLP Syndrome Figure 2: Promising Biomarkers and Indication of Timepoints

Norepinephrine IL-6/IL-10 ratio sFlt-1

sFlt-1

IL-6 Mid pregnancy

Third trimester

1-year PP

3-years PP

5-years PP

6-years PP

PlGF

8-years PP

10-years PP

20-years PP

PlGF Activin A sHLA-G

hs-cTnI

PAPPA

Biomarker categories and associated markers Angiogenic

Inflammation

• sFlt-1 • PlGF

• IL-6 • IL-6/IL-10 ratio

Cardiac • hs-cTnI

Caption Increased biomarker level in cases compared with controls Decreased biomarker level in cases compared with controls Biomarker is measured at one time and levels are not known for other time periods

Remaining • • • •

Activin A PAPPA sHLA-G Norepinephrine

Time period in which biomarker level is different between cases and controls Time period in which biomarker level is comparable between cases and controls

hs-cTnI = high-sensitivity cardiac troponin I; IL = interleukin; PAPPA = pregnancy-associated plasma protein A; PlGF = placental growth factor; PP = postpartum; sFlt-1 = soluble fms-like tyrosine kinase-1; sHLA-G = soluble human leukocyte antigen G.

there might be some technical variability between studies, i.e. different analysing methods, within- and between-person variation in biomarker levels and the biomarker’s stability during sample storage. The overall conclusion on the potential value of the biomarkers in this review should therefore be interpreted with some caution. Additionally, all studies were performed during or after pregnancy, making it unclear whether differences in biomarker levels were already present prepartum. Studies assessing pre-pregnancy levels do not (yet) exist, but would give information whether PE/HELLP syndrome is at least partly caused by preexisting cardiovascular risk factors, thus potentially due to reverse causality. Furthermore, as we conducted a narrative review, the quality of the included studies has not been systematically been assessed by multiple reviewers and according to strict criteria. Of note, many studies used small sample sizes of dozens of women with a history of PE/HELLP syndrome. Also, studies compared biomarker levels at a certain time postpartum in women with a history of PE and women with a prior uncomplicated pregnancy, without discussion of the clinical relevance and implication of found statistically significant differences. For some biomarkers the (postpartum) reference range is not known, making it questionable if increased values actually are abnormal. Additionally, due

to the retrospective designs of most included studies, they are able to measure association between biomarkers and CVD risk factors, but such designs are not strong enough to draw conclusions on causality. Finally, the review’s conclusion of the biomarkers in the remaining category is based on just a single published study on each particular biomarker.

Perspective

This narrative review summarises current evidence in literature on potential of non-traditional cardiovascular biomarkers in the postpartum period of PE/HELLP syndrome. At this time, sFlt-1, PlGF, IL-6, IL-6/IL-10, hs-cTnI, Activin A, sHLA-G, PAPPA and norepinephrine appear to be potential biomarkers that warrant further investigation in this population of women. Further investigations should focus on the prospective assessment of these biomarkers in women with preeclampsia and investigate whether these markers are able to distinguish women who subsequently develop hypertension and CVD, compared to those who don’t. Biomarker validation might benefit from combination with imaging or functional tests in such prospective studies to establish a link with clinical implication and predictive value for CVD in this particular population.

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Women and Heart Disease

The Role of Mental Stress in Ischaemia with No Obstructive Coronary Artery Disease and Coronary Vasomotor Disorders Roos ET van der Meer1 and Angela HEM Maas

1. Utrecht University, Utrecht, the Netherlands; 2. Department of Cardiology, Radboud University Medical Center, Nijmegen, the Netherlands

Abstract

Ischaemic heart disease has been estimated to affect 126.5 million people globally. Approximately 70% of patients with angina and suspected myocardial ischaemia show no signs of obstructed coronary arteries after coronary angiography, but may still demonstrate ischaemia. Ischaemia with no obstructive coronary artery disease (INOCA) is increasingly acknowledged as a serious condition because of its association with poor quality of life and elevated risk for cardiovascular events. The negative effects of psychological stress on INOCA are gaining more attention. Psychological stress is associated with adverse cardiovascular outcomes such as mental stress-induced myocardial ischaemia. Psychological stress includes anxiety, depression, anger and personality disturbances. Coronary microvascular dysfunction and coronary arterial spasm are phenotypes of coronary vasomotor disorders that are triggered by psychological distress and depression, thereby increasing cardiovascular disease risk. Coronary vasomotor disorders are often co-existent in INOCA patients and might be considered as a contributing factor to mental stress-associated adverse cardiovascular outcomes. Additionally, psychological stress induces endothelial dysfunction more often in (young) women with INOCA than in men. Overall, many studies demonstrate an association between mental stress, coronary microvascular dysfunction and coronary vasospasm in patients with INOCA – especially women. Future research on stress-reducing therapies that target coronary vasomotor disorders in patients with INOCA is needed. This is particularly the case in young adolescents, in whom this type of ischaemic heart disease is increasing.

Keywords

Coronary vasomotor disorders, ischaemia with no obstructive coronary artery disease, mental stress, microvascular angina, psychological disorders, coronary artery spasm Disclosure: AM is a section editor on the European Cardiology Review editorial board; this did not influence peer review. RvdM has no conflicts of interest to declare. Received: 9 June 2021 Accepted: 12 July 2021 Citation: European Cardiology Review 2021;16:e37. DOI: https://doi.org/10.15420/ecr.2021.20 Correspondence: Angela HEM Maas, Radboud University Medical Center, Geert Grooteplein-Zuid 10, Route 616, 6525GA Nijmegen, the Netherlands. E: angela.maas@radboudumc.nl Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Ischaemic heart disease (IHD) has been estimated to affect 126.5 million people globally.1 It is the global leading cause of premature disability and death.2,3 The classical cause of IHD is obstructive coronary artery disease (CAD) in the epicardial coronary arteries. However, other causes of IHD are at least equally important and increasingly recognised, including coronary vasomotor disorders.4–6 Approximately 70% of patients with angina and suspected myocardial ischaemia show no signs of obstructed coronary arteries after coronary angiography but still demonstrate ischaemia.7 Ischaemia with no obstructive coronary artery disease (INOCA) is increasingly acknowledged as a serious condition because of its association with poor quality of life and elevated risk for adverse cardiac events.8,9 There is only partial understanding of the pathophysiology of INOCA. In four in five INOCA patients, microvascular angina and/or vasospastic angina are observed, which are phenotypes of coronary vasomotor disorders.10–12 These can cause myocardial ischaemia by mismatching the supply and demand of myocardial blood flow and nutrients relative to the requirements of the heart.10,11 Coronary microvascular dysfunction (CMD) causes endothelial dysfunction and structural changes leading to a higher microvascular resistance in these smallest branches of the coronary arteries.9,13 Coronary artery spasm

(CAS) is the sudden focal or diffuse narrowing of (epicardial) coronary arteries due to smooth muscle hyperactivity.14 CMD and/or CAS can ultimately result in myocardial ischaemia and acute coronary syndromes.

Risk Factors for Coronary Vasomotor Disorders

The risk factors for coronary vasomotor disorders remain partly unclear. Studies have shown an association between CMD and the traditional cardiovascular risk factors, such as smoking, age, diabetes, hypertension and dyslipidaemia.15,16 Sex differences are important in INOCA. Women are more likely than men to have INOCA with or without coronary vasomotor disorders when presenting with myocardial ischaemia symptoms.17–20 An important risk factor that has been receiving more attention over the past years is psychological stress. Research has demonstrated how psychological factors like chronic stress, anxiety, depression and social stressors can negatively affect cardiovascular health.21–26 Of note is that the association between psychological stress and IHD is bidirectional, as both cause and consequence. Acute mental stress causes an increase in heart rate, contractility and blood pressure. Normally, during mental stress the epicardial arteries and

The Role of Mental Stress in INOCA and Coronary Vasomotor Disorders Table 1: The COVADIS Criteria for Diagnosing Coronary Microvascular Dysfunction

patient.47–49 Invasive testing techniques include diagnostic guidewire and adenosine test and the acetylcholine test for vasoreactivity.50

Criteria

Symptoms

Symptoms suggestive of myocardial ischaemia

Objective evidence of ischaemia

Absence of obstructive CAD (<50% diameter reduction or FFR >0.80)

Impaired CFR and/or evidence of coronary microvascular spasm

The consensus document by Kunadian et al. describes five INOCA endotypes: microvascular angina; vasospastic angina, also named CAS; a combination of microvascular angina and vasospastic angina; non-cardiac chest pain; and non-flow-limiting CAD, which is described as diffuse atherosclerosis with <50% stenosis severity.50 Establishing the exact phenotype is important to be able to advise the most suitable medical treatment.

CAD = coronary artery disease; CFR = coronary flow reserve; COVADIS = Coronary Vasomotor Disorders International Study; FFR = fractional flow reserve. Source: Ong et al. 2018.45 Adapted with permission from Elsevier.

Table 2: The COVADIS Criteria for Diagnosing Coronary Artery Spasm Criteria Symptoms 1

Angina that responds to nitrates

Transient ECG changes suggestive of myocardial ischaemia

Provocation tested or spontaneous coronary artery spasm on angiography

COVADIS = Coronary Vasomotor Disorders International Study. Source: Beltrame et al. 2017.44 Adapted with permission from Oxford University Press.

microvessels will dilate to increase coronary blood flow in order to match the increased demand of oxygen.27–29 In patients with obstructive CAD or INOCA, acute stress results in impaired dilation of the resistance vessels while the epicardial coronary arteries paradoxically constrict. Consequently, the demand cannot be met with increased coronary flow, which can ultimately lead to myocardial ischaemia.27–31 Many articles have been published regarding psychological stress and obstructive CAD, with varying results.29,32–37 However, only a few studies have looked specifically at INOCA patients.38–42 This review will provide an overview of the research on the effect of psychosocial stress in patients with INOCA and/or coronary vasomotor disorders. Furthermore, sex differences in pathophysiology will be described, as the impact of psychological stress is different between women and men.43

Definitions Coronary Vasomotor Disorders

Microvascular angina can result from structural remodelling of the microvasculature and/or vasomotor disorders in the coronary arterioles. The definition and terminology of coronary vasomotor disorders and CMD has been clarified in recent years by the Coronary Vasomotor Disorders International Study group (COVADIS; Table 1).44,45 CAS leads to anginal chest pain – also named vasospastic angina – that cannot be distinguished from angina due to CMD.46 It is often underreported and underdiagnosed and can co-exist with (non-) obstructive CAD and/or CMD.14 Functional abnormalities of endothelial and vascular smooth muscle cells are a substrate of CAS.11 The COVADIS criteria for the clinical syndrome of CAS are presented in Table 2.44

INOCA Endotypes

INOCA is still underdiagnosed and undertreated. An important reason contributing to this is the lack of provocative spasm testing and measurement of microvascular resistance in clinical practice. Nevertheless, invasive testing is proven to be safe and should be used more widely to obtain an appropriate diagnosis for each individual

Types of Psychological Stress

Psychological distress – whether chronic or acute or both – has been linked to IHD risk.51,52 Chronic stress can originate both in early life, with causes that include poor socioeconomic status, parental illness and sexual abuse, but also in adulthood when loneliness and job-strain may play a role.53,54 Early-life traumas in particular seem to affect behavioural and lifestyle factors such as smoking and substance abuse and unhealthy eating habits. Other chronic psychological conditions include posttraumatic stress disorder, anxiety and depression.52 These severe chronic stress conditions impact neurobiological and cognitive functions, which negatively affect physical health. On the contrary, disorders caused by acute stress are mostly a result of a sudden spike of the major stress mediators in combination with a vulnerable background.54 Acute stress can be experienced on the individual level (e.g. anger, fear or bereavement) and/or population-wide level (e.g. natural disasters, terrorist attacks or sporting events).52,54 Studies have shown an increase in mental health issues in young adults over the past decade.55–57 In particular, the rate of anxiety, depression, suicidal ideation and self-injury in young adults is increasing. The emergence of digital media and electronic communication are thought to be contributors to this problem. Digital media seems to have the biggest impact on the younger generation by causing insecurities, anxiety and reductions in sleep duration.57

The Role of Psychological Stress in Patients with INOCA

In past decades, many studies have focused on the effect of types of psychological stress on IHD. Psychological stress can induce MI, as reported in the large INTERHEART study by Rosengren et al.33 In addition, having had a prior MI may also result in increased mental stress, so the association is therefore bidirectional. Acute stress seems to worsen endothelial function, increases arterial stiffness and induces microvascular constriction in patients with established CAD.37

Stress and the Coronary Microvasculature

The response of the coronary microvessels to mental stress is determined by endothelium-dependent coronary microvascular function. Furthermore, the response is reflected in the peripheral microvascular circulation.36 Endothelial dysfunction could be a mechanism for causing mental stressinduced myocardial ischaemia (MSIMI) in CAD patients.36 This arises at a lower workload compared to exercise-induced ischaemia and is associated with an increased risk of MI and cardiovascular death.34,58

Sex Differences

Young women with stable CAD have a higher chance of MSIMI than older women or age-matched men.58,59 Furthermore, young women with a previous MI have a twofold higher chance of developing MSIMI compared to men.60 Men and women appear to have different predictors for MSIMI.

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The Role of Mental Stress in INOCA and Coronary Vasomotor Disorders CAD severity and the rate-pressure product response to psychological stress are strong predictors for MSIMI in men, whereas among women peripheral vasoconstriction and CMD have been shown to be associated with MSIMI.60,61 Women were more likely to have a lower income, be ethnic minorities and have a history of sexual and emotional abuse.58,59 Psychological risk factors are considered a higher burden for women than men, especially in women with INOCA.39,58 Some studies suggest an association between a history of anxiety and INOCA, while others did not find a link between depression or general anxiety and INOCA. These associations remain to be further elucidated.39,62–64 CMD is often present in women with INOCA and endothelial dysfunction appears more frequently in young women as a response to psychological stress than in similar aged men.65–67 In the WISE (551 women) and the WISE-CVD (350 women) cohorts, the effects of home and work stress were investigated with additional measurement of financial stress in the second cohort. Both studies used comparable methods and showed significant associations between cardiac symptoms, CAD risk and psychological distress. One important difference between the cohorts was home/work stress being the stronger predictor for cardiovascular disease in WISE, and financial stress being the stronger predictor for cardiovascular disease in WISE-CVD.40 The WISE cohort also determined that CMD predicted MI, heart failure hospitalisation, stroke and death in these women.68 Moreover, patients with CMD had elevated mental stressinduced peripheral vasoreactivity.14

Stress and Microvascular Dysfunction in Takotsubo Syndrome

Women in particular are more vulnerable to MSIMI and a takotsubo syndrome when a significant physical or emotional stressor occurs.69,70 Multiple studies have shown the involvement of CMD in the pathogenesis of takotsubo syndrome.71–73 It is mostly observed in post-menopausal women without epicardial CAD.71 Women with a history of takotsubo syndrome show excessive vasoconstriction and impaired peripheral vasodilation after being exposed to acute mental stress.70,71 Studies suggest that an acute dysfunction of the coronary microvasculature might serve as a cause for takotsubo syndrome.70,71,73

Potential Effects of Stress in Coronary Artery Spasm

The exact role of psychological factors in CAS remains unclear, as there few studies in patients with only CAS. Psychosocial stress might play a role in inducing smooth muscle cells in the vasculature to become hyperactive as a result of autonomic nervous system dysfunction, which can lead to oxidative stress, inflammation and endothelial dysfunction.14 The neuroendocrine and autonomic nervous system appears to mediate these effects because certain brain areas contribute to autonomic outflow, emotional regulation and vascular reactivity.74 Imaging of the coronary arteries in patients with vasospastic angina showed a localised inflammation in the perivascular adipose tissue and coronary adventitia.75 Both epicardial coronary spasm and microvascular spasm seem to be mediated by rho-kinase.76 Potential triggers of these spasms include hyperventilation, autonomic imbalance and platelet activation.75 Because autonomic dysfunction and inflammation also play a role in the connection between psychological stress and IHD, it was hypothesised by Hung et al. that anxiety and depression may influence CAS.77 They studied the prevalence of history of anxiety and depression in 10,473 CAS patients, 10,473 CAD patients and 10,325 healthy individuals. They found a higher prevalence of anxiety and depression in patients with established CAS

compared to patients with obstructed CAD (anxiety: OR 2.29; 95% CI [2.14–2.45], depression: OR 1.34; 95% CI [1.08–1.66]) and controls (anxiety: OR 5.20; 95% CI [4.72–5.74], depression: OR 1.98; 95% CI [1.50–2.62]). Most patients with CAS were younger women. However – even though this was a large study – no sex differences were found between the association of CAS with anxiety and depression.77 These observations show a possible involvement of CAS in the aetiology of INOCA through anxiety and depression.

Stress-reducing Therapies

Coronary endothelial dysfunction in patients with INOCA can serve as a therapeutic target for medical therapy (statins, angiotensin-converting enzyme inhibitors) and lifestyle interventions. Stress-reducing medication such as anti-depressants might reduce cardiac risk, but most studies to date have been underpowered to prove this.78 Stress-reducing therapies such as mindfulness-based interventions and meditation training might reduce types of psychological stress like anxiety while also decreasing blood pressure, non-fatal MI and cardiovascular mortality.78 Overall, stress reducing interventions seem to have a promising positive impact on psychological and cardiovascular health.

Stress and Inflammation in Women

An enhanced inflammatory state due to psychological distress increases inflammatory markers and subsequently the progression of CAD.79–84 The coronary microvascular response in INOCA patients seems to be modulated by the level of inflammation, even without the presence of conventional risk factors.85 Basal levels of interleukin (IL)-6 are higher in young women with CAD compared to age-matched men, and thus could have enhanced immune reactivity to stress.86 Levels of IL-6 increase in women with CAD after exposure to psychological stress. Furthermore, IL-6 levels are much higher in young women. Oestrogens and glucocorticoid sensitivity might play a role. Cytokine production may be enhanced by oestrogens, resulting in increased secretion of proinflammatory cytokines.87 This would also explain why IL-6 levels in postmenopausal women may be lower. However, the exact role of oestrogens in inflammation is still largely unknown. Rohleder et al. showed an increase in glucocorticoid sensitivity after 1 hour of mental stress testing in men but a decrease in sensitivity in women. Glucocorticoid sensitivity is important for inhibiting pro-inflammatory cytokine production. This means that in women, a decreased glucocorticoid sensitivity might enhance proinflammatory cytokine levels after acute psychological stress.88 Stress-related mental disorders like depression and post-traumatic stress disorder are more frequent in women than in men. The link between stress related disorders and IHD is closely related to behavioural and lifestyle factors such as smoking, substance abuse and poor diet. However, these do not entirely explain the connection between stress and IHD. Increased inflammation, hypercoagulability, endothelial dysfunction and genetic factors also play a role.89–91 For example, the association of depression and IHD is more often attributed to genetic factors in women than in men, where the heritability of depression is approximately 42% in women and 29% in men.92,93 Reproductive function might serve as another mechanism through which stress increases IHD risk in women. Stress is closely related to ovarian disruption, which is present in almost 20% of women during their reproductive years.94 Ovarian disruption increases the risk for IHD and thus women who are exposed to a lot of stress are thought to have increased IHD risk, in some ways, due to ovarian dysfunction.95 Because younger women are more susceptible to the adverse effects of

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The Role of Mental Stress in INOCA and Coronary Vasomotor Disorders Figure 1: Associated Cardiovascular Risk as a Result of Acute and Chronic Stress Chronic stress

Acute stress Individual: anger, fear, bereavement

Early life: socioeconomic status, parental disease, abuse

Population-wide: natural disasters, terrorist attacks, sporting events

Adulthood: loneliness, job strain Modern: social media, electronic communication

Healthy

CVD risk

Dilation Inflammation Resistance

CAD

MSIMI risk

Dilation

MSIMI risk Inflammation

Resistance

INOCA

MVA

Dilation

VSA

MSIMI + takotsubo Inflammation

Resistance

CAD = coronary artery disease; CVD = cardiovascular disease; INOCA = ischaemia with no obstructive coronary artery disease; MSIMI = mental-stress-induced myocardial ischaemia; MVA = microvascular angina; VSA = vasospastic angina.

psychosocial factors and MSIMI is more common in this group, the functional status of the ovaries might serve as a mechanism to the IHD risk in younger women.59

Conclusion

Acute and/or chronic psychological stress can lead to increased risk of cardiovascular diseases. CMD seems to be linked to psychological stress 1. Virani SS, Alonso A, Benjamin EJ, et al. Heart disease and stroke statistics—2020 update: a report from the American Heart Association. Circulation 2020;141:e139–596. https://doi. org/CIR.0000000000000757; PMID: 31992061. 2. GBD 2017 Disease and Injury Incidence and Prevalence Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Disease study 2017. Lancet 2018;392:1789–858. https://doi.org/10.1016/ S0140-6736(18)32279-7; PMID: 30496104. 3. GBD 2017 Causes of Death Collaborators. Global, regional, and national age-sex-specific mortality for 282 causes of death in 195 countries and territories, 1980–2017: a systematic analysis for the Global Burden of Disease study 2017. Lancet 2018;392:1736–88. https://doi.org/10.1016/ S0140-6736(18)32203-7; PMID: 30496103. 4. Bairey Merz CN, Pepine CJ, Walsh MN, Fleg JL. Ischemia and No Obstructive Coronary Artery Disease (INOCA): developing evidence-based therapies and research agenda for the next decade. Circulation 2017;135:1075–92. https:// doi.org/10.1161/CIRCULATIONAHA.116.024534; PMID: 28289007. 5. Kaski JC, Crea F, Gersh BJ, Camici PG. Reappraisal of

9. 10.

and depression, thereby increasing cardiovascular disease risk. CMD is prevalent in INOCA patients and might be considered as a contributing factor to mental-stress-associated adverse cardiovascular outcomes (Figure 1). It is important that future research regarding psychological stress and INOCA uses the consensus criteria of INOCA with standardised stress testing protocols and questionnaires. This offers the opportunity to compare studies, which could shed more light on this growing patient population.

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disease: insights gained from epidemiological, clinical and experimental studies. Brain Behav Immun 2015;50:18–30. https://doi.org/10.1016/j.bbi.2015.08.007; PMID: 26256574. 53. Miller GE, Chen E, Parker KJ. Psychological stress in childhood and susceptibility to the chronic diseases of aging: moving toward a model of behavioral and biological mechanisms. Psychol Bull 2011;137:959–97. https://doi. org/10.1037/a0024768; PMID: 21787044. 54. Steptoe A, Kivimäki M. Stress and cardiovascular disease. Nat Rev Cardiol 2012;9:360–70. https://doi.org/10.1038/ nrcardio.2012.45; PMID: 22473079. 55. Mucci N, Giorgi G, Ceratti SDP, et al. Anxiety, stress-related factors, and blood pressure in young adults. Front Psychol 2016;7:1682. https://doi.org/10.3389/fpsyg.2016.01682; PMID: 27840615. 56. Duffy ME, Twenge JM, Joiner TE. Trends in mood and anxiety symptoms and suicide-related outcomes among U.S. undergraduates, 2007–2018: evidence from two national surveys. J Adolesc Health 2019;65:590–8. https://doi. org/10.1016/j.jadohealth.2019.04.033; PMID: 31279724. 57. Twenge JM, Cooper AB, Joiner TE, et al. Age, period, and cohort trends in mood disorder indicators and suiciderelated outcomes in a nationally representative dataset, 2005–2017. J Abnorm Psychol 2019;128:185–99. https://doi. org/10.1037/abn0000410; PMID: 30869927. 58. Vaccarino V, Wilmot K, Mheid I Al, et al. Sex differences in mental stress-induced myocardial ischemia in patients with coronary heart disease. J Am Heart Assoc 2016;5:1–11. https:// doi.org/10.1161/JAHA.116.003630; PMID: 27559072. 59. Vaccarino V, Shah AJ, Rooks C, et al. Sex differences in mental stress-induced myocardial ischemia in young survivors of an acute myocardial infarction. Psychosom Med 2014;76:171–80. https://doi.org/10.1097/ PSY.0000000000000045; PMID: 24608039. 60. Vaccarino V, Sullivan S, Hammadah M, et al. Mental stressinduced-myocardial ischemia in young patients with recent myocardial infarction: sex differences and mechanisms. Circulation 2018;137:794–805. https://doi.org/10.1161/ CIRCULATIONAHA.117.030849; PMID: 29459465. 61. Almuwaqqat Z, Sullivan S, Hammadah M, et al. Sex-specific association between coronary artery disease severity and myocardial ischemia induced by mental stress. Psychosom Med 2019;81:57–66. https://doi.org/10.1097/ PSY.0000000000000636; PMID: 30571661. 62. Rutledge T, Reis SE, Olson M, et al. History of anxiety disorders is associated with a decreased likelihood of angiographic coronary artery disease in women with chest pain: the WISE study. J Am Coll Cardiol 2001;37:780–5. https://doi.org/10.1016/S0735-1097(00)01163-3; PMID: 11693752. 63. Rutledge T, Kenkre TS, Bittner V, et al. Anxiety associations with cardiac symptoms, angiographic disease severity, and healthcare utilization: the NHLBI-sponsored Women’s Ischemia Syndrome Evaluation. Int J Cardiol 2013;168:2335– 40. https://doi.org/10.1016/j.ijcard.2013.01.036; PMID: 23410495. 64. Rutledge T, Linke SE, Krantz DS, et al. Comorbid depression and anxiety symptoms as predictors of cardiovascular events: results from the NHLBI-sponsored Women’s Ischemia Syndrome Evaluation (WISE) study. Psychosom Med 2009;71:958–64. https://doi.org/10.1097/ PSY.0b013e3181bd6062; PMID: 19834049. 65. Reis SE, Holubkov R, Smith AJC, et al. Coronary microvascular dysfunction is highly prevalent in women with chest pain in the absence of coronary artery disease: results from the NHLBI WISE study. Am Heart J 2001;141:735–41. https://doi.org/10.1067/mhj.2001.114198; PMID: 11320360. 66. Buchthal SD, den Hollander JA, Bairey Merz CN, et al. Abnormal myocardial phosphorus-31 nuclear magnetic resonance spectroscopy in women with chest pain but normal coronary angiograms. N Engl J Med 2000;342:829– 35. https://doi.org/10.1056/nejm200003233421201; PMID: 10727587. 67. Martin EA, Tan SL, MacBride LR, et al. Sex differences in vascular and endothelial responses to acute mental stress. Clin Auton Res 2008;18:339–45. https://doi.org/10.1007/ s10286-008-0497-5; PMID: 18850310. 68. AlBadri A, Bairey Merz CN, Johnson BD, et al. Impact of abnormal coronary reactivity on long-term clinical outcomes in women. J Am Coll Cardiol 2019;73:684–93. https://doi. org/10.1016/j.jacc.2018.11.040; PMID: 30765035. 69. Prasad A, Lerman A, Rihal CS. Apical ballooning syndrome (Tako-Tsubo or stress cardiomyopathy): a mimic of acute myocardial infarction. Am Heart J 2008;155:408–17. https:// doi.org/10.1016/j.ahj.2007.11.008; PMID: 18294473. 70. Templin C, Ghadri JR, Diekmann J, et al. Clinical features and outcomes of takotsubo (stress) cardiomyopathy. N Engl J Med 2015;373:929–38. https://doi.org/10.1056/ nejmoa1406761; PMID: 26332547. 71. Patel SM, Lerman A, Lennon RJ, Prasad A. Impaired

The Role of Mental Stress in INOCA and Coronary Vasomotor Disorders coronary microvascular reactivity in women with apical ballooning syndrome (Takotsubo/stress cardiomyopathy). Eur Hear J Acute Cardiovasc Care 2013;2:147–52. https://doi. org/10.1177/2048872613475891; PMID: 24222824. 72. Collste O, Tornvall P, Alam M, Frick M. Coronary flow reserve during dobutamine stress in Takotsubo stress cardiomyopathy. BMJ Open 2015;5:8–14. https://doi. org/10.1136/bmjopen-2015-007671; PMID: 26185178. 73. Kume T, Akasaka T, Kawamoto T, et al. Assessment of coronary microcirculation in patients with takotsubo-like left ventricular dysfunction. Circ J 2005;69:934–9. https://doi. org/10.1253/circj.69.934; PMID: 16041162. 74. Shah A, Chen C, Campanella C, et al. Brain correlates of stress-induced peripheral vasoconstriction in patients with cardiovascular disease. Psychophysiology 2019;56:1–14. https://doi.org/10.1111/psyp.13291; PMID: 30276815. 75. Ohyama K, Matsumoto Y, Takanami K, et al. Coronary adventitial and perivascular adipose tissue inflammation in patients with vasospastic angina. J Am Coll Cardiol 2018;71:414–25. https://doi.org/10.1016/j.jacc.2017.11.046; PMID: 29389358. 76. Suda A, Takahashi J, Hao K, et al. Coronary functional abnormalities in patients with angina and nonobstructive coronary artery disease. J Am Coll Cardiol 2019;74:2350–60. https://doi.org/10.1016/j.jacc.2019.08.1056; PMID: 31699275. 77. Hung MY, Mao CT, Hung MJ, et al. Coronary artery spasm as related to anxiety and depression: a nationwide populationbased study. Psychosom Med 2019;81:237–45. https://doi. org/10.1097/PSY.0000000000000666; PMID: 30652987. 78. Levine GN, Cohen BE, Commodore-Mensah Y, et al. Psychological health, well-being, and the mind-heart-body connection: a scientific statement from the american heart association. Circulation 2021;143:e763–83. https://doi. org/10.1161/CIR.0000000000000947; PMID: 33486973. 79. Endrighi R, Hamer M, Steptoe A. Post-menopausal women exhibit greater interleukin-6 responses to mental stress than older men. Ann Behav Med 2016;50:564–71. https://doi. org/10.1007/s12160-016-9783-y; PMID: 26943141. 80. Hackett RA, Hamer M, Endrighi R, et al. Loneliness and

stress-related inflammatory and neuroendocrine responses in older men and women. Psychoneuroendocrinology 2012;37:1801–9. https://doi.org/10.1016/j.psyneuen.2012. 03.016; PMID: 22503139. 81. Miller GE, Cohen S, Ritchey AK. Chronic psychological stress and the regulation of pro-inflammatory cytokines: a glucocorticoid-resistance model. Health Psychol 2002;21:531–41. https://doi.org/10.1037/0278-6133.21.6.531; PMID: 12433005. 82. Maes M, Song C, Lin A, et al. The effects of psychological stress on humans: increased production of pro-inflammatory cytokines and a Th1-like response in stress-induced anxiety. Cytokine 1998;10:313–8. https://doi.org/10.1006/ cyto.1997.0290; PMID: 9617578. 83. Kop WJ, Gottdiener JS, Tangen CM, et al. Inflammation and coagulation factors in persons >65 years of age with symptoms of depression but without evidence of myocardial ischemia. Am J Cardiol 2002;89:419–24. https://doi. org/10.1016/S0002-9149(01)02264-0; PMID: 11835923. 84. Lu XT, Zhao YX, Zhang Y, Jiang F. Psychological stress, vascular inflammation, and atherogenesis: potential roles of circulating cytokines. J Cardiovasc Pharmacol 2013;62:6–12. https://doi.org/10.1097/FJC.0b013e3182858fac; PMID: 23318990. 85. Recio-Mayoral A, Rimoldi OE, Camici PG, Kaski JC. Inflammation and microvascular dysfunction in cardiac syndrome X patients without conventional risk factors for coronary artery disease. JACC Cardiovasc Imaging 2013;6:660–7. https://doi.org/10.1016/j.jcmg.2012.12.011; PMID: 23643286. 86. Sullivan S, Hammadah M, Wilmot K, et al. Young women with coronary artery disease exhibit higher concentrations of interleukin-6 at baseline and in response to mental stress. J Am Heart Assoc 2018;7:e010329. https://doi. org/10.1161/JAHA.118.010329; PMID: 30571600. 87. Da Silva JAP. Sex hormones and glucocorticoids: interactions with the immune system. Ann N Y Acad Sci 1999;876:102–18. https://doi.org/10.1111/j.1749-6632.1999. tb07628.x; PMID: 10415599.

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88. Rohleder N, Schommer NC, Hellhammer DH, et al. Sex differences in glucocorticoid sensitivity of proinflammatory cytokine production after psychosocial stress. Psychosom Med 2001;63:966–72. https://doi.org/10.1097/00006842200111000-00016; PMID: 11719636. 89. Sullivan S, Hammadah M, Al Mheid I, et al. Sex differences in hemodynamic and microvascular mechanisms of myocardial ischemia induced by mental stress. Arterioscler Thromb Vasc Biol 2018;38:473–80. https://doi.org/10.1161/ ATVBAHA.117.309535; PMID: 29269515. 90. Sullivan S, Young A, Hammadah M, et al. Sex differences in the inflammatory response to stress and risk of adverse cardiovascular outcomes among patients with coronary heart disease. Brain Behav Immun 2020;90:294–302. https:// doi.org/10.1016/j.bbi.2020.09.001; PMID: 32916271. 91. Samad Z, Boyle S, Ersboll M, et al. Sex differences in platelet reactivity and cardiovascular and psychological response to mental stress in patients with stable ischemic heart disease: insights from the REMIT study. J Am Coll Cardiol 2014;64:1669–78. https://doi.org/10.1016/j. jacc.2014.04.087; PMID: 25323254. 92. Kendler KS, Gardner CO, Neale MC, Prescott CA. Genetic risk factors for major depression in men and women: similar or different heritabilities and same or partly distinct genes? Psychol Med 2001;31:605–16. https://doi.org/10.1017/ S0033291701003907; PMID: 11352363. 93. Kendler KS, Gatz M, Gardner CO, Pedersen NL. A Swedish national twin study of lifetime major depression. Am J Psychiatry 2006;163:109–14. https://doi.org/10.1176/appi. ajp.163.1.109; PMID: 16390897. 94. Berga SL. Stress and reprodution: a tale of false dichotomy? Endocrinology 2008;149:867–8. https://doi.org/10.1210/ en.2008-0004; PMID: 18292197. 95. Kaplan JR, Manuck SB. Ovarian dysfunction and the premenopausal origins of coronary heart disease. Menopause 2008;15:768–76. https://doi.org/10.1097/ gme.0b013e31815eb18e; PMID: 18709705.

Women and Heart Disease

Hypertension in Women: Should There be a Sex-specific Threshold? Eva Gerdts

and Giovanni de Simone

1. Department of Clinical Science, Center for Research on Cardiac Disease in Women, University of Bergen, Bergen, Norway; 2. Department of Advanced Biomedical Sciences and Hypertension Center, Federico II University, Naples, Italy

Abstract

Conventionally, hypertension is defined by the same blood pressure (BP) threshold (systolic BP ≥140 and/or diastolic BP ≥90 mmHg) in both women and men. Several studies have documented that women with hypertension are more prone to develop BP-associated organ damage and that high BP is a stronger risk factor for cardiovascular disease (CVD) in women than men. While healthy young women have lower BP than men, a steeper increase in BP is found in women from the third decade of life. Studies have documented that the BP-attributable risk for acute coronary syndromes (ACS), heart failure and AF increases at a lower level of BP in women than in men. Even high normal BP (130–139/80–89 mmHg) is associated with an up to twofold higher risk of ACS during midlife in women, but not in men. Whether sex-specific thresholds for definition of hypertension would improve CVD risk detection should be considered in future guidelines for hypertension management and CVD prevention.

Keywords

Hypertension, sex, women, men, blood pressure trajectories, hypertensive heart disease, cardiovascular disease Disclosure: EG is on the European Cardiology Review editorial board; this did not influence peer review. GdS has no conflicts of interest to declare. Received: 2 May 2021 Accepted: 18 July 2021 Citation: European Cardiology Review 2021;16:e38. DOI: https://doi.org/10.15420/ecr.2021.17 Correspondence: Eva Gerdts, Center for Research on Cardiac Disease in Women, Department of Clinical Science, University of Bergen, PO Box 7804, 5020 Bergen, Norway. E: eva.gerdts@med.uib.no Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Sex Differences in Hypertension Over the Course of Life

The WHO has estimated that one in four men and one in five women worldwide have hypertension, identified as a systolic blood pressure (BP) ≥140 mmHg and/or a diastolic BP ≥90 mmHg in both sexes. Using this definition, the NHANES performed in the US in 2015–16, found a higher prevalence of hypertension in men than women among adults aged 19– 39 years (9.2% versus 5.6%) and 40–59 years (37.2% versus 29.4%), whereas hypertension was more common in women among adults aged 60 years and over (66.8% versus 58.5%; Figure 1).1 The observed age-related sex difference in hypertension prevalence has traditionally been related to hormonal changes during menopause in women, and associated loss of beneficial vascular health effects, reduced sodium excretion and weight gain.2,3 This traditional interpretation was challenged by results from a sex-specific analysis of BP trajectories over the adult life course based on four longitudinal community-based cohorts from the US.4 In this analysis, Ji et al. demonstrated that women have a steeper increase in BP that started in the third decade of life and continued throughout the life course.4 This sex difference was evident for systolic, diastolic and mean BP and for pulse pressure.4 These findings probably reflect differences in vascular biology between women and men. Anatomic and physiologic sex differences in the cardiovascular (CV) system are well described. Furthermore, socioeconomic, sociocultural and environmental factors, and sex differences in BP regulators including the sympathetic nervous system, the renin–angiotensin–aldosterone system, bradykinin, nitric oxide and brain natriuretic peptides are documented.3,5 Vascular inflammation, oxidative stress and organ damage

may influence development of high BP in a sex-specific manner.2,6,7 Taken together, vascular compliance is physiologically lower in women, while arterial elasticity is higher during the reproductive age, reflecting vascular effects of progesterone and oestrogen.8,9 Weight gain and obesity are particularly relevant to the steeper increase in BP during the third decade of life in women because these factors influence CV organ function in a sex-specific manner.6,9 Furthermore, pre-eclampsia in pregnancy is associated with endothelial dysfunction and vascular inflammation, which is likely to persist beyond delivery.

Sex differences in Hypertension-associated Cardiovascular Organ Damage

Chronic hypertension causes structural and functional changes in the heart and arteries.10 Several studies have reported that hypertension-mediated organ damage in the heart and arteries is more prevalent in women than men, including left ventricular hypertrophy (LVH), left atrial (LA) dilatation and high arterial stiffness.11–15 Current guidelines recommend use of sexspecific partition values for optimal detection of hypertension-mediated organ damage, reflecting asymptomatic cardiovascular disease (CVD).10 LVH is the hallmark of hypertensive heart disease and a powerful prognostic marker in hypertension. In older patients in the LIFE echocardiography substudy, LVH was more prevalent in women both at study baseline (80% versus 70%) and after 4.8 years of systematic antihypertensive treatment (50% versus 34%).14 Of note, findings were similar in both obese and non-obese women, and persistent LVH was particularly associated with higher arterial stiffness. In middle-aged American Indians with hypertension participating in the Strong Heart

Hypertension in Women Figure 1: Sex-specific Prevalence of Hypertension

Prevalence of hypertension (%)

80 70 60 50 40 30 20 10 0

19–39 years

40–59 years Men

60 years and over

Women

Sex-specific prevalence of hypertension in young, middle-aged and old subjects using blood pressure ≥140/90 mmHg as partition value in both sexes. Source: Fryar et al. 2017.1

Figure 2: Sex differences in the Association Between Elevated Blood Pressure and Acute Coronary Syndromes HR for acute coronary syndrome

3 2.5

2.18*

1.30 1.01

1.24

1.01

0.5 0

BP 130–139/80–89 mmHg**

Systolic BP 130–139 mmHg

Women

Arterial stiffness may be assessed by several prognostically validated methods including brachial or central pulse pressure, pulse pressure:stroke index ratio, augmentation index and carotid–femoral pulse wave velocity (cf-PWV).10 While pulse pressure, pulse pressure:stroke index ratio and augmentation index are all normally higher in women than men of a similar age, cf-PWV is higher in men.19,20 Increased arterial stiffness may antecede the onset of hypertension, in particular systolic hypertension, but is also a common type of organ damage in chronic hypertension, reflecting that age and BP are both important confounders. In the Framingham Heart Study, increased arterial stiffness assessed by cf-PWV was common, even in treated hypertension, and was found in 63% of controlled and 90% of uncontrolled subjects.19 CV risk increases in parallel with increasing cf-PWV or pulse pressure:stroke index ratio, independent of presence of hypertension.19,20

Sex Differences in the Association Between Mildly Elevated Blood Pressure with Cardiovascular Disease

2.79*

2 1.5

older women and 38% of older men had LA dilatation, and antihypertensive treatment did not reduce LA size much in these subjects over a median of 4.8 years of follow-up.11 Furthermore, in middle-aged obese subjects without known CVD, participating in the FAT-associated Cardiovascular Dysfunction Study, LA dilatation was found in 77% of women and 62% of men, and was particularly associated with higher arterial stiffness.12

Diastolic BP 80–89 mmHg**

Men

Sex differences in the association of mildly elevated blood pressure (130–139/80–89 mmHg) with incident acute coronary syndromes during midlife. *p<0.01; **p<0.01 for sex interaction. Models adjusted for diabetes, smoking, serum total cholesterol, BMI and physical activity. BP = blood pressure. Source: Millett et al. 2018.26

Study, LVH was found in 36% of women and 23% of men.15 During the 4-year follow-up, a net increase in LVH prevalence was found despite antihypertensive treatment and good BP control. This lack of LVH reduction was attributed to persistent obesity and progressive reduction in renal function.15 Finally, among 12,329 middle-aged southern Italian subjects with treated hypertension, participating in the Campania Salute Network project, LVH was more prevalent in women than men (43% versus 32%).13 During follow-up of this Italian cohort, new-onset LVH was detected in 21% of participants, more commonly in women and in obese patients.16 Further analysis demonstrated that among subjects without LVH, women had a 35% lower risk than men of major CV events (hospitalisation for acute coronary syndromes [ACS], heart failure [HF] or AF or CV death) during a median of 4 years follow-up. However, when LVH was present, this sex difference disappeared and women and men had similar risk.13 A dilated LA is considered an early sign of hypertensive heart disease and has been associated with increased risk for AF, HF and ACS, irrespective of presence of LVH in hypertension.17 Although the LA is normally larger in men than women, several studies have documented that LA dilatation is more common in women in hypertension.11,18 In the LIFE study, 56% of

The 2019 Global Burden of Disease study report confirmed that elevated systolic BP was the most important risk factor for CV death in women worldwide and the second most important risk factor in men, after smoking.21 Elevated systolic BP was also the most important risk factor for disabilityadjusted life years both in women and men above the age of 50 years. Emerging evidence suggests that elevated BP is particularly important for ACS risk in young and middle-aged women. While the overall incidence rates and mortality from ACS have decreased in western societies over the past decades, an increase in hospitalisation for ACS has been observed in young and middle-aged women in several countries.22,23 Although healthy young and middle-aged women have lower BP than men, women with ACS are more likely to have hypertension than men.22 In a meta-analysis including 61 prospective studies of BP and mortality, a slightly stronger association between systolic BP and ischaemic heart disease mortality was found in women, particularly in the age group 40– 50 years.24 At that time, the observation was not considered important. However, further publications have repeatedly documented a stronger association between BP and ACS in women than men. In the Norwegian Tromsø Study including 33,859 subjects aged 35–94 years, the associations between systolic and diastolic BP and MI were both stronger for women.25 In the UK Biobank study including 471,998 subjects free from CVD, with a mean age of 56 years, both BP 130–139/80–89 mmHg and BP ≥140/90 mmHg were associated with a 40% higher risk for MI in women compared with men during 8-year follow-up.26 Furthermore, in the Norwegian Hordaland Health Study, among 12,329 subjects initially aged 41 years followed for a median of 16 years, BP 130–139/80–89 mmHg was associated with a twofold higher risk for ACS during midlife in women, while no significant association was found in men (Figure 2).27 These studies all documented significant sex interaction tests. In a meta-analysis of 16 population-based trials including 3,212,447 participants, mostly of Asian ethnicity, Han et al. found a stronger association between BP 130–139/80–89 mmHg and CVD in women than

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Hypertension in Women in men.28 In contrast, a pooled analysis of three prospective Chinese cohorts including 154,407 subjects aged 40–80 years found a comparable risk for CV death in women and men with BP 130–139/80–89 mmHg or hypertension, respectively.29 Hypertension is documented as the most important risk factor for HF in women, while previous MI is the most important risk factor for HF in men.6 While the lifetime risk of HF is similar in women and men, HF affects more women than men in absolute numbers.2 The Framingham Heart Study found HF with preserved ejection fraction (ejection fraction ≥50%) to be twice as common in women as in men.30 In a sex-specific pooled analysis of four community-based cohorts in the US, including 27,542 participants followed over a mean of 28 years, the risk for HF in women with systolic BP 110–119 mmHg was comparable to HF risk in men with systolic BP 120–129 mmHg. The association was more pronounced for women younger than 52 years, but the analysis did not differentiate between HF subtypes.31 In the same study, systolic BP was also a stronger risk factor for MI and stroke in women compared with men. Women with systolic BP 110–119 mmHg or 120–129 mmHg had comparable risk of MI and stroke to men with systolic BP 150–159 mmHg.31

Figure 3: Sex Differences in Blood Pressure Development, Cardiac Organ Damage and Cardiovascular Disease Compared with men, women: • have lower BP in midlife and higher BP in older age • experience a steeper increase in BP from the third decade of life

Compared with men, women: • are more prone to developing cardiac organ damage • experience less regression of organ damage during BP treatment

Compared with men, women: • high–normal BP predicts increased risk for ACS in midlife • ACS, HF and AF risks begin at lower thresholds of BP

Key sex differences in blood pressure development over the life course and associated cardiac organ damage and cardiovascular disease. ACS = acute coronary syndromes; BP = blood pressure; HF = heart failure.

Figure 4: Improving Management of Hypertension and Cardiovascular Disease Prevention in Women

Although women have lower age-adjusted incidence and prevalence of AF, the absolute number of women and men with AF is similar, probably reflecting the greater longevity of women.32 Among AF risk factors, hypertension, obesity and valvular heart disease are more prevalent in women, whereas coronary artery disease is more prevalent in men.33 A stronger association between systolic BP and risk for AF was reported in the Norwegian Tromsø Study.34 Among 16,046 40-year-old women and men followed for a median of 12.9 years, a persistently elevated systolic BP ≥140 mmHg during follow-up was associated with a twofold higher risk of AF in women, compared with a 50% increased risk in men. In further analysis expanding follow-up time to 17.6 years, increased systolic BP was associated with higher risk for both paroxysmal/persistent and permanent AF in women, but only for paroxysmal/persistent AF in men.35 Of note, increased AF risk was evident starting from systolic BP range 130– 139 mmHg.

Should Sex-specific Thresholds for Hypertension be Introduced?

As presented above, publications exploring the sex-specific association of BP with risk for ACS, AF and HF have documented that CVD risk increases at a lower BP level in women than in men (Figure 3).25–28,31,34,35 The analyses have all been performed in community-based cohorts, and detailed data on antihypertensive drug use are limited. Furthermore, the findings reported in a research letter by Ji et al. need to be replicated in other data sets.31 However, the results are consistent and particularly strong for ACS, for which similar results have been documented from several cohorts.26,27,31,36 The more striking results in younger and middle-aged women suggest a potential for improved prevention of CVD, the most common cause of death and reduced disability-adjusted life years in women.21 The finding that CVD risk increases at a lower BP level in women may also offer an alternative explanation for the higher prevalence of hypertension-mediated organ damage in women than in men, which has traditionally been attributed to older age and sex differences in obesity and inflammatory disorders. Few clinical studies in hypertension have reported results stratified by sex. In the DASH trial a pronounced antihypertensive effect of dietary sodium restriction was demonstrated in women.37 In the LIFE study, treatment effect was consistent in women and men, but more women in

Knowledge gaps: • Sex-specific hypertension thresholds • Mechanisms for uncontrolled BP in older women • Mechanisms for development and persistence of hypertensionmedicated organ damage • Sex-specific BP targets for treatment Next steps: • Sex-specific reanalysis of data from clinical studies • Further exploration of sex-specific BP development over the life course • Test the effect of treating high–normal BP and lower treatment targets on hypertension-mediated organ damage and CVD • Sex-specific recommendations in guidelines for hypertension and CVD prevention

Knowledge gaps and next steps to improve management of hypertension and CVD prevention in women. BP = blood pressure; CVD = cardiovascular disease.

the losartan group were hospitalised for angina.38 The benefit of angiotensin-converting enzyme inhibitor treatment in reducing incident MI in the Second Australian National Blood Pressure Study Group was restricted to men only.39 Finally, similar benefits were demonstrated for women and men in the NORDIL study and the TOMHS.40,41 Taken together, results from sex-stratified and sex-specific analyses in clinical trials are limited, and reanalysis of data from older trials can be useful to rapidly increase knowledge and, at least in part, fill the knowledge gaps about optimal treatment of hypertension in women to prevent CVD. Clinical studies testing the benefit of initiating antihypertensive drug treatment in women with BP 130–139/80–89 mmHg for reduction of CVD are lacking. In a systematic review and meta-analysis of 74 clinical trials, including 306,273 participants (39.9% women, mean age 64 years), Brunström et al. found null treatment effect of BP-lowering treatment in subjects with initial systolic BP <140 mmHg regarding all-cause mortality or CV morbidity or mortality in primary preventive trials.42 In contrast, in patients with known CHD, a reduction in incident stroke and HF was documented in patients with baseline systolic BP <140 mmHg. Unfortunately, no sex-specific results were presented in their publication.42 SPRINT, performed in 9,361 subjects with hypertension over the age of 50 years (36% women), documented that tighter BP control (systolic BP <120 mmHg) compared with standard BP control (systolic BP <140 mmHg) reduced major CV events (first occurrence of non-fatal MI, other ACS,

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Hypertension in Women stroke, HF hospitalisation, or CV death), but failed to demonstrate a statistically significant benefit for women, probably as a result of the lower proportion of included women.43 Still, SPRINT changed the US definition and management of hypertension for both sexes.

damage is not known. Thus, more knowledge on sex-specific underlying mechanisms is necessary to advance CVD prevention. This knowledge is necessary to optimise personalised prevention and management of hypertension and associated CVD in women.

The limited information from clinical studies on benefit and treatment targets for women represents an important knowledge gap in effective CVD prevention in women (Figure 4). In particular, BP targets and the definition of hypertension in women need to be confirmed by sex-specific reanalysis of clinical data repositories and population-based cohorts complementing previous publications. Sex-related differences in pharmacokinetics and pharmacodynamics may impact optimal dosage, adverse effects and tolerability of antihypertensive drugs. Furthermore, based on the present criteria, uncontrolled hypertension remains more common in older women than their male counterparts.9 Whether this is related to sex differences in adherence, adverse effects or tolerability, or a result of higher prevalence of irreversible hypertension-mediated organ

Conclusion

1. Fryar CD, Ostchega Y, Hales CM, et al. Hypertension prevalence and control among adults: United States, 20152016. NCHS Data Brief 2017;289:1–8. PMID: 29155682. 2. EUGenMed Cardiovascular Clinical Study Group. Gender in cardiovascular diseases: impact on clinical manifestations, management, and outcomes. Eur Heart J 2016;37:24–34. https://doi.org/10.1093/eurheartj/ehv598; PMID: 26530104. 3. Barton M, Meyer MR. Postmenopausal hypertension: mechanisms and therapy. Hypertension 2009;54:11–8. https:// doi.org/10.1161/HYPERTENSIONAHA.108.120022; PMID: 19470884. 4. Ji H, Kim A, Ebinger JE, et al. Sex Differences in blood pressure trajectories over the life course. JAMA Cardiol 2020;5:19–26. https://doi.org/10.1001/jamacardio.2019.5306; PMID: 31940010. 5. Redfield MM, Rodeheffer RJ, Jacobsen SJ, et al. Plasma brain natriuretic peptide concentration: impact of age and gender. J Am Coll Cardiol 2002;40:976–82. https://doi. org/10.1016/s0735-1097(02)02059-4; PMID: 12225726. 6. Gerdts E, Regitz-Zagrosek V. Sex differences in cardiometabolic disorders. Nat Med 2019;25:1657–66. https://doi.org/10.1038/s41591-019-0643-8; PMID: 31700185. 7. Guzik TJ, Touyz RM. Oxidative stress, inflammation, and vascular aging in hypertension. Hypertension 2017;70:660–7. https://doi.org/10.1161/HYPERTENSIONAHA.117.07802; PMID: 28784646. 8. Barbagallo M, Dominguez LJ, Licata G, et al. Vascular effects of progesterone : role of cellular calcium regulation. Hypertension 2001;37:142–7. https://doi.org/10.1161/01. hyp.37.1.142; PMID: 11208769. 9. Wenger NK, Arnold A, Bairey Merz CN, et al. Hypertension across a woman’s life cycle. J Am Coll Cardio 2018;71:1797– 813. https://doi.org/10.1016/j.jacc.2018.02.033; PMID: 29673470. 10. Williams B, Mancia G, Spiering W, et al. 2018 ESC/ESH guidelines for the management of arterial hypertension. Eur Heart J 2018;39:3021–104. https://doi.org/10.1093/eurheartj/ ehy339; PMID: 30165516. 11. Gerdts E, Oikarinen L, Palmieri V, et al. Correlates of left atrial size in hypertensive patients with left ventricular hypertrophy: the Losartan Intervention For Endpoint Reduction in Hypertension (LIFE) Study. Hypertension 2002;39:739–43. https://doi.org/10.1161/hy0302.105683; PMID: 11897755. 12. Halland H, Lonnebakken MT, Pristaj N, et al. Sex differences in subclinical cardiac disease in overweight and obesity (the FATCOR study). Nutr Metab Cardiovasc Dis 2018;28:1054–60. https://doi.org/10.1016/j.numecd.2018.06.014; PMID: 30177273. 13. Gerdts E, Izzo R, Mancusi C, et al. Left ventricular hypertrophy offsets the sex difference in cardiovascular risk (the Campania Salute Network). Int J Cardiol 2018;258:257– 61. https://doi.org/10.1016/j.ijcard.2017.12.086; PMID: 29544940. 14. Gerdts E, Okin PM, de Simone G, et al. Gender differences in left ventricular structure and function during antihypertensive treatment: the Losartan Intervention for Endpoint Reduction in Hypertension Study. Hypertension 2008;51:1109–14. https://doi.org/10.1161/ HYPERTENSIONAHA.107.107474; PMID: 18259011. 15. de Simone G, Devereux RB, Izzo R, et al. Lack of reduction of left ventricular mass in treated hypertension: the Strong

It is well demonstrated that BP increases are steeper in women than men from the third decade of life, women are more prone to developing BPassociated cardiac organ damage and the BP-attributable risk for CVD starts at a lower level of BP in women than men (Figure 3). Based on current knowledge, we suggest that future guidelines on arterial hypertension and CVD prevention take into account the potential for implementing recommendations based on sex-specific association of high BP with CVD to improve risk assessment in young and middle-aged women with high normal BP. Whether different thresholds for sex-specific definitions of arterial hypertension would improve CVD risk detection should also be considered.

Heart Study. J Am Heart Assoc 2013;2:e000144. https://doi. org/10.1161/JAHA.113.000144; PMID: 23744404. 16. Izzo R, Losi MA, Stabile E, et al. Development of left ventricular hypertrophy in treated hypertensive outpatients: The Campania Salute Network. Hypertension 2017;69:136– 42. https://doi.org/10.1161/HYPERTENSIONAHA.116.08158; PMID: 27895192. 17. Mancusi C, Canciello G, Izzo R, et al. Left atrial dilatation: A target organ damage in young to middle-age hypertensive patients. The Campania Salute Network. Int J Cardiol 2018;265:229–33. https://doi.org/10.1016/j. ijcard.2018.03.120; PMID: 29628278. 18. Losi MA, Mancusi C, Midtbo H, et al. Impact of estimated left atrial volume on prognosis in patients with asymptomatic mild to moderate aortic valve stenosis. Int J Cardiol 2019;297:121–5. https://doi.org/10.1016/j.ijcard.2019.10.004; PMID: 31604654. 19. Niiranen TJ, Kalesan B, Hamburg NM, et al. Relative contributions of arterial stiffness and hypertension to cardiovascular disease: The Framingham Heart Study. J Am Heart Assoc 2016;5:e004271. https://doi.org/10.1161/ JAHA.116.004271; PMID: 27912210. 20. Mancusi C, Losi MA, Izzo R, et al. Prognostic impact of increased pulse pressure/stroke index in a registry of hypertensive patients: the Campania Salute Network. Blood Press 2019;28:268–75. https://doi.org/10.1080/08037051.201 9.1612705; PMID: 31068016. 21. GBD 2019 Risk Factors Collaborators. Global burden of 87 risk factors in 204 countries and territories, 1990-2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet 2020;396:1223–49. https://doi.org/10.1016/ S0140-6736(20)30752-2; PMID: 33069327. 22. Arora S, Stouffer GA, Kucharska-Newton AM, et al. Twenty year trends and sex differences in young adults hospitalized with acute myocardial infarction. Circulation 2019;139:1047– 56. https://doi.org/10.1161/CIRCULATIONAHA.118.037137; PMID: 30586725. 23. Sulo G, Igland J, Nygard O, et al. Favourable trends in incidence of AMI in Norway during 2001-2009 do not include younger adults: a CVDNOR project. Eur J Prev Cardiol 2014;21:1358–64. https://doi.org/10.1177/2047487313495993; PMID: 23847184. 24. Lewington S, Clarke R, Qizilbash N, et al. Prospective Studies Collaboration. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet 2002;360:1903–13. https://doi.org/10.1016/s01406736(02)11911-8; PMID: 12493255. 25. Albrektsen G, Heuch I, Lochen ML, et al. Risk of incident myocardial infarction by gender: Interactions with serum lipids, blood pressure and smoking. The Tromso Study 19792012. Atherosclerosis 2017;261:52–9. https://doi.org/10.1016/j. atherosclerosis.2017.04.009; PMID: 28448842. 26. Millett ERC, Peters SAE, Woodward M. Sex differences in risk factors for myocardial infarction: cohort study of UK Biobank participants. BMJ 2018;363:k4247. https://doi. org/10.1136/bmj.k4247; PMID: 30404896. 27. Kringeland E, Tell GS, Midtbo H, et al. Factors associated with increase in blood pressure and incident hypertension in early midlife: the Hordaland Health Study. Blood Press 2020;29:267–75. https://doi.org/10.1080/08037051.2020.176 2070; PMID: 32400220.

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28. Han M, Chen Q, Liu L, et al. Stage 1 hypertension by the 2017 American College of Cardiology/American Heart Association hypertension guidelines and risk of cardiovascular disease events: systematic review, metaanalysis, and estimation of population etiologic fraction of prospective cohort studies. J Hypertens 2020;38:573–8. https://doi.org/10.1097/HJH.0000000000002321; PMID: 31790053. 29. Liu N, Yang JJ, Meng R, et al. Associations of blood pressure categories defined by 2017 ACC/AHA guidelines with mortality in China: pooled results from three prospective cohorts. Eur J Prev Cardiol 2020;27:345–54. https://doi.org/10.1177/2047487319862066; PMID: 31288541. 30. Lee DS, Gona P, Vasan RS, et al. Relation of disease pathogenesis and risk factors to heart failure with preserved or reduced ejection fraction: insights from the Framingham Heart Study of the National Heart, Lung, and Blood Institute. Circulation 2009;119:3070–7. https://doi.org/10.1161/ CIRCULATIONAHA.108.815944; PMID: 19506115. 31. Ji H, Niiranen TJ, Rader F, et al. Sex differences in blood pressure associations with cardiovascular outcomes. Circulation 2021;143:761–3. https://doi.org/10.1161/ CIRCULATIONAHA.120.049360; PMID: 33587655. 32. Ko D, Rahman F, Schnabel RB, et al. Atrial fibrillation in women: epidemiology, pathophysiology, presentation, and prognosis. Nat Rev Cardiol 2016;13:321–32. https://doi. org/10.1038/nrcardio.2016.45; PMID: 27053455. 33. Cheung JW, Cheng EP, Wu X, et al. Sex-based differences in outcomes, 30-day readmissions, and costs following catheter ablation of atrial fibrillation: the United States Nationwide Readmissions Database 2010-14. Eur Heart J 2019;40:3035–43. https://doi.org/10.1093/eurheartj/ehz151; PMID: 30927423. 34. Sharashova E, Wilsgaard T, Ball J, et al. Long-term blood pressure trajectories and incident atrial fibrillation in women and men: the Tromso Study. Eur Heart J 2020;41:1554–62. https://doi.org/10.1093/eurheartj/ehz234; PMID: 31050731. 35. Espnes H, Ball J, Lochen ML, et al. Sex-specific associations between blood pressure and risk of atrial fibrillation subtypes in the Tromso Study. J Clin Med. 2021;10:1514. https://doi.org/10.3390/jcm10071514; PMID: 33916428. 36. Li FR, He Y, Yang HL, et al. Isolated systolic and diastolic hypertension by the 2017 American College of Cardiology/ American Heart Association guidelines and risk of cardiovascular disease: a large prospective cohort study. J Hypertens 2021;39:1594–601. https://doi.org/10.1097/ HJH.0000000000002805; PMID: 33560057. 37. Sacks FM, Svetkey LP, Vollmer WM, et al. Effects on blood pressure of reduced dietary sodium and the Dietary Approaches to Stop Hypertension (DASH) diet. N Engl J Med 2001;344:3–10. https://doi.org/10.1056/ NEJM200101043440101; PMID: 11136953. 38. Os I, Franco V, Kjeldsen SE, et al. Effects of losartan in women with hypertension and left ventricular hypertrophy: results from the Losartan Intervention for Endpoint Reduction in Hypertension Study. Hypertension 2008;51:1103–8. https:/doi.org/10.1161/ HYPERTENSIONAHA.107.105296; PMID: 18259029. 39. Wing LM, Reid CM, Ryan P, et al. A comparison of outcomes with angiotensin-converting--enzyme inhibitors and diuretics for hypertension in the elderly. N Engl J Med 2003;348:583– 92. https://doi.org/10.1056/NEJMoa021716; PMID: 12584366.

Hypertension in Women 40. Kjeldsen SE, Hedner T, Syvertsen JO, et al. Influence of age, sex and blood pressure on the principal endpoints of the Nordic Diltiazem (NORDIL) Study. J Hypertens 2002;20:1231– 7. https://doi.org/10.1097/00004872-200206000-00038; PMID: 12023696. 41. Lewis CE, Grandits A, Flack J, et al. Efficacy and tolerance of antihypertensive treatment in men and women with stage 1

diastolic hypertension. Results of the Treatment of Mild Hypertension study. Arch Intern Med 1996;156:377–85. https://doi.org/10.1001/archinte.1996.00440040047006; PMID: 8607723. 42. Brunstrom M, Carlberg B. Association of blood pressure lowering with mortality and cardiovascular disease across blood pressure levels: a systematic review and meta-

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analysis. JAMA Intern Med 2018;178:28–36. https://doi. org/10.1001/jamainternmed.2017.6015; PMID: 29131895. 43. Ahmad A, Oparil S. Hypertension in women: recent advances and lingering questions. Hypertension 2017;70:19– 26. https://doi.org/10.1161/HYPERTENSIONAHA.117.08317; PMID: 28483918.

Ischaemic Heart Disease

Association Between Colchicine Treatment and Clinical Outcomes in Patients with Coronary Artery Disease: Systematic Review and Meta-analysis Francesco Condello ,1,2 Matteo Sturla ,1,2 Bernhard Reimers ,1,2 Gaetano Liccardo ,1,2 Giulio G Stefanini ,1,2 Gianluigi Condorelli 1,2 and Giuseppe Ferrante 1,2 1. Humanitas University, Department of Biomedical Sciences, Pieve Emanuele, Milan, Italy; 2. Department of Cardiovascular Medicine, Humanitas Research Hospital, IRCCS, Rozzano, Milan, Italy

Abstract

Background: The authors examined the association between colchicine treatment and clinical outcomes in patients with coronary artery disease. Methods: They performed a meta-analysis of randomised controlled trials (RCTs) involving patients with coronary artery disease receiving addon colchicine to standard treatment compared with standard treatment. They used a mixed-effects Poisson regression model with random intervention effects to estimate the pooled incidence rate ratios (IRR) with 95% CI. Results: Ten RCTs were identified, including 12,819 participants followed up for a median of 6 months. Colchicine was associated with a lower risk of major adverse cardiovascular events (IRR 0.69; 95% CI [0.60–0.79]; number needed to treat for an additional beneficial outcome [NNTB] = 28); MI (IRR 0.77; 95% CI [0.64–0.93]; NNTB = 95) and ischaemic stroke (IRR 0.48; 95% CI [0.30–0.76]; NNTB = 155) and with a higher risk of gastrointestinal adverse events (IRR 1.69; 95% CI [1.12–2.54]; number needed to treat for an additional harmful outcome [NNTH] = 10). Colchicine did not affect all-cause death (IRR 1.09; 95% CI [0.85–1.40]), or cardiovascular death (IRR 0.75; 95% CI [0.51–1.12]), while it was associated with a higher risk of non-cardiovascular death (IRR 1.45; 95% CI [1.04–2.02]; NNTH = 396). Conclusion: The meta-analysis showed that the relative and absolute beneficial treatment effects of colchicine on cardiovascular outcomes outweigh the potential harm for non-cardiovascular mortality. Registration: PROSPERO 2021 CRD42021248874.

Keywords

Colchicine, coronary artery disease, myocardial infarction, mortality Disclosure: GF is a European Cardiology Review section editor; this did not affect peer review. All other authors have no conflicts of interest to declare. Received: 5 July 2021 Accepted: 2 August 2021 Citation: European Cardiology Review 2021;16:e39. DOI: https://doi.org/10.15420/ecr.2021.31 Correspondence: Giuseppe Ferrante, Department of Cardiovascular Medicine, Humanitas Research Hospital IRCCS, Rozzano, Milan, Italy. E: giu.ferrante@hotmail.it Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

The burden of residual cardiovascular risk remains an important concern for patients with coronary artery disease (CAD) despite major advances in secondary cardiovascular prevention having been achieved over the past decades.1 Further reduction in low-density lipoprotein cholesterol by treatment with statins and more recently with proprotein convertase subtilisin/kexin type-9 (PCSK9) inhibitors, or reducing triglyceride levels using high-dose icosapent ethyl are associated with better clinical outcomes, underscoring the importance of the lipid component of this residual risk.2–5 Nevertheless, recent randomised controlled trials (RCTs) have demonstrated that selectively targeting inflammation further improves clinical outcomes in patients with atherosclerosis, indicating that inflammation plays an important role in the burden of cardiovascular risk.6 Indeed, the use of canakinumab, which inhibits interleukin (IL)-1β without lowering cholesterol or blood pressure, was associated with a significant reduction in major adverse cardiovascular events (MACE) in the CANTOS study, with the greatest clinical benefit being observed among patients with the greatest reductions in IL-6 and C-reactive protein.7 Colchicine is an old drug with several anti-inflammatory properties, preventing microtubule polymerisation at low dose and promoting microtubule depolymerisation at high dose, acting on neutrophils and

endothelial cells and inhibiting the nucleotide-binding and oligomerisation domain (NOD)-like receptor protein 3 (NLRP3) inflammasome, thus blocking the downstream upregulation of pro-inflammatory IL 1β and IL 18.8–12 Recent RCTs and meta-analyses have shown that colchicine may reduce MACE in patients with CAD, supporting the inflammation hypothesis of atherosclerosis.6,13–15 Nevertheless, uncertainty exists about the effects of colchicine on mortality outcomes. In addition, absolute treatment effects of colchicine on clinical outcomes are yet to be reported.15,16 We systematically reviewed evidence from trials to determine the association between colchicine treatment and specific cardiovascular outcomes, adverse events and mortality outcomes.

Methods

We performed a systematic review and meta-analysis of RCTs examining the association between add-on colchicine treatment and clinical outcomes in patients with CAD. The study is reported according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines.17 The study protocol was registered on PROSPERO (the international prospective register of systematic reviews), and the number CRD42021248874 was assigned.

Colchicine in Patients with Coronary Artery Disease Search Strategy

We searched Medline, Embase, Cochrane Central Register of Controlled Trials (CENTRAL, Cochrane Library), ClinicalTrials.gov databases and the main international conference proceedings for all RCTs assessing the effects of colchicine treatment on clinical outcomes in patients with CAD. Searches were undertaken independently by two reviewers (FC and MS) from inception of the databases until 1 March 2021. No language, publication date or publication status restrictions were applied. We used the following MeSH terms: “colchicine” and “coronary artery disease” or “CAD” or “chronic ischaemic heart disease” or “atherosclerosis” or “angina” or “acute coronary syndrome” or “myocardial infarction” or “percutaneous coronary intervention” or “PCI” or “angioplasty” or “drug eluting stent” or “DES” or “bare metal stent” or BMS”.

Selection of Studies and Inclusion and Exclusion Criteria

Study eligibility was independently assessed by two reviewers (FC, MS) on the basis of titles, abstracts and full-text reports. Discrepancies in the study selection were discussed and resolved with another reviewer (GF). Eligible studies included participants with CAD and compared individuals receiving add-on colchicine with those receiving placebo or no treatment; and provided clinical outcome data at follow-up. We excluded studies without a randomised design as they are prone to bias from confounding by indication and studies including participants not affected by CAD or specific groups of patients requiring colchicine treatment, such as those affected by familial Mediterranean fever or gout.

Outcome Measures

The primary efficacy outcome was the composite of MACE according to the definition used in each study, which usually comprised a combination of either all-cause or cardiovascular mortality, MI, stroke, with or without coronary revascularisation. Nevertheless, we excluded all-cause mortality from the definition of MACE and included cardiovascular mortality to reduce heterogeneity. The primary safety outcome was gastrointestinal adverse events. Secondary clinical endpoints were MI, stroke and any coronary revascularisation. With respect to mortality outcomes, we assessed all-cause death, cardiovascular death and non-cardiovascular death. The latter was obtained directly from the study reports or was calculated as the difference between all-cause deaths and cardiovascular deaths when it was not directly reported in the study.

Data Extraction and Quality Assessment

Two reviewers (FC and MS) independently extracted data from eligible studies using a standardised data abstraction form and independently entered outcome data into a Microsoft Excel spreadsheet (2016 version). Another reviewer then manually cross-checked these, referring to the original source data when discrepancies were identified. Any disagreements of collected information between the two reviewers were reconciled through discussion with a third reviewer (GF). Data were extracted on populations studied, colchicine dose, length of follow-up, outcome definitions, inclusion and exclusion criteria, sample size, number of patients experiencing adverse events, mortality outcomes and follow-up time. Two independent reviewers (FC, MS) evaluated the methodological quality of the included studies using the revised Cochrane risk-of-bias tool (RoB 2.0) assessing five domains of bias for each outcome:18

• Randomisation process;

• • • •

Deviation from intended interventions; Missing outcome data; Measurement of the outcome; and Selection of the reported results.

Any disagreement was resolved with a third reviewer (GF).

Data Synthesis and Analyses

Outcome data were treated as incidence rate which is based on counts of events over time per person-year recorded separately for each study arm, for example colchicine group and control group, owing to the heterogeneity of follow-up duration among studies. We used the pooled incidence rate ratio (IRR) with 95% confidence intervals (CI) to measure the effect size. A mixed-effects Poisson regression model with random intervention effects at the study level was used to estimate the pooled IRR as this method is without bias and held with a large number of zeros in the data as well as when there is high heterogeneity.19–21 Risk differences with their 95% CI for each endpoint between the colchicine arm and the control group were estimated by the Poisson model using the delta method. The number of patients needed to treat for an additional beneficial outcome (NNTB) and the number needed to treat for an additional harmful (NNTH) outcome with a 95% CI were calculated from risk differences and defined the inverse of risk difference.22,23 The presence of heterogeneity among studies was evaluated with the Cochran Q test with p≤0.1 considered of statistical significance, estimating the between-study variance tau square. The proportion of variability in effect estimates due to between-study heterogeneity was summarised using the I2 test to evaluate inconsistency. I2 values of 25%, 50% and 75% have been assigned adjectives of low, moderate and high heterogeneity, respectively.24 The presence of publication bias for each endpoint was investigated by visual estimation with the use of contour-enhanced funnel plots.25 To address potential sources of heterogeneity, we performed a pre-specified subgroup analysis according to colchicine dose, <1 mg /daily or ≥1 mg/ daily, with respect to main clinical outcomes including MACE, MI, stroke, all-cause death and gastrointestinal adverse events. Another prespecified subgroup analysis based on the type of clinical presentation, i.e. acute coronary syndrome (ACS) versus chronic coronary syndrome (CCS), was performed although this analysis was restricted to a limited number of studies which reported data split according to clinical syndrome. A formal interaction test between treatment effects of each subgroup was done as previously recommended.26 No other subgroup analyses were undertaken by patient level characteristics owing to the risk of ecological bias. A leave-one-out sensitivity analysis was performed by leaving out exactly one study to assess the consistency of the results. The statistical level of significance was two-tailed p<0.05 for treatment effects and p<0.1 for the interaction test. All analyses were undertaken using R 3.6.3 and Stata/MP version 16 (StataCorp LP) software.

Results Study Selection and Characteristics

The search strategy and selection process are summarised in Supplementary Material Figure 1. A total of 840 unique articles were identified from the literature searches. After screening of the title, abstract and full text, 10 articles originating from 10 RCTs were eligible for inclusion.13,14,16,27–32 Cohort characteristics are summarised in Table 1 and

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Greece

France

COLIN 201631 Australia

LoDoCo-MI 201913 12 countries

COLCOT 201933

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Hypertension n (%)

Dyslipidaemia NA n (%)

Current smoker n (%)

8 (12)

58 (87)

7 (17.5)

18 (45)

19 (47.5)

34 (85)

57.2 (11.7)

6 (15)

92 (33)

17 (42.5) 10 (4)

19 (47.5) NA

15 (37.5) NA

37 (92.5) 251 (89)

57.2 (8.7) 66 (9.6)

69 (28)

14 (6)

222 (89)

67 (9.2)

6 months

100 (100)

36 (36)

48 (48)

63 (63)

96 (100)

38 (40)

47 (49)

65 (68)

3 (13)

17 (73.9)

8 (34.8)

9 (39.1)

19 (82.5)

63.7 (6.9) 63.5 (7.2) 60.1 (13.1)

3 (14.3)

14 (66.7)

8 (38.1)

10 (47.6)

16 (76.2)

59.7 (11.4)

CRP peak during the index hospitalisation

1 month

118

27 (23)

64 (54)

89 (75)

61 (13.6)

2,379

Composite of death from CV causes, resuscitated cardiac arrest, MI, stroke, or urgent hospitalisation for angina leading to coronary revascularisation

22.6 months

Within 30 days post MI

2,366

22.6 months

RCT, double-blind, placebo-controlled

25 (21)

48 (41)

93 (79)

462 (19.5) 497 (20.9) 75 (19)

708 (29.9) 708 (29.8) 128 (32)

180 (46)

1,185 (50.1) 1,236 (52) 201 (51) NA

348

30 days

Undergoing PCI

366

1 day

RCT, double-blind, placebo-controlled

76 (19)

188 (51.4)

149 (37) 84 (23)

Placebo

2,760

65.9 (8.7)

311 (89.4)

1,421 (51.4)

318 (11.5) 196 (56.3) 632 (22.9)

87 (25)

662 (23)

330 (12)

1,387 (50.3)

324 (93.1) 2,305 (83.5) 2,371 (85.9)

65.8 (10.7) 65.8 (8.4)

Composite of CV death, spontaneous (non-procedural) MI, ischaemic stroke, or ischaemia-driven coronary revascularisation

28.6 months

Stable coronary artery disease

2,762

28.6 months

RCT, double-blind, placebo-controlled

Colchicine 0.5 mg once daily

2 countries

LoDoCo2 202014

185 (46) 324 (88.5) 306 (87.9) NA

199 (50) 327 (89.3)

310 (78) 336 (91.8)

60 (10.4) 66.1 (9.7)

Composite of death PCI-related myocardial from any cause, ACS, injury ischaemia-driven urgent revascularisation and non-cardioembolic ischaemic stroke

400 days

1,894 (81.1) 1,942 (81.6) 322 (81)

399

Presenting with acute coronary syndrome

396

12 months

RCT, double-blind, placebo-controlled

61 (12.5) 60.6 (10.7) 60.5 (10.6) 59.7 (10.2)

Proportion of patients with a residual CRP level ≥2 mg/l at 30 days

30 days

Within 7 days from type 1 acute MI

119

30 days

RCT, double-blind, placebo-controlled

COLCHICINPCI 202032

Colchicine Placebo Colchicine Placebo 0.5 mg 1.8 mg 1–2 twice daily hours for the first perimonth, procedure then once daily for 11 months

Australia

COPS 202016

ACS = acute coronary syndrome; CRP = C-reactive protein; CV = cardiovascular; hs-CRP = high sensitivity C-reactive protein; ISR = in-stent restenosis; IVUS-ISR = intravascular ultrasound in-stent-restenosis; PCI = percutaneous coronary intervention; RCT = randomised controlled trial.

Diabetes n (%) 16 (12)

111 (85)

Men n (%)

62 (NA)

1 month

RCT, open-label

Undergoing PCI in a ST-elevation MI coronary artery with a diameter of at least 2.5 mm with a bare metal stent

100

6 months

RCT, double-blind, placebo-controlled

Composite of acute Angiographic-ISR coronary syndrome, and IVUS-ISR out of hospital cardiac arrest and noncardioembolic stroke

3 years

59 (NA)

30 days

Age, years, mean (SD)

250

Rate of angiographic Blood levels of restenosis hs-CRP at 30 days

282

Primary outcome

6 months

3 years

Follow-up duration

30 days

Undergoing Acute coronary Stable coronary artery angioplasty for silent syndrome and acute disease (for at least 6 ischaemia and ischaemic stroke months) stable or unstable angina

130

6 months

RCT, open-label

Population

Treatment duration

RCT, double-blind, placebo-controlled

Australia

Defteros et al. 201330

Study design

Canada

LoDoCo 201329

Colchicine Placebo Colchicine Placebo Colchicine No Colchicine Placebo Colchicine No Colchicine Placebo Colchicine Placebo 0.5 mg 1 mg once 0.5 once treatment 0.5 mg 1 mg once treatment 0.5 mg 0.5 mg twice daily daily daily twice daily once daily once daily daily

COOL 201128

Treatment

Country

O’Keefe et al. 199227

Table 1. Baseline Clinical Characteristics of Included Studies

Colchicine in Patients with Coronary Artery Disease

Colchicine in Patients with Coronary Artery Disease Figure 1: Pooled Analysis of Studies Comparing Add-on Colchicine Versus Standard Treatment Forest Plots Reporting Trial-specific and Summary Incidence Rate Ratios with 95% CI for the Primary Endpoint of MACE MACE Control Events Person-years

Study

Colchicine Events Person-years

O’Keefe et al. 199227

59.71

3.39

847.74

751.54

50.10

48.10

COOL 201128 LoDoCo 201329 Defteros et al. 201330

Incidence rate ratio

Incidence rate ratio [95% CI]

30.77 1.00 [0.06–15.99] 0.33 [0.18–0.60]

COLIN 201631

1.92

1.75

0.91 [0.31–6.48]

LoDoCo-MI 201913

9.77

9.69

0.20 [0.01–4.13]

COLCOT 201933

131

4,465.12

170

4,489.65

0.77 [0.62–0.97]

COLCHICIN-PCI 202032

16.92

15.93

0.90 [0.51–1.60]

COPS 202016

433.68

436.96

0.47 [0.27–0.80]

LoDoCo2 202014

187

6,596.28

264

6,591.51

0.71 [0.59–0.85]

Overall (random-effects model) 2

0.69 [0.60–0.79]

Heterogeneity: I = 37%, T <0.0001, p=0.13

0.01

0.1

Favours colchicine

100

Favours control

Figure 2: Pooled Analysis of Studies Comparing Add-on Colchicine Versus Standard Treatment Forest Plots Reporting Trial-specific and Summary Incidence Rate Ratios with 95% CI for the Endpoint of Gastrointestinal Adverse Events Gastrointestinal adverse events Study

Colchicine Events Person-years

Events

Control Person-years

Incidence rate ratio [95% CI]

Incidence rate ratio

O’Keefe et al. 199227

59.71

30.77

6.18 [1.90–20.08]

COOL 201128

3.39

2.00 [0.81–4.96]

847.74

751.54

50.10

48.10

1.92

1.75

LoDoCo 201329 Defteros et al. 201330 COLIN 201631 LoDoCo-MI 201913

2.19 [0.90–5.33]

9.77

9.69

1.98 [0.74–5.28]

408

4,397.18

414

4,427.37

0.99 [0.87–1.14]

COLCHICIN-PCI 202032

30.96

28.58

2.94 [1.49–5.80]

COPS 202016

433.68

436.96

1.10 [0.82–1.49]

LoDoCo2 202014

6,596.28

6,591.51

1.06 [0.72–1.56]

COLCOT 201933

1.69 [1.12–2.54]

Overall (random-effects model) Heterogeneity: I2 = 73%, T2 <0.2044, p=0.01

0.1

0.5

Favours colchicine

Supplementary Material Table 1, extracting data for the present analyses from the primary trial reports. A total of 12,819 participants were included in the primary analyses from 10 unique RCTs. Eight studies compared add-on colchicine with placebo and two studies compared add-on colchicine with standard treatment.13,14,16,27,28–32 The mean (SD) age of trial participants ranged from 57.2 (11.7) years to 67 (9.2) and 10,680 (83.3%) participants were men.28,29 The sample size of the individual studies ranged from 44 to 5,522. The overall prevalence of diabetes ranged from 12 to 100%.27,30 Across the 10 trials, median follow-up was 6 months (interquartile range 1–23, minimum to maximum 1–28.6 months). Treatment duration exactly matched follow-up duration in all included studies except the Colchicine-PCI study where treatment duration was limited to 1 day while follow-up was 30 days, and the COPS study where it was 1 year, and follow-up duration was 400 days.16,32

Favours control

Quality Assessment

Supplementary Material Figure 2 presents the risk-of-bias assessment for individual trials. Overall, six (60%) studies were judged to have ‘some concerns’, and one (10%) to have ‘high risk’ of bias. The main reasons for some concerns were bias in selection of the reported results (6; 60%) and bias due to missing outcome data (6; 60%). Treatment effects of two (20%) of the studies could be contaminated owing to the open label design. Contour-enhanced funnel plots showed the presence of significant asymmetry for non-mortality endpoints, potentially due to publication bias and other issues, whereas mild asymmetry was found for mortality endpoints (Supplementary Material Figures 3–10).

Study Heterogeneity

Significant heterogeneity was observed for the primary safety outcome of gastrointestinal adverse events, as well as for stroke, and non-

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Colchicine in Patients with Coronary Artery Disease Figure 3: Pooled Analysis of Studies Comparing Add-on Colchicine Versus Standard Treatment Forest Plots Reporting Trial-specific and Summary Incidence Rate Ratios with 95% CI for the Endpoint of MI MI Study

Colchicine Events Person-years

Control Events Person-years

O’Keefe et al. 199227

59.71

COOL 201128

3.39

LoDoCo 201329

847.74

751.54

50.10

48.10

Defteros et al. 201330

Incidence rate ratio

Incidence rate ratio [95% CI]

30.77

1.00 [0.02–50.40] 0.25 [0.08–0.77]

COLIN 201631

1.92

1.75

0.30 [0.01–7.47]

LoDoCo-MI 201913

9.77

9.69

0.20 [0.01–4.13]

COLCOT 201933

4,465.12

4,489.65

0.91 [0.69–1.22]

COLCHICIN-PCI 202032

16.92

15.93

0.90 [0.51–1.60]

433.68

436.96

0.64 [0.25–1.65]

6,596.28

117

6,591.51

0.73 [0.55–0.96]

COPS 202016 LoDoCo2 202014

Overall (random-effects model)

0.77 [0.64–0.93]

Heterogeneity: I2 = 5%, T2 <0.0001, p=0.39

0.01

0.1

Favours colchicine

100

Favours control

Figure 4: Pooled Analysis of Studies Comparing Add-on Colchicine Versus Standard Treatment Forest Plots Reporting Trial-specific and Summary Incidence Rate Ratios with 95% CI for the Endpoint of Stroke Stroke Study O’Keefe et al. 199227 COOL 201128 LoDoCo 201329 Defteros et al. 201330 COLIN 201631 LoDoCo-MI 201913 COLCOT 201933 COLCHICIN-PCI 202032 COPS 202016 LoDoCo2 202014

Colchicine Events Person-years

Control Events Person-years

59.71

3.39

847.74

751.54

0.22 [0.02–1.98]

50.10

48.10

2.88 [0.12–70.70]

1.92

1.75

9.77

9.69

4,465.12

4,489.65

30.96

28.58

2.85 [0.12–70.02]

433.68

436.96

0.34 [0.07–1.66]

6,596.28

6,591.51

0.67 [0.35–1.25]

Incidence rate ratio

Incidence rate ratio [95% CI]

30.77

0.33 [0.01–8.18]

0.26 [0.10–0.71]

0.48 [0.30–0.76]

Overall (random-effects model) Heterogeneity: I2 = 61%, T2 = 0, p=0.02

0.1

0.5 1

Favours colchicine

cardiovascular death (Supplementary Material Table 2). Moderate inconsistency was found for the primary endpoint of MACE, coronary revascularisation and mild inconsistency was detected for the remaining outcome measures (Supplementary Material Table 2).

Primary Outcomes

Associations between colchicine use and the relative and absolute risks for outcomes are presented in Supplementary Material Tables 3 and 4. Overall, there was strong evidence that, add-on colchicine therapy reduced the risk of MACE compared to standard treatment (IRR 0.69; 95% CI [0.60–0.79]; NNTB = 28, number of events avoided = 35 per 1,000 patients treated, n=8 studies, Figure 1) and significantly increased the risk of gastrointestinal adverse events (IRR 1.69; 95% CI [1.12–2.54]; NNTH = 10, number of events caused = 99 per 1,000 patients treated, n=8 studies, Figure 2).

10 Favours control

Secondary Outcomes

Colchicine use was associated with a lower risk of MI (IRR 0.77; 95% CI [0.64–0.93]; NNTB = 95, number of events avoided = 10 per 1,000 patients treated; n = 8 studies, Figure 3), and of ischaemic stroke (IRR 0.48; 95% CI [0.30–0.76]; NNTB = 155, number of events avoided = 6 per 1,000 patients treated, n=7 studies, Figure 4). Weak evidence was found for an association between colchicine and a lower risk of coronary revascularisation (IRR 0.66; 95% CI [0.41–1.05]; NNTB = 51, number of events avoided 20 per 1,000 patients treated, n=4 studies, Supplementary Material Figure 11).

Mortality Outcomes

There was no evidence of an association between colchicine and an increased risk of all-cause death (IRR 1.09; 95% CI [0.85–1.40], n=10 studies, Figure 5), or of cardiovascular death (IRR 0.75; 95% CI [0.51–1.12],

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Colchicine in Patients with Coronary Artery Disease Figure 5: Pooled Analysis of Studies Comparing Add-on Colchicine Versus Standard Treatment Forest Plots Reporting Trial-specific and Summary Incidence Rate Ratios with 95% CI for the Endpoint of All-cause Death All-cause death Study

Events

Colchicine Person-years

Events

Control Person-years

Incidence rate ratio [95% CI]

Incidence rate ratio

O’Keefe et al. 199227

59.71

30.77

0.26 [0.02–2.84]

COOL 201128

3.39

1.00 [0.02–50.40]

LoDoCo 201329

847.74

751.54

Defteros et al. 201330

50.10

48.10

0.96 [0.06–15.35]

COLIN 201631

1.92

1.75

0.91 [0.02–46.01]

LoDoCo-MI 201913

9.77

9.69

0.99 [0.02–49.97]

4,465.12

4,489.65

COLCHICIN-PCI 202032

16.92

15.93

0.94 [0.06–15.06]

COPS 202016

433.68

436.96

8.06 [1.01–64.45]

6,596.28

6,591.51

COLCOT 201933

LoDoCo2 202014

0.35 [0.11–1.13]

0.98 [0.65–1.50]

1.22 [0.86–1.71]

Overall (random-effects model)

1.09 [0.85–1.40]

Heterogeneity: I2 = 34%, T2 = 0, p=0.17

0.1

0.5 1

Favours colchicine

n=9 studies, Supplementary Material Figure 12). Weak evidence of an association of colchicine with a higher risk of non-cardiovascular death was found (IRR 1.45; 95% CI [1.04–2.02], NNTH 396, number of events caused 3 per 1,000 patients treated, n=9 studies, Supplementary Material Figure 13).

Subgroup Analyses

We conducted two pre-specified analyses on colchicine dose and clinical syndrome – ACS versus CCS. With respect to the analysis of colchicine dose, we found a significant interaction with the risk of gastrointestinal adverse events (IRR 1.03; 95% CI [0.91–1.15]) in patients receiving lowdose colchicine and IRR 2.91; 95% CI [1.91–4.44] in patients receiving highdose colchicine; p<0.0001 for interaction (Supplementary Material Table 5 and Figure 14). Of note I2 and the between-study heterogeneity was zero in stratified analyses of colchicine dose for gastrointestinal adverse events and I2 largely decreased for the endpoint of stroke (Supplementary Material Table 6). By contrast, no evidence for a modification of treatment effect of colchicine dose for the endpoints of MACE, MI, stroke and allcause death (Supplementary Material Table 5 and Figures 15–18) was observed. With respect to the analysis of the type of clinical syndrome, we found little evidence for an interaction with the risk of MI (IRR 0.91; 95% CI [0.71– 1.18]) in patients presenting with ACS and IRR 0.65; 95% CI [0.50–0.84] in patients presenting with CCS, p=0.07 for interaction (Supplementary Material Table 6 and Figure 20). Supplementary Material Table 8 reports the heterogeneity measures of this subgroup analysis. No evidence for a modification of treatment effect for the type of clinical syndrome was observed for MACE, stroke and all-cause death (Supplementary Material Table 7 and Figures 19, 21 and 22)

Sensitivity Analyses

The results of the leave-one-out sensitivity analyses for each outcome obtained by leaving out exactly one study are presented in Supplementary Table 9. Overall results were consistent with the main analysis for the primary endpoint of MACE, all-cause death and cardiovascular death. Nevertheless, the following small variations in treatment effects were

10 Favours control

observed: the omission of the LodoCo2 study slightly attenuated the treatment effect on the risk of MI and non-cardiovascular death, the omission of COLCOT slightly attenuated the treatment effect on stroke and increased the beneficial effect of colchicine on revascularisation, finally the omission of one study attenuated the harm for gastrointestinal adverse events.13,14,27

Discussion

The present study is a comprehensive meta-analysis including clinical outcomes data from 10 RCTs and more than 12,800 patients with CAD showing the benefit of an add-on colchicine to standard treatment in reducing the risk of MACE, MI, stroke and to a lower extent any coronary revascularisation at follow-up. These data also found an association between colchicine and gastrointestinal adverse events and showed that this association is dependent on colchicine dose, with low-dose colchicine (<1 mg daily) having a better safety profile and high-dose colchicine (≥1 mg daily) carrying an increased risk of adverse events. Of note, the protective effects on cardiovascular outcomes were not affected by colchicine dose, while the benefit of colchicine on the risk of MI was attenuated in patients presenting with ACS, compared to patients presenting with CCS. The study data show no evidence of an association between colchicine and mortality either from any cause or cardiovascular causes and provide weak evidence for an association of colchicine with an increased risk of non-cardiovascular death as indicated by a wide CI. These data will inform shared decision-making around initiation and optimal dosage of colchicine treatment for secondary cardiovascular prevention, especially in patients with a high absolute risk of future cardiovascular outcomes. Such discussions will become increasingly important among patients for whom traditional treatment strategies for the reduction of cardiovascular residual risk may not be implemented, such as patients at high risk of bleeding who cannot tolerate a prolonged dual antiplatelet therapy or dual antithrombotic strategy, or patients who are unable to receive aggressive LDL cholesterol reduction therapy owing to intolerance to high-dose or any statin treatment and/or may not undergo PCSK-9 inhibitor treatment owing to prohibitive treatment costs.

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Colchicine in Patients with Coronary Artery Disease Compared with previous meta-analyses of clinical outcomes of colchicine use in this setting, one important difference in the present analysis includes the use of incidence rate and IRR for all eligible trials and the estimation of absolute treatment effect measures.15,33–35 By contrast, previous meta-analyses limited extraction to analyses reporting relative risks or HRs which do not account for heterogeneity of follow-up duration and may introduce bias. Analyses of absolute treatment effects show that the benefits of colchicine on MACE are of clinical relevance given the NNTB = 28 corresponding to 35 events avoided per 1,000 patients treated. While the highest relative risk reduction associated with colchicine was observed for stroke (IRR 0.48), a higher absolute risk reduction was found for MI (NNTB = 95) and coronary revascularisation (NNTB = 51). Our pre-specified subgroup analysis showed an interaction between colchicine and the type of clinical presentation with the risk of MI, indicating the highest benefit among patients with CCS. This finding is in agreement with a previous meta-analysis showing a higher benefit of colchicine on cardiovascular outcomes in patients with CCS compared with patients with ACS.34 Nevertheless, the included studies in the ACS group were heterogeneous with respect to timing of colchicine administration. A previous post-hoc analysis of the COLCOT study suggested that an earlier onset of colchicine administration could be associated with better clinical outcomes among patients with ACS with the greatest benefit observed when colchicine was started within 3 days from MI, during the highest inflammatory window.36 Our data also provide important evidence with respect to the effects of colchicine on mortality outcomes. COPS reported a signal towards higher total mortality in the colchicine group that was driven by a higher rate of non-cardiovascular death.16 Analyses of causes of death revealed that non-cardiovascular death was related to sepsis in four out of five cases, however three out of four patients with sepsis-related deaths in the colchicine group discontinued study medication early in the trial (within the first 30 days) and were not taking colchicine at the time of death.16 In LoDoCo2, the incidence rates of death from any cause and noncardiovascular death were higher with colchicine than with placebo.14 The observed between-group difference in the incidence of non-cardiovascular death was not significant, as shown by the 95% CI, although the HR of 1.51 was deemed of potential concern. We found no evidence that colchicine could affect the risk of all-cause death or cardiovascular death and provided weak evidence for an association of colchicine with an increased risk of non-cardiovascular death. In interpreting the latter finding, one should consider that the definition of non-cardiovascular death could be subject to bias and misclassification as there was no systematic distinction between unknown or missing causes of death and all other causes of death in the included studies. Also, we calculated non-cardiovascular deaths as the difference between all-cause deaths and cardiovascular deaths when not specifically reported in each study. Further, the mixed-effects Poisson regression model with random intervention effects that we used in these analyses could not be extended to handle the situation of competing risks, such as between cardiovascular and non-cardiovascular deaths given the lack of data on individual participants, therefore we cannot rule out that a small non-significant advantage in terms of cardiovascular death associated with colchicine use could translate into an apparently higher, yet overestimated, risk of non-cardiovascular mortality. Also, the absolute treatment effect of colchicine on non-cardiovascular death was small with an NNTH of 396, corresponding to less than three events caused per

1,000 patients treated. Finally, we cannot rule out the role of chance underlying a potential association between colchicine and noncardiovascular death at follow-up, therefore ongoing studies, such as CONVINCE (NCT02898610) and CLEAR SYNERGY (NCT03048825), will provide important evidence about this issue.

Limitations

We observed statistically significant heterogeneity across studies for several outcomes, therefore caution should be used when interpreting the results. For the outcomes of stroke and gastrointestinal adverse events, the observed heterogeneity was largely explained by pooling according to two different colchicine dosages – low-dose or high-dose. For other outcomes, the observed heterogeneity could not be explained by differences in colchicine dose or the type of clinical presentation – ACS or CCS. However, other differences in populations of interest and study designs could have contributed to the observed variation. Evidence was found of publication bias for certain outcomes confirming the findings of previous studies that showed adverse events are more likely to be reported in RCTs when they are statistically significant. We also acknowledge the lack of individual patient-level data which does not allow us to assess the effect of baseline patient characteristics on treatment effects and limits the ability to identify population subgroups both at potentially elevated risk and at potentially greater drug-derived benefit. Across all included trials, the definition of the primary endpoint and of other outcomes varied. For instance, several studies referred to MACE as an outcome including coronary revascularisation in addition to all-cause death, MI and stroke, but in other studies MACE did not comprise coronary revascularisation. Another limitation includes the notion that RCTs often select populations with less frailty and multimorbidity which may not be representative of the real world. Further, only 16.7% of participants included in the meta-analysis were women and therefore our findings cannot be directly applied to this patient population. Finally, the median follow-up duration was 6 months and additional studies with longer follow-up are needed to confirm the long-term efficacy of colchicine, and the time points at which clinical outcomes occurred varied across studies, yet the use of a mixed-effects Poisson regression model with random intervention effects is appropriate when dealing with different follow-up durations.

Conclusion

This study found strong evidence to suggest that colchicine treatment is associated with a lower risk of MACE, including MI and stroke in patients with CAD, in particular among those with CCS, and found no evidence of increased risk of all-cause or cardiovascular death. Colchicine is associated with a higher risk of gastrointestinal adverse events that can be prevented by using a low-dose regimen. The evidence for an association of colchicine with non-cardiovascular death is weak and the absolute treatment effect is small. Nevertheless, adequately powered larger studies with longer follow-up are needed to dispel any doubts about any potential harm of colchicine with respect to noncardiovascular death. The relative and absolute beneficial treatment effects of colchicine treatment on cardiovascular outcomes outweigh the potential harm of non-cardiovascular death, which is of debatable clinical relevance, thus supporting colchicine use for cardiovascular risk reduction in secondary prevention.

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Colchicine in Patients with Coronary Artery Disease

Clinical Perspective

• Among patients with coronary artery disease, add-on colchicine therapy compared to standard treatment is associated with a significant reduction of the risk of major adverse cardiovascular events by 31% of MI by 23% and stroke by 52%.

• There is no evidence that colchicine is associated with an increased risk of all-cause death or cardiovascular death and there is weak evidence of an association of colchicine with a higher risk of non-cardiovascular death.

• Colchicine is associated with a higher risk of gastrointestinal adverse effects that can be prevented by using a low-dose regimen (<1 mg daily).

• The absolute beneficial treatment effect of colchicine treatment on cardiovascular outcomes largely outweighs the absolute harmful

treatment effect on non-cardiovascular death, which is of debatable clinical relevance, thus supporting colchicine use for cardiovascular risk reduction in secondary prevention.

1. Libby P. The forgotten majority: unfinished business in cardiovascular risk reduction. J Am Coll Cardiol. 2005;46:1225–8. https://doi.org/10.1016/j.jacc.2005.07.006; PMID: 16198835. 2. Cholesterol Treatment Trialists’ (CTT) Collaboration. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet 2010;376:1670–81. https://doi. org/10.1016/S0140-6736(10)61350-5; PMID: 21067804. 3. Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med 2017;376:1713–22. https://doi. org/10.1056/NEJMoa1615664; PMID: 28304224. 4. Schwartz GG, Steg PG, Szarek M, et al. Alirocumab and cardiovascular outcomes after acute coronary syndrome. N Engl J Med 2018;379:2097–107. https://doi.org/10.1056/ NEJMoa1801174; PMID: 30403574. 5. Bhatt DL, Steg PG, Miller M, et al. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med 2019;380:11–22. https://doi.org/10.1056/ NEJMoa1812792; PMID: 30415628. 6. Shapiro MD, Fazio S. From lipids to inflammation: new approaches to reducing atherosclerotic risk. Circ Res 2016;118:732–49. https://doi.org/10.1161/ CIRCRESHAHA.115.306471; PMID: 26892970. 7. Ridker PM, Everett BM, Thuren T, et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med 2017;377:1119–31. https://doi.org/10.1056/ NEJMoa1707914; PMID: 28845751. 8. Dalbeth N, Lauterio TJ, Wolfe HR. Mechanism of action of colchicine in the treatment of gout. Clin Ther 2014;36:1465– 79. https://doi.org/10.1016/j.clinthera.2014.07.017; PMID: 25151572. 9. Bhattacharyya B, Panda D, Gupta S, Banerjee M. Anti-mitotic activity of colchicine and the structural basis for its interaction with tubulin. Med Res Rev 2008;28:155–83. https://doi.org/10.1002/med.20097; PMID: 17464966. 10. Terkeltaub RA. Colchicine update: 2008. Semin Arthritis Rheum 2009;38:411–9. https://doi.org/10.1016/j. semarthrit.2008.08.006; PMID: 18973929. 11. Cronstein BN, Molad Y, Reibman J, et al. Colchicine alters the quantitative and qualitative display of selectins on endothelial cells and neutrophils. J Clin Invest 1995;96:994– 1002. https://doi.org/10.1172/JCI118147; PMID: 7543498. 12. Martínez GJ, Celermajer DS, Patel S. The NLRP3 inflammasome and the emerging role of colchicine to inhibit atherosclerosis-associated inflammation. Atherosclerosis 2018;269:262–71. https://doi.org/10.1016/j. atherosclerosis.2017.12.027; PMID: 29352570. 13. Tardif JC, Kouz S, Waters DD, et al. Efficacy and safety of low-dose colchicine after myocardial infarction. N Engl J Med 2019;381:2497–505. https://doi.org/10.1056/NEJMoa1912388; PMID: 31733140.

14. Nidorf SM, Fiolet ATL, Mosterd A, et al. Colchicine in patients with chronic coronary disease. N Engl J Med 2020;383:1838–47. https://doi.org/10.1056/NEJMoa2021372; PMID: 32865380. 15. Fiolet ATL, Opstal TSJ, Mosterd A, et al. Efficacy and safety of low-dose colchicine in patients with coronary disease: a systematic review and meta-analysis of randomized trials. Eur Heart J 2021;42:2765–75. https://doi.org/10.1093/ eurheartj/ehab115; PMID: 33769515. 16. Tong DC, Quinn S, Nasis A, et al. Colchicine in patients with acute coronary syndrome: the Australian COPS randomized clinical trial. Circulation 2020;142:1890–900. https://doi. org/10.1161/CIRCULATIONAHA.120.050771; PMID: 32862667. 17. Page MJ, McKenzie JE, Bossuyt PM, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ 2021;372:n71. https://doi.org/10.1136/bmj.n71; PMID: 33782057. 18. Higgins JPT, Sterne JAC, Savović J, et al. A revised tool for assessing risk of bias in randomized trials. Cochrane Database Syst Rev 2016;10(Suppl 1):29–31. https://doi. org/10.1002/14651858.CD201601. 19. Bagos PG, Nikolopoulos GK. Mixed-effects Poisson regression models for meta-analysis of follow-up studies with constant or varying durations. International Journal of Biostatistics 2009;5:21. https://doi.org/10.2202/15574679.1168. 20. Stijnen T, Hamza TH, Ozdemir P. Random effects metaanalysis of event outcome in the framework of the generalized linear mixed model with applications in sparse data. Stat Med 2010;29:3046–67. https://doi.org/10.1002/ sim.4040; PMID: 20827667. 21. Spittal MJ, Pirkis J, Gurrin LC. Meta-analysis of incidence rate data in the presence of zero events. BMC Med Res Methodol 2015;15:42. https://doi.org/10.1186/s12874-015-00310; PMID: 25925169. 22. Nuovo J, Melnikow J, Chang D. Reporting number needed to treat and absolute risk reduction in randomized controlled trials. JAMA 2002;287:2813–4. https://doi. org/10.1001/jama.287.21.2813; PMID: 12038920. 23. Walter SD, Sinclair JC. Uncertainty in the minimum event risk to justify treatment was evaluated. J Clin Epidemiol 2009;62:816–24. https://doi.org/10.1016/j. jclinepi.2008.09.017; PMID: 19216053. 24. Higgins JPT, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analysis. BMJ 2003;327:557–60; https://doi.org/10.1136/bmj.327.7414.557; PMID: 12958120. 25. Peters JL, Sutton AJ, Jones DR, et al. Contour-enhanced meta-analysis funnel plots help distinguish publication bias from other causes of asymmetry. J Clin Epidemiol 2008;61:991–6. https://doi.org/10.1016/j.jclinepi.2007.11.010; PMID: 18538991. 26. Altman DG, Bland JM. Interaction revisited: the difference

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between two estimates. BMJ 2003;326:219. https://doi. org/10.1136/bmj.326.7382.219; PMID: 12543843. 27. O’Keefe JH Jr, McCallister BD, Bateman TM, et al. Ineffectiveness of colchicine for the prevention of restenosis after coronary angioplasty. J Am Coll Cardiol 1992;19:1597– 600. https://doi.org/10.1016/0735-1097(92)90624-v; PMID: 1593057. 28. Raju NC, Yi Q, Nidorf M, et al. Effect of colchicine compared with placebo on high sensitivity C-reactive protein in patients with acute coronary syndrome or acute stroke: a pilot randomized controlled trial. J Thromb Thrombolysis 2012;33:88–94. https://doi.org/10.1007/s11239-011-0637-y; PMID: 21918905. 29. Nidorf SM, Eikelboom JW, Budgeon CA, Thompson PL. Lowdose colchicine for secondary prevention of cardiovascular disease. J Am Coll Cardiol 2013;61:404–10. https://doi. org/10.1016/j.jacc.2012.10.027; PMID: 23265346. 30. Deftereos S, Giannopoulos G, Raisakis K, et al. Colchicine treatment for the prevention of bare-metal stent restenosis in diabetic patients. J Am Coll Cardiol 2013;61:1679–85. https://doi.org/10.1016/j.jacc.2013.01.055; PMID: 23500260. 31. Akodad M, Lattuca B, Nagot N, et al. Value of colchicine in the treatment of patients with acute myocardial infarction and inflammatory response. Arch Cardiovasc Dis 2017;110:395–402. https://doi.org/10.1016/j.acvd.2016.10.004; PMID: 28065445. 32. Shah B, Pillinger M, Zhong H, et al. Effects of acute colchicine administration prior to percutaneous coronary intervention: COLCHICINE-PCI randomized trial. Circ Cardiovasc Interv 2020;13:e008717. https://doi.org/10.1161/ CIRCINTERVENTIONS.119.008717; PMID: 32295417. 33. Bouabdallaoui N, Tardif JC, Waters DD, et al. Time-totreatment initiation of colchicine and cardiovascular outcomes after myocardial infarction in the Colchicine Cardiovascular Outcomes Trial (COLCOT). Eur Heart J 2020;41:4092–9. https://doi.org/10.1093/eurheartj/ehaa659; PMID: 32860034. 34. Xia M, Yang X, Qian C. Meta-analysis evaluating the utility of colchicine in secondary prevention of coronary artery disease. Am J Cardiol 2021;140:33–8. https://doi.org/10.1016/j. amjcard.2020.10.043; PMID: 33137319. 35. Aimo A, Pascual-Figal DA, Barison A, et al. Colchicine for the treatment of coronary artery disease. Trends Cardiovasc Med 2020. https://doi.org/10.1016/j.tcm.2020.10.007; PMID: 33096241; epub ahead of press. 36. Andreis A, Imazio M, Piroli F, et al. Efficacy and safety of colchicine for the prevention of major cardiovascular and cerebrovascular events in patients with coronary artery disease: a systematic review and meta-analysis on 12,869 patients. Eur J Prev Cardiol 2021. https://doi.org/10.1093/ eurjpc/zwab045; PMID: 33779702; epub ahead of press.

Women and Heart Disease

Women and Diabetes: Preventing Heart Disease in a New Era of Therapies Giuseppe Galati ,1 Pierre Sabouret ,2 Olga Germanova

and Deepak L Bhatt

1. Heart Failure Unit and Division of Cardiology, Cardiothoracic and Vascular Department, San Raffaele Hospital and Scientific Institute (IRCCS), Milan, Italy; 2. Heart Institute, Cardiology Department, Pitié-Salpétrière, Sorbonne University and Collège National des Cardiologues Français, Paris, France; 3. Department of Diagnostic Medicine and Imaging, Samara State Medical University, Samara, Russia; 4. Brigham and Women’s Hospital Heart and Vascular Center, Harvard Medical School, Boston, MA, US

Abstract

Despite major advances in cardiovascular research over the past decade, women with type 2 diabetes have a high risk of cardiovascular events. Several factors contribute to the poor prognosis for women, including higher levels of frailty and comorbidities, but their cardiovascular risk is underestimated and there is suboptimal implementation and uptitration of new evidence-based therapies, leading to high morbidity and mortality. Recent studies highlight the need for better management of diabetes in women that can be pursued and achieved in light of recent results from randomised controlled trials demonstrating evidence of the benefits of new therapeutic strategies in improving cardiovascular outcomes and quality of life of women covering the entire cardiovascular continuum. This review critically discusses the multiple benefits for women of new pharmacological treatments, such as glucagon-like peptide-1 receptor agonists, sodium–glucose cotransporter type 2 inhibitors (SGLT2i), proprotein convertase subtilisin/kexin type 9 inhibitors, inclisiran, icosapent ethyl and bempedoic acid in preventing cardiovascular events, and treatments, such as angiotensin receptor neprilysin inhibitors, SGLT2i, vericiguat and omecamtiv mecarbil, for preventing heart failure.

Keywords

Women’s health, cardiovascular prevention, heart failure, diabetes, sodium–glucose cotransporter type 2 inhibitors. Disclosure: PS has received personal fees from Amgen, Bayer, Novartis, Sanofi-Regeneron, Servier and Vifor. DLB is on advisory boards for Cardax, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, Janssen, Level Ex, Medscape Cardiology, MyoKardia, Novo Nordisk, PhaseBio, PLx Pharma and Regado Biosciences; is on the board of directors for Boston VA Research Institute, Society of Cardiovascular Patient Care and TobeSoft; is chair of the American Heart Association Quality Oversight Committee; is on data monitoring committees for Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial, funded by St Jude Medical, now Abbott), Cleveland Clinic (including for the ExCEED trial, funded by Edwards), Contego Medical (Chair, PERFORMANCE 2), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi Sankyo) and Population Health Research Institute; has received honoraria from American College of Cardiology, Baim Institute for Clinical Research (RE-DUAL PCI clinical trial steering committee funded by Boehringer Ingelheim; AEGIS-II executive committee funded by CSL Behring), Belvoir, Canadian Medical and Surgical Knowledge Translation Research Group, Duke Clinical Research Institute (including for the PRONOUNCE trial, funded by Ferring Pharmaceuticals), HMP Global, Journal of the American College of Cardiology, K2P, Level Ex, Medtelligence/ReachMD, MJH Life Sciences, Population Health Research Institute (for COMPASS, funded by Bayer), Slack Publications, Society of Cardiovascular Patient Care, WebMD; declares Clinical Cardiology, NCDR-ACTION Registry Steering Committee, VA CART Research and Publications Committee; has received research funding from Abbott, Afimmune, Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Cardax, Chiesi, CSL Behring, Eisai, Ethicon, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Janssen, Lexicon, Lilly, Medtronic, MyoKardia, Novo Nordisk, Owkin, Pfizer, PhaseBio, PLx Pharma, Regeneron, Roche, Sanofi, Synaptic and The Medicines Company; has received royalties from Elsevier; is site co-investigator for Abbott, Biotronik, Boston Scientific, CSI, St Jude Medical (now Abbott) and Svelte; is a trustee of American College of Cardiology; and has unfunded research from FlowCo, Merck and Takeda. All other authors have no conflicts of interest to declare. Received: 13 May 2021 Accepted: 27 July 2021 Citation: European Cardiology Review 2021;16:e40. DOI: https://doi.org/10.15420/ecr.2021.22 Correspondence: Giuseppe Galati, Heart Failure Unit and Division of Cardiology, Cardiothoracic and Vascular Department, San Raffaele Hospital and Scientific Institute (IRCCS), Via Olgettina 60, 20132 Milan, Italy. E: galati.giuseppe@hsr.it Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

During the past decade, new therapeutic strategies have been progressively showing a reduction in major adverse cardiac events (MACE). Nevertheless, women with type 2 diabetes (T2D) remain at very high risk of events, not only due to the disease but also because their risk is underestimated, leading to a suboptimal initiation and uptitration of new evidence-based therapies. This risk causes the progressive development of structural cardiac disease and invariably to heart failure (HF) and advanced HF, covering the full spectrum of American Heart Association/American College of Cardiology HF staging.1 This article reviews the main randomised clinical trials (RCTs) that prove the significant

cardiovascular (CV) benefits of using new pharmacological treatments, whose implementation in clinical practice would address an urgent need for the reduction of morbidity and mortality in women with T2D.

Prevention

CV events remain high in people with diabetes, especially in women.2 Indeed, recent RCTs report a high rate of MACE (MI, stroke and CV death) under optimal medical therapy (OMT), highlighted by a rate of 9.4–14.9% for 3–4 years follow-up.3–5 To optimise CV prevention in women, three specific periods present themselves as an appropriate time to check

Women and Diabetes clinical status and provide healthy lifestyle advice: when discussing contraceptive choices; before, during and after pregnancy; and during the menopause. A primary care visit for contraception is a good opportunity to check the clinical status of the patient and to provide key messages promoting healthy habits, including food intake, physical activities, stress management and lifestyle. Information about T2D and its associated risks should be given to help reduce the risk of CV events. During pregnancy, detection of diabetes is crucial, because gestational diabetes is a strong risk factor for future MACE. A glucose screening test should be performed for every pregnancy. If diabetes is suspected, the diagnosis should be confirmed with a 2-hour glucose tolerance test. Management of gestational diabetes includes a healthy diet, regular exercise (150 minutes per week of moderate-intensity activity) and, if needed, metformin ± insulin with advice and information on preventing episodes of hypoglycaemia. An ultrasound exam between gestational weeks 18 and 20 will detect potential abnormalities in the foetus. Further ultrasound scans at weeks 28, 32 and 36 to monitor the growth of the foetus and the volume of amniotic fluid are recommended, in combination with regular visits from week 38 onwards. The optimal time for delivery is usually considered to be between weeks 38 and 40. After 40 weeks and 6 days, induction of labour or a caesarean are the two medical options to be discussed. Earlier delivery is recommended in cases where diabetes control is poor despite diet and pharmacological options, in order to protect both the baby and the mother. It is recommended that the baby is fed within 30 minutes of delivery, then every 2–3 hours until the baby’s glycaemic levels become stable.6 The glycaemia of the newborn is tested starting 2–4 hours after birth until it becomes stable. If the glycaemic levels of the newborn are not well controlled, a temporary transfer to the neonatal unit may be required for closer monitoring. After discharge, the baby should have a new glycaemic test 6–12 weeks after birth. An early test to check new diabetes in a woman who has had gestational diabetes is mandatory due to the increased risk of developing T2D. At 10 years follow-up, after adjustment for ethnicity and age, gestational diabetes is associated with an increased relative risk of CV morbidity between 1.8 and 2.3.7 Therefore, long-term monitoring of women who have had gestational diabetes is highly recommended, with a calcium coronary score performed after the age of 40 to better define the CV risk.

disease (ASCVD) but also for HF, because diabetes causes structural myocardial, coronary and vascular disease, and leads to chronic neurohormonal activation of the angiotensin–aldosterone system and sympathetic nervous system that in the long run is deleterious and causes hydrosaline retention, congestion and translates to a high risk of CV death.8 Optimal management of diabetes in women is challenging due to the under-representation of women in RCTs and registries, highlighting the need of dedicated studies for women (Table 1). Ageing and the high prevalence of comorbidities also represent documented barriers to optimal management. Nevertheless, underestimation of the CV risk and therapeutic inertia contribute to the poorer prognosis of women with diabetes which has been underlined by several registries, where the detection of CV risk is inadequate and women receive fewer recommended treatments with the target dose when compared to men. Recently, new therapeutic classes have emerged which provide additional CV and renal benefits. The development of new classes acting not only on glycaemic control but also by multiple mechanisms already represent valid options to further reduce CV events in women. The modern approach should not only focus only on HbA1c level but much more on a holistic strategy to improve life expectancy and quality of life (QoL). The glucagon-like peptide-1 receptor agonists (GLP-1 RA) are the first class with further CV benefits reported in several RCTs, with heterogeneity between molecules, whereas CV and renal benefits have been proven with several sodium-glucose cotransporter 2 inhibitors (SGLT2i) in EMPAREG Outcome, EMPEROR-Reduced (empagliflozin), CANVAS Program and CREDENCE (canagliflozin), DECLARE-TIMI 58, DAPA-HF (dapagliflozin), SCORED and SOLOIST-WHF (sotagliflozin), and seem homogenous, even if only sotagliflozin provided a stroke reduction.3–5,9 Once again, women are under-represented in these RCTs, but the reported results were homogenous among groups with no sex differences.

New Anti-diabetic Classes That Act on Glycaemic Levels and Reduce Cardiovascular Events Sodium–Glucose Cotransporter 2 Inhibitors

The third crucial period is the transition leading to menopause when the risk of CV events increases whereas management remains poor. Hypertension, dyslipidaemia, obesity and other issues with the metabolic syndrome represent the main risk factors for T2D in the peri-menopausal period, but these remain insufficiently detected and treated in women. Hypertension is a very strong risk factor at this stage and the control of blood pressure is pivotal. Although hormone replacement therapy is effective for decreasing vasomotor symptoms linked to menopause, this option is not recommended due to its negative effects on the CV system.6 Collaboration between GPs, cardiologists and gynaecologists is crucial to better identify high-risk perimenopausal women. Collaboration centred on the individual woman, with shared decision-making, would provide better detection and long-term management of women with diabetes to prevent MACE.

SGLT2is act by inhibiting glucose reabsorption in the kidneys, which increases urinary excretion of glucose and allows for better glycaemic control in people with T2D. SGLT2i work independently of insulin regulation and β-cell function. Major RCTs have reported CV benefits and renal protection with five SGLT2is (empagliflozin, canagliflozin, dapagliflozin, ertugliflozin and sotagliflozin). Recent meta-analyses reported that SGLT2is not only reduce the risk of new-onset HF, hospitalisations for HF (HHF), protect from worsening renal function and end-stage renal disease (ESRD), but also reduce all-cause as well as CV death, with similar benefits in patients in primary or secondary prevention and with and without a history of HF.10,11 Moreover, these meta-analyses report a reduction in MI by 25% compared to OMT – with a specific benefit regarding this endpoint proved by canagliflozin in the CREDENCE trial and sotagliflozin in the SCORED trial – without apparent benefits in stroke reduction, except for the recent SCORED trial, requiring further investigation to better understand the underlying mechanisms providing these benefits.9 The magnitude of benefits varied according to baseline CV risk and renal function. Furthermore, two SGLT2i demonstrated efficacy in HF not only in patients with diabetes but also in the prespecified group of non-diabetic patients.

This call for action for women with diabetes is motivated by the cumulative data that shows they have a very high risk not only for atherosclerotic CV

The same limitations concerning women’s inclusion and sample size were observed and no heterogeneity was found according to sex for

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Women and Diabetes Table 1: Women’s Benefit in Randomised Controlled Trials Dedicated to Prevention for Different Class of Drugs Total Population, Women Enrolled, n (%)

Primary Endpoint

CV Death

Selected Major Secondary Outcome Benefit

EMPA-REG OUTCOME3

Total 7,020 Women 2,004 (28.5%)

CV death + non-fatal MI + non-fatal stroke HR 0.86; 95% CI [0.74–0.99]; p=0.04 for superiority RRR 14%

HR 0.62; 95% CI [0.49–0.77]; p<0.001 RRR 38%

HHF HR 0.65; 95% CI [0.50–0.85]; p=0.002 RRR 35%

CANVAS4

Total 10,142 Women 3,633 (35.8%)

CV death + non-fatal MI + non-fatal stroke: HR 0.86; 95% CI [0.75–0.97]; p=0.02 for superiority RRR 14%

HR 0.87; 95% CI [0.72–1.06]; p=not significant

HHF HR 0.67; 95% CI [0.52–0.87] RRR 23%

DECLARE-TIMI 585

Total 17,160 Women 6,422 (37.4%)

CV death or HHF HR 0.83; 95% CI [0.73–0.85]; p=0.005 RRR 17%

HR 0.98; 95% CI [0.82−1.17] p=not significant

HHF HR 0.73; 95% CI [0.61–0.88] RRR 27%

HR 0.90; 95% CI [0.73–1.12]; p=not significant

Total HHF + urgent visit for HF HR 0.67; 95% CI [0.55–0.82]; p<0.001 RRR 33%

Trial

SGLT2is

Co-primary efficacy endpoint: CV death + MI + ischaemic stroke HR 0.76; 95% CI [0.84–1.03]; p=0.17 (not significant) SCORED9

Total 10,584 Women 4,754 (44.9%)

CV death + HHF + urgent visit for HF HR 0.74; 95% CI [0.63–0.88]; p=0.0004 RRR 26% Co-primary endpoint: CV death + MI + stroke HR 0.84; 95% CI [0.72–0.99]; p=0.035 RRR 16%

GLP1-RA LEADER12

Total 9,340 Women 3,337 (35.7%)

CV death + non-fatal MI + non-fatal stroke HR 0.87; 95% CI [0.78–0.97]; p=0.01 for superiority RRR 13%

HR 0.78; 95% CI [0.66–0.93]; p=0.007 RRR 22%

MI HR: 0.86; 95% CI [0.73–1.00]; p=0.046 RRR 14%

REWIND14

Total 9,901 Women 4,589 (46.3%)

CV death + non-fatal MI + non-fatal stroke HR 0.88; 95% CI [0.79-0.99]; p=0.026 RRR 12%

HR 0.91; 95% CI [0.78–1.06]; p=not significant

MI HR 0.88; 95% CI [0.79–0.99]; p=0.026 RRR 12%

SUSTAIN-615

Total 3,297 Women 1,215 (36.8%)

CV death + non-fatal MI + non-fatal stroke HR 0.74; 95% CI [0.58–0.95]; p<0.001 for non-inferiority RRR 26%

HR 0.98; 95% CI [0.65–1.48]; p=not significant

MI HR 0.74; 95% CI [0.51–1.08]; p= not significant RRR 26%

FOURIER18

Total 27,564 Women 6,769 (24.6%)

CV death + MI + stroke + hospitalisation for UA HR 1.05; 95% CI [0.88–1.25]; + coronary revascularisation p=not significant HR 0.85; 95% CI [0.79–0.92]; p<0.001 RRR 15%

MI HR 0.73; 95% CI [0.65–0.82]; p<0.001 RRR 27%

ODYSSEY-OUTCOME19

Total 18,924 Women 4,762 (25.2%)

Coronary heart disease-death, non-fatal MI + ischaemic stroke + hospitalisation for UA HR 0.85; 95% CI [0.78–0.93]; p<0.001 RRR 15%

HR 0.88; 95% CI [0.74–1.05]; p=not significant

MI HR 0.86; 95% CI [0.77–0.96] RRR 14%

ORION 10 and 1122

Total 3,178 Women 935 (29.4%)

LDL cholesterol decrease HR 0.50; p<0.01 for superiority RRR 49.9 %

NA*

Total 8,179 Women 2,357 (28.8%)

CV death + non-fatal MI + non-fatal stroke + UA HR 0.80; 95% CI [0.66–0.98]; + coronary revascularisation p=0.03 HR 0.75; 95% CI [0.68–0.83]; p<0.001 RRR 20% RRR 25%

MI HR 0.69; 95% CI [0.58–0.81]; p<0.001 RRR 31%

Total 2,230 Women 602 (27%)

Any adverse event HR 0.95; p=0.91 RRR 5%

NA*

PCSK9i

Icosapent Ethyl REDUCE-IT23

Bempedoic Acid CLEAR HARMONY26

NA*

*Trials designed for safety and lipid level reduction. CV = cardiovascular; GLP-1 RA = glucagon-like peptide-1 receptor agonists; HF = heart failure; HHF = hospitalisation for heart failure; NA = not available; PCSK9i = proprotein convertase subtilisin/kexin type 9; RRR = relative risk reduction; SGLT2i = sodium-glucose co-transporter type 2 inhibitors; UA = unstable angina.

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Women and Diabetes this therapeutic class. Therefore, even if specific studies in women are warranted to better define the magnitude of benefits in this major population, it is already crucial that women with diabetes benefit early from these two classes in the therapeutic strategy. Choice of the class should be a shared decision according to the woman’s preferences (one weekly injection versus one daily pill), BMI (as weight loss is more pronounced with GLP-1 RA), HbA1c level (SGLT2is lower HbA11c by 0.4– 0.6%; GLP-1 RA by 0.8–1%), renal function, atherothrombotic profile and documented HF. The optimal time to initiate treatment may be discussed, but the strong trend in preventing CV events is to start as soon as possible to decrease the loading of glycaemia, dyslipidaemia and blood pressure.

Glucagon-like Peptide-1 Receptor Agonists

GLP-1 RA work via multiple mechanisms. Their incretin effect – a pleiotropic mechanism – reduces gastric emptying, but mainly acts on plasma glucose modulation through the stimulation of insulin release and reduction of hepatic glucose release (partially mediated by suppressing glucagon secretion). GLP-1 RA initially have been approved for the treatment of T2D because their glucose-lowering effect was associated with a reduction in weight and blood pressure. Liraglutide was the first in class to report CV benefits in the LEADER trial, with a reduction of the primary composite outcome (CV death, MI or stroke) by 13% in the liraglutide group (p<0.001 for non-inferiority; p=0.01 for superiority), a 22% relative RR (RRR) for CV death (p=0.007), and a 15% RRR for all-cause mortality (p=0.02).12,13 Further benefits have been reported in two additional RCTs (REWIND and SUSTAIN-6), with no sex differences observed.14,15 Therefore, European Society of Cardiology (ESC)/ European Association for the Study of Diabetes (EASD) guidelines recommended both classes early in the treatment algorithm, either as monotherapy or in combination with metformin, without sex-related specificities.16 In the setting of HF and/or chronic kidney disease (CKD), SGLT2is provide more benefits than GLP-1RA and are the preferred option for women with diabetes.17

New Therapies Providing Benefits in Women with Diabetes Outside Glucose Metabolism Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitors and Inclisiran

These two classes of drugs inhibit the proprotein convertase subtilisin/ kexin type 9 (PCSK9), which modulates the cholesterol level, mainly by reducing the numbers of LDL receptors on the plasma membrane. Two RCTs evaluating PCSK9 inhibitors (FOURIER and ODYSSEY Outcomes) reported CV benefits for a short-term follow-up (about 2 years), one in ASCVD patients including chronic coronary stable patients, peripheral artery disease and people who have had a stroke, the other in patients with post-acute coronary syndromes.18–20 In patients with LDL cholesterol levels of 1.8 mmol/l or higher under maximal tolerated dose of statin therapy, both PCSK9is reduce the primary combined endpoint with a RRR of 15%, without a warning signal on safety even for very low LDL cholesterol levels. As the CV risk was higher in people with diabetes, the clinical benefits of PCSK9i were more pronounced without sex differences. Glycaemic parameters remained unchanged with either PCSK9is. Inclisiran is a small interfering RNA molecule, which targets the hepatic production of PCSK9. Inclisiran induces gene silencing through repression of transcription of specific genes, promoting cleavage and elimination of PCSK9, and reduces LDL cholesterol by 50–70% without any safety signals to date. This safety and biological efficacy were first observed in

Phase II clinical trials, and the on-going RCT Phase III ORION 4 (NCT03705234) is evaluating the clinical efficacy of inclisiran versus placebo in ASCVD patients, including women with diabetes.21 The results are expected in 2025.

Icosapent Ethyl

Icosapent ethyl (EPA) is a purified eicosapentaenoic acid formulation which reduces hepatic production and secretion of very low-density lipoproteins, increasing triglycerides clearance without major safety concerns. The clinical efficacy has been proven in the REDUCE-IT trial, which enrolled ASCVD patients (70.7%) or patients with diabetes and associated CV risk factors.22,23 Almost all patients (99.5%) were on statin therapy with a triglyceride level of 3.5–12.9 mmol/l at inclusion, and 8,179 patients (2,357 women) were randomised to 4 g/day of EPA or placebo. EPA reduced the primary composite endpoint (CV death, non-fatal MI, non-fatal stroke, coronary revascularisation or unstable angina) by 25% RRR (p<0.0001) after a mean follow-up of 4.9 years. The clinical efficacy of EPA was more pronounced in people with diabetes without sex differences, and seems to be unrelated either to achieved triglycerides or LDL cholesterol levels, suggesting other underlying mechanisms. As in Phase II trials, no major safety issues were reported, except a slight increased risk of hospitalisation for AF (3.1% versus 2.1%; p=0.004). EPA therefore represents an option to reduce MACE in women with diabetes following the National Lipid Association statement.24

Bempedoic Acid

Bempedoic acid (ETC-1002) inhibits adenosine triphosphate citrate lyase, which decreases cholesterol production in the liver. The decreased cholesterol synthesis promotes LDL receptor upregulation and thereby decreases plasma LDL cholesterol. ETC-1002 is converted to its active moiety in the liver by the very long-chain acyl-CoA synthetase-1, an enzyme absent in skeletal muscle, which explains why ETC-1002 is not associated with muscle symptoms and can be particularly useful in patients with statin intolerance.25 In summary, prevention in women with T2D remains suboptimal and may be improved by combining these novel therapeutic strategies with nonpharmacological measures. All these pharmacological agents have proven clinical efficacy without serious safety issues. Further efforts are needed to promote widespread use of these strategies for women, who are frequently under-treated despite recent educational campaigns to better assess and manage their CV risk. Dedicated studies in women with diabetes are warranted.

Heart Failure Management

Even if good preventive therapies are started, T2D patients who are in Stage A maintain a high risk of developing structural heart diseases (Stage B) and progressing to overt HF (Stages C and D).1 As shown by a large number of registries and meta-analyses including millions of patients, this portends a risk of 5-year mortality higher than many cancers and an extremely low QoL, influenced by the high rate of rehospitalisation and by symptoms and reduced activity as measured by several dedicated questionnaires, such as the Kansas City Cardiomyopathy Questionnaire (KCCQ).26–29 The major impact of HF development is even more ominous in women. Indeed, as recently highlighted by reviews and meta-analyses, women receive later referrals to HF treatment centres compared with men, are under-enrolled in dedicated HF RCTs, receive cardiac resynchronisation therapy/ICD and left ventricular assist device/heart transplant less frequently, have higher mortality on the heart transplant waiting list and have worse QoL.30,31

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Women and Diabetes Despite HF being more frequent in women than in men, women are systematically under-enrolled in RCTs so that the specific benefits of HF drugs are less well known.32 In fact, women represent a specific population in which not only the exact dosages (that can be lower or equal), but also the pathophysiological pathways (that can be involved with different magnitude or can even be different) of HF drugs are less studied and understood because women have been treated as ‘smaller men’ which is evidently wrong. RCTs dedicated to HF usually enrol a maximum of 30% of women – at least in part due to under-enrolment of older patients, a higher percentage of whom are women. We strongly hope that will change and we encourage researchers to conduct dedicated RCTs for women or to enrol higher percentages of women to fill our knowledge gap. On the other hand, T2D patients are well represented in some of the most recent HF RCTs (ranging from 34.9–49.8%), reflecting the percentage of T2D in HF reported by large clinical registries (about 40%).33,34 After more than 30 years of triple therapy – angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blocker (ARB), β-blockers and mineralocorticoid receptor antagonists (MRA) – ivabradine represented a first, small improvement in reducing HHF and HF death without any improvements on CV death and all-cause death.35 The real revolution in HF with reduced ejection fraction (HFrEF) therapy started in 2014 with PARADIGM-HF, which proved a further reduction of major outcomes using the angiotensin receptor neprilysin inhibitor (ARNI) sacubitril/valsartan compared with the ACEi enalapril, and continued from 2019 to now with the new class of drugs SGLT2is and with the new drugs vericiguat and omecamtiv mecarbil.36

SGLT2is: The New Pillar of Cardiorenal Benefit in HF and Chronic Kidney Disease

As previously mentioned, meta-analyses of RCTs dedicated to prevention in T2D have demonstrated a significant benefit on CV death and MACE, but the magnitude of benefit was unexpectedly greater on the endpoints of CV death and HHF, and significant for each individual RCT and not only in the pooled analysis.10

Chronic Heart Failure with Reduced Ejection Fraction

Noticing this evident benefit, all the developers of SGLT2is designed RCTs exclusively dedicated to HF patients with and without T2D, such as EMPEROR-Reduced (empagliflozin in HFrEF), EMPEROR-Preserved (empagliflozin in heart failure with preserved ejection fraction [HFpEF]), CHIEF-HF (canagliflozin in both HFrEF and HFpEF), DAPA-HF (dapagliflozin in HFrEF), DELIVER (dapagliflozin in HFpEF) and SOLOIST-WHF (sotagliflozin in AHF).38,41,44,50 The first published RCT was DAPA-HF on dapagliflozin in HFrEF.37 DAPA-HF enrolled and randomised 4,744 patients with the following characteristics mean age 66.4 years, 23% women, T2D 41.8%, New York Heart Association (NYHA) stage II 67.5%, median N-terminal pro-B type natriuretic peptide (NTpro-BNP) was 1,437 pg/ml, mean estimated glomerular filtration rate (eGFR) was 66 ml/min/1.73 m2, 40.2% had eGFR <60 ml/min/1.73 m2. Key inclusion criteria are shown in Supplementary Material Table 1 and detailed demographic and clinical characteristics are shown in Table 2. Considering OMT, patients were well treated: ACEi/ARB/ARNI pooled 94% (split: ACEi 56%, ARB 28%, ARNI 11%), β-blockers 96%, MRA 71%, ivabradine 5%. The OMT percentages of DAPA-HF were even better than that of PARADIGM-HF. Noticeably, as in PARADIGM-HF, the percentages of CRT/ICD were particularly low in DAPA-HF (7% and 26%, respectively), showing the intention to test the efficacy of the drug before the implantation of any devices (Table 2).

After a mean follow-up of 18.2 months, dapagliflozin 10 mg/day versus placebo significantly reduced the primary endpoint: a composite of CV death and first HHF and urgent visit for worsening HF (WHF; (HR 0.74; 95% CI [0.65–0.85] p=0.00001) with a RRR of 27% and a number needed to treat (NNT) of 21. Note that WHF is considered an equivalent of HHF in the last ESC criteria for advanced HF. See Table 3 for the effect on other major outcomes.38 Beyond the remarkable results achieved in reducing CV death and all-cause death, the secondary endpoint dedicated to QoL in HFrEF was significantly reduced, as demonstrated by the improvement in the total symptoms score of the KCCQ.39 In DAPA-HF there were no differences regarding the incidence of the secondary endpoint ‘worsening renal function’ – a composite of sustained ≥50% reduction in eGFR, ESRD or death from renal causes (HR 0.71; 95% CI [0.44–1.16]; p=0.17). By far the most remarkable result has been the pre-specified subgroup analyses, which did not show any difference regarding the reduction of primary endpoint between diabetic patients (HR 0.75; 95% CI [0.63–0.90]) and non-diabetic patients (HR 0.73; 95% CI [0.60–0.88]). In particular, non-diabetic patients had a RRR of 27% for the primary endpoint, representing the real and unexpected result of DAPA-HF. Importantly, there was no difference between the magnitude of reduction of the primary endpoint in patients with eGFR >60 versus <60 ml/min/1.73m2. Consistently, dapagliflozin did not signal safety concerns, indeed, there were no significant differences versus placebo in terms of volume depletion, renal adverse events, fractures, limb amputations, major hypoglycaemia (also shown in patients without T2D), diabetic ketoacidosis, urinary infections or all infections; whereas any serious adverse events were significantly higher in the placebo than in the dapagliflozin group. These results represented a breakthrough in HFrEF management because dapagliflozin provided additional benefits on top of OMT (including 11% of patients on ARNI) irrespective of diabetic status and this is also valid for women. The second RCT published on HF was EMPEROR-Reduced, dedicated to empagliflozin in HFrEF.40 EMPEROR-Reduced enrolled and randomised 3,730 patients with a similar design to DAPA-HF. However, EMPERORReduced studied a population with a more compromised renal function (mean eGFR 62 ml/min/1.7m2, 48.3% had eGFR<60 ml/min/1.73 m2) and a more severe HFrEF, characterised by a lower mean LVEF (27.5%), higher levels of median NT-pro-BNP (1,906 pg/ml), and an annual placebo event rate of 20% (compared to the 15% of the population enrolled in DAPA-HF) despite a better OMT, i.e. a greater percentage of patients in ARNI (19.5%; Table 2). After a mean follow-up of 16 months, empagliflozin 10 mg/day versus placebo on top of HFrEF standard of care, significantly reduced (HR 0.75; 95% CI [0.65–0.86]; p<0.001) the primary endpoint – a composite of CV death and first HHF with a RRR of 25% and an NNT of 19 – the first hierarchical secondary endpoint (total HHF; Table 3) and significantly improved the second hierarchical secondary endpoint, the mean slope of change in eGFR (HR 1.3; 95% CI [1.10–2.37] p<0.001). The renal benefit has also proved by the reduction of the composite renal endpoint (ESRD + sustained profound eGFR decrease) (HR 0.50; 95% CI [0.32–0.77]) with a RRR of 50%. Beyond the results achieved on primary and secondary endpoints, empagliflozin also showed a significant benefit on QoL in HFrEF measured by the symptoms score of the KCCQ that was significantly better than placebo (p=0.0058; absolute difference 1.7). As in DAPA-HF, the prespecified subgroup analyses did not show any significant difference regarding the reduction or primary endpoint between diabetic patients (HR 0.72; 95% CI [0.60–0.87]; RRR 28%) and non-diabetic patients

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Women and Diabetes Table 2: Comparison of Different Populations Enrolled and of Different Outcomes in Major RCTs in Chronic HFREF PARADIGM-HF37

DAPA-HF38

EMPERORReduced41

GALACTIC-HF76

VICTORIA70

Main Baseline Characteristics of Different Populations Enrolled Total population enrolled

8,442

4,744

3,730

8,256

5,050

Mean age, years

63.8

66.4

66.9

64.5

67.3

Women

22%

23%

24%

21.3%

23.9%

Class II

70.9%

67.5%

75.1%

53.2%

59.0%

Class III

24.1%

31.6%

24.4%

43.8%

39.7%

Class IV

0.7%

0.9%

0.5%

3.0%

1.3%

LVEF (%; mean)

29.5

31.1

27.5

26.6

28.9

NT-pro-BNP, median, pg/ml

1,608

1,437

1,906

1,971

2,816

Previous HF hospitalisations Any time

63%

47.4%

30.8%

74.4%

83.9%

N/A

27%

30.8%

74.4%

83.9%

31.1%

16.4%

N/A

54.6%

83.9%

19.1%

7.8%

N/A

36.2%

66.7%

Currently hospitalised for AHF (worsening)

N/A

25.2%

N/A

Ischaemic aetiology

59.7%

56.4%

51.7%

54.0%

58.3%

Stroke

8.7%

9.9%

11.3%

9.1%

11.5 %

Hypertension

71.2%

74%

72.3%

70.3%

79.1%

Anaemia

20.3%

27.6%

N/A

20.9%

COPD

12.9%

12.3%

11.9%

16.3%

17.2%

AF/flutter

37%

38.3%

36.7%

42.1%

44.9%

Systolic blood pressure (mmHg mean)

121

122

117

121

Heart rate (beats/min mean)

NYHA classification

≤12 months randomisation ≤6 months randomisation ≤3 months randomisation

eGFR (ml/min/1.73 m ) Mean

65.8

60.3

61.5

<60 ml/min/1.73 m2

33%

40.2%

48.3%

52.5%

52%

T2D

34.9%

41.8%

49.8%

40.1%

46.9%

Comparison of HFREF GDMT ACE-I/ARB

100%

83.7%

69.7%

67.4%

73.5%

ARNI

N/A

10.7%

19.5%

19.3%

14.5%

β-blocker

93.6%

96.1%

94.7%

94.0%

93.1%

MRA

55.3%

71%

71.3%

77.0%

70.3%

Ivabradine

N/A

6.5%

N/A

SGLT2i

N/A

2.7%

N/A

ICD

14.9%

26.2%

31.4%

31.7%

27.8%

CRT

6.8%

7.5%

11.8%

14.0%

14.7%

Annualised Event Rate in the Comparator Group CV death

7.5%

7.9%

8.1%

10.8%

13.9%

First HF hospitalisation

8.5%

9.8%

15.5%

15.2%

29.1%

All-Cause Death Observed in the Total Follow-up in the Comparator Group Mean follow-up (months)

18.2

16.0

21.8

10.8

All-cause death

19.8%

13.9%

14.2%

25.9%

21.2%

AHF = acute heart failure; CV = cardiovascular; COPD = chronic obstructive pulmonary disease; CRT = cardiac resynchronisation therapy; eGFR = estimated glomerular filtration rate; HF = heart failure; LVEF = left ventricular ejection fraction; NT-pro-BNP = N-terminal pro-B type natriuretic peptide; NYHA = New York Heart Association; SGLT2i = sodium-glucose cotransporter type 2 inhibitors; T2D = type 2 diabetes.

(HR 0.78;95% CI [0.64–0.97]; RRR 22%) and between patients with eGFR>60 versus <60 ml/min/1.73 m2. Empagliflozin showed the same safety profile dapagliflozin in HFrEF, especially regarding volume

depletion, hypotension, bone fractures, limb amputations, severe hypoglycaemia (also in patients without T2D), diabetic ketoacidosis and urinary infections. As in the RCTs dedicated to prevention, empagliflozin

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Women and Diabetes Table 3: Women’s Benefit in RCTs Dedicated to HF for SGLT2is Trial

Primary Endpoint

CV Death

HF Events

Total HHF and CV Death

Total HHF

All-cause Mortality

Chronic HFrEF DAPA-HF

CV death + first HHF + urgent visits for WHF HR 0.74; 95% CI [0.65-0.85] p=0.00001 RRR 26%

HR 0.82; 95% CI [0.69–0.98]; p=0.029 RRR 18%

First HHF and urgent visits for WHF HR 0.70; 95% CI [0.59–0.83]; p=0.00003 RRR 30%

0.75; 95% CI [0.65–0.88]; p=0.0002 RRR 25%

HR 0.71; 95% CI [0.61–0.82]; p<0.01 RRR 29%

HR 0.83; 95% CI [0.71–0.97) p=0.022 RRR 17%

EMPERORReduced

CV death + first HHF HR 0.75; 95% CI [0.65–0.86]; p<0.001 RRR 25%

HR 0.92; 95% CI [0.75–1.12]; p=not significant RRR 8%

First HHF HR 0.69; 95% CI [0.59–0.81]; p<0.001 RRR 31%

HR 0.70; 95% CI [0.58–0.85]; p<0.01 RRR 30%

HR 0.92; 95% CI [0.77–1.10]; p=not significant RRR 8%

CV death + total HHF + urgent visits for WHF HR 0.67; 95% CI [0.52–0.85]; p=0.0009 RRR 33%

HR 0.84; 95% CI [0.58–1.22]; p=not significant RRR 16%

Total HHF + urgent visits for WHF HR 0.64; 95% CI [0.49–0.83]; p<0.001 RRR 36%

HR 0.82; 95% CI [0.59–1.14]; p=not significant RRR 18%

Acute HF SOLOIST-WHF

CV = cardiovascular; HF = heart failure, HFrEF = heart failure with reduced ejection fraction; HHF = hospitalisation for heart failure; NA = not applicable; RCT = randomised clinical trial; RRR = relative risk reduction; SGLT2i = sodium-glucose cotransporter type 2 inhibitors; WHF = worsening heart failure.

significantly increased genital infections compared to placebo, but these represented only 1.7% of patients in the empagliflozin arm (1,863); this data is not available for DAPA-HF. Finally, in EMPEROR-Reduced, CV death and all-cause death were not significantly reduced, so some authors have speculated about the impact of empagliflozin on mortality. The reasons of the lack of statistical significance have been elegantly discussed in a recent editorial.41 Previously, we mentioned that the population enrolled in EMPERORReduced had a higher annual placebo event rate of the primary endpoint when compared to the population of DAPA-HF (24.7 versus 15.3 per 100 person-years). A further analysis of the placebo event rate showed that the rate of CV death was nearly the same between the two RCTs (8.1 versus 7.9 per 100 person-years in the placebo group for EMPERORReduced and for DAPA-HF, respectively) whereas the rate of first HHF of EMPEROR-Reduced was significantly higher than in DAPA-HF (15.5 versus 9.8 per 100 person-years; Table 2). This shows that in EMPEROR-Reduced the higher primary endpoint rate was driven by an elevated rate of HHF but not rate of death, and this higher primary endpoint rate led to a shorter mean follow-up of this RCT when compared to DAPA-HF (16.0 versus 18.2 months). On the other side, the sample size of patients enrolled in EMPEROR-Reduced was significantly smaller than in DAPA-HF (3,730 versus 4,744), this had the final effect to significantly reduce the statistical power of the RCT. Indeed, there were 111 fewer CV deaths and 90 fewer all-cause deaths in EMPEROR-Reduced than in DAPA-HF (389 versus 500 and 515 versus 605). A further element aggravating this reduced statistical power on mortality was the higher study treatment discontinuation rate in EMPERORReduced, compared with DAPA-HF (17.1% versus 10.7%). Considering the significant reduction of CV death in EMPAREG-OUTCOME that was not seen in DECLARE-TIMI58, it is very likely that both drugs have the same effect in reducing CV death in T2D and in HFrEF, and the differences outlined above are related to the design and conduction of each trial. EMPEROR-Reduced demonstrated the efficacy of SGLT2i on a more severe HFrEF population and provided complementary data to those of DAPA-HF, strengthening the evidence of benefit of this class of drugs in HF.

The first meta-analysis dedicated to SGLT2i in HFrEF showed that when considered together (empagliflozin and dapagliflozin) consistently reduce CV death (p=0.027 for efficacy; HR 0.86; 95% CI [0.76–0.98]; RRR 14%; p=0.39 for heterogeneity), all-cause death (p=0.018 for efficacy; HR 0.87 95% CI [0.77–0.98]; RRR 13%; p=0.39 for heterogeneity), CV death and first HHF (p<0.0001 for efficacy; HR 0.74; 95% CI [0.68–0.82]; RRR 26%; p=0.89 for heterogeneity), CV death and total HHF (p<0.0001 for efficacy; HR 0.75; 95% CI [0.68–0.84]; RRR 25%; p=0.91 for heterogeneity), first kidney composite outcome (p=0.013 for efficacy; HR 0.62; 95% CI [0.43– 0.90]; RRR 38%; p=0.42 for heterogeneity). Furthermore, the effect on the primary endpoint is independent of the fact that patients had T2D, were receiving ARNI or had an eGFR >60 versus <60 ml/min/1.73 m2.42

Acute Heart Failure

The other major RCT in HF is SOLOIST-WHF dedicated to sotagliflozin (an SGLT1i and SGLT2i) which enrolled a population with AHF.43 Following the encouraging results of EMPA-RESPONSE-AHF (a pilot study on empagliflozin in very early phases of AHF), SOLOIST-WHF enrolled 1,222 patients with the following characteristics: median age 70 years; 33.7% women; NYHA II 45.2%, NYHA III 45.8% and NYHA IV 4.4%; median LVEF 35% (79.1% had an LVEF <50%, 20.9%, LVEF ≥50%); median HbA1c 7.1%; median NT-pro-BNP was 1,799.7 pg/ml; median eGFR: 49.7 ml/min/1.73 m2; and 47.1% had a history of AF (key inclusion criteria in Supplementary Material Table 1).44 Patients were very well treated: ACEi/ARB/ARNI pooled 99.4% (ACEi: 40.5%, ARB: 42.1%, ARNi: 16.8%), β-blockers 92.1%, MRA 64.5%, loop-diuretic 95%, CRT/ICD 20.3%, any glucose-lowering medications (metformin/insulin/GLP1-RA/dipeptidyl peptidase-4 inhibitors/ sulfonylurea): 85.4%. Sotagliflozin could be started prior to discharge from the hospital until a maximum of 3 days post-discharge. Half of the patients started the drug during HHF. After a median follow-up of 9.2 months, sotagliflozin 200 mg/day (uptitrated to 400 mg/day as tolerated) versus placebo on top of HF treatments significantly reduced the primary endpoint, a composite of CV death + total HHF + urgent visits for WHF, with a RRR of 33% and NNT of 4 (HR 0.67; 95% CI [0.52–0.85]; p=0.0009). The first secondary hierarchical endpoint: total HHF + urgent visits for WHF was significantly reduced whereas CV death (the second secondary hierarchical endpoint) considered alone as well as all-cause death were not significantly reduced (Table 3).

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Women and Diabetes Beyond the endpoints on major outcomes, sotagliflozin significantly improved QoL as reported by a 4.1 point increase in KCCQ (p=0.005) and showed a significant renal benefit confirmed by the lower mean reduction in the eGFR compared to placebo after the initial treatment period (p=0.02). Similar to DAPA-HF and EMPEROR-Reduced, there were no major safety issues with sotagliflozin, with the difference of significant increase of diarrhoea (6.9% versus 4.1%) and severe hypoglycaemia (1.5% versus 0.3%) with respect to placebo.

A press release on EMPEROR-Preserved (a dedicated RCT of empagliflozin in HFmREF and HFpEF) revealed that empagliflozin has met the primary endpoint of CV death and HHF (Supplementary Material Table 1).49 The reduction of the primary endpoint is significant, so that this is the first RCT in the history of cardiology that has a significant impact on prognosis in this population. Moreover, this will confirm that SGLT2is have multiple benefits in HF irrespective of LVEF.

SOLOIST-WHF was the first RCT in the history of cardiology to demonstrate a significant reduction of major combined endpoints such as total HHF + CV death + urgent visits for WHF. Despite that, CV death, as well as allcause death, have not been significantly reduced when considered alone, but the same considerations for EMPEROR-Reduced are even more valid for SOLOIST-WHF which was largely underpowered for mortality. Indeed, loss of funding from the sponsor during enrolment – also affected by the coronavirus disease 2019 pandemic – led to the trial enrolling only 1,222 of the planned 4,000 patients and it being stopped earlier than planned.

As mentioned above, meta-analyses of RCTs dedicated to prevention in T2D provided another unexpected benefit – the significant reduction (both for each RCT and for the pooled analysis) of the composite endpoint: worsening renal function + ESRD + renal death not only in patients with an established ASCVD but also in T2D patients without ASCVD.10 Equal to what happened for HF, the developers of these drugs designed and conducted RCTs dedicated to patients with CKD, such as CREDENCE, DAPA-CKD, and EMPA-KIDNEY, the results of the first two RCTs are already published and a detailed discussion of these trials is outside of the purpose of this review.50,51 In summary, CREDENCE – dedicated to canagliflozin 100 mg/day in CKD – enrolled 4,401 patients with the following main characteristics: mean age 63 years, 33.9% women, mean eGFR 56.2 ml/min/1.73 m2 (key inclusion criteria in Supplementary Material Table 1).50 DAPA-CKD – dedicated to dapagliflozin 10 mg/day in CKD – enrolled 4,304 patients with the following main characteristics: mean age 61.9 years, 33.1% women, mean eGFR 43 ml/min/1.73 m2, 67.5% T2D, 32.5% without T2D (key inclusion criteria in Supplementary Material Table 1).51 In short, these two RCTs showed a significant reduction in the same primary endpoint – a composite of ESRD, doubling of serum creatinine, renal death, and CV death. All the secondary endpoints were significantly reduced as well, both for CREDENCE (CV death + first HHF, MACE, first HHF) and for DAPA-CKD (ESRD + renal-death + ≥50% sustained eGFR decline, CV death + first HHF, all-cause death). The most important result is probably that of DAPA-CKD because this was achieved irrespective of diabetic status.

The major conclusion is that in AHF an initiation of an SGLT2i in a late phase of hospitalisation provided significant benefits, and this is just the beginning of evidence because RCTs with a similar design such as EMPULSE (empagliflozin) and DAPA ACT HF-TIMI68 are ongoing, while DICTATE-AHF is enrolling patients with AHF who will start dapagliflozin in the early phase of HHF.45

Heart Failure with Preserved Ejection Fraction

HFpEF is a multifaceted syndrome and over the past 20 years, several efforts have been made to identify, recognise and characterise this complex syndrome that under this general label hides dozens of different diseases ranging from hypertensive heart disease, obesity, metabolic syndrome, pulmonary hypertension to cardiac amyloidosis, hypertrophic cardiomyopathy and restrictive cardiomyopathies.46 Several studies and registries showed that HFrEF and HFpEF number or comorbidities are very similar and their number is related to the patient’s age. 33,34 Furthermore, HFpEF due to its kaleidoscopic nature had several problems of definition so that recently the Heart Failure Association of the ESC redefined the diagnostic criteria to reduce the possibility of misdiagnosis.47 However, the complexity of HFpEF has never been correctly assessed over time and consequently a large number of molecules have been tested in RCTs by the ‘all-comers’ or ‘one-size-fitsall’ approach, with several failures. As a major consequence, no therapies have been shown to convincingly modify prognosis in HFpEF. This has pushed researchers to better identify specific phenotypes and to develop specific therapies for different phenotypes or different aetiologies of HFpEF. One of the clearly identified phenotypes is constituted by women with the metabolic syndrome (or even T2D) who develop concentric hypertrophy without chamber dilatation and dominant diastolic dysfunction.48 In this area, pooled data from SOLOIST + SCORED in HFpEF patients were presented. The opportunity given by this analysis is to have a larger sample size (one derived from an RCT dedicated to chronic kidney disease and the other one to HF, constituted by 739 HFpEF patients. Sotagliflozin significantly reduced the endpoint total CV death, HHF and urgent heart failure visits, with RRR 37% (HR 0.63; 95% CI [0.45–0.89]; p=0.009). The same happened with the 456 HFmrEF, with RRR 39% (HR 0.61; 95% CI [0.40–0.94]).

Chronic Kidney Disease

In conclusion, we can state that the four domains of SGLT2is are: T2D, CHF, AHF and CKD (Figure 1) and after the publication of EMPERORPreserved we will probably be able to add a fifth domain of HFpEF. Recently, we published a review in which we discussed the multiple mechanisms of cardiorenal benefits of this class of drugs with respect to the previous review we underline a recent discovery of a new mechanism that can be highly beneficial particularly to women.52,53 Indeed, two separate research groups were able to demonstrate (in human, mouse and pig models) that SGLT2i activate, both in HFrEF and in HFpEF, the pathway of nitric oxide (NO)/cyclic guanosine monophosphate (cGMP)/protein kinase G (PKG) that provokes the titin phosphorylation and ends in reducing cardiomyocyte stiffness and interstitial myocardial fibrosis, with particular benefit on diastolic function.54,55 Moreover, this pathway has important effects on vessel function and remodelling (see vericiguat) and this can be highly beneficial in particular for women that are older than men at HF diagnosis and have a more compromised vascular function. Another important clue to underline is a recent subanalysis of DAPA-HF, which demonstrated that SGLT2is cause a ‘smart’ reduction of systolic blood pressure (SBP).56 In fact, they reduce SBP only in patients with hypertension but in hypotensive patients (SBP ≤110 mmHg) they do not have any impact on blood pressure. This is a particular advantage in specific groups of HFrEF patients who have low SBP and cannot tolerate

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Women and Diabetes Figure 1: The Four Domains of Sodium–Glucose Cotransporter Type 2 Inhibitors

AHF

CKD

SGLT2i

CHF HFrEF

T2D

AHF = acute heart failure; CHF = chronic heart failure; CKD = chronic kidney disease; HFrEF = heart failure with reduced ejection fraction, SGLT2i = sodium–glucose cotransporter type 2 inhibitors; T2D = type 2 diabetes.

ACEi/ARB/ARNI or high doses of β-blockers. Women in clinical practice are more exposed and often present with lower SBP than men so drugs with minimal or no impact on that offer a specific practical advantage.

Sacubitril/Valsartan: A Drug with Potential Higher Impact on Women Chronic Heart Failure with Reduced Ejection Fraction and Acute Heart Failure

The multiple benefits of the ARNI sacubitril/valsartan have been well established since 2014 when PARADIGM-HF was published.36 The design of this RCT is similar to DAPA-HF. PARADIGM-HF is the largest RCT by population enrolled in the history of HFrEF so far, enrolling 8,442 patients, 22% of whom were women. The major clinical and demographic characteristics are summarised in Table 2. After a mean follow-up of 27 months, sacubitril/valsartan (uptitrated to 200 mg twice a day) versus enalapril on top of HFrEF standard of care, significantly reduced the primary endpoint: a composite of CV death and first HHF (HR 0.80; 95% CI [0.73–0.87]; p<0.0001), with RRR 20% and NNT 21, as well as the split separate components of the primary endpoint, i.e. CV death (HR 0.80; 95% CI [0.71–0.89]; p<0.001, RRR 20%) and the first HHF (HR 0.79; 95% CI [0.71–0.89]; p<0.001, RRR 21%].36 Also, the secondary endpoint all-cause death has been significantly reduced (HR 0.84; 95% CI [0.76–0.93]; p=0.0009, RRR 16%). Beyond this major outcome, sacubitril/valsartan compared to enalapril significantly reduced sudden cardiac death, total HHF, total hospitalisations, as well as total emergency department admissions for WHF, total stays in the intensive care unit and significantly improved symptoms (measured by NYHA) and QoL measured by

KCCQ. A detailed analysis of PARADIGM-HF is outside of the scope of this review, but after this RCT, ARNI have been recommended globally from all the international HF guidelines in substitution of an ACEi/ARB in chronic HFrEF as a class I indication. The RCTs TITRATION, PIONEER-HF and TRANSITION extensively proved the safety of this drug when compared to an ACEi both in the chronic ambulatory HFrEF setting and in the AHF hospitalised setting in terms of worsening renal function, renal adverse events, hyperkalaemia and angioedema.57–59 Hypotension and symptomatic hypotension are more frequent than with ACEi/ARB, but in those RCTs this did not lead to drug discontinuation and has been managed with lowering ARNI dosage. A slower uptitration regimen – as TITRATION showed – reduces the incidence of hypotension and this is even more useful in women with HFrEF who often have lower blood pressure in the clinical scenario.57 PIONEER-HF and TITRATION showed important benefits in terms of efficacy in key secondary exploratory endpoints (CV death and HHF), so that they are suggested in recent ACC and CCS guidelines as first-line treatments in the AHF setting. PROVE-HF and EVALUATE-HF proved that ARNI improve cardiac remodelling in terms of ventricular volume reduction and systolic function improvement. More trials (PARADISE-MI and LIFE) were presented at the American College of Cardiology’s 2021 scientific session.60,61

Heart Failure with Mid-range (Mildly Reduced) and Preserved Ejection Fraction

The most important RCT that showed particular benefit for women is PARAGON-HF, dedicated to sacubitril/valsartan versus valsartan in

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Women and Diabetes HFpEF.62 PARAGON-HF enrolled 4,822 HF patients with an LVEF >45% (indicating a mix of HFmrEF and HFpEF), NYHA class II–IV, elevated level of natriuretic peptides (with different cut-offs depending on the occurrence of a recent HHF and the presence of AF), evidence of structural heart disease, and on diuretic therapy (Supplementary Material Table 1). Noticeably, 51.7% of patients were women, NYHA class II 77.7% and NYHA class III 19.4%. After a median follow-up of 35 months, PARAGON-HF failed to demonstrate a significant reduction of the primary endpoint of total HHF + CV death (HR 0.87; 95% CI [0.75–1.01]; p=0.059; RRR 13%). The reasons for this lack of efficacy have been explored in several papers and discussed in heated debates, but invariably lie in the elevated number of exclusion criteria (with 5,537 patients excluded during the screening phase) who made the population of PARAGON-HF far from the real population of HFpEF patients, the allcomers approach (that had already proved to be disastrous in HFpEF), and a likely wrong primary endpoint that, unlike the DAPA-HF, did not include urgent visits for HF (a recent post-hoc analysis showed that in this case, the reduction of primary endpoint would have been significant).63–65 Interestingly, prespecified analyses, showed a significant benefit for two specific subgroups – HF with an LVEF <57% (substantially the HFmrEF population; HR 0.78; 95% CI [0.64–0.95]; p=0.03 for interaction) and women (HR 0.73; 95% CI [0.59–0.90]; p=0.017 for interaction). The women in the trial were older than men, had more HF symptoms (indicated by worsening NYHA class), a lower median NT-pro-BNP level, worse QoL measured by KCCQ, higher median LVEF (60% versus 55%) than men. Moreover, women had a lower mean eGFR, had a greater incidence of obesity, had less coronary heart disease, T2D, and chronic obstructive pulmonary disease. More detailed analysis showed that the higher benefit of ARNI in women than in men was covered mostly by HHF with RRR of 33% (HR 0.67; 95% CI [0.54–0.84]; p=0.0048 for interaction), without reduction in CV death (HR 1.05; 95% CI [0.78–1.41], p=0.37 for interaction). The improvement in NYHA class was similar in women and men, whereas the improvement in KCCQ seemed to be lower in women than in men.66 These results can be explained by the activation of different pathways in women or more likely by the activation of the same pathways but with different strength and intensity in women than in men. Indeed, despite worse symptoms and QoL, the lower median level of natriuretic peptides in women enrolled in PARAGON-HF was mostly driven by a higher prevalence of obesity and NT-pro-BNP is just a marker and the non-active part of the effective hormones (ANP/BNP). Other studies coming from a subanalysis of PROVE-HF have demonstrated the greater importance of the increase of ANP level with sacubitril/valsartan and the increase of cGMP.67 In women, there is the possibility that the decrease of oestrogendependent stimulation of natriuretic peptides after menopause cause a further reduction of the NO/cGMP/PKG pathway, whose activation can be highly beneficial in women compared with men, and this benefit can be higher with the same serum and urinary levels of cGMP (therefore the same level of urinary cGMP in both sexes in PARAGON-HF does not exclude this hypothesis). Finally, the inhibition by ARNI of neprilysin has multiple benefits that we still only partially know because neprilysin inactivates multiple biological substances with potentially different repercussions in each sex. Taking these considerations together, the use of ARNI in HFpEF in specific populations of women, such as those who are older and obese, can be considered to improve QoL by reducing HHF.

New Molecules with Impact on Quality of Life in HFrEF Vericiguat

Vericiguat is a new drug that increases cGMP with a double mechanism, one side directly stimulates the soluble guanylate cyclase (sGC) through a binding site independent of NO and the other sensitises sGC to endogenous NO by stabilising the NO-sGC binding site. The final effect is an important boost of the NO/cGMP/PKG pathway. We previously mentioned this pathway because it is partially activated also by ARNI and SGLT2i. However, vericiguat specifically activates this pathway that has beneficial effects both in diastolic and in systolic ventricular dysfunction and in patients with HF in whom the oxidative stress leads to a reduction of NO and to cGMP deficiency. VICTORIA trial – dedicated to vericiguat in HFrEF – enrolled and randomised 5,050 patients (key inclusion criteria in Table 2).68,69 Vericiguat was started at a dosage of 2.5 mg/day at randomisation and biweekly uptitrated in a blinded fashion to reach the target dose of 10 mg per day (if tolerated based on mean SBP and clinical symptoms). After 10.8 months of mean follow-up, vericiguat significantly reduced the primary endpoint: a composite of CV death and first HHF [HR 0.90 [0.82–0.98]; p=0.02, RRR 10%). However, the benefit was significant only for the first HHF (HR 0.90; 95% CI [0.81–1.00]; p=0.048, RRR 10%] but not for CV death (HR 0.93; 95% CI [0.81–1.06]; p=0.269). The secondary endpoints confirmed the benefit on HHF, indeed total (first and recurrent) HHF were significantly reduced (HR 0.91; 95% CI [0.84–0.99]; p=0.023, RRR 9%) with no effect on all-cause death (HR 0.95; 95% CI [0.84–1.07] p=0.38). Although at a first and superficial glance the results achieved in VICTORIA do not seem to be remarkable, the understanding of the characteristics of the enrolled population explains their important impact on HFrEF. Indeed, the population enrolled in VICTORIA had very severe HF when compared to all the recent RCTs dedicated to HFrEF (Table 2), which included 23.9% of women, with higher NYHA III class 39.7%, mean LVEF 28.9%, very high levels of median NT-pro-BNP = 2,816 pg/ml (double DAPA-HF and significantly higher than the other RCTs), ~84% had an HHF within 6 months, with the remaining ~16% on IV diuretics managed as outpatients, a compromised renal function superimposable to that of EMPERORReduced (mean eGFR 61.5 ml/min/1.7m2, 52% had eGFR <60 ml/min/1.73 m2), and 46.9% with T2D. The HFrEF OMT was comparable to that of DAPA-HF and EMPEROR-Reduced and included 14.5% of patients on ARNI, 59.7% having triple therapy (ACE-I/ARB/ARNI, β-blocker, MRA), 27.8% with an ICD and 14.7% with a CRT (Table 2). The HFrEF severity of VICTORIA’s population is well described by the annualised event rate in the comparator group. indeed the annual rate of CV death was two times higher than that of PARADIGM-HF, DAPA-HF, and EMPEROR-Reduced and the annual rate of first HHF rate was three times higher than that of PARADIGM-HF and DAPA-HF and twice as high as that of EMPEROR-Reduced (Table 2). Add to this, the rate of all-cause death in the comparator group was 21.2% in 10.8 months similar to that of PARADIGM-HF (19.8%) with the noticeable difference that this rate was achieved in 27 months. These numbers are close to the event rate that we observe in clinical registers and in our clinical practice in HFrEF patients and explain what type of patients were enrolled in this trial. The benefit of VICTORIA on primary endpoint in terms of absolute RR was comparable to that of DAPA-HF and was mostly due to the benefit on HHF.70 Furthermore, this benefit was achieved in a very short mean follow-up and it is likely that if the mean follow-up was longer, the benefit would have been even greater.

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Women and Diabetes There were no major safety issues with vericiguat. In particular, there were no significant differences in terms of syncope and hypotension, while there was an increase in the rate of anaemia (7.6% versus 5.7% of placebo). Particularly, if the SBP was ≥90 and <100 mmHg the dosage was maintained, whereas in the case of SBP <90 mmHg the vericiguat dose was reduced. Therefore, this drug has no negative impact on hypotensive patients. In summary, this drug is highly beneficial in patients with recent HHF (<6 months) who have severe HF (as defined by the characteristics of the enrolled population) and present evident (clinical and laboratory) signs of congestion and can be considered in hypotensive patients not able to tolerate ACEi/ARB/ARNI, as already discussed for SGLT2is. Furthermore, the selective activation and boosting of the NO/cGMP/PKG pathway combines the myocardial benefits (inhibition of hypertrophy, fibrosis, inflammation and increase of coronary blood flow) that cause an improvement of diastolic function, ventricular-arterial coupling and an anti-remodelling effect with the vascular benefits (inhibition of inflammation, vasodilative properties and positive effect on vasal remodelling) that may have positive consequences, especially in women. Recently our group provided a proof-of-concept study that demonstrated a compensatory active role of arteries in HF across the LVEF spectrum. New drugs, such as vericiguat specifically act on arterial function and can be more beneficial in specific populations with a more compromised arterial function – such as older women with HF and HFpEF patients.71

Table 4: Pharmacological Pathways and Indications of the New Medical Treatments Indication

Drugs

Pathways

Type 2 diabetes

SGLT2i

Multiple (see text)

GLP1-RA

Multiple (see text)

Prevention and/or PCSK9i Dyslipidaemia Inclisiran (Hypercholesterolaemia, Icosapentyl ethyl Hypertriglyceridaemia)

LDL-C reduction

Bempedoic acid

LDL-C reduction

Acute heart failure

SGLT2i and SGLT1i (sotagliflozin)

Multiple (see text)

Chronic HFrEF

ARNI

Neprilysin inhibition/ upregulation of natriuretic peptides RAAS inhibition NO/cGMP/PKG boosting Multiple (see text) Selective stimulation of NO/ cGMP/PKG Selective cardiac myosin activation

SGLT2i Vericiguat Omecamtiv Mecarbil

GALACTIC-HF – dedicated to OM in HFrEF – enrolled and randomised 8,442 patients with a severe HF when compared to other recent RCTs (Supplementary Material Table 1 and Table 2): 21.3% were women, NYHA III represented 43.8% of patients, median LVEF was particularly low 26.6%, median NT-proBNP was similar to that of EMPEROR-Reduced 1,971 pg/ml, 54.6% had a recent HHF (within 6 months), interestingly 25.2% had AHF, median eGFR:60.3 ml/min/1.73 m2, T2D patients were 40.1%. Patients were very well treated as for other RCTs (Table 2).76 After 21.8 months of mean follow-up, OM – titrated from 25 to 50 mg twice daily to reach a specific plasmatic concentration – significantly reduced the primary endpoint: a composite of CV death and first HF event (defined by an HHF or emergency department access for HF or urgent visit for WHF), HR 0.92 95% CI [0.86–0.99]; p=0.025; RRR 9%. However, when considered alone none of the individual components of primary endpoint were significantly reduced (CV death: HR 1.01 95% CI [0.92–1.11]; p=0.86; first HF event: HR 0.93 95% CI [0.86–1.00], p=0.06) as well as the secondary endpoint all-

VLDL and triglycerides reduction

Chronic HFmrEF

ARNI and SGLT2i

Neprilysin inhibition/ upregulation of natriuretic peptides RAAS inhibition NO/cGMP/PKG boosting

Chronic HFpEF

ARNI only in women

Neprilysin inhibition/ upregulation of natriuretic peptides RAAS inhibition NO/cGMP/PKG boosting

SGLT2i and SGLT1i(?)

Multiple (see text)

SGLT2i

Multiple (see text)

Omecamtiv Mecarbil

Omecamtiv mecarbil (OM), is a selective cardiac myosin activator that increases cardiac contractility by specifically binding to myosin, stabilising the pre-powerstroke state prior to onset of cardiac contraction with the effect of increasing the number of myosin heads that can bind to the actin filament and undergo a powerstroke once the cardiac cycle starts. Its action can be described as ‘more hands pulling on the rope’. Moreover, OM decreases the turnover of adenosine triphosphate in the absence of an interaction with the actin filament, potentially increasing the overall energetic efficiency of the system by diminishing adenosine triphosphate use not associated with mechanical work.72 This peculiar mechanism does not increase myocyte calcium and does not increase myocardial consumption of oxygen. This clearly differentiates this drug from other inotropes (such as β-adrenergic receptor agonists, phosphodiesterase inhibitors and levosimendan). OM has the final effect to increase the stroke volume, the left ventricle ejection time and systole duration, also reducing heart rate. OM has shown multiple benefits in HFrEF patients in Phase II trials, which has led to the development of a large Phase III RCT.73,74

LDL-C reduction

Chronic kidney disease

ARNI = angiotensin receptor neprilysin inhibitor; cGMP = cyclic guanosine monophosphate; GLP-1 RA = glucagon-like peptide-1 receptor agonists; HDL-C = HDL cholesterol; HFmrEF = heart failure with mid-range ejection fraction; HFpEF = heart failure with preserved ejection fraction; HFrEF = heart failure with reduced ejection fraction; LDL-C = LDL cholesterol; NO = nitric oxide; PCSK9i = proprotein convertase subtilisin/kexin type 9 inhibitors; PKG = protein kinase G; RAAS = renin–angiotensin–aldosterone system; SGLT2i = sodium-glucose cotransporter type 2 inhibitors; VLDL = very low-density lipoprotein.

cause death (HR 1.00 95% CI [0.92–1.09]; p=not significant). Beyond the major outcome, QoL measured by KCCQ (another secondary endpoint) was significantly improved. As we previously mentioned for VICTORIA, the severity of the population enrolled in GALACTIC-HF is well described by the annualised event rate of CV death in the comparator group – 10% higher than in other recent HFrEF RCTs (only inferior to that of VICTORIA) and of first HF event rate 15.2% (the same as EMPEROR-Reduced; Supplementary Material Table 1). Pre-specified group analysis showed that the benefit for primary endpoint was particularly significant for people with a median LVEF <28.0% (HR 0.84; 95% CI [0.77–0.92], p=0.03 for interaction:).76 Regarding safety, OM did not significantly increase ventricular tachyarrhythmias, torsades de pointes or QT prolongation, MI or any serious adverse events. Further, post-hoc analysis provided generator hypotheses of greater benefit in more advanced HF populations (LVEF <28% plus one of the following: HHF within 3 months, NYHA III/IV, NT-pro-BNP >2,000 pg/ml, SBP 2.85 mmol/l.) that need to be confirmed in future studies. On the other hand, COSMIC-HF has also demonstrated that OM significantly increases

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Women and Diabetes stroke volume, systolic ejection time, reduces ventricular volumes, NTpro-BNP levels and heart rate and these actions are demonstrated as also significant for the right ventricle.77 In summary, this is the first inotrope in the history of cardiology that does not increase CV death and all-cause death, does not have any adverse events and that is active (significantly reducing the primary endpoint) on a population of advanced HF acting on both ventricles without any reduction of SBP. Further studies will clarify the benefits of OM, but its introduction to HF therapies can be an added value in women with severe HF who are unable to tolerate ACEi/ARB/ARNI or high dosage of β-blockers because of hypotension. In this population of advanced HFrEF, a combination of drugs without any effect on SBP, such as SGLT2i, MRA, vericiguat and OM should be considered, not only improving outcomes and QoL but also generating amelioration myocardial and vascular function that makes it possible to start and titrate ACEi/ARB/ARNI. Table 4 summarises the indications of the new medical treatments in women from prevention to heart failure management. 1. Bozkurt B, Coats AJS, Tsutsui H, et al. Universal definition and classification of heart failure. Eur J Heart Fail 2021;23:352–80. https://doi.org/10.1002/ejhf.2115; PMID: 33605000. 2. Abtan J, Bhatt DL, Elbez Y, et al. Residual ischemic risk and its determinants in patients with previous myocardial infarction and without prior stroke or TIA: insights from the REACH registry: residual cardiovascular risk after myocardial infarction. Clin Cardiol 2016;39:670–7. https://doi.org/10.1002/ clc.22583; PMID: 27588731. 3. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015;373:2117–28. https://doi.org/10.1056/ NEJMoa1504720; PMID: 26378978. 4. Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med 2017;377:644–57. https://doi.org/10.1056/ NEJMoa1611925; PMID: 28605608. 5. Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2019;380:347–57. https://doi.org/10.1056/NEJMoa1812389; PMID: 30415602. 6. Valente AM, Bhatt DL, Lane-Cordova A. Pregnancy as a cardiac stress test: time to include obstetric history in cardiac risk assessment? J Am Coll Cardiol 2020;76:68–71. https://doi.org/10.1016/j.jacc.2020.05.017; PMID: 32616165. 7. Kessous R, Shoham-Vardi I, Pariente G, et al. An association between gestational diabetes mellitus and long-term maternal cardiovascular morbidity. Heart 2013;99:1118–21. https://doi.org/10.1136/heartjnl-2013-303945; PMID: 23749791. 8. Tan Y, Zhang Z, Zheng C, et al. Mechanisms of diabetic cardiomyopathy and potential therapeutic strategies: preclinical and clinical evidence. Nat Rev Cardiol 2020;17:585–607. https://doi.org/10.1038/s41569-020-03392; PMID: 32080423. 9. Bhatt DL, Szarek M, Pitt B, et al. Sotagliflozin in patients with diabetes and chronic kidney disease. N Engl J Med 2021;384:129–39. https://doi.org/10.1056/NEJMoa2030186; PMID: 33200891. 10. Zelniker TA, Wiviott SD, Raz I, et al. SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet 2019;393:31–9. https://doi.org/10.1016/S01406736(18)32590-X; PMID: 30424892. 11. Cardoso R, Graffunder FP, Ternes CMP, et al. SGLT2 inhibitors decrease cardiovascular death and heart failure hospitalizations in patients with heart failure: a systematic review and meta-analysis. EClinicalMedicine 2021;36:100933. https://doi.org/10.1016/j.eclinm.2021.100933; PMID: 34308311. 12. Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2016;375:311–22. https://doi.org/10.1056/ NEJMoa1603827; PMID: 27295427. 13. Mann JFE, Ørsted DD, Brown-Frandsen K, et al. Liraglutide and renal outcomes in type 2 diabetes. N Engl J Med 2017;377:839–48. https://doi.org/10.1056/NEJMoa1616011; PMID: 28854085.

Conclusion

Cardiovascular risk remains high for women with diabetes and is particularly underestimated – because the SCORE chart does not take into account specific women’s risk factors, such as premature menopause or peripartum complications, and this contributes to inadequate prevention strategies in this population. The suboptimal management of women with diabetes leads them to progress to overt HF. New therapeutic approaches offered by new drugs have shown evidence of multiple benefits on CV morbidity and mortality in women. A better implementation of new pharmacological treatments both in CV prevention and in HF is an unmet need for women with diabetes and requires a greater commitment from the medical community to improve women’s health. A specific focus on benefits of new drugs that potentially have greater effect in women than in men – as may be the case for ARNI as shown in PARAGON-HF – and on specific pathways, potentially more important in women than in men – as is the case of NO/cGMP/PKG – can lead us to develop a tailored-approach using ‘precision medicine’.

14. Gerstein HC, Colhoun HM, Dagenais GR, et al. Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial. Lancet 2019;294:121–30. https://doi.org/10.1016/S01406736(19)31149-3; PMID: 31189511. 15. Marso SP, Bain SC, Consoli A, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med 2016;375:1834–44. https://doi.org/10.1056/ NEJMoa1607141; PMID: 27633186. 16. Cosentino F, Grant PJ, Aboyans V, et al. 2019 ESC guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD. Eur Heart J 2020;41:255–323. https://doi.org/10.1093/eurheartj/ehz486; PMID: 31497854. 17. Margulies KB, Hernandez AF, Redfield MM, et al. Effects of liraglutide on clinical stability among patients with advanced heart failure and reduced ejection fraction: a randomized clinical trial. JAMA 2016;316:500–8. https://doi.org/10.1001/ jama.2016.10260; PMID: 27483064. 18. Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med 2017;376:1713–22. https://doi. org/10.1056/NEJMoa1615664; PMID: 28304224. 19. Schwartz GG, Steg PG, Szarek M, et al. Alirocumab and cardiovascular outcomes after acute coronary syndrome. N Engl J Med 2018;379:2097–2107. PMID: 30403574. 20. Bays HE. Alirocumab, decreased mortality, nominal significance, p values, Bayesian statistics, and the duplicity of multiplicity. Circulation 2019;140:113–6. https://doi. org/10.1161/CIRCULATIONAHA.119.041496; PMID: 31283369. 21. Ray KK, Landmesser U, Leiter LA, et al. Inclisiran in patients at high cardiovascular risk with elevated ldl cholesterol. N Engl J Med 2017;376:1430–40. https://doi.org/10.1056/ NEJMoa1615758; PMID: 28306389. 22. Bhatt DL, Steg PG, Miller M, et al. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med 2019;380:11–22. https://doi.org/10.1056/ NEJMoa1812792; PMID: 30415628. 23. Bhatt DL, Steg PG, Miller M, et al. REDUCE-IT USA. J Am Coll Cardiol 2019;73:2791–802. https://doi.org/10.1016/j. jacc.2019.02.032; PMID: 30898607. 24. Orringer CE, Jacobson TA, Maki KC. National Lipid Association Scientific Statement on the use of icosapent ethyl in statin-treated patients with elevated triglycerides and high or very-high ASCVD risk. J Clin Lipidol 2019;13:860– 72. https://doi.org/10.1016/j.jacl.2019.10.014; PMID: 31787586. 25. Ray KK, Bays HE, Catapano AL, et al. Safety and efficacy of bempedoic acid to reduce ldl cholesterol. N Engl J Med 2019;380:1022–32. https://doi.org/10.1056/NEJMoa1803917; PMID: 30865796. 26. Meta-analysis Global Group in Chronic Heart Failure (MAGGIC). The survival of patients with heart failure with preserved or reduced left ventricular ejection fraction: an individual patient data meta-analysis. Eur Heart J 2012;33:1750–7. https://doi.org/10.1093/eurheartj/ehr254; PMID: 21821849. 27. Jones NR, Roalfe AK, Adoki I, et al. Survival of patients with chronic heart failure in the community: a systematic review and meta-analysis. Eur J Heart Fail 2019;21:1306–25. https://

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doi.org/10.1002/ejhf.1594; PMID: 31523902. 28. Senni M, Gavazzi A, Oliva F, et al. In-hospital and 1-year outcomes of acute heart failure patients according to presentation (de novo vs. worsening) and ejection fraction. Results from IN-HF Outcome Registry. Int J Cardiol 2014;173:163–9. https://doi.org/10.1016/j.ijcard.2014.02.018; PMID: 24630337. 29. Mamas MA, Sperrin M, Watson MC, et al. Do patients have worse outcomes in heart failure than in cancer? A primary care-based cohort study with 10-year follow-up in Scotland. Eur J Heart Fail 2017;19:1095–104. https://doi.org/10.1002/ ejhf.822; PMID: 28470962. 30. Blumer V, Greene SJ, Wu A, et al. Sex differences in clinical course and patient-reported outcomes among patients hospitalized for heart failure. JACC Heart Fail 2021;9:336–45. https://doi.org/10.1016/j.jchf.2020.12.011; PMID: 33714746. 31. Sullivan K, Doumouras BS, Santema BT, et al. Sex-specific differences in heart failure: pathophysiology, risk factors, management, and outcomes. Can J Cardiol 2021;37:560–71. https://doi.org/10.1016/j.cjca.2020.12.025; PMID: 33383166. 32. Whitelaw S, Sullivan K, Eliya Y, et al. Trial characteristics associated with under-enrolment of females in randomized controlled trials of heart failure with reduced ejection fraction: a systematic review. Eur J Heart Fail 2021;23:15–24. https://doi.org/10.1002/ejhf.2034; PMID: 33118664. 33. Pandey A, Vaduganathan M, Arora S, et al. Temporal trends in prevalence and prognostic implications of comorbidities among patients with acute decompensated heart failure: the ARIC study community surveillance. Circulation 2020;142:230–43. https://doi.org/10.1161/ CIRCULATIONAHA.120.047019; PMID: 32486833. 34. Iorio A, Senni M, Barbati G, et al. Prevalence and prognostic impact of non-cardiac co-morbidities in heart failure outpatients with preserved and reduced ejection fraction: a community-based study. Eur J Heart Fail 2018;20:1257–66. https://doi.org/10.1002/ejhf.1202; PMID: 29917301. 35. Swedberg K, Komajda M, Böhm M, et al. Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study. Lancet 2010;376:875–85. https:// doi.org/10.1016/S0140-6736(10)61198-1; PMID: 20801500. 36. McMurray JJ, Packer M, Desai AS, et al. Angiotensinneprilysin inhibition versus enalapril in heart failure. N Engl J Med 2014;371:993–1004. https://doi.org/10.1056/ NEJMoa1409077; PMID: 25176015. 37. McMurray JJV, Solomon SD, Inzucchi SE, et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med 2019;381:1995–2008. https://doi.org/10.1056/ NEJMoa1911303; PMID: 31535829. 38. Crespo-Leiro MG, Metra M, Lund LH, et al. Advanced heart failure: a position statement of the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail 2018;20:1505–35. https://doi.org/10.1002/ejhf.1236; PMID: 29806100. 39. Kosiborod MN, Jhund PS, Docherty KF, et al. Effects of dapagliflozin on symptoms, function, and quality of life in patients with heart failure and reduced ejection fraction: results from the DAPA-HF Trial. Circulation 2020;141:90–99. https://doi.org/10.1161/CIRCULATIONAHA.119.044138; PMID: 31736335.

Women and Diabetes 40. Packer M, Butler J, Filippatos GS, et al. Evaluation of the effect of sodium-glucose co-transporter 2 inhibition with empagliflozin on morbidity and mortality of patients with chronic heart failure and a reduced ejection fraction: rationale for and design of the EMPEROR-Reduced trial. Eur J Heart Fail 2019;21:1270–8. https://doi.org/10.1002/ejhf.1536; PMID: 31584231. 41. McMurray JJV. EMPEROR-Reduced: confirming sodiumglucose co-transporter 2 inhibitors as an essential treatment for patients with heart failure with reduced ejection fraction. Eur J Heart Fail 2020;22:1987–90. https://doi.org/10.1002/ ejhf.2006; PMID: 32946169. 42. Zannad F, Ferreira JP, Pocock SJ, et al. SGLT2 inhibitors in patients with heart failure with reduced ejection fraction: a meta-analysis of the EMPEROR-Reduced and DAPA-HF trials. Lancet 2020;396:819–29. https://doi.org/10.1016/S01406736(20)31824-9; PMID: 32877652. 43. Bhatt DL, Szarek M, Steg PG, et al. Sotagliflozin in patients with diabetes and recent worsening heart failure. N Engl J Med 2021;384:117–28. https://doi.org/10.1056/ NEJMoa2030183; PMID: 33200892. 44. Damman K, Beusekamp JC, Boorsma EM, et al. Randomized, double-blind, placebo-controlled, multicentre pilot study on the effects of empagliflozin on clinical outcomes in patients with acute decompensated heart failure (EMPA-RESPONSE-AHF). Eur J Heart Fail 2020;22:713– 22. https://doi.org/10.1002/ejhf.1713; PMID: 31912605. 45. Tromp J, Ponikowski P, Salsali A, et al. Sodium-glucose co-transporter 2 inhibition in patients hospitalized for acute decompensated heart failure: rationale for and design of the EMPULSE trial. Eur J Heart Fail 2021;23:826–34. https:// doi.org/10.1002/ejhf.2137; PMID: 33609072. 46. Seferović PM, Polovina M, Bauersachs J, et al. Heart failure in cardiomyopathies: a position paper from the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail 2019;21:553–76. https://doi.org/10.1002/ejhf.1461; PMID: 30989768. 47. Pieske B, Tschöpe C, de Boer RA, et al. How to diagnose heart failure with preserved ejection fraction: the HFA-PEFF diagnostic algorithm: a consensus recommendation from the Heart Failure Association (HFA) of the European Society of Cardiology (ESC). Eur Heart J 2019;40:3297–317. https:// doi.org/10.1093/eurheartj/ehz641; PMID: 31504452. 48. Bourlag BA. Defining HFpEF: where do we draw the line? Eur Heart J 2016;37:463–65. https://doi.org/10.1093/eurheartj/ ehv561; PMID: 26530107. 49. Anker SD, Butler J, Filippatos GS, et al. Evaluation of the effects of sodium-glucose co-transporter 2 inhibition with empagliflozin on morbidity and mortality in patients with chronic heart failure and a preserved ejection fraction: rationale for and design of the EMPEROR-Preserved Trial. Eur J Heart Fail 2019;21:1279–87. https://doi.org/10.1002/ ejhf.1596; PMID: 31523904. 50. Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med 2019;380:2295–306. https://doi.org/10.1056/NEJMoa1811744; PMID: 30990260. 51. Heerspink HJL, Stefánsson BV, Correa-Rotter R, et al. Dapagliflozin in patients with chronic kidney disease. N Engl J Med 2020;383:1436–46. https://doi.org/10.1056/ NEJMoa2024816; PMID: 32970396. 52. Sabouret P, Galati G, Angoulvant D, et al. The interplay between cardiology and diabetology: a renewed

collaboration to optimize cardiovascular prevention and heart failure management. Eur Heart J Cardiovasc Pharmacother 2020;6:394–404. https://doi.org/10.1093/ ehjcvp/pvaa051; PMID: 32402065. 53. Margonato D, Galati G, Mazzetti S, et al. Renal protection: a leading mechanism for cardiovascular benefit in patients treated with SGLT2 inhibitors. Heart Fail Rev 2020;26: 337– 45. https://doi.org/10.1007/s10741-020-10024-2; PMID: 32901315. 54. Santos-Gallego CG, Requena-Ibanez JA, San Antonio R, et al. Empagliflozin ameliorates diastolic dysfunction and left ventricular fibrosis/stiffness in nondiabetic heart failure: a multimodality study. JACC Cardiovasc Imaging 2021;14:393– 407. https://doi.org/10.1016/j.jcmg.2020.07.042; PMID: 33129742. 55. Kolijn D, Pabel S, Tian Y, et al. Empagliflozin improves endothelial and cardiomyocyte function in human heart failure with preserved ejection fraction via reduced proinflammatory-oxidative pathways and protein kinase Gα oxidation. Cardiovasc Res 2021;117:495–507. https://doi. org/10.1093/cvr/cvaa123; PMID: 32396609. 56. Serenelli M, Böhm M, Inzucchi SE, et al. Effect of dapagliflozin according to baseline systolic blood pressure in the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure trial (DAPA-HF). Eur Heart J 2020;41:3402–18. https://doi.org/10.1093/eurheartj/ehaa496; PMID: 32820334. 57. Senni M, McMurray JJ, Wachter R, et al. Initiating sacubitril/ valsartan (LCZ696) in heart failure: results of TITRATION, a double-blind, randomized comparison of two uptitration regimens. Eur J Heart Fail 2016;18:1193–202. https://doi. org/10.1002/ejhf.548; PMID: 27170530. 58. Velazquez EJ, Morrow DA, DeVore AD, et al. Angiotensinneprilysin inhibition in acute decompensated heart failure. N Engl J Med 2019;380:539–48. https://doi.org/10.1056/ NEJMoa1812851; PMID: 30415601. 59. Wachter R, Senni M, Belohlavek J, et al. Initiation of sacubitril/valsartan in haemodynamically stabilised heart failure patients in hospital or early after discharge: primary results of the randomised TRANSITION study. Eur J Heart Fail 2019;21:998–1007. https://doi.org/10.1002/ejhf.1498; PMID: 31134724. 60. Januzzi JL Jr, Prescott MF, Butler J, et al. Association of change in N-terminal pro-B-type natriuretic peptide following initiation of sacubitril-valsartan treatment with cardiac structure and function in patients with heart failure with reduced ejection fraction. JAMA 2019;322:1085–95. https://doi.org/10.1001/jama.2019.12821; PMID: 31475295. 61. Desai AS, Solomon SD, Shah AM, et al. Effect of sacubitrilvalsartan vs enalapril on aortic stiffness in patients with heart failure and reduced ejection fraction: a randomized clinical trial. JAMA 2019;322:1077–84. https://doi.org/10.1001/ jama.2019.12843; PMID: 31475296. 62. Solomon SD, McMurray JJV, Anand IS, et al. Angiotensinneprilysin inhibition in heart failure with preserved ejection fraction. N Engl J Med 2019;381:1609–20. https://doi. org/10.1056/NEJMoa1908655; PMID: 31475794. 63. O’Connor CM, deFilippi C. PARAGON-HF – why we do randomized, controlled clinical trials. N Engl J Med 2019;381:1675–6. https://doi.org/10.1056/NEJMe1912402; PMID: 31644849. 64. Ferrari R, Fucili A, Rapezzi C. Understanding the results of the PARAGON-HF trial. Eur J Heart Fail 2020;22:1531–5. https://doi.org/10.1002/ejhf.1797; PMID: 32212295.

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65. Vaduganathan M, Cunningham JW, Claggett BL, et al. Worsening heart failure episodes outside a hospital setting in heart failure with preserved ejection fraction: the PARAGON-HF trial. JACC Heart Fail 2021;9:374–82. https:// doi.org/10.1016/j.jchf.2021.01.014; PMID: 33839075. 66. McMurray JJV, Jackson AM, Lam CSP, et al. Effects of sacubitril-valsartan versus valsartan in women compared with men with heart failure and preserved ejection fraction: insights from PARAGON-HF. Circulation 2020;141:338–51. https://doi.org/10.1161/CIRCULATIONAHA.119.044491; PMID: 31736337. 67. Murphy SP, Prescott MF, Camacho A, et al. Atrial natriuretic peptide and treatment with sacubitril/valsartan in heart failure with reduced ejection fraction. JACC Heart Fail 2021;9:127–36. https://doi.org/10.1016/j.jchf.2020.09.013; PMID: 33189632. 68. Pieske B, Patel MJ, Westerhout CM, et al. Baseline features of the VICTORIA (Vericiguat Global Study in Subjects with Heart Failure with Reduced Ejection Fraction) trial. Eur J Heart Fail 2019;21:1596–604. https://doi.org/10.1002/ ejhf.1664; PMID: 31820546. 69. Armstrong PW, Pieske B, Anstrom KJ, et al. Vericiguat in patients with heart failure and reduced ejection fraction. N Engl J Med 2020;382:1883–93. https://doi.org/10.1056/ NEJMoa1915928; PMID: 32222134. 70. Butler J, Anstrom KJ, Armstrong PW. Comparing the benefit of novel therapies across clinical trials: insights from the VICTORIA trial. Circulation 2020;142:717–9. https://doi. org/10.1161/CIRCULATIONAHA.120.047086; PMID: 32223438. 71. Galati G, Germanova O, Iozzo RV, et al. Hemodynamic arterial changes in heart failure: a proposed new paradigm of “heart and vessels failure (HVF)”. Minerva Cardiol Angiol 2021. https://doi.org/10.23736/S2724-5683.21.05786-0; PMID: 34100570; epub ahead of press. 72. Teerlink JR, Diaz R, Felker GM, et al. Omecamtiv mecarbil in chronic heart failure with reduced ejection fraction: rationale and design of GALACTIC-HF. JACC Heart Fail 2020;8:329–40. https://doi.org/10.1016/j.jchf.2019.12.001; PMID: 32035892. 73. Teerlink JR, Felker GM, McMurray JJ, et al. Chronic oral study of myosin activation to increase contractility in heart failure (COSMIC-HF): a phase 2, pharmacokinetic, randomised, placebo-controlled trial. Lancet 2016;388:2895–903. https://doi.org/10.1016/S01406736(16)32049-9; PMID: 27914656. 74. Teerlink JR, Felker GM, McMurray JJV, et al. Acute treatment with omecamtiv mecarbil to increase contractility in acute heart failure: the ATOMIC-AHF study. J Am Coll Cardiol 2016;67:1444–55. https://doi.org/10.1016/j.jacc.2016.01.031; PMID: 27012405. 75. Teerlink JR, Diaz R, Felker GM, et al. Cardiac myosin activation with omecamtiv mecarbil in systolic heart failure. N Engl J Med 2021;384:105–16. https://doi.org/10.1056/ NEJMoa2025797; PMID: 33185990. 76. Teerlink JR, Diaz R, Felkeret GM, al. Effect of ejection fraction on clinical outcomes in patients treated with omecamtiv mecarbil in GALACTIC-HF John. J Am Coll Cardiol 2021;78:97–108. https://doi.org/10.1016/j.jacc.2021.04.065; PMID: 34015475. 77. Biering-Sørensen T, Minamisawa M, Liu J, et al. The effect of the cardiac myosin activator, omecamtiv mecarbil, on right ventricular structure and function in chronic systolic heart failure (COSMIC-HF). Eur J Heart Fail 2021;23:1052–6. https:// doi.org/10.1002/ejhf.2181; PMID: 33826209.

Women and Heart Disease

Secondary Prevention of Cardiovascular Disease in Women: Closing the Gap Aarti Thakkar ,1 Anandita Agarwala

and Erin D Michos

1. Ciccarone Center for the Prevention of Cardiovascular Disease, Johns Hopkins University School of Medicine, Baltimore, MD, US; 2. Division of Cardiology, Baylor Scott and White Health Heart Hospital Baylor Plano, Plano, TX, US

Abstract

Cardiovascular disease (CVD) remains the leading cause of death in women globally. Younger women (<55 years of age) who experience MI are less likely to receive guideline-directed medical therapy (GDMT), have a greater likelihood of readmission and have higher rates of mortality than similarly aged men. Women have been under-represented in CVD clinical trials, which limits the generalisability of results into practice. Available evidence indicates that women derive a similar benefit as men from secondary prevention pharmacological therapies, such as statins, ezetimibe, proprotein convertase subtilisin/kexin type 9 inhibitors, icosapent ethyl, antiplatelet therapy, sodium–glucose cotransporter 2 inhibitors and glucagon-like peptide-1 receptor agonists. Women are less likely to be enrolled in cardiac rehabilitation programs than men. Mitigating risk and improving outcomes is dependent on proper identification of CVD in women, using appropriate GDMT and continuing to promote lifestyle modifications. Future research directed at advancing our understanding of CVD in women will allow us to further develop and tailor CVD guidelines appropriate by sex and to close the gap between diagnoses, treatment and mortality.

Keywords

Women, coronary heart disease, acute MI, secondary prevention, disparities Disclosure: Unrelated to this work, EDM is on advisory boards for Esperion, Amarin, Novartis and Astra Zeneca. All other authors have no conflicts of interest to declare. Funding: EDM is supported by the Amato Fund in Women’s CV Health Research at Johns Hopkins University. Received: 26 May 2021 Accepted: 24 August 2021 Citation: European Cardiology Review 2021;16:e41. DOI: https://doi.org/10.15420/ecr.2021.24 Correspondence: Erin D Michos, Ciccarone Center for the Prevention of Cardiovascular Disease, Johns Hopkins University School of Medicine, Blalock 524-B, 600 N Wolfe St, Baltimore, MD 21287, US. E: edonnell@jhmi.edu Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Cardiovascular disease (CVD) is the leading cause of death among women in the US and globally.1 Although the overall death rates from CVD have decreased in recent years, rates of acute MI (AMI) and CVD mortality have actually been increasing among young US women aged <65 years.2–4 One analysis found that the prevalence of AMI among young women aged 35–54 years increased from 21% in 1995 to 31% in 2004; in comparison, the prevalence of AMI in men over the same time period increased from 30% to 33%.4 Between 2011 and 2017, middle-aged women, defined as those aged 45–64 years, had a 7% increase in death rates, compared with a 3% increase among men during this time period.3 Women are at risk of a broad spectrum of CVDs, including, but not limited to, CHD including AMI, stroke and heart failure (HF).1 Women typically present with atherosclerotic CVD (ASCVD) approximately a decade later than men during their postmenopausal period due to decreases in oestrogen and a loss of its protective effects.5,6 Loss of the protective effects of oestrogen leads to worsening of traditional risk factors: weight gain, insulin resistance and higher blood pressures.7 Thus, older women presenting with CVD are also more likely to present with comorbid conditions such as diabetes and hypertension.5,8 Available evidence suggests that some traditional risk factors, such as diabetes and smoking, confer a greater relative risk of ASCVD in women than men.9,10 In addition, women are at risk of CVD due to female-specific risk factors (e.g. adverse pregnancy outcomes, polycystic ovary syndrome and

premature menopause) or factors that are more prevalent in women (e.g. autoimmune disorders, including lupus and rheumatoid arthritis, and radiation or chemotherapies for breast cancer).7,11,12 These added risks are often unaccounted for, leading to underestimation of cardiovascular risk and the under-treatment of women.13 Recognition of the multitude of factors that predispose women to CVD can be instrumental in addressing the burden of disease. However, current risk scores do not take into account such comorbidities, although some guidelines do consider them ‘risk-enhancing’ factors.13,14 Both primary prevention (before initial presentation of disease) and secondary prevention (after initial presentation of disease) strategies are crucial to decrease the burden of CVD for women. Primary prevention of CVD in women has been covered in other recent reviews.10,15 Given space limitations, this review will focus primarily on secondary prevention strategies and guidelines. This review serves to highlight multidisciplinary guidelines for women across a broad spectrum of CVD, including known atherosclerotic disease, HF and post-MI, post-cardiac catheterisation and post-coronary artery bypass grafting (CABG) surgery.

Outcomes After MI and CABG

Women across all age groups are susceptible to poor outcomes from CVD. Older women are more likely to experience mortality after a percutaneous intervention for an ST-elevation MI (STEMI), but not after non-ST-elevation MI (NSTEMI).8 Younger women <55 years who experience AMI are less

Secondary Prevention of CVD in Women Figure 1: Mitigating Risk and Improving Outcomes in Women with Cardiovascular Disease

Proper identification of CVD in women

Starting and titrating appropriate GDMT

Continuing to engage with lifestyle modifications (cardiac rehabilitation, if applicable)

Increasing representation of women in cardiovascular clinical trials

CVD = cardiovascular disease; GDMT = guideline-directed medical therapy. Figure created with BioRender.

likely to receive guideline-directed medical therapy (GDMT), have a greater likelihood of readmission within 1 year, have worse self-reported recovery outcomes and have higher rates of all-cause mortality.16–19 Women have also been shown to be less likely to undergo CABG than men and to have worse outcomes after CABG.20 This discrepancy is thought to be due to women presenting at older ages, with more comorbidities and with laterstage CVD. Despite women being at such high risk for secondary cardiovascular events, most cardiovascular trials to date have been predominantly male, with females being under-represented in trials for CHD, acute coronary syndrome (ACS) and HF relative to their disease burden in the population.21–25 This limits the knowledge base of the efficacy and safety of cardiovascular preventive interventions and limits generalisability of trial results into clinical practice. Even so, available evidence does indicate that women derive a nearly similar benefit from existing secondary prevention pharmacological treatment modalities such as statins, ezetimibe, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors and icosapsent ethyl as men, as discussed further below.26–31 Thus, more attention for secondary CVD prevention in women is sorely needed, with additional attention to mental health and social determinants of health. Figure 1 outlines some strategies for mitigating risk and improving outcomes after CVD in women. It should be further noted that there are knowledge gaps on how to reduce cardiovascular risk among transwomen and transmen, which warrants further study

Atypical Presentations and Obstacles to Treatment

Difficulty in treating women with GDMT for CVD begins with the initial diagnosis. Compared with men, women describe overall milder symptoms and are more likely to describe weakness, shortness of breath and fatigue as opposed to squeezing pressure, heart burn and palpitations.6 Women are also more likely to report pain in the chest, back or jaw without chest pain.6 In the setting of AMI, women do experience chest discomfort to a similar degree as men (~90% of cases), but are more likely to report three or more additional symptoms that may distract patients and their clinicians from initial recognition of the true diagnosis.32,33 As a result of these different presentations and overall lower perceived risk of CVD, women often have delayed diagnoses and are less likely to get urgent revascularisation of their MI.34–36 One study examining revascularisation times of young individuals (<55 years of age) presenting with AMI found that 35% of women presented

more than 6 hours after any initial symptoms, compared with 23% of men.36 In that study, women had 1.72-fold (95% CI [1.28–2.33]) the odds of exceeding the reperfusion time goal, and 2.31-fold (95% CI [1.32–4.06]) the odds of not receiving reperfusion at all.36 After the cardiovascular event, despite the strong evidence behind secondary prevention guidelines, women are not placed on appropriate GDMT and have worse patientreported outcomes.37,38 For example, women are less likely to be treated with statin or aspirin therapy and have controlled hypertension, and, overall, are less likely to be linked to appropriate cardiac rehabilitation (CR) programmes.37,39 Disparities in access to care for women extend throughout all ages and stages of CVD. Previous reviews have demonstrated that minimising modifiable risk factors at every aspect of care from diagnosis to treatment can help close the gap and improve outcomes.40

Sex Differences in Medication Side-effects

Women often report greater overall medication side-effects than men, which often leads patients or their clinicians to stop medications or decrease dosages to a more tolerable side-effect profile.41,42 Side-effect profiles of cardiovascular medications for women are variable and stem from differences in gastrointestinal absorption, body composition, metabolic consumption and kidney excretion. For example, one large US survey found that women were 28% more likely to have new or worsening muscle symptoms with statin therapy (adjusted OR 1.28; 95% CI [1.16, 1.42]) and 48% more likely to discontinue their statin therapy due to muscle symptoms (adjusted OR 1.48; 95% CI [1.25–1.75]) than men.42 This is worrisome in light of the substantial benefit that women derive from statin therapy.27 As another example, women have greater hospitalisations as a result of side-effects from torsemide, with higher circulating plasma concentrations of the drug.43 There are certainly many more examples. In such cases of intolerability, often a lower dose of medication can still provide benefit without the added risk. In situations where a reduced dosage is used due to side-effects, clinicians should consider titrating up to the maximum tolerated dose to make best use of benefits. Acknowledging and educating both clinicians and patients on the sideeffect profile of cardiovascular medications is crucial in mitigating the risk of such medications and helping tailor the appropriate medication regimen. These discrepancies further highlight the need for increased representation of women in pharmacological cardiovascular trials.

MINOCA, INCOCA and Coronary Microvascular Dysfunction

Women presenting with AMI are also twice as likely to present with MI with non-obstructive coronary arteries (MINOCA) over obstructive coronary artery disease (CAD).44,45 Women who present with MINOCA more often present with NSTEMI as a result of plaque erosion or rupture, coronary embolus or thrombosis, microvascular dysfunction, coronary artery dissection or spasm.45 Plaque erosions are thought to evolve from endothelial apoptosis, whereas plaque rupture is the result of inflammation. Both are associated with some coronary evidence of atherosclerotic burden. Women who are predisposed to a hypercoagulable state from antiphospholipid syndrome or inherited thrombophilia are at risk for MINOCA from coronary thrombosis and embolism of the microcirculatory system. Another cause of MINOCA results from spontaneous coronary artery dissection (SCAD), where there is separation of the layers of the epicardial coronary artery wall from an intimal tear or an intramural haemorrhage, which results in decreased arterial flow. SCAD may account for up to onethird of MIs among young women aged <50 years. SCAD is managed

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Secondary Prevention of CVD in Women Table 1: Modalities for the Secondary Prevention of Cardiovascular Disease in Women Modality

Goals/Indication

Intervention

Diet

CVD prevention

• Predominantly plant-based, minimally processed, rich in fruits, vegetables, legumes, nuts and whole grains; may include fish

• Most evidence for Mediterranean diet • Decrease alcohol and decrease sodium (<2.4 g/day) • Saturated fats <7% total calories • Trans fats <1% of total calories • Cholesterol intake <200 mg/day

Hypertension Dyslipidaemia

Exercise and cardiac rehabilitation Antiplatelet therapy

• At least 30 min 5 days/week or 150 min/week of moderate-intensity activity (1 min of vigorous activity = 2 min of moderate intensity) • Strength training twice a week; older adults may benefit from activities to promote balance • Exercised-based cardiac rehabilitation after MI, revascularisation or HF event All CAD • Aspirin 81 mg daily (first-line, lifetime) • Clopidogrel 75 mg daily (second-line, if patient cannot take aspirin, or in combination with aspirin after ACS and/or coronary stenting)

Acute coronary syndrome

Aspirin and P2Y12 inhibitor for ≥1 year§

Stent placement: Bare metal stent Drug-eluting stent

Aspirin and P2Y12 inhibitor for ≥1 month§ Aspirin and P2Y12 inhibitor for ≥1 year§

Hypertension management

BP goal <130/80 mmHg

β-blockers +ACEI/ARBs (first-line plus β-blockers if post-MI or β-blockers and/ or amlodipine if concomitant angina)

Smoking cessation

Complete cessation

Counselling and five As: • Asking about smoking status at each visit • Advising individuals to quit • Assessing readiness to quit • Assisting with cessation strategies • Arranging follow-up Pharmacotherapy (e.g. nicotine replacement therapy, bupropion, varenicline)

Cholesterol management

≥50% reduction in LDL and LDL <1.81 mmol/l* or <1.42 mmol/l†

Diabetes management

Use agents with CV outcome benefits Agents have CV prevention beyond HbA1c lowering HbA1c <7% or individualised‡

• High-dose or maximally tolerated statin • First-line: atorvastatin 40–80 mg daily or rosuvastatin 20–40 mg daily • Ezetimibe 10 mg daily (additive to meet goal) • Other additives to meet goal: PCSK9 inhibitors, BA, inclisiran • SGLT2 inhibitors (e.g. empagliflozin, canagliflozin, dapagliflozin) • GLP1-RA (e.g. dulaglutide, semaglutide, liraglutide)

*AHA/ACC guidelines.63 †ESC guidelines.106 ‡In individuals at risk of hypoglycaemia or in older patients, the HbA1c target is <8%. §Individualised dual antiplatelet therapy (DAPT) recommendations per patient. The duration of DAPT may be shorter in individuals at high risk of bleeding or longer in those at high risk of thrombosis. The use of risk decision tools, such as the DAPT calculator or PRECISE-DAPT, should be considered. ACEI = angiotensin-converting enzyme inhibitors; ARBs = angiotensin II receptor blockers; BA = bempedoic acid; BP = blood pressure; CAD = coronary artery disease; CV = cardiovascular; CVD = cardiovascular disease; GLP1-RA = glucagon-like peptide-1 receptor agonists; PCSK9 = proprotein convertase subtilisin/kexin type 9; SGLT2 = sodium–glucose cotransporter 2.

differently than other atherosclerotic-type MIs and thus is not discussed here; however, the topic has been comprehensively reviewed elsewhere.46 Although the underlying pathophysiology of each of the above causes of MINOCA is distinct, all result in decreased forward flow and poor perfusion of myocardial tissue, thus leading to ischaemia and infarct. A combination of coronary optical coherence tomography (OCT) or intravascular ultrasound (IVUS) plus cardiac MRI may help elucidate the aetiology of MINOCA in the vast majority of women.45,47 IVUS/OCT has been shown to be useful in detecting plaque disruption, coronary embolus or thrombus and SCAD.48 Despite overall better outcomes for individuals with MINOCA than those with complete occlusive disease, young women have higher mortality and adverse events from MINOCA than young men. The cause of this differential in mortality has not been studied, but is thought to be due, in part, to failure of placing women on appropriate goal-directed therapy.48 Preliminary studies from the SWEDEHEART registry indicate beneficial effects of statins, angiotensin-converting enzyme inhibitors (ACEI) or angiotensin II receptor blockers (ARB), and β-blockers for women with MINOCA.49

Whereas MINOCA reflects AMI, women can also have stable angina and/or evidence of coronary ischaemia with non-obstructive coronary arteries (INOCA).50,51 Among individuals with stable angina and evidence of ischaemia, one study found that 65% of women had no obstructive CAD, compared with 32% of men.50 Among individuals with moderate to severe ischaemia discovered on stress testing who were screened for eligibility to participate in the ISCHEMIA trial, 66% of those found to have no obstructive disease (the population enrolled in CIAO-ISCHEMIA registry) were female, compared with 26% of those with obstructive CAD (the population enrolled in the main ISCHEMIA trial).52 The frequency of angina symptoms and the amount of abnormalities seen on stress echocardiography testing (i.e. inducible wall motion abnormalities) were actually surprisingly similar between patients with and without obstructive CAD (i.e. patients enrolled in the ISCHEMIA trial versus those enrolled in the CIAO-ISCHEMIA registry). Furthermore, the degree of ischaemia on stress testing was not significantly correlated with symptom burden (i.e. angina). One may have assumed that the more ischaemia, the more symptoms and that if one could reduce ischaemia, that would reduce symptoms, but that is not the case. Ischaemia and angina were found to be not that well correlated.52

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Secondary Prevention of CVD in Women Figure 2: Secondary Prevention of Cardiovascular Disease in Women Antiplatelet therapy • All ASCVD: aspirin 81 mg/day indefinitely • After ACS or PCI: DAPT for 12 months duration may be adjusted based on bleeding or thrombosis risk factors

Cholesterol • High dose or maximally tolerated statin for LDL reduction of ≥50% • Goal LDL <1.81 mmol/l per AHA/ACC guidelines (or <1.42 mmol/l per ESC guidelines) for high-risk patients • Add-on therapy of ezetimibe (and PCSK9 inhibitor as needed) to achieve goal

Diet • Mediterranean, DASH or healthy vegetarian diets

Exercise • 150 min/week of moderate-intensity exercise (or 75 min/week of vigorousintensity exercise)

Diabetes management • Goal HbA1c of <7% if it can be achieved without hypoglycaemia • Consider SGLT2 inhibitor and GLP1-RA for CVD prevention

Cardiac rehabilitation • After MI, revascularisation, angina or HF

Smoking cessation • Counselling, Five As and pharmacotherapy

Hypertension control • Goal BP <130/80 mmHg • Lifestyle + pharmacotherapy

ACS = acute coronary syndrome; ASCVD = atherosclerotic cardiovascular disease; BP = blood pressure; CVD = cardiovascular disease; DAPT = dual antiplatelet therapy; DASH = Dietary Approaches to Stop Hypertension; GLP1-RA = glucagon-like peptide-1 receptor agonists; HF = heart failure; PCI = percutaneous coronary intervention; PCSK9 = proprotein convertase subtilisin/kexin type 9; SGLT2 = sodium–glucose cotransporter 2. Figure created using BioRender.

Nevertheless, INOCA in women is not benign and is associated with an elevated 5-year risk of major adverse cardiovascular events (MACE) compared with women without angina.53 Non-obstructive plaque is prognostic of MACE risk in women and should not be ignored when detected on imaging evaluation, and plaques with high-risk features may confer even greater relative risk in women than in men.54–57 INOCA can be the result of coronary microvascular dysfunction, vasospastic angina (VSA) or a combination of both, but is often underdiagnosed and undertreated and often has a poor prognosis.58 INOCA from microvascular dysfunction is defined as typical chest pain, non-obstructive coronary arteries and impaired flow specifically seen through one of the following: poor coronary flow reserve (CFR); spasm during provocative testing; or decreased coronary blood flow.59 Both anatomical and functional testing are frequently used for the work-up of women with suspected angina, and provide complementary information. Anatomical approaches (e.g. invasive coronary angiography or coronary CT angiography) rule out obstructive disease and can identify non-obstructive atherosclerotic plaque that warrants implementation of preventive therapies. Functional testing is used to evaluate for ischaemia. Ischaemia can be first identified through a number of non-invasive methods, including PET scans or dobutamine stress echocardiography. PET can be useful in detecting microvascular dysfunction and thus CFR, which is a strong indicator of prognosis.60 However, nuclear PET scans cannot identify coronary vasomotor disorders, which are common causes of INOCA in women.58 Elucidating coronary artery spasm requires acetylcholine to test vasoreactivity, which can only be administered during invasive coronary

angiography. Thus, once non-invasive methodologies have ruled out obstructive disease, the European Society of Cardiology (ESC) guidelines specify diagnostic guidewire coronary function testing as a Class IIa recommendation to assess CFR, and further recommend intracoronary acetylcholine testing for microvascular spasm as a Class IIb recommendation.61 If VSA is considered, the ESC notes acetylcholine testing as a Class IIa recommendation.61 There is a paucity of clinical trials specifically relating to treatment and risk mitigation for patients with INOCA; however, medications should be tailored to specifically target the underlying cause. Women with INOCA identified to have plaque on imaging should be treated with anti-atherosclerotic therapies (i.e. statins and ACEI/ARB) to reduce the risk of MACE. Anti-anginal therapies are used to control symptoms. For individuals with microvascular dysfunction, β-blockers, calcium channel blockers or ACEI/ARB may help decrease workload and improve microvascular perfusion. Ranolazine may also significantly improve symptoms and quality of life in women with microvascular angina.62 Individuals with INOCA from VSA derive greater benefit from calcium channel blockers or long-acting nitrates.58

Treatment Modalities for Secondary Prevention of CVD

Treatment modalities for the secondary prevention of CVD in women are summarised in Table 1 and Figure 2, and discussed below.

Lifestyle Modifications Diet

Lifestyle modifications are considered first-line treatment and are critical for mitigating the risk factors of CVD, including diabetes, lipids and blood

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Secondary Prevention of CVD in Women pressure. The American Heart Association (AHA)/American College of Cardiology (ACC) guidelines recommend a diet that emphasises fruits, vegetables, whole grains, legumes, nuts and healthy protein sources, such as low-fat dairy, low-fat poultry (without the skin) and fish/seafood.63,64 It is recommended that the intake of red meat, sugar-sweetened beverages, sweets and highly refined grains is limited.63 Dietary patterns can be adapted to cultural preferences and to specific comorbid conditions (e.g. diabetes). It is recommended that saturated fats be replaced with healthy mono- and polyunsaturated fats.14 For those with high LDL cholesterol (LDL-C), fat intake goals are specified: saturated fats should account for <7% of total calories and trans fats for <1% of total calories, and cholesterol intake should be reduced to <200 mg/day.65 For individuals with hypertension, the recommendations also include minimising sodium and alcohol intake.65 Guidelines recommend sodium consumption of <2,400 mg/day, with a goal of 1,500 mg/day.65 The ESC guidelines provide similar recommendations to the ACC/AHA guidelines, with a particular endorsement of the Mediterranean diet.66 Among high-risk patients with stable CAD, adherence to the Mediterranean diet was associated with a reduced risk of MACE.67 Furthermore, in the Lyon Heart Study, post-MI patients who were randomised to the Mediterranean diet experienced a 72% reduction in recurrent non-fatal MI, as well as a 56% decline in mortality risk at 4 years of follow-up, compared with <30% in those randomised to a control low-fat diet.68 Across guidelines, the Dietary Approaches to Stop Hypertension (DASH) diet and Mediterranean diet are commonly recommended as heart healthy diets for hypertension and CVD, respectively.69 The DASH and Mediterranean diets share similar tenets of being primarily rich in fruits and vegetables and low in saturated fat or refined grains; a healthy plant-based diet would also align with these recommendations. The studied effects of these diets on secondary prevention are mixed and limited by difficulties with adherence; however, the use of a dietician has shown effectiveness in reducing risk factors.69–72 For individuals with a known CVD history or post-MI, having a high-quality diet is associated with a decreased risk of recurrent cardiovascular events and lower all-cause mortality respectively.73,74

Exercise and Cardiac Rehabilitation

Exercise improves metabolic control, cardiorespiratory fitness (leading to improvements in blood pressure and endurance) and is thought to improve myocardial function from weight loss.75 These effects are heightened when combined with dietary modifications and pharmacotherapy.76 The ESC and ACC/AHA guidelines both recommend regular physical activity, defined as at least 150 min/week of moderate aerobic exercise, divided into 30 min sessions 5 days a week, or 75 min/ week of vigorous exercise for patients with known CVD and or peripheral artery disease.14,69,77 Moderate aerobic exercise has been defined as a brisk walk at 5–6 km/h and other equivalent exercises, such as swimming and biking, or house and garden work.78 CR programmes are AHA Class 1, Level A-recommended multidisciplinary and multifaceted programmes that often extend beyond exercise training to include diet, counselling, education and risk reduction.64 Compared with no exercise, exercise-based CR has been shown to reduce cardiovascular mortality after an acute event.77 Many CR programmes suffer from low enrolment and retention.79 Women are less likely to be referred and enrolled in CR programmes than men.39,80 Lack of familiarity with CR programmes, negative perceptions and a lack of transport, social support and systemic referral practices are causes of decreased enrolment numbers for women.39

CR is indicated after any ACS event or diagnosis of HF and is associated with overall increased survival, as well as improved functional status and psychosocial well-being and decreased hospitalisations.79 Women enrolled in CR programmes show an increase in exercise tolerance and decrease in body fat percentage similar to that of men, despite starting from a lower baseline, which further demonstrates the need for engagement.81

Antiplatelet Therapy

Following ACS or ischaemic stroke, all individuals are recommended to start aspirin 81–162 mg/day, which should be continued indefinitely for secondary prevention.64 The Antithrombotic Trialists conducted a metaanalysis that examined 16 secondary prevention trials with 17,000 individuals.82 Women were included in 14 of the 16 trials, making up an average of 10% of the sample population post-MI and 30% of the population post-transient ischaemic attack (TIA) or stroke.82,83 These studies did not show any evidence of sex interaction with aspirin efficacy for secondary prevention. Despite evidence for secondary prevention, women with stable ASCVD are 35% less likely than men to report being on aspirin therapy (OR 0.65; 95% CI [0.58–0.72]).37 For patients who are unable to tolerate aspirin, clopidogrel 75 mg/day is recommended as an alternative antiplatelet therapy.64 After stent placement, dual treatment with a P2Y12 inhibitor (such as clopidogrel, prasugrel or ticagrelor) and aspirin is recommended for ≥1 month in those in whom a bare metal stent was placed and ≥1 year after for those implanted with a drug-eluding stent.84 Other major trials compared prasugrel or ticagrelor to clopidogrel on a background of aspirin and showed similar results for men and women.83,85,86 Women made up approximately one-quarter of the population studied in these trials. Although studies to date demonstrate no sex effect on the benefit of antiplatelet therapy in secondary prevention or on the adverse effects of antiplatelet therapy, women are overall under-represented in the majority of therapeutic trials. Meta-analyses suggest equal efficacy (i.e. ASCVD reduction) and safety (i.e. bleeding) between women and men and do not justify any differential dual antiplatelet therapy (DAPT) treatment by sex.87,88 Among individuals at high risk of bleeding after percutaneous coronary intervention (PCI), one emerging strategy is to stop aspirin after 3 months of DAPT and to continue with a P2Y12 inhibitor as monotherapy.89 In the TWILIGHT study, which tested this strategy, women did have higher bleeding rates after PCI than men, but this was largely due to differences in baseline characteristics.89 There was no difference between women and men with regard to the benefit of early aspirin withdrawal and ticagrelor monotherapy on ischaemic endpoints.89 Aspirin (81–325 mg) is also recommended both preoperatively and indefinitely after CABG to reduce the risk of cardiac events and graft occlusion.90 Clopidogrel 75 mg daily is the recommended alternative in the event that aspirin is not tolerated. One year of DAPT with aspirin and prasugrel or ticagrelor is a Class Ic recommendation for patients who initially present with ACS.91 The antiplatelet regimen to be used for women with a SCAD-type of MI, who are managed conservatively without PCI, is not well established given the absence of trials, and experts differ in their opinions. However, one large registry (DISCO) suggested worse outcomes at 1 year when DAPT was used instead of single antiplatelet therapy.92 This requires further evaluation and study, ideally through a randomised control trial.

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Secondary Prevention of CVD in Women Hypertension Control

Women tend to develop hypertension later in life than men, largely due from falling oestrogen levels after menopause. Recent US data suggest hypertension control has been getting worse in women since 2013.93 Although lifestyle changes, a low-sodium diet and weight control are regularly recommended for hypertension, individuals with a history of CVD and a blood pressure (BP) >130/80 mmHg should also be promptly started on antihypertensive medications for a target BP of <130/80.94 Initial therapy should be targeted to follow specific guidelines for CHD, previous MI, HF or stroke, as indicated. For example, β-blockers, ACEI or ARBs are first-line antihypertensive treatments in patients with a history of ASCVD; diuretics and mineralocorticoid receptor antagonists could also be considered as adjuvants for individuals with HF after ACEI or ARB.94 β-blockers have been shown to improve outcomes after CABG, particularly for individuals who initially presented with MI.90 There are no sex-related differences in drug classes for men versus women in BP lowering and cardiovascular risk protection.95 However, ACEI and ARBs are contraindicated for use during pregnancy due to teratogenicity and women should be transitioned to nifedipine, labetalol or methyldopa for BP management.94 One cross-sectional study from the National Health and Nutrition Examination Survey found that women were more likely to be on pharmacotherapy than men (61.4% versus 56.8%; p=0.001), but women were less likely to have BP controlled (44.8% versus 51.1%; p=0.018).96 The authors of that study hypothesised that this was a result of less intensive BP management for women, as evidenced by women being less likely to be on three or more antihypertensive agents.96

Smoking Cessation

Women have a 25% greater relative risk of a CVD event than men who smoke.97 Although predominantly associated with men, the number of young women who smoke, particularly in low- and middle-income strata, is on the rise. However, women are 50% more likely to be advised to quit than similarly aged men.98 Secondary prevention strategies for smoking cessation overlap with primary prevention recommendations; however, the necessity for quitting becomes more salient after an acute event and offers a fresh opportunity to discuss strategies with patients. Continuing to smoke after an MI confers an increased risk for a recurrent event.99 In contrast, cessation of smoking after an acute cardiovascular event has been shown to be associated with a 36% risk reduction in mortality from CHD and to decrease the risk of any recurrent vascular effect.100,101 Combined counselling and pharmacotherapy have proven effective for smoking cessation.102 Successful counselling strategies include group therapy, as well as individualised and telephone counselling. The ‘Five As’ strategy is a popular smoking cessation approach in the outpatient setting that involves:

• • • • •

asking about smoking status at every visit; advising individuals to quit; assessing readiness to quit; assisting with cessation strategies; and arranging follow-up.

Cholesterol Management

As per the 2018 AHA/ACC/multisociety guideline for cholesterol management, all individuals <75 years with clinical ASCVD should be started on a high-intensity statin with the goal of reducing LDL-C by ≥50%.63 In individuals >75 years of age, at least moderate statin therapy should be initiated and up-titrated as tolerated. Women (compared with men) are less likely to be prescribed statins (67% versus 78%; p<0.001) and less likely to prescribed the appropriate guideline-recommended intensity of statin for their CVD (37% versus 45%; p<0.001).103 In a large meta-analysis of statin trials, among patients with vascular disease, statins reduced the risk of MACE similarly in women (RR 0.84; 95% CI [0.77–0.91]) and men (RR 0.79; 95% CI [0.76–0.82]; p for interaction by sex=0.43) for every 1 mmol/l reduction in LDL.26 After CABG, statins have also been recommended to slow the progression of disease in new grafts and, as per other secondary prevention recommendations, highintensity statins should be used.90 Pregnant women should use statins during pregnancy and breastfeeding with caution due to a lack of cohesive data about the teratogenic effects of statins.104 However, it should be noted that recently the Food and Drug Administration (FDA) lifted its strongest warning label about statin use in pregnancy, which will allow clinicians some flexibility to consider this option for their highest-risk patients as part of shared decision-making.105 For secondary prevention, the 2018 AHA/ACC guidelines also recommend that if LDL-C remains above a threshold of 1.81 mmol/l after treatment with maximally tolerated statin, then ezetimibe should be added.63 If LDL still remains above 1.81 mmol/l despite maximally tolerated statin and ezetimibe, then a PCSK9 inhibitor, such as evolocumab or alirocumab, should be started.63 The ESC lipid targets are more aggressive, setting an LDL threshold goal of <1.42 mmol/l for high-risk patients.106 The FOURIER and ODYSSEY clinical trials evaluated PCSK9 inhibitor therapy among patients with either stable CHD or recent ACS, respectively.107,108 Both trials included approximately 25% women and demonstrated that adding PCSK9 inhibitors to a high-intensity statin decreased the risk of ischaemic CVD events, with similar benefits in women as in men.30 Novel approaches to dyslipidaemia continue to emerge. Bempedoic acid was recently approved by the FDA as an addition to maximally tolerated statin for patients with ASCVD if additional LDL lowering was needed.109,110 The cardiovascular outcomes trial for bempedoic acid is still underway. Women made up approximately 29% of the population studied in the published bempedoic acid Phase III trials but represent approximately half of population in the ongoing cardiovascular outcome trial for bempedoic acid (CLEAR Outcomes; NCT02993406).110 This further demonstrates that although women have been more robustly included in clinical trials over the past four decades, they continue to be underrepresented.21–23,111 Inclisiran, a novel small interfering RNA inhibitor of PCSK9, has been demonstrated to reduce LDL by approximately 50% with twice-a-year injections.112 Approved in Europe, inclisiran is currently undergoing FDA regulatory approval.

Diabetes Management

Nicotine-replacement therapy, bupropion and varenicline are among the pharmacotherapy options proven to aid smoking cessation.14

Optimal glycaemic control is imperative for patients with known CVD, because type 2 diabetes (T2D) increases the risk of adverse events.113 The AHA guidelines recommend a target HbA1c of <7.0% for patients with a life expectancy of more than 10–20 years.114 The HbA1c goal could be liberalised to <8.0% or 8.5% in older patients if there is a risk of hypoglycaemia. More stringent glycaemic control has demonstrated a

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Secondary Prevention of CVD in Women decreased risk of microvascular endpoints, with less certainty about macrovascular endpoints.114 For individuals with known atherosclerotic disease and T2D, the use of sodium glucose co-transporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP1-RA) is recommended in conjunction with lifestyle modifications for CVD prevention.115 Note that the cardiovascular benefits conferred by SGLT2 inhibitors and GLP1-RA are independent of the HbA1c-lowering effects. SGLT2 inhibitors have been shown to reduce MACE, cardiovascular deaths and hospitalisations for HF, as well as to reduce the progression of chronic kidney disease.115–117 SGLT2 inhibitors confer similar CVD risk reduction in women as in men, with a similar safety profile.118 Meta-analyses of GLP1-RA in placebo-controlled trials demonstrated a reduction in MACE of approximately 12%, as well as a reduction in allcause mortality and fewer admissions for HF.115,119 A meta-analysis of trials suggested that women and men experience similar benefit in ASCVD reduction with GLP1-RA.120 Real-world data suggest that women may benefit from GLP1-RA even more than men.121 GLP1-RA therapy also can 1. Virani SS, Alonso A, Aparicio HJ, et al. Heart disease and stroke statistics – 2021 update: a report from the American Heart Association. Circulation 2021;143:e254–743. https://doi. org/10.1161/CIR.0000000000000950; PMID: 33501848. 2. Khan SU, Yedlapati SH, Lone AN, et al. A comparative analysis of premature heart disease- and cancer-related mortality in women in the USA, 1999–2018. Eur Heart J Qual Care Clin Outcomes 2021. https://doi.org/10.1093/ehjqcco/ qcaa099; PMID: 33555018; epub ahead of press. 3. Curtin SC. Trends in cancer and heart disease death rates among adults aged 45–64: United States, 1999–2017. Natl Vital Stat Rep 2019;68:1–9. PMID: 32501204. 4. Arora S, Stouffer GA, Kucharska-Newton AM, et al. Twenty year trends and sex differences in young adults hospitalized with acute myocardial infarction. Circulation 2019;139:1047– 56. https://doi.org/10.1161/CIRCULATIONAHA.118.037137; PMID: 30586725. 5. Hochman JS, Tamis JE, Thompson TD, et al. Sex, clinical presentation, and outcome in patients with acute coronary syndromes. N Engl J Med 1999;341:226–32. https://doi. org/10.1056/NEJM199907223410402; PMID: 10413734. 6. Keteepe-Arachi T, Sharma S. Cardiovascular disease in women: understanding symptoms and risk factors. Eur Cardiol 2017;12:10–3. https://doi.org/10.15420/ecr.2016:32:1; PMID: 30416543. 7. Sciomer S, Moscucci F, Maffei S, et al. Prevention of cardiovascular risk factors in women: the lifestyle paradox and stereotypes we need to defeat. Eur J Prev Cardiol 2019;26:609–10. https://doi.org/10.1177/2047487318810560; PMID: 30373379. 8. de Boer SP, Roos-Hesselink JW, van Leeuwen MA, et al. Excess mortality in women compared to men after PCI in STEMI: an analysis of 11,931 patients during 2000–9. Int J Cardiol 2014;176:456–63. https://doi.org/10.1016/j. ijcard.2014.07.091; PMID: 25127966. 9. Peters SA, Huxley RR, Woodward M. Diabetes as risk factor for incident coronary heart disease in women compared with men: a systematic review and meta-analysis of 64 cohorts including 858,507 individuals and 28,203 coronary events. Diabetologia 2014;57:1542–51. https://doi.org/10.1007/ s00125-014-3260-6; PMID: 24859435. 10. Elder P, Sharma G, Gulati M, Michos ED. Identification of female-specific risk enhancers throughout the lifespan of women to improve cardiovascular disease prevention. Am J Prev Cardiol 2020;2:100028. https://doi.org/10.1016/j. ajpc.2020.100028; PMID: 34327455. 11. Agarwala A, Michos ED, Samad Z, et al. The use of sexspecific factors in the assessment of women’s cardiovascular risk. Circulation 2020;141:592–9. https://doi. org/10.1161/CIRCULATIONAHA.119.043429; PMID: 32065772. 12. Peters SA, Woodward M. Women’s reproductive factors and incident cardiovascular disease in the UK Biobank. Heart 2018;104:1069–75. https://doi.org/10.1136/ heartjnl-2017-312289; PMID: 29335253. 13. Sciomer S, Moscucci F, Dessalvi CC, et al. Gender differences in cardiology: is it time for new guidelines? J Cardiovasc Med 2018;19:685–8. https://doi.org/10.2459/

confer meaningful weight loss reduction, which may be helpful for many patients with T2D. However, women only made up approximately 30– 40% of the participants in the GLP1-RA trials.

Conclusion

Women are at high risk of secondary cardiovascular events and, compared with men, have poorer outcomes within the first 5 years. Mitigating risk and improving outcomes is dependent on:

• the proper identification of CVD in women through imaging and understanding atypical presentations;

• starting and titrating appropriate GDMT while also continuing to engage with lifestyle modifications; and

• increasing representation of women in cardiovascular clinical trials. As our understanding of the CVD burden in women continues to grow, women are beginning to make up a more significant proportion of the studied population, which will allow us to further develop and tailor CVD guidelines and close the gap between diagnoses, treatment and mortality.

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female representation in the most-cited randomized controlled trials of cardiology of the last 20 years. Circ Cardiovasc Qual Outcomes 2018;11:e004713. https://doi. org/10.1161/CIRCOUTCOMES.118.004713; PMID: 29853466. 112. Ray KK, Wright RS, Kallend D, et al. Two Phase 3 trials of inclisiran in patients with elevated LDL cholesterol. N Engl J Med 2020;382:1507–19. https://doi.org/10.1056/ NEJMoa1912387; PMID: 32187462. 113. van der Heijden AA, Van’t Riet E, Bot SD, et al. Risk of a recurrent cardiovascular event in individuals with type 2 diabetes or intermediate hyperglycemia: the Hoorn study. Diabetes Care 2013;36:3498–502. https://doi.org/10.2337/ dc12-2691; PMID: 23877981. 114. Arnold SV, Bhatt DL, Barsness GW, et al. Clinical management of stable coronary artery disease in patients with type 2 diabetes mellitus: a scientific statement from the American Heart Association. Circulation 2020;141:e779–806. https://doi.org/10.1161/CIR.0000000000000766; PMID: 32279539. 115. Das SR, Everett BM, Birtcher KK, et al. 2020 expert consensus decision pathway on novel therapies for cardiovascular risk reduction in patients with type 2 diabetes: a report of the American College of Cardiology Solution Set Oversight Committee. J Am Coll Cardiol 2020;76:1117–45. https://doi.org/10.1016/j.jacc.2020.05.037; PMID: 32771263. 116. Zelniker TA, Wiviott SD, Raz I, et al. SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet 2019;393:31–9. https://doi.org/10.1016/S01406736(18)32590-X; PMID: 30424892. 117. Bhatia K, Jain V, Gupta K, et al. Prevention of heart failure events with sodium–glucose co-transporter 2 inhibitors across a spectrum of cardio-renal-metabolic risk. Eur J Heart Fail 2021;23:1002–8. https://doi.org/10.1002/ejhf.2135; PMID: 33609071. 118. Radholm K, Zhou Z, Clemens K, et al. Effects of sodium– glucose co-transporter-2 inhibitors in type 2 diabetes in women versus men. Diabetes Obes Metab 2020;22:263–6. https://doi.org/10.1111/dom.13876; PMID: 31486272. 119. Kristensen SL, Rorth R, Jhund PS, et al. Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet Diabetes Endocrinol 2019;7:776–85. https://doi.org/10.1016/ S2213-8587(19)30249-9; PMID: 31422062. 120. Singh AK, Singh R. Gender difference in cardiovascular outcomes with SGLT-2 inhibitors and GLP-1 receptor agonist in type 2 diabetes: a systematic review and meta-analysis of cardio-vascular outcome trials. Diabetes Metab Syndr 2020;14:181–7. https://doi.org/10.1016/j.dsx.2020.02.012; PMID: 32142999. 121. Raparelli V, Elharram M, Moura CS, et al. Sex differences in cardiovascular effectiveness of newer glucose-lowering drugs added to metformin in type 2 diabetes mellitus. J Am Heart Assoc 2020;9:e012940. https://doi.org/10.1161/ JAHA.119.012940; PMID: 31902326.

Heart Failure

Levosimendan in Europe and China: An Appraisal of Evidence and Context Xiangqing Kong ,1 Xinqun Hu ,2 Baotong Hua ,3 Francesco Fedele ,4 Dimitrios Farmakis

and Piero Pollesello

1. First Affiliated Hospital, Nanjing Medical University, Nanjing, China; 2. Second Xiangya Hospital, Zhongnan University, Changsha, China; 3. First Affiliated Hospital, Kunming Medical University, Kunming, China; 4. Department of Clinical, Internal, Anaesthesiology and Cardiovascular Sciences, University ‘La Sapienza’, Rome, Italy; 5. University of Cyprus Medical School, Nicosia, Cyprus; 6. Critical Care, Orion Pharma, Espoo, Finland

Abstract

The calcium sensitiser levosimendan (SIMDAX; Orion Pharma) has been in clinical use for the management of acute heart failure and a range of related syndromes in many countries around the world for two decades. More recently, levosimendan has become available in China. The authors have examined the profile of levosimendan in clinical trials conducted inside and outside China and grouped the findings under six headings: effects on haemodynamics, effects on natriuretic peptides, effect on symptoms of heart failure, renal effects, effect on survival, and safety profile. Their conclusions are that under each of these headings there are reasonable grounds to expect that the effects and clinical benefits established in trials and with wider clinical use in Europe and elsewhere will accrue also to Chinese patients. Therefore, the authors are confident that global experience with levosimendan provides a reliable guide to its optimal use and likely therapeutic effects in patients in China.

Keywords

Levosimendan, calcium sensitisation, acute heart failure, haemodynamics, China, randomised controlled trials Disclosure: FF and DF have recevied speaker honoraria and consultancy fees from Orion Pharma. PP is an employee of Orion Pharma. All other authors have no conflicts of interest to declare. Acknowledgements: The authors thank Shrestha Roy (Orion Pharma, Mumbai, India) for the graphic renditions and Peter Hughes (Hughes Associates, Oxford, UK) for editorial assistance. Received: 10 August 2021 Accepted: 27 August 2021 Citation: European Cardiology Review 2021;16:e42. DOI: https://doi.org/10.15420/ecr.2021.41 Correspondence: Piero Pollesello, Critical Care, Orion Pharma, PO Box 65, FIN-02101, Espoo, Finland. E: piero.pollesello@orionpharma.com Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

The term acute heart failure (AHF) describes the rapid onset or worsening of symptoms and/or signs of heart failure (HF) arising either de novo or, more frequently, as a consequence of acute decompensation of chronic HF. A wide range of possible causes or precipitants may initiate an episode of AHF; to that extent, AHF is an umbrella term for an extensive pathophysiological syndrome that may require widely differing clinical responses. In any event, AHF is a life-threatening situation that requires an urgent medical response, usually including speedy hospital admission. AHF-related mortality rates are very high. In the European Society of Cardiology (ESC) Heart Failure Long-Term registry, which enrolled 12,440 patients from 21 European and/or Mediterranean countries, the 1-year mortality rate for AHF was almost fourfold that for chronic HF (23.6% versus 6.4%).1 The corresponding rates for the combined outcome of mortality or HF hospitalisation were 36% for AHF and 14.5% for chronic HF.1 The burden of illness associated with AHF is encountered globally.2 As an exemplar of countries that have achieved notable economic progress in recent decades, China has recorded an increasing burden of coronary artery disease, hypertension, diabetes and obesity.3–5 This, combined with population aging, has created the conditions for many of the diseases of affluence to flourish. HF now affects >4 million individuals in China, and approximately 500,000 new cases are diagnosed every year.3 The prevalence and incidence rates of HF in China are comparable to those

recorded in many other countries (Figure 1).2 However, it should be noted that many of these estimates are based on administrative data: echocardiography-based research in various countries returns higher percentages, as, for example, in the work of Guo et al. concerning northern China.6 Given these working estimates of prevalence and incidence, the implied morbidity and mortality rates for a population of >1 billion people is considerable, even though 1-year mortality in Chinese AHF patients was the lowest recorded in the Inter-CHF registry of lowand middle-income countries (7% versus an average of 16.5%).6 In an episode of AHF, when a patient decompensates despite optimal oral medications, IV cardioactive and vasoactive drugs may be required to stabilise the patient’s haemodynamics and augment peripheral perfusion. This is also necessary to address the involvement of systemic organs, such as the lungs, kidney and liver, which is typical of HF.7 However, the available repertoire of such drugs is relatively narrow, and evidence for their sustained benefits is limited, inconclusive and often unpersuasive, especially with regard to longer-term effects on morbidity and survival.8 There have been strikingly few successful introductions in this field of therapeutics in recent times; some of us (DF, FF, PP) have contributed to a recent survey of the field that includes an overview of some of the reasons for this lack of success.8 Levosimendan is a notable exception to the frustrations associated with drug development in this field and has recently marked two decades in

Levosimendan in Europe and China Clinical Experience with Levosimendan

Figure 1: Prevalence and Incidence of Heart Failure in Various Countries Incidence (%) 0.5 0.4 0.3 0.2 0.1 0.1–0.2

0.39

0.27

0.31–0.39 0.39–0.44 0.38 0.9

0.1–0.2

0.05–0.17

0.2

1 Portugal Spain Germany Sweden Italy UK Netherlands US China Japan India Malaysia Singapore South America Australia

5 Prevalence (%)

1–2 2.1 1.6–1.8 1.8–2.2 1.44

1.3

A summary of key findings of the first generation of major clinical trials of levosimendan is a useful starting point for such a comparison.

1.5–1.9

1 0.12–0.44

Levosimendan has been extensively evaluated for the management of AHF in Europe in placebo- and active-controlled studies, and currently has marketing authorisation as SIMDAX in >60 countries.28–31 Detailed clinical evaluations have also been conducted recently in China, and instructive comparisons may be made between trials performed in China and those conducted elsewhere.

4.5

6.7

1–2

Source: Savarese et al.2 Reproduced with permission from Radcliffe Cardiology.

mainstream clinical use in many countries of Europe and elsewhere for the management of AHF.9 A consideration of its properties and clinical impact is therefore relevant as part of a wider discussion about the development of HF care in China.

The Inodilator Levosimendan

IV levosimendan (SIMDAX®) emerged from a research and development program by Orion Pharma (Espoo, Finland) that focused on expanding treatment options for patients with AHF or acutely decompensated HF (ADHF). IV levosimendan is notable for the fact that its inotropic effects are exerted through calcium sensitisation, not calcium mobilisation.10 This novel mode of action, which clearly differentiates it from adrenergic inotropic agents, made levosimendan a first-in-class agent at the time of its introduction, and it remains the only drug of its kind widely approved for clinical use.11–14 A recently published 20-year perspective on levosimendan is instructive.9 In addition to its calcium-sensitising effect, levosimendan mediates the opening of ATP-dependent potassium (KATP) channels in vascular smooth muscle cells.15 This causes systemic vasodilatation at usual therapeutic doses, and the drug should therefore be regarded as an inodilator rather than an inotrope. Levosimendan also opens KATP channels in mitochondria, exerting potentially cardioprotective effects.16–19 Several reports have shown that the vasodilator effect of levosimendan, and possibly its antioxidant and anti-apoptotic effects, are mediated by a mechanism involving both the opening of mitochondrial KATP channels and the modulation of nitric oxide release by different nitric oxide synthase isoforms.20–22 Importantly, the combined effects of levosimendan on cardiomyocytes, the coronary circulation and cardiac mitochondria have a favourable effect on the overall energy balance of cardiac function, which has not been shown for any other inodilator.23 Various other ‘pleiotropic’ actions of levosimendan may theoretically be relevant in certain scenarios, but further studies are needed before firm conclusions can be reached about their broader clinical significance.24–26 These properties of levosimendan will not be discussed further in this review, but Chinese medical scientists at Zhejiang University have produced a commentary that will be informative for readers interested in those topics.27

First, levosimendan resulted in dose-dependent increases in cardiac output and stroke volume, accompanied by reductions in pulmonary capillary wedge pressure (PCWP), mean blood pressure (BP), mean pulmonary artery pressure, mean right atrial pressure and total peripheral resistance.32 These effects persisted after termination of drug administration due to a long-acting metabolite designated OR-1896. Second, rapid and sustained reductions in levels of natriuretic peptides were seen in response to an infusion of levosimendan.32 (This effect has been corroborated in a meta-analysis of studies in AHF undertaken by Chinese investigators at Chongqing Medical University.33) Third, there were consistent benefits in symptom control with levosimendan.28,30 However, there were mixed findings for hospitalisation and mortality: positive numerical trends were observed, but did not attain statistical significance.29,31 Fourth, as summarised by Yilmaz et al., numerous studies have indicated an improvement in renal function with levosimendan in AHF.25 However, this finding must be interpreted after consideration has been given to the variation in study designs and the lack of any robust effect in the REVIVE program.30 Technical and mechanistic studies suggest that levosimendan is differentiated from agents such as dobutamine by the fact that it exerts a preglomerular vasodilator action via its effect on KATP channels in arteriolar vascular smooth muscle cells.34 A renoprotective effect of pharmacological preconditioning has also been proposed.35 Finally, the safety of levosimendan in predominantly non-Chinese patients with AHF has been the subject of a meta-analysis (n=5,349) conducted by Gong et al. from the First Affiliated Hospital of Jinan University.36 In that study, Gong et al. concluded that there were increased risks of recurrence of extrasystoles (RR 1.88; 95% CI [1.26–2.81]; p=0.002); headache or migraine (RR 1.94; 95% CI [1.54–2.43]; p<0.00001) and hypotension (RR 1.33; 95% CI [1.15–1.53]; p=0.0001) with levosimendan compared with combined control therapy comprising placebo or dobutamine. Levosimendan also lowered systolic BP (SBP) to a significantly greater extent than placebo or dobutamine (p≤0.02).

Levosimendan Clinical Research in China Acute Heart Failure Studies

The first multicentre randomised active-controlled parallel-group study of levosimendan in China for the management of AHF was reported by Wang et al.37 In that study, 225 patients with decompensated HF refractory to conventional therapy were randomised to treatment with either levosimendan (12 µg/kg over 10 minutes, followed by continuous infusion of 0.1 µg/kg/min for 1 hour and then 0.2 µg/kg/min for 23 hours; n=119) or dobutamine (2 µg/kg/min for 1 hour and then 4 µg/kg/min for 23 hours; n=106) for 24 hours. Haemodynamic responses at 24 hours were evaluated using echocardiography in both groups and a Swan–Ganz catheter in the levosimendan group.37

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Levosimendan in Europe and China Table 1: Haemodynamic, Echocardiographic and Biomarker Data from the Study of Wu et al.40 Variable

Levosimendan (n=20)

Placebo (n=10)

Baseline

24 h

48 h

Baseline

24 h

48 h

HR (BPM)

82 ± 9

86 ± 6

81 ± 6

81 ± 7

81 ± 9

82 ± 7

MAP (mmHg)

88 ± 7

84 ± 10

87 ± 7

87 ± 6

86 ± 6

mPAP (mmHg)

37 ± 2

30 ± 1*†

25 ± 1*†

38 ± 1

37 ± 1

37 ± 2

PCWP (mmHg)

26 ± 2

20 ± 3*†

17 ± 2*†

25 ± 2

26 ± 3

23 ± 2

CI (l/min/m2)

1.9 ± 0.3

2.3 ± 0.2*†

2.6 ± 0.2*†

1.9 ± 0.2

1.8 ± 0.2

2.0 ± 0.1

SVR (dyn×s/cm )

1,636 ± 125

1,320 ± 112*†

1,108 ± 98*†

1,701 ± 165

1,759 ± 178

1,595 ± 128

CPI (W/m2)

0.36 ± 0.06

0.43 ± 0.06*†

0.51 ± 0.05*†

0.36 ± 0.05

0.35 ± 0.05

0.38 ± 0.03

RV CPI (W/m )

0.15 ± 0.02

0.16 ± 0.01

0.15 ± 0.01

0.16 ± 0.02

0.15 ± 0.02

0.16 ± 0.01

NYHA class

3.6 ± 0.5

2.8 ± 0.6*

2.3 ± 0.5*

3.5 ± 0.5

3.7 ± 0.5

3.5 ± 0.7

E/A ratio

1.1 ± 0.5

1.5 ± 0.5*

1.6 ± 0.7*

1.2 ± 0.3

1.1 ± 0.6

1.3 ± 0.4

LV ESV (ml)

78 ± 24

61 ± 19*

54 ± 16

76 ± 26

78 ± 23

73 ± 21

LV EDV (ml)

112 ± 55

108 ± 48

105 ± 45

115 ± 49

116 ± 56

118 ± 45

LVEF (%)

36 ± 3

43 ± 5*

50 ± 8*

35 ± 4

34 ± 5

37 ± 5

BNP (pg/ml)

1,234 ± 867

556 ± 503*†

275 ± 330*†

1,217 ± 734

1,182 ± 845

967 ± 898

TnI (ng/ml)

76 ± 12

30 ± 9*†

10 ± 6*†

73 ± 16

48 ± 12*

21 ± 7*

CK-MB (U/ml)

43 ± 15

24 ± 12

12 ± 10*

46 ± 19

28 ± 10

18 ± 9*

Data are the mean ± SD. *p<0.05 compared with baseline within the levosimendan group; †p<0.05 compared with placebo at the same time point after treatment. BNP = B-type natriuretic peptide; CI = cardiac index; CK-MB = creatine kinase myocardial band; CPI = cardiac power index; E/A ratio = ratio of early to late peak velocity blood flow during left ventricular diastole; EDV = end-diastolic volume; ESV = end-systolic volume; HR = heart rate; LV = left ventricular; LVEF = left ventricular ejection fraction; MAP = mean arterial pressure; mPAP = mean pulmonary artery pressure; NYHA = New York Heart Association; PCWP = pulmonary capillary wedge pressure; RV = right ventricular; SVR = systemic vascular resistance; TnI = troponin I. Source: Wu et al.40 Reproduced with permission from Karger.

The end-of-treatment haemodynamic findings in that study favoured levosimendan, with numerically more frequent improvement in left ventricular ejection fraction (LVEF) in the levosimendan than dobutamine group (6.4% versus 4.6%; p>0.05) and significantly greater stroke volume enhancement with levosimendan (+11.1 versus +2.8 ml; p<0.05).37 The ‘clinical effectiveness rate’ was also significantly higher in the levosimendan than dobutamine group (32% versus 18%; p<0.01) and there were significantly (p<0.05) fewer adverse events in the levosimendan group, including hypokalaemia, hypotension and ventricular premature beats. Overall, levosimendan was well tolerated and both haemodynamically and clinically superior to dobutamine. In a study by Zhang et al., 114 patients with ADHF were randomised to receive levosimendan for 24 hours and another 114 were randomised to dobutamine.38 The ejection fraction increased by ~3% in both groups, but PCWP decreased significantly more in the levosimendan than dobutamine group (−8.90 ± 7.14 mmHg versus −5.64 ± 6.83 mmHg; mean ± SD; p=0.04), as did the plasma N-terminal pro B-type natriuretic peptide (NT-proBNP) concentration (−22.36 ± 38.98% versus −8.56 ± 42.42%; mean ± SD; p<0.01). The improvement in dyspnoea at the conclusion of drug infusion was significantly more pronounced in the levosimendan group. The incidence of adverse reactions was similar in the two groups. The same authors confirmed these findings in another randomised control study, also reporting a significantly more pronounced increase of the cardiac index from baseline value in the levosimendan group when compared to the dobutamine group.39

Acute Heart Failure Associated With MI

Two studies published simultaneously in 2014 have been conducted in this field of cardiology in China.40,41

In a pilot study by Wu et al., 30 consecutive patients with an acute MI (AMI) who exhibited signs of myocardial stunning despite undergoing an emergency percutaneous coronary intervention within 12 hours after the infarction were enrolled in an open-label randomised placebo-controlled trial.40 Twenty patients were randomised to receive levosimendan (0.1 µg/ kg/min for 24 hours), and 10 were assigned to matching placebo. All patients were in New York Heart Association (NYHA) class III or IV at baseline, all were taking aspirin or other antiplatelet drugs, angiotensinconverting enzyme inhibitors and diuretics and most (70–85% depending on treatment group assignment) were also taking β-blockers and spironolactone.40 Patients in the two groups were also well matched regarding the location of index infarction and pre-intervention coronary blood flow status. Comparison across multiple indices of haemodynamic performance and biomarkers identified broad-ranging statistically significant effects of levosimendan (Table 1). In addition, echocardiographic analysis established a lower percentage of stunned or infarcted myocardial segments in the levosimendan group (p<0.05 and p<0.01, respectively). In a study reported in the same issue of Cardiology, Jia et al. described the recruitment of 160 patients with HF complicated by AMI to a randomised single-centre single-blind study.41 In contrast with the study of Wu et al., this study was designed to address the significant proportion of patients with AMI who had not undergone cardiac revascularisation procedures, thus providing similarities to the enrolled population of the RUSSLAN study.29 Performed at 21 centres in Latvia and Russia, RUSSLAN was the principal regulatory study to examine the impact of SIMDAXbrand levosimendan in patients with AHF/AMI. For their study, Jia et al. selected patients who had AMI diagnosed according to established criteria during the previous 14 days, LVEF <40%, Killip class II–IV and either or both of: dyspnoea at rest and/or need for

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Levosimendan in Europe and China Figure 2: Treatment Effect of Levosimendan on the Composite Outcome of Death, Myocardial Ischaemia and Worsening Heart Failure

HF therapy if they fulfilled the following criteria: age >70 years, NYHA Class III–IV, LVEF ≤40% and plasma NT-proBNP ≥1,000 pg/ml. Patients (n=42) who still met all these criteria after 2 weeks were then divided into two groups well matched with regard to demographic criteria, and were randomly assigned to a continuation of standard therapy or to standard therapy plus an infusion of levosimendan (12 µg/kg for 10 min, followed by continuous infusion of 0.1 µg/kg/min for 1 hour and then 0.2 µg/kg/min for 23 hours).42 It is not clear from the original report whether the comparator group received a matching placebo infusion.

Placebo Levosimendan

Proportion of composite outcome

0.6

At assessment 1 week later, all 21 of the levosimendan-treated patients were classified in NYHA Class I or II, compared with 1 of 21 patients in the control group (p<0.05).42 Comparisons of changes in LVEF and NT-proBNP were also robustly in favour of levosimendan.42 Levosimendan was reported to be well tolerated in that study, but the authors acknowledged that the small patient numbers and the short duration of follow-up limited their ability to draw firm conclusions.42

0.4

0.2

Levosimendan group 43.7% versus placebo group 62.5%, HR=0.636, p=0.041

0 0

100 Time (days)

150

200

Source: Jia al.41 Adapted with permission from Karger.

mechanical ventilation for ADHF; and non-hypovolaemic oliguria.41 Eligible patients were randomised in a 1:1 ratio to receive levosimendan (0.1 µg/kg/ min for 24 hours) or placebo, and treatment effects were assessed via a composite primary endpoint that included death, myocardial ischaemia or worsening HF at both 14 days and 6 months. Although the percentage of patients who died or experienced worsening HF at 14 days was lower and the percentage of patients with myocardial ischaemia was higher in the levosimendan group, the differences did not reach statistical significance.41 Overall, the percentage of patients meeting the primary composite endpoint criteria at 14 days was lower, albeit not significantly, with levosimendan (21.2% versus 26.2%).41 At 6 months, the non-significant trends for death and worsening HF were supplemented by a significant trend for a lower incidence of MI in the levosimendan group between 14 days and 6 months (3.8% versus 13.8%; HR 0.261; p=0.036).41 As a result, there was a significant treatment effect of levosimendan on the composite primary endpoint (43.7% versus 62.5%; HR 0.636; 95% CI [0.413–0.981]; p=0.041; Figure 2).41 These findings are strikingly similar to those of the RUSSLAN trial.29 Stratification of outcomes by Killip class and revascularisation status indicated that favourable treatment effects of levosimendan were more likely to be recorded in patients in Killip class II (29.0% versus 52.6%; p=0.066) or in those who had undergone revascularisation (40.9% versus 67.4%; p=0.037).41 There was also a marked reduction in B-type natriuretic peptide (BNP) in response to levosimendan infusion and an enhancement of LVEF was apparent within 3 days of treatment (p=0.008 versus the control group).

Chronic or Refractory Heart Failure

The impact of a single 24-hour infusion of levosimendan on the clinical status of elderly patients with refractory HF was investigated in a two-stage study undertaken by researchers at Chongqing Medical University.42 In the first phase of this trial, 268 patients were assigned to maximal conventional

Practical Issues Concerning the Use of Levosimendan in the Chinese Clinical Setting

Cui et al. have recently commented on the need to develop an efficient HF management program in China, highlighting, among other things, the “importance of establishing the most cost-effective prevention and therapy strategies”.43 Defining the role and usage of levosimendan may be seen as one aspect of this requirement. The Chinese Society of Cardiology is affiliated with the ESC and its 2018 guidelines closely reflect the ESC recommendations.44,45 The uses of levosimendan identified in both sets of guidelines include:

• short-term, IV use in patients with hypotension (systolic blood

pressure [SBP] <90 mmHg) and/or signs or symptoms of hypoperfusion despite adequate filling status to increase cardiac output and BP, improve peripheral perfusion and maintain end-organ function (recommendation grade IIb C); and • reversing the effect of β-blockade if β-blockade is thought to be contributing to hypotension with subsequent hypoperfusion (recommendation grade IIb C). To these indications may be added the possibility of using intermittent infusions of levosimendan for long-term symptom relief or control in cases of AHF. This use is acknowledged by the Heart Failure Association of the ESC, which recognises the advantage of the prolonged haemodynamic effect conferred by the metabolite OR-1896.46 The use of levosimendan in Chinese patients for the management of AHF broadly conforms to international practice. For that indication, the drug is given as a continuous infusion of 0.05–0.2 μg/kg/min for 24 hours. Infusion may be preceded by a loading dose of 6–12 μg/kg over 10 min if an instant effect is sought, as long as baseline SBP is adequate.44,45 The use of an initial loading dose of levosimendan is not currently recommended, but was used in at least one of the Chinese trials described previously.37 Infusion is most often commenced initially at a dose of 0.1 µg/kg/min (or 0.05 µg/kg/min when SBP is marginal) and then up-titrated to 0.2 µg/kg/ min after the first 2–3 hours, provided that satisfactory BP is maintained. The recommended duration of infusion in AHF is 24 hours. If a faster onset of action is required, treatment can be initiated at a dose of 0.2 μg/kg/min, which has an acceptable risk–benefit profile for infusions of up to 6 hours.47 Hypovolaemia and hyperkalaemia should be corrected before infusion,

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Levosimendan in Europe and China and volume and potassium status monitored during treatment. In complicated cases, a pulmonary artery (Swan–Ganz) catheter may be considered to monitor filling pressures and cardiac output.48 These requirements profile levosimendan as a drug most appropriately used by experienced physicians, probably in tertiary cardiology centres.

and PCWP, as well as on echocardiographic indicators of ventricular function. These effects were apparent in the series of pivotal regulatory studies conducted in Europe and have been recapitulated in the Chinese studies reviewed in this paper.

HF is part of an emerging cardiovascular health challenge in China. Initiatives such as the China-PEACE study (NCT02877914) and the HERO registry have identified several new themes that may be pertinent to the successful deployment of levosimendan.3,49–53

Rapid, early and sustained reductions in BNP constitute a constant feature of the response to levosimendan in patients with acute or decompensated HF, and studies in Chinese patients confirm this effect, as discussed earlier. For example, a meta-analysis of randomised controlled trials in patients with advanced HF by Cui et al., from Chongqing Medical University, has confirmed this effect of levosimendan and associated it with improvement in LVEF compared with placebo, dobutamine, furosemide and prostaglandin E1 (standardised mean difference 0.74; 95% CI [0.22–1.25]; p=0.005).33

First, the use of several standard classes of drugs in HF patients in China is lower than that in international registries.53 In particular, the use of β-blockers currently appears to be notably low.53 The population of HF patients in China being treated with β-blockers can be expected to expand considerably in the coming years. If this is indeed the case, then the population of patients for whom levosimendan may be the preferred inotropic therapy can be expected to increase over time. Second, a large proportion of HF cases in China appear to have good LVEF (≥50%), so-called HF with preserved EF (HFpEF).53 Levosimendan has not been extensively studied in this segment of the HF population, and a meta-analysis of outcomes in patients undergoing cardiac surgery identified no survival benefit in those with preserved LVEF (RR 1.06; 95% CI [0.72–1.56]; p=0.78) compared with studies of patients with moderate and low LVEF (RR 0.44; 95% CI [0.27–0.70]; p<0.001).54 However, mortality reduction may not be the only legitimate aim of short-term treatment, and there are indications of the potential of levosimendan to improve diastolic function from a small prospective randomised study of patients undergoing aortic valve surgery.55 Some commentators think the latter may be relevant to HFpEF.56 In addition, a modest haemodynamic response has recently been reported from the Phase 2 HELP trial (NCT03541603) and more insights may emerge from its open-label extension (NCT03624010). Pending further research, the use of levosimendan in patients with HFpEF should be restricted to people fulfilling current guideline criteria and in whom active haemodynamic monitoring is performed. Finally, attention must be given to the widespread use of traditional Chinese medicines (TCMs) in the management of HF patients. These compounds have a prominent place in the Chinese health ecosystem, and it would be misplaced to dismiss them. However, few TCMs have been subjected to Western-style assessment and, although plans are in hand for a systematic review and network meta-analysis of HF-targeted TCMs, those plans are at an early stage.57 Given that levosimendan will, in most cases, be administered as a short-term treatment, the potential for meaningful adverse interactions with TCMs would appear to be limited. However, there is a need for care in monitoring and recording such interactions until potential hazards have either been identified or can be discounted. This requirement may gain further impetus if levosimendan becomes widely used in China as a recurring intermittent infusion to support people with episodic decompensations or with advanced HF.

Expert Assessment

We opened this short review with a list of the key characteristics of levosimendan in acute or decompensated HF which, with experience in China duly noted, may now usefully be revisited.

Haemodynamics

Levosimendan has consistently been shown to exert a range of favourable effects on several haemodynamic indices, including LVEF, cardiac index

Natriuretic Peptides

All in all, an effect on natriuretic peptide concentrations may be considered as one of the means for discriminating between levosimendan responders and non-responders (i.e. those in whom levosimendan has robust natriuretic peptide level decreasing effects, and those in whom this effect was not present, respectively).58 This reflects the general correlation existing between decreases in natriuretic peptide and treatment efficacy in HF, not only for levosimendan.59

Symptoms

Relief of HF-related symptoms such as dyspnoea is a robust finding in clinical studies of levosimendan in acute or decompensated HF: experience in the REVIVE trial may be considered as an exemplar of this fact, which has been broadly replicated in the Chinese studies we have summarised.

Renal Effects

Regarding AHF with accompanying renal dysfunction, Chinese data consistent with observations in non-Chinese populations are already available.34,60–62 A further contribution to understanding the renal effects of levosimendan may be found in the work of Chen et al., who conducted a network metaanalysis of 29 published trials to provide direct comparisons of levosimendan versus placebo or inotropes in patients undergoing cardiac surgery.63 They concluded that, compared with placebo, the use of levosimendan significantly decreases the risks of mortality (OR 0.74; 95% CI [0.56–0.97]) and acute renal injury (OR 0.61; 95% CI [0.45–0.82]), especially in patients with low systolic function.63 Comparisons with milrinone, dopamine, dobutamine and fenoldopam identified levosimendan as the best treatment based on p-values. In an associated development, the authors of a recently reported retrospective cohort study conducted in Taiwan showed that an estimated glomerular filtration rate of <30 ml/min/1.73 m2 was not necessarily a contraindication to the use of levosimendan in patients with AHF and reduced EF, albeit no substantive effect was observed on 30- to 180-day mortality.64

Survival

Effects on mortality remain the subject of debate, and the lack of a significant improvement in large regulatory studies offsets some of the more optimistic findings from meta-analyses, as in the work of Gong et al. and Pollesello et al.36,65 The meta-analysis and trial sequential analysis of randomised trials of levosimendan in patients with left ventricular dysfunction undergoing cardiac surgery undertaken by Xing et al. is

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Levosimendan in Europe and China another example of the need for further research on this theme.66 Nevertheless, we consider that levosimendan is likely associated at least with lower mortality rates than dobutamine, perhaps due, in part, to its more favourable impact on myocardial cellular energy balance. We further see no a priori reason that any treatment benefits identified in nonChinese patients will not extend to Chinese patients. However, we note that aside from any consideration of ethnic differences, mortality and rehospitalisation rates among patients with decompensated HF remain high for some time after the index admission.

Safety Profile

Safety and tolerability concerns associated with levosimendan are well characterised, expected by its mode of action and, for the most part, demonstrated to be avoidable with due attention to issues such as baseline BP and fluid and electrolyte status. In fact, it has been recognised that hypotension can be a limitation of levosimendan applications, and several reports have suggested that omission of the loading dose of levosimendan in patients with low baseline BP or at risk of hypovolaemia can be a way to limit the incidence of hypotension (e.g. see the expert consensus by Nieminen et al.).47 In this area, the research of Gong et al. is of note.36 It is rare for adverse events or tolerability issues to necessitate cessation of levosimendan therapy. We see no evidence or theoretical reason to expect a different response from Chinese patients, but continued surveillance is warranted.

Conclusion

In cases of refractory HF, the (limited) experience reported by Chinese clinical researchers supports the expectation from studies elsewhere that levosimendan will deliver short-term improvements in haemodynamics and clinical symptomatic status. The preliminary work of Bonios et al. encourages an expectation that prolonged levosimendan therapy, administered as a succession of intermittent infusions, may also be accompanied by survival advantages in advanced HF refractory to 1. Crespo-Leiro MG, Anker SD, Maggioni AP, et al. European Society of Cardiology Heart Failure Long-Term Registry (ESC-HF-LT): 1-year follow-up outcomes and differences across regions. Eur J Heart Fail 2016;18:613–25. https://doi. org/10.1002/ejhf.566; PMID: 27324686. 2. Savarese G, Lund LH. Global public health burden of heart failure. Card Fail Rev 2017;3:7–11. https://doi.org/10.15420/ cfr.2016:25:2; PMID: 28485469. 3. Yu Y, Gupta A, Wu C, et al. Characteristics, management, and outcomes of patients hospitalized for heart failure in China: the China PEACE Retrospective Heart Failure Study. J Am Heart Assoc 2019;8:e012884. https://doi.org/10.1161/ JAHA.119.012884; PMID: 31431117. 4. Li Y, Teng D, Shi X, et al. Prevalence of diabetes recorded in mainland China using 2018 diagnostic criteria from the American Diabetes Association: national cross sectional study BMJ 2020;369:m997. https://doi.org/10.1136/bmj.m997; PMID: 32345662. 5. Pan XF, Wang L, Pan A. Epidemiology and determinants of obesity in China. Lancet Diabetes Endocrinol 2021;9:373–92. https://doi.org/10.1016/S2213-8587(21)00045-0; PMID: 34022156. 6. Guo L, Guo X, Chang Y, et al. Prevalence and risk factors of heart failure with preserved ejection fraction: a populationbased study in northeast China. Int J Environ Res Publ Health 2016;13:770. https://doi.org/10.3390/ijerph13080770; PMID: 27483300. 7. Fedele F, Severino P, Calcagno S, Mancone M. Heart failure: TNM-like classification. J Am Coll Cardiol 2014;63:1959–60. https://doi.org/10.1016/j.jacc.2014.02.552; PMID: 24657683. 8. Pollesello P, Ben Gal T, Bettex D, et al. Short-term therapies for treatment of acute and advanced heart failure – why so few drugs available in clinical use, why even fewer in the pipeline? J Clin Med 2019;8:1834. https://doi.org/10.3390/ jcm8111834; PMID: 31683969. 9. Papp Z, Agostoni P, Alvarez J, et al. Levosimendan efficacy

10. 11.

12.

13.

14.

15.

16.

17.

conventional therapies.67 Indeed, a meta-analysis confirmed the association of repetitive levosimendan administration in advanced heart failure with a significant reduction in mortality at the longest follow-up available.68 However, confirmation of that finding is needed for patients of all ethnicities. A recent report by Wang and Luo offers assurance on the use of levosimendan in patents with refractory HF accompanied by hypotension.69 Additional AHF scenarios that may warrant the use of levosimendan include decompensation accompanied by worsening renal function, cardiac ischaemia or elevated pulmonary artery pressure, as well as cardiogenic shock or takotsubo syndrome.70,71 To the extent that experience with levosimendan in HF in the context of AMI or acute decompensation or chronic or refractory HF has been substantially similar in Chinese and non-Chinese patients, we are encouraged to the view that the effects of levosimendan demonstrated in these additional clinical scenarios in predominantly non-Chinese populations are likely to be replicated in Chinese patients with otherwise similar clinical presentations. However, for all these additional indications it will be necessary to substantiate these expectations through direct study of Chinese patients in controlled studies. For similar reasons, in this review we did not touch the perioperative use of the drug or its use in intensive care unit settings.72,73 Instead, we focused on its main indications in acute heart failure and acute cardiac care, as recently defined in the reviews by Farmakis et al. and Heringlake et al.74,75 From the data reviewed here, we conclude that there is enough evidence to show that the effects of levosimendan in acute and decompensated HF documented by studies in non-Chinese patients are replicated in Chinese patients and that experience accumulated by studies performed outside China may be regarded as a reasonable guide to the use of levosimendan in China.

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org/10.1016/j.ijcard.2008.10.003; PMID: 18973957. 59. Cohen-Solal A, Logeart D, Huang B, et al. Lowered B-type natriuretic peptide in response to levosimendan or dobutamine treatment is associated with improved survival in patients with severe acutely decompensated heart failure. J Am Coll Cardiol 2009;53:2343–8. https://doi. org/10.1016/j.jacc.2009.02.058; PMID: 19539144. 60. Hou ZQ, Sun ZX, Su CY, et al. Effect of levosimendan on estimated glomerular filtration rate in hospitalized patients with decompensated heart failure and renal dysfunction. Cardiovasc Ther 2013;31:108–14. https://doi.org/10.1111/1755922.12001; PMID: 23490237. 61. Lannemyr L, Ricksten S-E, Rundqvist B, et al. Differential effects of levosimendan and dobutamine on glomerular filtration rate in patients with heart failure and renal impairment: a randomized double-blind controlled trial. J Am Heart Assoc 2018;7:e008455. https://doi.org/10.1161/ JAHA.117.008455; PMID: 30369310. 62. Fedele F, Bruno N, Brasolin B, et al. Levosimendan improves renal function in acute decompensated heart failure: possible underlying mechanisms. Eur J Heart Fail 2014;16:281–8. https://doi.org/10.1002/ejhf.9; PMID: 24464960. 63. Chen WC, Lin MH, Chen CL, et al. Comprehensive comparisons among inotropic agents on mortality and risk of renal dysfunction in patients who underwent cardiac surgery: a network meta-analysis of randomized controlled trials. J Clin Med 2021;10:1032. https://doi.org/10.3390/ jcm10051032; PMID: 33802296. 64. Chan CC, Lee KT, Ho WJ, et al. Levosimendan use in patients with acute heart failure and reduced ejection fraction with or without severe renal dysfunction in critical cardiac care units: a multi-institution database study. Ann Intensive Care 2021;11:27. https://doi.org/10.1186/s13613-02100810-y; PMID: 33555483. 65. Pollesello P, Parissis J, Kivikko M, Harjola VP. Levosimendan meta-analyses: is there a pattern in the effect on mortality? Int J Cardiol 2016;209:77–83. https://doi.org/10.1016/j. ijcard.2016.02.014; PMID: 26882190. 66. Xing Z, Tang L, Chen P, et al. Levosimendan in patients with left ventricular dysfunction undergoing cardiac surgery: a meta-analysis and trial sequential analysis of randomized trials. Sci Rep 2018;8:7775. https://doi.org/10.1038/s41598018-26206-w; PMID: 29773835. 67. Bonios MJ, Terrovitis JV, Drakos SG, et al. Comparison of three different regimens of intermittent inotrope infusions for end stage heart failure. Int J Cardiol 2012;159:225–9. https://doi.org/10.1016/j.ijcard.2011.03.013; PMID: 21481958. 68. Silvetti S, Nieminen MS. Repeated or intermittent levosimendan treatment in advanced heart failure: An updated meta-analysis. Int J Cardiol 2016;202:138–43. https://doi.org/10.1016/j.ijcard.2015.08.188; PMID: 26386941 69. Wang M, Luo B. Levosimendan is safe to patients with advanced heart failure and hypotension. Int J Cardiol 2021;338;153. https://doi.org/10.1016/j.ijcard.2021.05.057; PMID: 34118325. 70. Agostoni P, Farmakis DT, García-Pinilla JM, et al. Haemodynamic balance in acute and advanced heart failure: an expert perspective on the role of levosimendan. Card Fail Rev 2019;5:155–61. https://doi.org/10.15420/ cfr.2019.01.R1; PMID: 31768272. 71. Bouchez S, Fedele F, Giannakoulas G, et al. Levosimendan in acute and advanced heart failure: an expert perspective on posology and therapeutic application. Cardiovasc Drugs Ther 2018;32:617–24. https://doi.org/10.1007/s10557-0186838-2; PMID: 30402660. 72. Guarracino F, Heringlake M, Cholley B, et al. Use of levosimendan in cardiac surgery: an update after the LEVOCTS, CHEETAH, and LICORN trials in the light of clinical practice. J Cardiovasc Pharmacol 2018;71:1–9. https://doi. org/10.1097/FJC.0000000000000551; PMID: 29076887. 73. Herpain A, Bouchez S, Girardis M, et al. Use of levosimendan in intensive care unit settings: an opinion paper. J Cardiovasc Pharmacol 2019;73:3–14. https://doi. org/10.1097/FJC.0000000000000636; PMID: 30489437. 74. Farmakis D, Agostoni P, Baholli L, et al. A pragmatic approach to the use of inotropes for the management of acute and advanced heart failure: an expert panel consensus. Int J Cardiol 2019;297:83–90. https://doi. org/10.1016/j.ijcard.2019.09.005; PMID: 31615650. 75. Heringlake M, Alvarez J, Bettex D, et al. An update on levosimendan in acute cardiac care: applications and recommendations for optimal efficacy and safety. Expert Rev Cardiovasc Ther 2021;19:325–35. https://doi.org/10.1080/1477 9072.2021.1905520; PMID: 33739204.

APSC Consensus Recommendations

2021 Asian Pacific Society of Cardiology Consensus Recommendations on the Use of P2Y12 Receptor Antagonists in the Asia-Pacific Region: Special Populations Jack Wei Chieh Tan ,1,2 Derek P Chew ,3 Kin Lam Tsui ,4 Doreen Tan ,5 Dmitry Duplyakov ,6 Ayman Hammoudeh ,7 Bo Zhang ,8 Yi Li,9 Kai Xu,10 Paul J Ong ,11,12 Doni Firman ,13 Habib Gamra ,14 Wael Almahmeed ,15 Jamshed Dalal,16 Li-Wah Tam ,17 Gabriel Steg ,18 Quang N Nguyen ,19 Junya Ako ,20 Jassim Al Suwaidi ,21 Mark Chan ,22 Mohamed Sobhy,23 Abdulla Shehab ,24 Wacin Buddhari,25 Zulu Wang,10 Alan Yean Yip Fong ,26 Bilgehan Karadag ,27 Byeong-Keuk Kim ,28 Usman Baber,29 Chee Tang Chin1 and Ya Ling Han9 1. National Heart Centre, Singapore; 2. Sengkang General Hospital, Singapore; 3. College of Medicine and Public Health, Flinders University, Adelaide, Australia; 4. Pamela Youde Nethersole Eastern Hospital, Hong Kong, China; 5. Department of Pharmacy, Faculty of Science, National University of Singapore, Singapore; 6. Samara Regional Cardiology Dispensary, Samara, Russia; 7. Cardiology Department, Istishari Hospital, Amman, Jordan; 8. Department of Cardiology, First Affiliated Hospital, Dalian Medical University, Dalian, China; 9. Department of Cardiology, General Hospital of Northern Theatre Command, Shenyang, China; 10. Department of Cardiology, General Hospital of Shenyang Military, Shenyang, China; 11. Heart Specialist International, Mount Elizabeth Novena Hospital, Singapore; 12. Tan Tock Seng Hospital, Singapore; 13. Harapan Kita National Cardiovascular Center/Department of Cardiology and Vascular Medicine, Faculty of Medicine, Universitas Indonesia Harapan Kita, Jakarta, Indonesia; 14. Cardiology Department, Fattouma Bourguiba University Hospital and University of Monastir, Monastir, Tunisia; 15. Cleveland Clinic Abu Dhabi, United Arab Emirates; 16. Centre for Cardiac Sciences, Kokilaben Dhirubhai Ambani Hospital, Mumbai, India; 17. Kwong Wah Hospital, Hong Kong, China; 18. Department of Cardiology, Hôpital Bichat, Paris, France; 19. Department of Cardiology, Hanoi Medical University, Hanoi, Vietnam; 20. Department of Cardiovascular Medicine, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan; 21. Adult Cardiology, Hamad Medical Corporation, Doha, Qatar; 22. National University Heart Centre, Singapore; 23. Faculty of Medicine, Alexandria University, Egypt; 24. College of Medicine and Health Sciences, UAE University, Al Ain, United Arab Emirates; 25. King Chulalongkorn Memorial Hospital, Bangkok, Thailand; 26. Sarawak Heart Centre, Kota Samarahan, Malaysia; 27. Istanbul UniversityCerrahpasa School of Medicine, Istanbul, Turkey; 28. Division of Cardiology, Department of Internal Medicine, Severance Cardiovascular Hospital, Yonsei University College of Medicine, Seoul, South Korea; 29. University of Oklahoma Health Sciences Center, Oklahoma City, OK, US

Abstract

Advanced age, diabetes, and chronic kidney disease not only increase the risk for ischaemic events in chronic coronary syndromes (CCS) but also confer a high bleeding risk during antiplatelet therapy. These special populations may warrant modification of therapy, especially among Asians, who have displayed characteristics that are clinically distinct from Western patients. Previous guidance has been provided regarding the classification of high-risk CCS and the use of newer-generation P2Y12 inhibitors (i.e. ticagrelor and prasugrel) after acute coronary syndromes (ACS) in Asia. The authors summarise evidence on the use of these P2Y12 inhibitors during the transition from ACS to CCS and among special populations. Specifically, they present recommendations on the roles of standard dual antiplatelet therapy, shortened dual antiplatelet therapy and single antiplatelet therapy among patients with coronary artery disease, who are either transitioning from ACS to CCS; elderly; or with chronic kidney disease, diabetes, multivessel coronary artery disease and bleeding events during therapy.

Keywords

Platelet aggregation inhibitors, Asia, myocardial ischaemia, consensus, dual antiplatelet therapy, comorbidity Disclosure: This work was funded through the Asian Pacific Society of Cardiology (APSC) with unrestricted educational grants from Abbott Vascular, Amgen, AstraZeneca, Bayer and Roche Diagnostics. JWCT reports honoraria from AstraZeneca, Bayer, Amgen, Medtronic, Abbott Vascular, Biosensors, Alvimedica, Boehringer Ingelheim and Pfizer; research and educational grants from Medtronic, Biosensors, Biotronik, Philips, Amgen, AstraZeneca, Roche, Otsuka, Terumo and Abbott Vascular; and consulting fees from Elixir and CSL Behring; and is on the European Cardiology Review editorial board; this did not influence peer review. JA reports honoraria from AstraZeneca, Daiichi Sankyo, Bayer and Sanofi; and grants/grants pending from Daiichi Sankyo. DPC reports consulting fees from APSC; support for travel to meetings for the study or otherwise from APSC; grants/grants pending from Roche Diagnostics; payment for development of educational presentations including service on speakers’ bureaus from AstraZeneca. JD reports honoraria from Bayer and Pfizer. CTC reports honoraria from Abbott Vascular, AstraZeneca, Boston Scientific, Biotronik, Biosensors, Medtronic; consulting and ad boards from AstraZeneca, Boston Scientific; and research and educational support from AstraZeneca, Eli Lilly. AH reports consulting fee or honorarium from AstraZeneca. MC reports consulting fee or honorarium from AstraZeneca. AYYF reports honoraria and educational support from AstraZeneca. BK reports consulting fee or honorarium from AstraZeneca, Abbott, IE Menarini, Daiichi Sankyo, Sanovel and ARIS. UB reports honoraria from Amgen and AstraZeneca. All other authors have no conflicts of interest to declare. Acknowledgement: Medical writing support was provided by Tristan Marvin Uy and Ivan Olegario of MIMS Pte Ltd. JWCT and DPC are joint first authors. Received: 13 July 2021 Accepted: 4 September 2021 Citation: European Cardiology Review 2021;16:e43. DOI: https://doi.org/10.15420/ecr.2021.35 Correspondence: Ya Ling Han, Department of Cardiology, General Hospital of Northern Theatre Command, 83 Wenhua Rd, 110016, Shenyang, China. E: hanyaling@263.net Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

P2Y12 Inhibitors for Special Populations in the Asia-Pacific Region Chronic coronary syndromes (CCS) have been defined as a clinical presentation of coronary artery disease (CAD), encompassing all evolutionary phases except episodes wherein acute thrombosis predominates, which constitutes acute coronary syndromes (ACS).1 However, the transition from ACS to CCS has not been well-defined. Certain conditions may increase the risk for future cardiovascular events in CCS.1 Old age, co-morbidities such as diabetes and chronic kidney disease (CKD), and complex CAD have been established as risk factors for ischaemia.2–9 On the other hand, some of these conditions may also affect bleeding risk from antiplatelet therapy. Advanced age, diabetes and CKD have been found to confer an increased risk for haemorrhagic events among patients taking antiplatelet agents for CAD or after percutaneous coronary intervention (PCI).10–23 Consequently, for such specific populations, modification of usual therapy may be warranted. European guidelines have recently suggested careful consideration of dual antiplatelet therapy (DAPT) for these patient subgroups.1 DAPT with aspirin plus a P2Y12 inhibitor has already been established as a mainstay preventive therapy after ACS and/or PCI.24–26 Meanwhile recommendations on its use for special populations with CCS, and their applicability to Asian patients, have yet to be well elaborated.

Table 1: High Thrombotic Risk ‘Coronary– Vascular–Disease’ Algorithm Assessment of High-risk Chronic Coronary Syndrome C = CORONARY

V = VASCULAR

• Prior coronary event • High-risk coronary

• Established peripheral • Diabetes on treatment artery disease‡ • eGFR <60 mg/min/1.73 m2 • Cerebrovascular • Micro- and macro-

anatomy*

• Documented multi-vessel coronary disease

In this consensus paper, we aimed to summarise key evidence and present recommendations on the use of P2Y12 inhibitors, with a focus on newer-generation P2Y12 inhibitors, for CCS among special populations in Asia. These include those transitioning from ACS to CCS, those with CKD, the elderly, those with diabetes, those with multivessel CAD and those who bled with the use of antiplatelet therapy.

Methods

The Asian Pacific Society of Cardiology (APSC) convened a panel of experts from various regions and countries in Asia with clinical and research expertise in P2Y12 inhibitors, to develop consensus statements regarding the use of these drugs among special populations in Asia. The experts were members of the APSC who were nominated by national societies and endorsed by the APSC consensus board. We conducted a comprehensive literature search (Figure 2), with preference for randomised trials that evaluated the efficacy (in terms of

albuminuria

• Heart failure due to

coronary artery disease

Figure 1: High Bleeding Risk ‘ABO’ Algorithm ASSESSMENT OF BLEEDING RISK FACTORS IN PATIENTS

A number of characteristics may limit transferability of results from predominantly Western trial populations to Asian patients. These include – but are not limited to – reduced bioactivation of certain drugs (i.e. clopidogrel) from genetic polymorphisms, a lower risk of ischaemic events and higher bleeding risk among East Asians undergoing stent implantation, a higher risk of major bleeding among patients with ACS, a high rate of stroke and low rate of cardiovascular death or non-fatal MI among patients with CCS, and a higher prevalence of diabetes among CAD patients – particularly in the Middle East – and local differences in clinical practice.27–31 Clopidogrel and the more potent agents ticagrelor and prasugrel constitute the P2Y12 inhibitors in current practice. Previously, we had provided recommendations on the use of these agents for Asian patients with ACS, including general statements for special populations.26 We subsequently produced a consensus paper on the management of highrisk CCS, where we proposed two sets of criteria: the Coronary–Vascular– Disease criteria, distinguishing high-risk from very-high risk CCS (Table 1); and the Age–Bleeding–Organ failure (ABO) criteria, describing bleeding risk among Asian patients with CCS (Figure 1).32

disease§

†

D = DISEASE

A AGE

• Frail elderly >75 years* • Advanced age >85 years* • Life expectancy <1 year * Must be accompanied by an additional risk factor

BLEEDING

O ORGAN FAILURE

• Spontaneous intracranial haemorrhage • Recurrent gastrointestinal bleeding • Haemoglobin <9 g/dl

• Liver cirrhosis • End-stage renal failure, requiring dialysis • Bone marrow failure, e.g. severe thrombocytopaenia, platelet count < 50,000/μl • Stroke in the last 6 months

ischaemic outcomes) and safety (in terms of haemorrhagic outcomes) of antiplatelet regimens containing the newer-generation P2Y12 inhibitors, among patients with CAD. Relevant articles were reviewed and appraised for quality and risk of bias using the Grading of Recommendations Assessment, Development, and Evaluation system, as follows:33 1. High (authors have high confidence that the true effect is similar to the estimated effect). 2. Moderate (authors believe that the true effect is probably close to the estimated effect). 3. Low (true effect might be markedly different from the estimated effect). 4. Very low (true effect is probably markedly different from the estimated effect). The collected relevant body of evidence was then extracted, presented, and discussed during two consensus meetings, during which consensus statements were constructed. Each statement was subsequently put to an online vote, where every panel member voted using a three-point scale

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P2Y12 Inhibitors for Special Populations in the Asia-Pacific Region Figure 3: Proposed Role of Ticagrelor Monotherapy in Patients Transitioning from DAPT Transitioning from DAPT or considering long-term management for CCS

SAPT • Aspirin • Clopidogrel DAPT • Aspirin + clopidogrel • Aspirin + ticagrelor • Aspirin + prasugrel*

Assess ‘CVD’ risk factors ‘CVD’ risk factors

DPI • Aspirin + rivaroxaban

No ‘CVD’ risk factors

High risk (with ‘ABO’ risk factor)

− No excessive bleeding risk

DAPT Complex PCI*

Adherent and tolerated 3 months of DAPT with ticagrelor

Excessive bleeding risk

DPI

SAPT

Residual multi-vessel coronary disease, poly-vascular bed disease, prior stroke or prior MI

Ticagrelor monotherapy

Agree 84%, neutral 12%, disagree 4%. *Only considered following complex percutaneous coronary intervention. ‘ABO’ = Age–Bleeding–Organ failure algorithm; CCS = chronic coronary syndrome; ‘CVD’ = Coronary–Vascular–Disease algorithm; DAPT = dual antiplatelet therapy; DPI = dual pathway inhibition; SAPT = single antiplatelet therapy. Source: Tan et al. 2021.32 Reproduced with permission from Radcliffe Cardiology.

(agree, neutral or disagree). Consensus was reached when 80% of votes for a statement were agree or neutral. In case of non-consensus, the statements were further discussed via email communication and revised accordingly until consensus was reached.

Consensus Statements Single Antiplatelet Therapy in Patients Transitioning from Acute Coronary Syndrome To Chronic Coronary Syndrome

In the aforementioned APSC consensus statement on the management of high-risk CCS, the APSC recommended various antithrombotic management strategies based on the patient’s ischaemic and bleeding risk.32 However, since its development, several studies and guidelines have been published, which warranted a review of the treatment of patients with CCS, particularly those transitioning from ACS to CCS. The 2020 European Society of Cardiology (ESC) guidelines on non-STelevation MI recommended the use of various regimens of shortened DAPT in selected patients, based on four trials: TWILIGHT, GLOBAL LEADERS, SMART-CHOICE, and SMART-DATE.34–37 For our consensus statements, the primary references were TWILIGHT, SMART-CHOICE, and two other Asian trials: STOPDAPT-2 and HOST-EXAM.34,36,38,39 TWILIGHT (NCT02270242) was a double-blind, randomised trial that involved 7,119 adult subjects from North America, Europe, and Asia who

Figure 2: PRISMA Flowchart Articles identified by searching Medline and Cochrane library from 2011 to May 2021. Search terms: ‘antiplatelet’ AND ‘Asia’ (listed by MeSH headings) (n=1,117)

Studies after duplicates removed for screening (n=1,005)

193 Full-text review screened

812 Not relevant after screening

146 studies not relevant to statement development

47 Papers used in statement development

MeSH = medical subject headings.

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P2Y12 Inhibitors for Special Populations in the Asia-Pacific Region underwent successful PCI.34,40 While all patients enrolled in the trial were deemed by the investigators to be at high risk for either ischaemia or bleeding, only a few of the subjects would be considered at high bleeding risk if the APSC ‘ABO’ criteria were used.40 Almost a quarter (~23%) of patients were Asian, compared with ~1% in GLOBAL LEADERS.34,41 More than half of the subjects (~65%) had ACS at presentation.34 After 3 months of treatment with ticagrelor plus aspirin, patients who had not had a major bleeding event or ischaemic event continued to take ticagrelor and were randomly assigned to continue aspirin or receive placebo for 1 year.34 Patients in the single antiplatelet therapy (SAPT) arm experienced a lower risk of bleeding than those in the DAPT arm.34 In contrast, there was no significant difference in ischaemic outcomes between the two groups.34 SMART-CHOICE (NCT02079194) was an open-label, single-blind, randomised trial that studied 2,993 adult patients from Korea who had undergone successful PCI for either CCS (~42%) or ACS (~58%).42 All subjects underwent 3 months of DAPT and were then randomly assigned to receive either SAPT with a P2Y12 inhibitor or continuous DAPT for 9 more months.42 The P2Y12 inhibitor used in the regimen, subject to the investigator’s discretion, was any of the three following agents: clopidogrel (77.2%), ticagrelor (18.4%), and prasugrel (4.3%).36 The study found SAPT to be non-inferior to DAPT in terms of ischaemic and bleeding outcomes.36 STOPDAPT-2 (NCT02619760) was an open-label, randomised trial conducted among 3,009 Japanese subjects who had undergone successful PCI.38 Compared to the previous two trials, this study enrolled a smaller population presenting as ACS (~38%).38 After PCI, all subjects received 1 month of DAPT using aspirin plus clopidogrel or prasugrel.38 The experimental group discontinued aspirin after 1 month and shifted to clopidogrel monotherapy while the control group continued DAPT with aspirin plus clopidogrel for 1 year.38 The study revealed that SAPT was superior to DAPT in terms of bleeding outcomes and non-inferior to DAPT in terms of ischaemic outcomes.38 HOST-EXAM (NCT02044250) was an open-label, single-blind, randomised trial conducted in South Korea among 5,438 adult participants.39 Prior to enrolment, the subjects had undergone PCI for either ACS (~72%) or CCS (~28%) and had already been taking DAPT using aspirin and a P2Y12 inhibitor (clopidogrel ~82%, ticagrelor ~10%, prasugrel ~8%) for 6–18 months, without any ischaemic or haemorrhagic complication.39 They were then randomly assigned to receive either clopidogrel or aspirin monotherapy for 24 months.39 In this study, subjects in the clopidogrel group were found to have a significantly lower risk of thrombotic and haemorrhagic events compared to the aspirin group.39 The open-label design of the three Asian trials conferred a risk for performance bias. Nevertheless, given the results of these trials, the consensus panel concluded that the use of ticagrelor monotherapy was reasonable among patients with high ischaemic risk, low bleeding risk and good adherence to 3 months of ticagrelor-based DAPT (Figure 3). On the other hand, based on data from SMART-CHOICE, STOPDAPT-2, and HOST-EXAM, clopidogrel monotherapy may be used for patients with low ischaemic risk or patients with high ischaemic risk and excessive bleeding risk.

Chronic Kidney Disease

Most of the statements on patients with CKD pertain to the setting of ACS where ischaemic risk is highest.

Statement 1. CKD patients should be assessed for bleeding risk before P2Y12 inhibitor initiation. Level of evidence: High. Level of agreement: Agree 85%, neutral 15%, disagree 0%. Statement 2. Patients with estimated glomerular filtration rate (eGFR) of 15 to 60 ml/min/1.73m2 (stage 3A [moderate] to stage 4 [severe]) with previous major adverse cardiovascular event and without excessive bleeding risk should receive DAPT for ACS. Level of evidence: Moderate. Level of agreement: Agree 85%, neutral 11%, disagree 4%. Statement 3. CKD patients with eGFR of <60 ml/min/1.73m2 with excessive bleeding risk may alternatively receive SAPT (aspirin or clopidogrel) Level of evidence: Moderate. Level of agreement: Agree 81%, neutral 11%, disagree 8%. Statement 4. For patients with end-stage renal failure on dialysis with ACS, a shortened duration of DAPT (including ticagrelorcontaining regimens) can be considered. Level of evidence: Low. Level of agreement: Agree 88%, neutral 8%, disagree 4%. Statement 5. Third-generation drug-eluting stent (DES) is recommended for use in PCI for patients with CKD Level of evidence: Low. Level of agreement: Agree 92%, neutral 8%, disagree 0%. Statement 6. Interventional strategies that potentially reduce ischaemic risk (intravascular ultrasound/optical coherence tomography/third-generation DES) can be considered. Level of evidence: Low. Level of agreement: Agree 81%, neutral 11%, disagree 8%. Propensity for bleeding in CKD may arise from quantitative defects (e.g. platelet consumption, redistribution, etc.) or qualitative dysfunction (blunted activation, weakened platelet-vessel wall interactions, etc.).43–48 Meanwhile high thrombopoietin levels, juvenile platelets, and thrombin receptor overactivation in CKD and dialysis may lead to a pro-thrombotic state.49,50 Clinically, post-PCI patients with CKD (eGFR <60 ml/min/1.73m2) have significantly higher rates of ischaemic and bleeding outcomes compared to non-CKD patients.51 This increased ischaemic risk among CKD patients supports the use of DAPT in those with ACS as well as those transitioning to CCS.51,52 A recent systematic review and meta-analysis also suggests that the newer P2Y12 inhibitors are plausible treatment alternatives in CKD patients who may have reduced clopidogrel response.53 A singlecentre, prospective, randomised study on patients with CKD and non-ST elevation-ACS also found that ticagrelor provided more potent platelet inhibition compared with clopidogrel in these patients.54 However, before initiating DAPT, risks and benefits must be carefully weighed by the healthcare professional. While the majority of the expert panel agree to the use of SAPT in patients with high bleeding risk, a few experts recommended a shortened DAPT regimen prior to SAPT. Published data on CAD patients with end-stage kidney disease (ESKD) or on dialysis have remained scarce.1 The European CCS guidelines allude to

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P2Y12 Inhibitors for Special Populations in the Asia-Pacific Region Table 2: Summary of Consensus Statements on the Use of P2Y12 Inhibitors in Patients With CKD CKD Stage (eGFR) Stage 3 to 4 (15 to <60 ml/min/1.73m2)

ACS

• Perform early revascularisation/ • DAPT or DPI* catheterisation • SAPT (aspirin or • 12-month DAPT, balancing risk clopidogrel) if with of ischaemia versus bleeding

Stage 5 (ESKD; <15 ml/min/1.73m2)

Transitioning to CCS

• Early revascularisation/

catheterisation • Shortened DAPT for high bleeding risk†

excessive bleeding risk

• Consider SAPT after 3 months of well-tolerated DAPT (post-PCI)

Agree 80%, neutral 16%, disagree 4%. Third-generation DES is recommended for use in PCI. Interventional strategies to potentially reduce DAPT duration (IVUS/third-generation stent) can be considered. *Residual multi-vessel coronary disease, poly-vascular bed disease, prior stroke, prior MI. †Including ticagrelor-containing regimens. SAPT: aspirin or clopidogrel. ACS = acute coronary syndrome; CCS = chronic coronary syndrome; CKD = chronic kidney disease; DAPT = dual antiplatelet therapy; DES = drug-eluting stent; DPI = dual platelet inhibition; eGFR = estimated glomerular filtration rate; ESKD = end-stage kidney disease; IVUS = intravascular ultrasound; PCI = percutaneous coronary intervention; SAPT = single antiplatelet therapy.

the presence of CKD with eGFR 15–59 ml/min/1.73m2 as conferring a moderate risk for ischaemia while the presence of ESKD confers a high bleeding risk.1 In a Korean retrospective cohort study among post-stenting patients on dialysis – composed mostly of subjects with ACS (>70%) – prolonged DAPT >12 months reduced the risk of major adverse cardiovascular events but tended to correlate with a higher probability of bleeding compared to DAPT <12 months.55 In another retrospective cohort study in Taiwan, involving mostly CCS patients (>70%), no significant difference was found between DAPT >6 months and DAPT <6 months in terms of risk of death, MI or bleeding among post-stenting patients on dialysis.56 Altogether, because of the markedly increased risk of bleeding among patients on dialysis relative to ischaemic risk, the expert panel voted in favour of the use of shortened DAPT in these patients, and to continue with SAPT among those transitioning to CCS therapy, with the aim of reducing bleeding risk while on the full course of antiplatelet therapy.51,57 Clopidogrel-based DAPT may also be recommended in those with severe CKD, including those on haemodialysis, due to the increased risk of bleeding in these patients.53 Some PCI strategies may render patients amenable to shortened DAPT. Indirect evidence suggests that a shortened DAPT may be used for a third-generation DES, with no additional risk of ischaemia. Among subjects in SMART-CHOICE who underwent PCI using Orsiro (Biotronik), a thirdgeneration DES, there was no significant difference between shortened DAPT and standard DAPT in terms of target vessel failure.58 However, these indirect findings represent low-quality evidence to support the use of third-generation DES for patients with CKD in countries where these types of stents are available. Table 2 summarises these consensus statements on the use of P2Y12 inhibitors in patients with CKD.

Elderly Patients Statement 7. Elderly patients should be assessed for bleeding risk prior to P2Y12 inhibitor initiation. Level of evidence: High. Level of agreement: Agree 96%, neutral 0%, disagree 4%.

Statement 8. Elderly patients aged >75 years post-ACS/post-PCI with stent implantation should receive DAPT if there are no high bleeding risk features by ‘ABO’ criteria. Level of evidence: Low. Level of agreement: Agree 100%, neutral 0%, disagree 0%. Statement 9. Elderly patients with unacceptably high bleeding risk may alternatively receive SAPT or shortened DAPT. Level of evidence: Low. Level of agreement: Agree 100%; neutral 0%, disagree 0%. Statement 10. Caution for excessive bleeding should be exercised when giving DAPT to elderly patients aged >80 years. Shortened DAPT may be considered. Level of evidence: Low. Level of agreement: Agree 96%, neutral 4%, disagree 0%. Statement 11. Ticagrelor has been shown to be effective and safe in elderly patients versus clopidogrel, but not prasugrel. Level of evidence: Low. Level of agreement: Agree 73%, neutral 19%, disagree 8%. Statement 12. In patients aged ≥75 years, prasugrel is generally not recommended. Level of evidence: Low. Level of agreement: Agree 88%, neutral 8%, disagree 4%. Statement 13. If aspirin would be included in SAPT or DAPT in elderly patients, low doses (75–100 mg) should be used. Level of evidence: Low. Level of agreement: Agree 100%, neutral 0%, disagree 0%. Statement 14. Elderly patients on DAPT may receive a proton pump inhibitor (PPI). Level of evidence: Low. Level of agreement: Agree 92%, neutral 4%, disagree 4%. Statement 15. Consider de-escalation strategies (shortened DAPT or appropriate dose reduction) for elderly patients, balancing ischaemic and bleeding risks. Level of evidence: Low. Level of agreement: Agree 92%, neutral 4%, disagree 4%. Statement 16. In elderly CCS patients, frailty or age >80 years old are considered excessively high bleeding risk features and should receive SAPT. Level of evidence: Low. Level of agreement: Agree 88%; neutral 12%, disagree 0%. A higher burden of co-morbidities and altered platelet function may add complexity to antiplatelet therapy in the elderly compared to younger populations.59,60 While cut-offs for age varied across the trials comparing shortened versus extended DAPT, age was generally not found to significantly influence the efficacy and safety of the treatment regimens.36,61–63 Nevertheless, despite the heterogeneous data from the trials, some evidence may be used to assist providers in tailoring antiplatelet therapy.

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P2Y12 Inhibitors for Special Populations in the Asia-Pacific Region Table 3: Summary of Consensus Statements for the Use of P2Y12 Inhibitors in Elderly Patients

findings, clopidogrel may be preferred over other P2Y12 inhibitors for elderly patients with high risk of bleeding.

Age/frailty

ACS

>75 to 85 years, not frail

• PCI/early revascularisation • DAPT • High bleeding risk features:

Regarding the optimal duration of shortened DAPT, evidence in the elderly is similarly scant. In STOPDAPT-2, the duration of shortened DAPT was 1 month while in SMART-CHOICE and TWILIGHT, it was 3 months.34,36,38 Reflecting this variation, a range from 1 to 6 months of shortened DAPT constitutes the current practice in Asia.

SAPT or shortened DAPT

>80 years >75 years and frail

• PCI over CABG • Shortened DAPT

Transitioning to CCS

• Extended DAPT if with other risk factors • DPI*

• SAPT

Agree 82%, neutral 8%, disagree 0%. Third-generation DES is recommended for use in PCI. Interventional strategies to potentially reduce DAPT duration (IVUS/third-generation stent) can be considered. *Residual multi-vessel coronary disease, poly-vascular bed disease, prior stroke, prior MI. SAPT: aspirin or clopidogrel. ACS = acute coronary syndrome; CABG = coronary artery bypass graft; CCS = chronic coronary syndrome; DAPT = dual antiplatelet therapy; DES = drug-eluting stent; DPI = dual platelet inhibition; IVUS = intravascular ultrasound; PCI = percutaneous coronary intervention; SAPT = single antiplatelet therapy.

Among patients ≥65 years old in SMART-CHOICE and TWILIGHT, there was no significant difference in efficacy between standard DAPT and shortened DAPT followed by SAPT using P2Y12 inhibitor.34,36 In contrast, an exploratory, possibly underpowered, subgroup analysis of GLOBAL LEADERS showed shortened DAPT followed by ticagrelor monotherapy was associated with a significantly lower risk of ischaemia compared to standard DAPT among patients >75 years of age.61 Interpretation of safety data in the elderly is likewise complicated by conflicting results among the trials. In SMART-CHOICE, there was no significant difference in bleeding rates between standard DAPT and shortened DAPT followed by SAPT using P2Y12 inhibitor among participants ≥65 years old.36 However, in the same age group in TWILIGHT, bleeding risk was significantly lower with shortened DAPT followed by ticagrelor monotherapy compared to standard DAPT.34 GLOBAL LEADERS had a high enrolment of subjects with advanced age (7.3% were octogenarians, 1.5% were ≥85 years old).61 Although this study found no significant difference between treatment arms in terms of bleeding risk among subjects >75 years old, a further subgroup analysis of ACS patients showed a significantly lower bleeding risk with shortened DAPT followed by ticagrelor monotherapy.61 In contrast, the subgroup analysis of CCS patients revealed a higher bleeding risk from shortened DAPT followed by ticagrelor monotherapy.60 The investigators surmised this latter finding may have been biased because ‘stable’ CCS patients in the experimental arm took a more potent P2Y12 inhibitor (ticagrelor) than the control arm (clopidogrel).61 Regarding choice of antiplatelet agent in regimens for the elderly, highquality evidence among Asian populations has been limited, which may explain the 19% neutral votes for Statement 11. In a Swedish observational study involving post-MI patients on DAPT, there was no significant difference between the ticagrelor group and the clopidogrel group in terms of combined ischaemic outcomes among patients ≥80 years old, but ticagrelor-treated patients were at higher risk of re-admission for bleeding.64 Lastly, the open-label, randomised controlled POPULAR AGE trial in the Netherlands found that in patients aged 70 years or older with non-STelevation ACS, clopidogrel was associated with lower bleeding rates compared with ticagrelor (p=0.02 for superiority) while having similar net clinical benefit outcomes (p=0.03 for non-inferiority).65 Given these

The totality of the current evidence, therefore, shows that while potent P2Y12 inhibitors such as ticagrelor and prasugrel may be used in elderly patients, caution should be exercised in those with high bleeding risk (i.e. extremes of age and frailty). Caution has been advised regarding the use of prasugrel in patients ≥75 years old in previous recommendations.1,26 The panel acknowledges that certain Asian countries and regions use a lower-dose preparation of prasugrel (3.75 mg), which may reduce the risk of bleeding compared to the standard 10-mg dose. As supported by the GENERATIONS study, the use of prasugrel at lower doses (5 mg) may be considered when available, after careful evaluation of the impact of such dose reduction on the patient’s on-going ischaemic risk.66 In contrast, no dosing adjustments have been required for ticagrelor.1,26 Most trials implemented a low-dose aspirin regimen, consistent with the dose recommended in previous guidelines (75–100 mg daily). In previous guidance documents, PPIs have been recommended for the following groups: ACS patients on a P2Y12 inhibitor with high bleeding risk; CCS patients receiving aspirin or combination therapy at high risk of gastrointestinal bleeding; and patients on DAPT with risk factors for bleeding.1,24,26 Generally, in these past recommendations, advanced age composed a criterion for high bleeding risk warranting PPI initiation. A recent Danish retrospective cohort study showed that the use of PPI reduced the risk of gastrointestinal bleeding among patients on DAPT, including those belonging to ESC-defined high-risk groups.67 However, the overall baseline risk for bleeding while on DAPT was found to be low.67 Furthermore, these marginal benefits of PPI use should be weighed against the possibility that omeprazole and esomeprazole, being cytochrome P450 2C19 inhibitors, may reduce response to clopidogrel.68 Extreme old age or frailty constitute criteria for high bleeding risk used in considering the initiation of DAPT for CCS patients in ESC guidelines.1 In their 2020 recommendations for ACS patients, the ESC has described frailty as a clinical syndrome of decreased biological and physiological reserves that lead to impaired responses to stress (i.e. longer hospital stay, higher risk of death).68 A number of scales for frailty or physical performance (Short Physical Performance Battery, Rockwood Clinical Frailty Scale, Columbia Frailty Index and the Edmonton Frail Scale) may predict the occurrence of major bleeding while on DAPT, although the APSC does not endorse the use of any particular scoring system for frailty.69 High-quality evidence is lacking regarding the optimal antiplatelet therapy for patients with frailty or age >80 years old. Given this data gap, the expert panel referred to the 2019 APSC consensus statements on highrisk CCS, which suggest the use of SAPT in such patients where excessive bleeding risk has been identified.32 Therapy for frail patients must be individualised and must consider other factors such as life expectancy, quality of life, and patient preferences.70 Table 3 summarises the consensus statements for the use of P2Y12 inhibitors in elderly patients.

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P2Y12 Inhibitors for Special Populations in the Asia-Pacific Region Diabetes

Multivessel Coronary Artery Disease

Statement 17. Antiplatelet therapy should be used for secondary prevention in patients with type 2 diabetes and established cardiovascular disease (with preference for ticagrelor for patients with low bleeding risks). Level of evidence: High. Level of agreement: Agree 96%, neutral 0%, disagree 4%. Statement 18. For diabetes patients with an MI or undergoing PCI, an extended DAPT regimen can be considered. Level of evidence: Moderate. Level of agreement: Agree 88%, neutral 8%, disagree 4%. Statement 19. For diabetes patients with complex PCI and high bleeding risk, ticagrelor monotherapy can be considered after 3 months of DAPT. Level of evidence: Moderate. Level of agreement: Agree 92%, neutral 8%, disagree 0%. The propensity for both ischaemia and bleeding in diabetes may be explained by endothelial dysfunction and altered haemostatic and thrombotic mechanisms.71 The PEGASUS-TIMI 54 trial found that among patients with prior MI, extended DAPT using ticagrelor plus aspirin, significantly reduced the primary composite efficacy endpoint in all subgroups, including those with diabetes.63 This study also indicated that ticagrelor 60 mg had a numerically lower rate of bleeding while having similar efficacy to the 90 mg dose. Furthermore, among diabetes patients in the THEMIS trial who had CCS but no prior stroke or MI, extended DAPT with aspirin plus ticagrelor significantly lowered the risk of ischaemic outcomes compared to SAPT with aspirin alone.62 However, because there was also significantly higher risk of bleeding associated with extended DAPT using aspirin plus ticagrelor, its use may need to be limited to patients with low bleeding risk.62 These findings show that there is a need for holistic assessment of ischaemic and bleeding risks among diabetes patients prior to initiation of DAPT. In a subgroup analysis of the THEMIS trial, diabetes patients who had history of previous PCI experienced significantly reduced ischaemic outcomes with DAPT using aspirin plus ticagrelor compared to SAPT using aspirin alone.72 However, DAPT was also associated with a significantly increased risk of major bleeding in this subgroup.72 These findings suggest that in CCS populations with diabetes, SAPT remains the treatment of choice, but DAPT with ticagrelor can be considered for patients who have high ischaemic risk, such as patients with history of PCI, as long as they have low bleeding risk. In contrast, if they have high bleeding risk and had undergone complex PCI, instead of standard DAPT with ticagrelor, shortened DAPT for 3 months followed by ticagrelor monotherapy can be considered, as suggested by Asian evidence from TWIILIGHT.73 In European guidelines, diabetes confers a moderate risk for ischaemia and warrants consideration of adding a second antiplatelet agent to aspirin among CCS patients without high bleeding risk.1 On the other hand, American guidelines have listed diabetes as a risk factor for bleeding, ischaemia, and stent thrombosis and as criteria in the DAPT risk score used to determine DAPT duration.24

Statement 20. Extended DAPT (>12 months) can be considered for patients with multivessel CAD post-revascularisation (PCI or coronary artery bypass graft [CABG]). Level of evidence: Low. Level of agreement: Agree 73%, neutral 23%, disagree 4%. Statement 21. Patients with multivessel CAD not amenable to revascularisation should receive antiplatelet therapy. Level of evidence: Low. Level of agreement: Agree 100%, neutral 0%, disagree 0%. Apart from multivessel disease (i.e. ≥3 vessels), the definition of complex PCI in TWILIGHT involved a number of angiographic features such as total stent length >60 mm, bifurcation with two stents, use of any atherectomy device, left main artery as target vessel and surgical bypass graft or chronic total occlusion as target lesions.74 Among these criteria, total stent length >60 mm was reported as the most common in the trial.74 In European guidelines for CCS, multivessel CAD comprises a criterion for moderate risk of ischaemia and also for high risk when combined with one other risk factor, warranting consideration of the addition of a second antiplatelet agent to aspirin.1 Patients with multivessel CAD post-revascularisation may be considered for extended DAPT, based on the results of PEGASUS-TIMI 54, where almost 60% of patients had multivessel CAD and >80% had previous PCI. Importantly, this study also suggests that ticagrelor 60 mg had a numerically lower rate of bleeding while having similar efficacy to the 90 mg regimen.63 It should be noted that no direct evidence was found on the benefit of extended DAPT in post-CABG patients without a history of MI or stenting. Indirect evidence from CHARISMA, in which 26% of patients underwent PCI and 17% underwent CABG, suggests that clopidogrel plus aspirin for a median of 28 months was associated with a significantly lower rate of cardiovascular death, MI or stroke compared with aspirin alone (p=0.01).75 Among Asians with multivessel CAD, the current body of evidence on optimal DAPT duration is scarce. Nonetheless, given the high ischaemic risk in this subset of patients, the consensus panel agreed that extended DAPT may be considered post-revascularisation in patients with low bleeding risk. The Asian evidence in more specific subgroups, such as patients with a history of previous CABG, is even more limited, which may explain the number of neutral votes (23%) for Statement 20. Patients with multivessel disease who are ineligible for revascularisation are similarly at high ischaemic risk. Although there has been no strong evidence available on the optimal treatment for this subgroup, the panel voted in favour of antiplatelet therapy to avert the high ischaemic risk.

Treatment Continuity After Bleeding During Antiplatelet Therapy Statement 22. The decision to discontinue antiplatelet therapy in patients should be based on an assessment of the severity of bleeding and the proximity of the bleeding event to the index ischaemic event or PCI. Level of evidence: High. Level of agreement: Agree 100%, neutral 0%, disagree 0%.

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P2Y12 Inhibitors for Special Populations in the Asia-Pacific Region

Statement 23. As much as possible, patients with bleeding within 1 month of the index event should continue antiplatelet therapy once stabilised to minimise ischaemic risk. Level of evidence: Low. Level of agreement: Agree 88%, neutral 8%, disagree 4%. Statement 24. Patients with bleeding who require a stepdown of antiplatelet therapy may consider switching to less potent antiplatelets, reduction in the antiplatelet dose or the use of single antiplatelet agents. Level of evidence: Low. Level of agreement: Agree 100%, neutral 0%, disagree 0%. In an effort to contribute to knowledge on de-escalation of antiplatelet therapy, investigators of GLOBAL LEADERS studied the association between any reported bleeding or MI during therapy and mortality.76 They showed that bleeding or MI during therapy was significantly associated with a sustained higher risk for subsequent mortality from 30 days to beyond 1 year after the event. Furthermore, they found that switching to a less potent antiplatelet (i.e. from ticagrelor or prasugrel to clopidogrel or aspirin) or discontinuing any antiplatelet agent for >5 days at the time of Bleeding Academic Research Consortium (BARC) 3 bleeding significantly decreased the risk of subsequent bleeding or MI compared to continuation of therapy. However, there was no sufficient evidence that de-escalation or discontinuation of therapy during BARC 2 bleeding had the same benefit.76 There is very little evidence in Asia to provide definitive guidance on treatment discontinuation or de-escalation. Notwithstanding, among Asian patients, the bleeding risk post-ACS tends to be overestimated compared to the ischaemic risk.77 Therefore, antiplatelet therapy should be discontinued only after a thorough assessment of, firstly, the severity of the bleeding event and, secondly, its proximity to the index ischaemic 1. Knuuti J, Wijns W, Saraste A, et al. 2019 ESC guidelines for the diagnosis and management of chronic coronary syndromes. Eur Heart J 2020;41:407–77. https://doi. org/10.1093/eurheartj/ehz425; PMID: 31504439. 2. Emerging Risk Factors Collaboration, Sarwar N, Gao P, et al. Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies. Lancet 2010;375:2215–22. https://doi. org/10.1016/S0140-6736(10)60484-9; PMID: 20609967. 3. Fox CS, Matsushita K, Woodward M, et al. Associations of kidney disease measures with mortality and end-stage renal disease in individuals with and without diabetes: a metaanalysis. Lancet 2012;380:1662–73. https://doi.org/10.1016/ S0140-6736(12)61350-6; PMID: 23013602. 4. Smilowitz NR, Gupta N, Guo Y, et al. Management and outcomes of acute myocardial infarction in patients with chronic kidney disease. Int J Cardiol 2017;227:1–7. https://doi. org/10.1016/j.ijcard.2016.11.026; PMID: 27846456. 5. Bangalore S, Guo Y, Samadashvili Z, et al. Revascularization in patients with multivessel coronary artery disease and chronic kidney disease: everolimus-eluting stents versus coronary artery bypass graft surgery. J Am Coll Cardiol 2015;66:1209–20. https://doi.org/10.1016/j.jacc.2015.06.1334; PMID: 26361150. 6. Wang Y, Zhu S, Gao P, Zhang Q. Comparison of coronary artery bypass grafting and drug-eluting stents in patients with chronic kidney disease and multivessel disease: a meta-analysis. Eur J Intern Med 2017;43:28–35. https://doi. org/10.1016/j.ejim.2017.04.002; PMID: 28400078. 7. Malkin CJ, Prakash R, Chew DP. The impact of increased age on outcome from a strategy of early invasive management and revascularisation in patients with acute coronary syndromes: retrospective analysis study from the ACACIA registry. BMJ Open 2012;2:e000540. https://doi. org/10.1136/bmjopen-2011-000540; PMID: 22344538. 8. Varenne O, Cook S, Sideris G, et al. Drug-eluting stents in

10.

11.

12.

13.

14.

15.

event or PCI, a factor that correlates directly with the patient’s ischaemic risk (i.e. the closer to the index event, the higher the ischaemic risk). Accordingly, to minimise ischaemic risk, the panel voted in favour of continuing antiplatelet therapy if bleeding occurs within 1 month of the index event.

Limitations

While large-scale trials on P2Y12 inhibitor regimens have been conducted worldwide, there is still a need for further Asian-specific data for generalisation to Asian populations. Hence, some recommendations are based on expert opinion. We did not perform meta-analyses, and these consensus statements are not exhaustive. Nonetheless, we have endeavoured to gather the best available evidence at the time of publication. Lastly, the consensus statements are not intended to replace clinical judgement.

Conclusion

Because of the increased risks for ischaemia and/or bleeding, special populations in CAD (i.e. advanced age, CKD, or diabetes) and particular settings (i.e. transitioning from ACS to CCS, presence of multivessel disease or bleeding during antiplatelet therapy) may require modification of standard therapy. The management of such cases may be different between Asian and Western populations. Some evidence from Asian trials supports the use of ticagrelor monotherapy during the transition to CCS among patients with high ischaemic and low bleeding risks. Although standard DAPT is generally recommended for CKD, elderly, and diabetes patients, there is some evidence to support the use of shortened DAPT or SAPT among those with high bleeding risk. Meanwhile, there is little evidence to provide definitive recommendations on antiplatelet therapy for multivessel CAD or de-escalation strategies after bleeding among Asian patients. In all situations, the risks for ischaemia must be weighed carefully with the risks for bleeding to individualise antiplatelet therapy accordingly.

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bleeding during ST-elevation and non-ST-elevation myocardial infarction care: derivation and validation of a model from the ACTION Registry®-GWTG™. Am J Cardiol 2011;107:1136–43. https://doi.org/10.1016/j. amjcard.2010.12.009; PMID: 21324428. 16. Rao SV, McCoy LA, Spertus JA, et al. An updated bleeding model to predict the risk of post-procedure bleeding among patients undergoing percutaneous coronary intervention: a report using an expanded bleeding definition from the National Cardiovascular Data Registry CathPCI Registry. JACC Cardiovasc Interv 2013;6:897–904. https://doi. org/10.1016/j.jcin.2013.04.016; PMID: 24050858. 17. Pasea L, Chung SC, Pujades-Rodriguez M, et al. Personalising the decision for prolonged dual antiplatelet therapy: development, validation and potential impact of prognostic models for cardiovascular events and bleeding in myocardial infarction survivors. Eur Heart J 2017;38:1048– 55. https://doi.org/10.1093/eurheartj/ehw683; PMID: 28329300. 18. Mehran R, Nikolsky E, Lansky AJ, et al. Impact of chronic kidney disease on early (30-day) and late (1-year) outcomes of patients with acute coronary syndromes treated with alternative antithrombotic treatment strategies: an ACUITY (Acute Catheterization and Urgent Intervention Triage strategY) substudy. JACC Cardiovasc Interv 2009;2:748–57. https://doi.org/10.1016/j.jcin.2009.05.018; PMID: 19695543. 19. Saltzman AJ, Stone GW, Claessen BE, et al. Long-term impact of chronic kidney disease in patients with ST-segment elevation myocardial infarction treated with primary percutaneous coronary intervention: the HORIZONSAMI (Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction) trial. JACC Cardiovasc Interv 2011;4:1011–9. https://doi.org/10.1016/j.jcin.2011.06.012; PMID: 21939942. 20. Latif F, Kleiman NS, Cohen DJ, et al. In-hospital and 1-year outcomes among percutaneous coronary intervention

P2Y12 Inhibitors for Special Populations in the Asia-Pacific Region patients with chronic kidney disease in the era of drugeluting stents: a report from the EVENT (Evaluation of Drug Eluting Stents and Ischemic Events) registry. JACC Cardiovasc Interv 2009;2:37–45. https://doi.org/10.1016/j. jcin.2008.06.012; PMID: 19463396. 21. Baber U, Li SX, Pinnelas R, et al. Incidence, patterns, and impact of dual antiplatelet therapy cessation among patients with and without chronic kidney disease undergoing percutaneous coronary intervention: Results from the PARIS registry (Patterns of Non-Adherence to AntiPlatelet Regimens in Stented Patients). Circ Cardiovasc Interv 2018;11:e006144. https://doi.org/10.1161/ CIRCINTERVENTIONS.117.006144; PMID: 29870385. 22. Baber U, Mehran R, Kirtane AJ, et al. Prevalence and impact of high platelet reactivity in chronic kidney disease: results from the Assessment of Dual Antiplatelet Therapy with Drug-Eluting Stents registry. Circ Cardiovasc Interv 2015;8:e001683. https://doi.org/10.1161/ CIRCINTERVENTIONS.115.001683; PMID: 26056248. 23. Ducrocq G, Wallace JS, Baron G, et al. Risk score to predict serious bleeding in stable outpatients with or at risk of atherothrombosis. Eur Heart J 2010;31:1257–65. https://doi. org/10.1093/eurheartj/ehq021; PMID: 20181681. 24. Levine GN, Bates ER, Bittl JA, et al. 2016 ACC/AHA guideline focused update on duration of dual antiplatelet therapy in patients with coronary artery disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines: an update of the 2011 ACCF/AHA/SCAI guideline for percutaneous coronary intervention, 2011 ACCF/AHA guideline for coronary artery bypass graft surgery, 2012 ACC/AHA/ACP/AATS/PCNA/SCAI/ STS guideline for the diagnosis and management of patients with stable ischemic heart disease, 2013 ACCF/AHA guideline for the management of st-elevation myocardial infarction, 2014 AHA/ACC guideline for the management of patients with non-st-elevation acute coronary syndromes, and 2014 ACC/AHA guideline on perioperative cardiovascular evaluation and management of patients undergoing noncardiac surgery. Circulation 2016;134:e123– 55. https://doi.org/10.1161/CIR.0000000000000404; PMID: 27026020. 25. Valgimigli M, Bueno H, Byrne RA, et al. 2017 ESC focused update on dual antiplatelet therapy in coronary artery disease developed in collaboration with EACTS: the Task Force for dual antiplatelet therapy in coronary artery disease of the European Society of Cardiology (ESC) and of the European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J 2018;39:213–60. https://doi.org/10.1093/ eurheartj/ehx419; PMID: 28886622. 26. Tan JWC, Chew DP, Abdul Kader MASK, et al. 2020 Asian Pacific Society of Cardiology consensus recommendations on the use of P2Y12 receptor antagonists in the Asia-Pacific region. Eur Cardiol 2021;16:e02. https://doi.org/10.15420/ ecr.2020.40; PMID: 33708263. 27. Scott SA, Sangkuhl K, Gardner EE, et al. Clinical Pharmacogenetics Implementation Consortium guidelines for cytochrome P450-2C19 (CYP2C19) genotype and clopidogrel therapy. Clin Pharmacol Ther 2011;90:328–32. https://doi.org/10.1038/clpt.2011.132; PMID: 2171627. 28. Kang J, Park KW, Palmerini T, et al. Racial differences in ischaemia/bleeding risk trade-off during anti-platelet therapy: individual patient level landmark meta-analysis from seven RCTs. Thromb Haemost 2019;119:149–62. https:// doi.org/10.1055/s-0038-1676545; PMID: 30597509. 29. Misumida N, Ogunbayo GO, Kim SM, et al. Higher risk of bleeding in Asians presenting with ST-segment elevation myocardial infarction: analysis of the National Inpatient Sample Database. Angiology 2018;69:548–54. https://doi. org/10.1177/0003319717730168; PMID: 28905638. 30. Sorbets E, Fox KM, Elbez Y, et al. Long-term outcomes of chronic coronary syndrome worldwide: insights from the international CLARIFY registry. Eur Heart J 2020;41:347–56. https://doi.org/10.1093/eurheartj/ehz660; PMID: 31504434. 31. Hammoudeh AJ, Alhaddad IA, Khader Y, et al. Cardiovascular risk factors in Middle Eastern patients undergoing percutaneous coronary intervention: results from the first Jordanian percutaneous coronary intervention study. J Saudi Heart Assoc 2017;29:195–202. https://doi. org/10.1016/j.jsha.2016.10.002; PMID: 28652673. 32. Tan JWC, Chew DP, Brieger D, et al. 2020 Asian Pacific Society of Cardiology consensus recommendations on antithrombotic management for high-risk chronic coronary syndrome. Eur Cardiol 2021;16:e26. https://doi.org/10.15420/ ecr.2020.45; PMID: 34249148. 33. Balshem H, Helfand M, Schünemann HJ, et al. GRADE guidelines: 3. Rating the quality of evidence. J Clin Epidemiol 2011;64:401–6. doi:10.1016/j.jclinepi.2010.07.015; PMID: 21208779. 34. Mehran R, Baber U, Sharma SK, et al. Ticagrelor with or

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org/10.1161/ATVBAHA.110.216531; PMID: 21071689. 51. Tomaniak M, Chichareon P, Klimczak-Tomaniak D, et al. Impact of renal function on clinical outcomes after PCI in ACS and stable CAD patients treated with ticagrelor: a prespecified analysis of the GLOBAL LEADERS randomized clinical trial. Clin Res Cardiol 2020;109:930–43. https://doi. org/10.1007/s00392-019-01586-9; PMID: 31925529. 52. Stefanini GG, Briguori C, Cao D, et al. Ticagrelor monotherapy in patients with chronic kidney disease undergoing percutaneous coronary intervention: TWILIGHTCKD. Eur Heart J 2021. https://doi.org/10.1093/eurheartj/ ehab533; PMID: 34423374; epub ahead of press. 53. Park S, Choi YJ, Kang JE, et al. P2Y12 antiplatelet choice for patients with chronic kidney disease and acute coronary syndrome: a systematic review and meta-analysis. J Pers Med 2021;11:222. https://doi.org/10.3390/jpm11030222; PMID: 33801161. 54. Wang H, Qi J, Li Y, et al. Pharmacodynamics and pharmacokinetics of ticagrelor vs. clopidogrel in patients with acute coronary syndromes and chronic kidney disease. Br J Clin Pharmacol 2018;84:88–96. https://doi.org/10.1111/ bcp.13436; PMID: 28921624. 55. Park S, Kim Y, Jo HA, et al. Clinical outcomes of prolonged dual antiplatelet therapy after coronary drug-eluting stent implantation in dialysis patients. Clin Kidney J 2020;13:803– 12. https://doi.org/10.1093/ckj/sfaa037; PMID: 33125004. 56. Chen YT, Chen HT, Hsu CY, et al. Dual antiplatelet therapy and clinical outcomes after coronary drug-eluting stent implantation in patients on hemodialysis. Clin J Am Soc Nephrol 2017;12:262–71. https://doi.org/10.2215/ CJN.04430416; PMID: 28174317. 57. Kim J, Jang WJ, Lee WS, et al. P2Y12 inhibitor monotherapy after coronary stenting according to type of P2Y12 inhibitor. Heart 2021;107:1077–83. https://doi.org/10.1136/ heartjnl-2020-318821; PMID: 33758008. 58. Yun KH, Lee SY, Cho BR, et al. Safety of 3-month dual antiplatelet therapy after implantation of ultrathin sirolimuseluting stents with biodegradable polymer (Orsiro): results from the SMART-CHOICE Trial. J Am Heart Assoc 2021;10:e018366. https://doi.org/10.1161/JAHA.120.018366; PMID: 33345567. 59. Li L, Geraghty OC, Mehta Z, et al. Age-specific risks, severity, time course, and outcome of bleeding on longterm antiplatelet treatment after vascular events: a population-based cohort study. Lancet 2017;390:490–9. https://doi.org/10.1016/S0140-6736(17)30770-5; PMID: 28622955. 60. Verdoia M, Pergolini P, Rolla R, et al. Advanced age and high-residual platelet reactivity in patients receiving dual antiplatelet therapy with clopidogrel or ticagrelor. J Thromb Haemost 2016;14:57–64. https://do.org/10.1111/jth.13177; PMID: 26512550. 61. Tomaniak M, Chichareon P, Modolo R, et al. Ticagrelor monotherapy beyond one month after PCI in ACS or stable CAD in elderly patients: a pre-specified analysis of the GLOBAL LEADERS trial. EuroIntervention 2020;15:e1605–14. https://doi.org/10.4244/EIJ-D-19-00699; PMID: 31845894. 62. Steg PG, Bhatt DL, Simon T, et al. Ticagrelor in patients with stable coronary disease and diabetes. N Engl J Med 2019;381:1309–20. https://doi.org/10.1056/NEJMoa1908077; PMID: 31475798. 63. Bonaca MP, Bhatt DL, Cohen M, et al. Long-term use of ticagrelor in patients with prior myocardial infarction. N Engl J Med 2015;372:1791–800. https://doi.org/10.1056/ NEJMoa1500857; PMID: 25773268. 64. Szummer K, Montez-Rath ME, Alfredsson J, et al. Comparison between ticagrelor and clopidogrel in elderly patients with an acute coronary syndrome: Insights from the SWEDEHEART Registry. Circulation 2020;142:1700–8. https:// doi.org/10.1161/CIRCULATIONAHA.120.050645; PMID: 32867508. 65. Gimbel M, Qaderdan K, Willemsen L, et al. Clopidogrel versus ticagrelor or prasugrel in patients aged 70 years or older with non-ST-elevation acute coronary syndrome (POPular AGE): the randomised, open-label, non-inferiority trial. Lancet 2020;395:1374–81. https://doi.org/10.1016/S01406736(20)30325-1; PMID: 32334703. 66. Erlinge D, Gurbel PA, James S, et al. Prasugrel 5 mg in the very elderly attenuates platelet inhibition but maintains noninferiority to prasugrel 10 mg in nonelderly patients: the GENERATIONS trial, a pharmacodynamic and pharmacokinetic study in stable coronary artery disease patients. J Am Coll Cardiol 2013;62:577–83. https://doi. org/10.1016/j.jacc.2013.05.023; PMID: 23747759. 67. Sehested TSG, Carlson N, Hansen PW, et al. Reduced risk of gastrointestinal bleeding associated with proton pump inhibitor therapy in patients treated with dual antiplatelet therapy after myocardial infarction. Eur Heart J 2019;40:1963–70. https://doi.org/10.1093/eurheartj/ehz104;

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APSC Consensus Statements

Asian Pacific Society of Cardiology Consensus Recommendations for Pre-participation Screening in Young Competitive Athletes Luokai Wang ,1,2 Tee Joo Yeo,3 Benedict Tan ,4 Bernard Destrube,5 Khim Leng Tong,4 Swee Yaw Tan,1 Gregory Chan,6 Zijuan Huang ,1 Frankie Tan,7 Yu Chen Wang,8 Jong-Young Lee ,9 Erik Fung ,10 Gary Yiu Kwong Mak,11 Raymond So,12 Chaisiri Wanlapakorn ,13 Ade Meidian Ambari ,14 Lucky Cuenza ,15 Choong Hou Koh 1 and Jack Wei Chieh Tan 1,2 1. National Heart Centre Singapore, Singapore; 2. Sengkang General Hospital, Singapore; 3. National University Heart Centre, Singapore; 4. Changi General Hospital, Singapore; 5. International Federation of Disabled Sailors, Nantes, France; 6. The Occupational and Diving Medicine Centre, Singapore; 7. Sports Science and Medicine Centre, Singapore Sports Institute, Singapore; 8. Department of Cardiology, Department of Internal Medicine, Asia University Hospital, Taichung City, Taiwan; 9. Division of Cardiology, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea; 10. The Chinese University of Hong Kong, Hong Kong; 11. Pro-Care Heart Clinic, Hong Kong; 12. Elite Training Science & Technology, Hong Kong Sports Institute, Hong Kong; 13. Cardiac Centre, King Chulalongkorn Memorial Hospital, Bangkok Thailand; 14. National Cardiovascular Center Harapan Kita, Department of Cardiology and Vascular Medicine, University of Indonesia, Jakarta, Indonesia; 15. Sports and Exercise Medicine Center, Medical Center Manila, Philippines

Abstract

Sports-related sudden cardiac death is a rare but devastating consequence of sports participation. Certain pathologies underlying sports-related sudden cardiac death could have been picked up pre-participation and the affected athletes advised on appropriate preventive measures and/or suitability for training or competition. However, mass screening efforts – especially in healthy young populations – are fraught with challenges, most notably the need to balance scarce medical resources and sustainability of such screening programmes, in healthcare systems that are already stretched. Given the rising trend of young sports participants across the Asia-Pacific region, the working group of the Asian Pacific Society of Cardiology (APSC) developed a sports classification system that incorporates dynamic and static components of various sports, with deliberate integration of sports events unique to the Asia-Pacific region. The APSC expert panel reviewed and appraised using the Grading of Recommendations Assessment, Development, and Evaluation system. Consensus recommendations were developed, which were then put to an online vote. Consensus was reached when 80% of votes for a recommendation were agree or neutral. The resulting statements described here provide guidance on the need for cardiovascular pre-participation screening for young competitive athletes based on the intensity of sports they engage in.

Keywords

Sports, Asia-Pacific, sudden cardiac death, consensus, young people Disclosure: This work was funded through the Asian Pacific Society of Cardiology by unrestricted educational grants from the Lee Foundation. JWCT has received honoraria from AstraZeneca, Bayer, Amgen, Medtronic, Abbott Vascular, Biosensors, Alvimedica, Boehringer Ingelheim and Pfizer; research and educational grants from Medtronic, Biosensors, Biotronik, Philips, Amgen, AstraZeneca, Roche, Ostuka, Terumo and Abbott Vascular; and consulting fees from Elixir, CSL Behring; and is on the European Cardiology Review editorial board; this did not influence peer review. All other authors have no conflicts of interest to declare. Acknowledgement: LW and TJY are joint first authors. Received: 9 June 2021 Accepted: 30 August 2021 Citation: European Cardiology Review 2021;16:e44. DOI: https://doi.org/10.15420/ecr.2021.26 Correspondence: Jack Wei Chieh Tan, National Heart Centre, Singapore, 5 Hospital Dr, Singapore 169609, Singapore. E: jack.tan.w.c@singhealth.com.sg Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Sports-related sudden cardiac death (SCD) is a rare but devastating consequence of sports participation. While its exact incidence remains elusive and varies with geographic localities and sports genre, available evidence suggests an overall incidence of between 1 in 50,000 and 7 in 100,000 per year in healthy young athletes (<35 years old).1–3 An 11-year review in Singapore found that 87% of sports-related sudden death in athletes were due to SCD.4 It should be noted that sport per se is not the cause of SCD in athletes. Rather, the presence of an underlying cardiovascular abnormality is the primary substrate upon which intensive physical exercise acts as a trigger for the athlete to develop SCD.

Given the threefold increased risk of SCD among athletes and the intense cardiovascular and cardiopulmonary demands required by training and competition, multiple guidelines have recommended pre-participation screening to identify at-risk athletes and provide appropriate medical advice for these athletes.5 In general, the most frequent pathological findings in SCD among young athletes aged <35 years in the Western world, either from survivors or from post-mortem series, are hereditary or congenital structural and electrical cardiovascular abnormalities. These include – but are not limited to – hypertrophic cardiomyopathy, arrhythmogenic cardiomyopathy and coronary artery anomalies,

APSC Consensus for Pre-participation Screening in Young Competitive Athletes premature coronary artery disease, abnormal vascular conditions related to connective tissue diseases such as Marfan syndrome, and channelopathies.6,7 The prevalence of such latent cardiovascular conditions, which may be unmasked or aggravated during strenuous physical training or competitive events, has led to the formulation of guidelines, along with cardiac and sports medicine professional societies worldwide recommending selective pre-participation screening to identify at-risk athletes, and subsequently to provide appropriate medical advice and assessment for further participation.1,8–13 However, epidemiological data from Asia remain incomplete or unavailable.4 While the Asia-Pacific region (comprising Asia, Western Pacific and Oceania) makes up slightly over one-third of the global landmass, it contains over 60% of the world’s population. This implicitly extrapolates to significantly more young athletes from these countries when compared with the rest of the world.14 Moreover, several differences exist between the Asia-Pacific and the West in terms of sports type, level of participation and the epidemiology of cardiovascular disease. Firstly, the types of sporting activities within Asia differ substantially from Western countries. Many martial arts are popular in Asia and these combat sport disciplines bear the potential risk for commotio cordis as a cause of SCD.14–17 Secondly, the prevalence of predisposing conditions such as arrhythmogenic cardiomyopathy, Brugada-type ECG patterns, Kawasaki disease, rheumatic heart disease and coronary artery disease in the young have been reported to be higher in some Asian populations compared to non-Asian populations.18–24 Lastly, there is a disparity between countries in the Asia-Pacific region in terms of economics, health resources, health systems, and costs of and access to medical services, which may have a substantial impact on the implementation of programmes aimed at minimising the impact of sportsrelated adverse cardiovascular events. Hence, it may not be appropriate to adopt standards of care from the West in its entirety to the Asia-Pacific region without careful consideration and contextualisation of these issues. With these differences in mind, this consensus statement was developed with the aim to guide medical practitioners involved in the screening and care of young competitive athletes, with a focus on select issues pertinent to the Asia-Pacific region.

Methods

The Asian Pacific Society of Cardiology (APSC) convened a 20-member multidisciplinary expert panel of cardiologists and sports medicine specialists to develop a consensus statement to provide guidance on preparticipation cardiovascular screening in young competitive athletes. The panel comprised experts from France, Hong Kong, Indonesia, Philippines, Singapore, South Korea, Taiwan and Thailand. The experts of the panel are members of the APSC who were nominated by national societies and endorsed by the APSC consensus board or were invited as international experts. After a comprehensive literature search, the available evidence was then appraised using the Grading of Recommendations Assessment, Development, and Evaluation system.25 Using this system, the level of evidence was assigned as follows: 1. High (authors have high confidence that the true effect is similar to the estimated effect). 2. Moderate (authors believe that the true effect is probably close to the estimated effect). 3. Low (true effect might be markedly different from the estimated effect). 4. Very low (true effect is probably markedly different from the estimated effect).

The available evidence was then discussed, and consensus statements developed, during a consensus meeting held online in December 2020. Each statement was then voted on by each panel member using a threepoint scale (agree, neutral or disagree), via online polling. Consensus was reached when 80% of votes for a statement were agree or neutral. In the case of non-consensus, the statements were further discussed via electronic communication, then revised accordingly until the criteria for consensus were reached. For these consensus statements, young competitive athletes are defined as those younger than 35 years of age (no lower age limit) who participate in an organised team or individual sport that requires regular competition against others as a central component, places a high premium on excellence and achievement, and requires some form of systematic and usually intense training.26

Classification of Exercise and Sports Intensity

Due to the variable impact of intensity of physical activity on the risk of cardiovascular events in susceptible athletes, the expert panel classified various sports according to the gradated intensity of their static (I. Low; II. Moderate; and III. High) and dynamic (A. Low; B. Moderate; and C. High) components (Figure 1).27–29 This system was adapted from the established American Heart Association (AHA)/American College of Cardiology (ACC) classification.12,30 Specifically, competitive sports unique to the Asia-Pacific region were curated from the Commonwealth Games, Asian Games, Southeast Asian Games and the Paralympics to ensure not only inclusiveness but also that such sports indigenous to this part of the world are adequately highlighted. In general, sports can be broadly dichotomised into static and dynamic elements. The static component is expressed as the relative intensity of static muscle contractions, while the dynamic component is reflected by the relative intensity of dynamic exercise (regular contraction of large muscle groups) or percentage of maximal aerobic power (VO2 max). Static contractions increase afterload; the greater the intensity of the contraction of skeletal muscles, the greater the rise in blood pressure and consequently the afterload on the left ventricle. Dynamic exercises primarily result in volume loading of the left ventricle. In this set of recommendations, a greater emphasis is placed on the dynamic component of sports because cardiorespiratory activity, as a function of maximal aerobic capacity, has been conventionally linked to adverse outcomes.31 Intuitively, this is congruent with haemodynamic principles, as increasing dynamic exercise intensities result in increased rate pressure product, flow states, and sympathetic tone, all of which are known triggers or aggravators of ischaemia, structural decompensation, and electrical instability in predisposed individuals – all with consequent downward spiral in haemodynamics. For the purpose of these consensus statements, sports in the IA category (Figure 1) are considered low-intensity sports while IIA, IIB and IB sports are considered moderate intensity, with IC, IIC, IIIA, IIIB and IIIC making up the remaining sports that are placed in the high-intensity domains. This classification system aims to provide an approximate guide in estimating the intensity of the selected sports and is not meant to be prescriptive. The panel acknowledges that in real-world practice, static and dynamic intensities in any given sport do not occur as distinct categories, but rather along a fluid scale. Sports intensities can be highly variable throughout the training–competition continuum and are confounded by individual fitness, motivation and environment.

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APSC Consensus for Pre-participation Screening in Young Competitive Athletes

II. Moderate (10–20%) I. Low (<10%)

Increasing static component

III. High (>30%)

Figure 1: Classification of Sports Intensity Artistic swimming Weightlifting Powerlifting* Gymnastics Sailing Windsurfing

Archery* Diving Equestrian*

Chess Petanque* Golf Boccia* Bowling Sailing* Shooting* Billiards/snooker Electronic sports

Pentathlon Muay Thai, Vovinam Kickboxing/boxing Mixed martial arts Canoe*/kayaking Cycling* Rowing* Triathlon*

Judo* Silat pencak Bodybuilding Wrestling, freestyle or Greco-roman

Wushu Fencing* Athletics* Cricket Rugby* Running (sprint) Taekwondo*/karate

Volleyball*/beach volleyball Running (middle-distance) Swimming*/water polo Basketball*/netball Sepak takraw* Handball Hockey* Tennis*

Dancesport* Baseball* Softball* Fencing* Table tennis*

Soccer* Athletics*: track/road Marathon* Racewalk Badminton*/squash Long-distance running

A. Low (<50%)

B. Moderate (50–75%)

C. High (>75%)

Increasing dynamic component *Sports activities with para-sports equivalent, as listed by the International Paralympic Committee.46

Consensus Statements

The expert panel developed three sets of statements for the preparticipation screening of young competitive athletes. Specifically these were for participation in high and moderate cardiovascular intensity sports, for participation in low-intensity sports and for athletes with preexisting cardiovascular disease. The panel voted to converge the recommendations for high- and moderate-intensity sports to simplify the overall approach for pre-participation screening. Figure 2 shows a flowchart summarising these recommendations.

Participation in High and Moderate Cardiovascular Intensity Sports Statement 1. Young competitive athletes are recommended to undergo a standardised history and physical examination as part of pre-participation screening, especially if the screening institution has the capacity for mass screening. A suggested checklist is the 14-element AHA Cardiovascular Screening Checklist for Congenital and Genetic Heart Disease or equivalent. Level of evidence: Low. Level of agreement: Agree 95%, neutral 5%, disagree 0%. Statement 2. Young competitive athletes are recommended to undergo a resting 12-lead ECG as part of pre-participation screening, provided that all of the following are fulfilled: 1. the screening institution has the capacity for mass ECG screening; 2. the ECG is performed to an acceptable standard; and 3. the ECG should be interpreted by a trained healthcare professional, with reference to prevailing standards. Level of evidence: Low. Level of agreement: Agree 100%, neutral 0%, disagree 0%.

Statement 3. Referral to a qualified and relevant healthcare professional/specialist for further evaluation should be considered in the presence of any of the following: 1. any positive element(s) in the standardised history questionnaire, or 2. abnormal physical finding(s) on physical examination, or 3. two or more borderline findings on ECG, or one or more abnormal ECG findings (based on the International Recommendations 2017). Level of evidence: Low. Level of agreement: Agree 95%, neutral 5%, disagree 0%. Where appropriate, a three-generation family history including sudden death, congenital heart disease, and premature cardiovascular disease and complications should be queried. As the risk of SCD is inherently elevated in sports of moderate and high intensity, routine pre-participation cardiovascular screening via standardised history-taking and physical examination must also be performed for young competitive athletes engaging in these categories of sports.27–29 Pre-participation screening allows the upstream identification of otherwise asymptomatic athletes who have underlying cardiovascular conditions that predispose them to SCD.32 As part of comprehensive medical history-taking for pre-participation, standardised checklists, including the 14-element AHA Cardiovascular Screening Checklist for Congenital and Genetic Heart Disease, can be implemented by any healthcare practitioner involved in sports screening.32 Such questionnaires include the presence or absence of suspicious symptoms (e.g. exertion-related symptoms), significant past medical history or prior sports restrictions, and family history of cardiovascular disease, especially inheritable conditions. A thorough physical examination of the cardiovascular system should also be conducted

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APSC Consensus for Pre-participation Screening in Young Competitive Athletes Figure 2: Flowchart for Pre-participation Cardiovascular Screening for Young Competitive Athletes Young competitive athletes

Low-intensity sports

Moderate- to high-intensity sports

Routine cardiovascular screening recommended • Standardised history and physical examination* • ECG†

Routine cardiovascular screening not necessary

Abnormal findings? NO

• Any positive elements in the standardised history questionnaire • Abnormal physical findings • Two or more borderline ECG findings, or one or more abnormal ECG findings YES

Eligible for participation

No evidence of CVD

Referral to a qualified healthcare professional or specialist for further evaluation

*All young athletes are recommended to undergo a standardised history and physical examination as part of pre-participation screening, especially if the screening institution has the capacity for mass screening. A suggested checklist is the 14-element American Heart Association Cardiovascular Screening Checklist for Congenital and Genetic Heart Disease or equivalent. †Depending on individual assessment, especially if there is an element of competition during events or training, it may be appropriate for them to undergo a resting 12-lead ECG as part of pre-participation screening, subject to ALL of the following: the screening institution has the capacity for mass ECG screening; the ECG is performed to an acceptable standard; and the ECG should be interpreted using the 2017 International Recommendations by a healthcare professional qualified to do so. CVD = cardiovascular disease.

during the encounter to assess for features that may suggest underlying cardiovascular conditions that preclude participation (e.g. heart murmurs, frequent ectopic beats, pulse delays, physical stigmata of Marfan syndrome and sitting brachial artery blood pressure).33 Importantly, the thorough medical history-taking and physical examination are relatively affordable and easily accessible even in developing countries, thus imposing a low barrier to enable effective sports screening. While medical history and physical examination constitute a useful first line of screening, there may have low sensitivity to detect latent cardiovascular diseases in the young because such conditions are often clinically silent, and unlikely to be easily detected during the initial clinical encounter.34 To improve the overall sensitivity of detection, the addition of a 12-lead ECG is recommended as a low-cost and widely available tool for the pre-participation screening of athletes involved in moderate- to highintensity sports.1 As an add-on, the ECG can enhance the screening sensitivity of pre-participation screening from 25% to >90%, to pick up cardiovascular conditions that may predispose to SCD.32,35–37 A recent meta-analysis reported that the ECG was more sensitive than history and physical examination alone in detecting significantly underlying cardiovascular conditions related to SCD.37 A common criticism of ECG screening is the high false-positive rate, leading to either unnecessary secondary evaluations or restriction from sports activities. However, it is critical to recognise that the false-positive rate for ECG screening is largely affected by the criteria used to define ‘abnormal’. With significant advances made in interpretation of an athlete’s ECG, the ECG has improved the ability to distinguish between physiological exercise-induced cardiac remodelling in athletes, vis-a-vis underlying pathology. Most recently, the 2017 International Recommendations for ECG Interpretation in Athletes has led to an enhancement in the screening specificity without compromising sensitivity. There is also an attendant improvement in interobserver variability for ECG detectable pathological conditions associated with SCD.10,38

Despite the aforementioned advantages and strengths of employing ECG as a screening tool, the panel acknowledges certain limitations of this modality. First, exercise-induced cardiac remodelling poses significant challenges in the interpretation of the ECG in an athlete. The ECG may still present with false positive results in up to 6.8% of cases even with the international criteria.39 Second, there is a lack of validated criteria for ECG interpretation for Asian people. Third, some conditions associated with SCD may not present with resting ECG changes, e.g. premature coronary artery disease, congenital coronary anomalies, aortic dilatation and valvular heart diseases. Finally, the current evidence on the survival benefit of ECG as a screening tool is mainly from observational studies. To date, only one observational study has reported a reduction in the annual incidence of SCD from an ECG-based pre-participation screening of athletes.40 Evidence from prospective studies on the efficacy of preparticipation screening with ECG remains lacking. In consideration of these potential shortcomings, it is then imperative that the interpretation of the athletes’ ECGs should be deferred to healthcare professionals trained and experienced to do so, such as a sports medicine physician or a cardiologist. The authors acknowledge that these recommendations could occasionally lead to some athletes being unnecessarily temporally withdrawn from competition but that this is balanced by the benefit of avoiding SCD in young competitive athletes at risk. Furthermore, patients with abnormalities in the initial evaluation who were later assessed by a specialist to be low risk despite the diagnosis of cardiovascular disease, physical activities could be resumed.

The Role of Transthoracic Echocardiography

Transthoracic echocardiography (TTE) plays an integral role in the evaluation of competitive athletes with suspected or confirmed cardiovascular disease. TTE has the capacity to characterise myocardial structure and systolic and diastolic function, valve morphology and function, and proximal coronary anatomy with sufficient accuracy and detail to confirm or exclude the presence of clinically relevant cardiovascular disease in the majority of competitive athletes. The main

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APSC Consensus for Pre-participation Screening in Young Competitive Athletes advantages of TTE include its accessibility, portability, relative low cost and freedom from ionising radiation. In addition, portable communitybased TTE in athletes is also feasible with high imaging success rate. Despite all these advantages, at present, the routine use of TTE is not recommended as a first-line investigation pre-participation screening by any professional societies. The impact of this strategy has not been rigorously assessed and the use of TTE outside of carefully controlled settings that are resourced with expertise in sports cardiology is not recommended.41

Participation in Low Cardiovascular Intensity Sports Statement 4. Routine pre-participation screening for athletes engaging in low-intensity sport (including master athletes) is generally not necessary. Level of evidence: Low. Level of agreement: Agree 85%, neutral 15%, disagree 0%. Evidence-based support for pre-participation screening of athletes participating in low-intensity sports is presently deficient. Several guidelines also do not recommend routine pre-participation screening in low-risk circumstances. For example, the American College of Sports Medicine pre-participation medical screening for non-athletes recommends that for people who participates in regular exercise, medical clearance for even moderate-intensity exercise is not required (even if they have known cardiovascular, metabolic or renal disease, provided they are not symptomatic).42 Existing guidelines also allow the participation in low-intensity competitive sports, even for those with certain cardiomyopathies such as hypertrophic cardiomyopathy, following shared decision making.8,13 The panel agreed that participation in low-intensity sports poses minimal risk and does not recommend routine pre-participation screening in young competitive athletes participating in low-intensity sports in order to optimise healthcare resources while minimising barriers to sports in low-risk situations.

Athletes with Pre-existing Cardiovascular Diseases Statement 5. Competitive athletes with pre-existing cardiovascular disease should be managed according to established eligibility and disqualification recommendations for: 1. cardiomyopathies, myocarditis and pericarditis; 2. coronary artery disease; 3. arrhythmias; 4. channelopathies; and 5. coronavirus disease 2019 (COVID-19). Level of evidence: Low. Level of agreement: Agree 100%, neutral 0%, disagree 0%. In situations whereby the young athletes have known or detected cardiovascular conditions that may predispose to adverse outcomes during competitive sports or training, it is recommended that they be managed according to established guidelines, specific to the given conditions, in order to determine their eligibility and disqualification status. Several international societies, including the European Association of Preventive Cardiology, the European Heart Rhythm Association (EHRA),

the European Society of Cardiology, and the AHA/ACC have published updated recommendation statements on the management of athletes with cardiovascular disease, and it is useful to refer to those consensus papers alongside this APSC consensus paper.8,9,11,43 Last, but not least, the COVID-19 pandemic has had a huge impact across the globe and numerous sports participants worldwide have been affected since its emergence. Cardiac involvement, both manifest and latent, can potentially occur even in mild COVID-19 infections, and management of athletes with active or recovered COVID-19 should be guided by emerging and evolving guidelines and advisories to ensure a safe return to sports participation.44,45

Limitations

The main limitation of this consensus document is the dearth of highquality evidence applicable to the Asia-Pacific region. As the recommendations are developed to provide broad guidance and standardised workflow to healthcare practitioners involved in sports screening, it is important that the approach to each young athlete should be individualised, with due consideration for the type of sports, the level of competition and the training intensities the athlete is engaged in (bearing in mind that training can be more intense than the actual competition8) , the local training and institutional policies in place, and their workforce and logistical resources for pre-participation cardiac screening. Furthermore, it must be emphasised that these statements are intended for competitive sports and their required training regimen, and not necessarily applicable to recreational sports participation. Lastly, the clinician should be aware that despite pre-screening, SCD may still occur during competitive sport games and should be prepared for this event (e.g. having automated external defibrillators accessible).

Conclusion

This consensus statement aims to guide medical practitioners in the conduct of pre-participation cardiac screening of young competitive athletes in the Asia-Pacific region, guided by sports intensity. Significantly, the panel proposes pre-participation screening only for athletes involved in moderate- to high-intensity sports and advises that practitioners contextualise the recommendations in accordance with available resources and expertise in their respective country or region. Athletes participating in low-intensity sport are not recommended to undergo routine pre-participation screening, because of the low risk involved and also for healthcare resource optimisation. The use of sports intensity to guide screening is a unique feature of this APSC consensus paper, and is not a feature in either the 2016 EHRA and European Association for Cardiovascular Prevention and Rehabilitation (EACPR) position paper or the 2015 AHA/ACC scientific statement.1,8 In addition, the APSC consensus included an intensity-based sports classification, which was built upon on the 2015 ACC sports classification framework, and included a substantial number of Asian-centric sports after deliberation and categorised based on intensity.12,30 With regards to the use of ECG, this consensus is similar to the 2015 AHA/ ACC scientific statement in that we do not give endorsement to universal ECG screening.8 This consensus stated that ECG is recommended for young athletes participating in high and moderate cardiovascular intensity sports only if certain conditions are met. These recommendations were

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APSC Consensus for Pre-participation Screening in Young Competitive Athletes made after taking into consideration disparities in countries within AsiaPacific in terms of available resources for screening. This is in contrast to the 2016 EHRA/EACPR position paper’s broad endorsement of ECG as an initial screening investigation for all competitive athletes.1 Lastly, with 1. Mont L, Pelliccia A, Sharma S, et al. Pre-participation cardiovascular evaluation for athletic participants to prevent sudden death: Position paper from the EHRA and the EACPR, branches of the ESC. Endorsed by APHRS, HRS, and SOLAECE. Eur J Prev Cardiol 2016;24:41–69. https://doi. org/10.1177/2047487316676042; PMID: 27815537. 2. Harmon KG, Drezner JA, Wilson MG, Sharma S. Incidence of sudden cardiac death in athletes: a state-of-the-art review. Heart 2014;100:1227–34. https://doi.org/10.1136/ heartjnl-2014-093872.rep; PMID: 25049314. 3. Malhotra A, Sharma S. Outcomes of cardiac screening in adolescent soccer players. N Engl J Med 2018;379:2084. https://doi.org/10.1056/NEJMc1813056; PMID: 30462935. 4. Oh YZ, Lee CT, Lim AT, Tong KL. Sports-related sudden cardiac deaths in singapore - an eleven-year review. Ann Acad Med Singap 2019;48:156–60; PMID: 31210253. 5. Corrado D, Basso C, Rizzoli G, et al. Does sports activity enhance the risk of sudden death in adolescents and young adults? J Am Coll Cardiol 2003;42:1959–63. https://doi. org/10.1016/j.jacc.2003.03.002; PMID: 14662259. 6. Thompson PD, Franklin BA, Balady GJ, et al. Exercise and acute cardiovascular events placing the risks into perspective: a scientific statement from the American Heart Association Council on Nutrition, Physical Activity, and Metabolism and the Council on Clinical Cardiology. Circulation 2007;115:2358–68. https://doi.org/10.1161/ CIRCULATIONAHA.107.181485; PMID: 17468391. 7. Chandra N, Bastiaenen R, Papadakis M, Sharma S. Sudden cardiac death in young athletes: practical challenges and diagnostic dilemmas. J Am Coll Cardiol 2013;61:1027–40. https://doi.org/10.1016/j.jacc.2012.08.1032; PMID: 23473408. 8. Maron BJ, Zipes DP, Kovacs RJ; American Heart Association Electrocardiography and Arrhythmias Committee of Council on Clinical Cardiology, Council on Cardiovascular Disease in Young, Council on Cardiovascular and Stroke Nursing, Council on Functional Genomics and Translational Biology, and American College of Cardiology. Eligibility and disqualification recommendations for competitive athletes with cardiovascular abnormalities: Preamble, principles, and general considerations: A Scientific Statement From the American Heart Association and American College of Cardiology. Circulation 2015;132:e256–61. https://doi. org/10.1161/CIR.0000000000000236; PMID: 26621642. 9. Borjesson M, Dellborg M, Niebauer J, et al. Recommendations for participation in leisure time or competitive sports in athletes-patients with coronary artery disease: a position statement from the Sports Cardiology Section of the European Association of Preventive Cardiology (EAPC). Eur Heart J 2018;40:13–18. https://doi. org/10.1093/eurheartj/ehy408; PMID: 30052887. 10. Drezner JA. 18 highlights from the International Criteria for ECG interpretation in athletes. Br J Sports Med 2020;54:197– 9. https://doi.org/10.1136/bjsports-2019-101537; PMID: 31704696. 11. Heidbuchel H, Adami PE, Antz M, et al. Recommendations for participation in leisure-time physical activity and competitive sports in patients with arrhythmias and potentially arrhythmogenic conditions: Part 1: Supraventricular arrhythmias. A position statement of the Section of Sports Cardiology and Exercise from the European Association of Preventive Cardiology (EAPC) and the European Heart Rhythm Association (EHRA), both associations of the European Society of Cardiology. Eur J Prev Cardiol 2020. https://doi. org/10.1177/2047487320925635; PMID: 32597206; epub ahead of press. 12. Levine BD, Baggish AL, Kovacs RJ, et al. Eligibility and disqualification recommendations for competitive athletes with cardiovascular abnormalities: Task Force 1: Classification of sports: dynamic, static, and impact. Circulation 2015;132:e262–6. https://doi.org/10.1161/ CIR.0000000000000237; PMID: 26621643. 13. Pelliccia A, Sharma S, Gati S, et al. 2020 ESC Guidelines on sports cardiology and exercise in patients with

regards to the utility of routine TTE screening, our APSC consensus is similar to both the American and European guidelines, in that there is currently no evidence to support the routine use of TTE as first line preparticipation screening investigation.1,8

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Cardio-oncology

Palpitations in the Cancer Patient Hani Essa

and Gregory YH Lip

1,2

1. Liverpool Centre for Cardiovascular Science, University of Liverpool, Liverpool Heart and Chest Hospital, Liverpool, UK; 2. Aalborg Thrombosis Research Unit, Department of Clinical Medicine, Aalborg University, Aalborg, Denmark

Abstract

Cancer and cardiovascular diseases (CVD) are among the leading causes of death worldwide. In response to the growing population of cancer patients and survivors with CVD, the sub-specialty of cardio-oncology has been developed to better optimise their care. Palpitations are one of the most common presenting complaints seen in the emergency room or by the primary care provider or cardiologist. Palpitations are defined as a rapid pulsation or abnormally rapid or irregular beating of the heart and present a complex diagnostic entity with no evidence-based guidelines currently available. Palpitations are a frequent occurrence in people with cancer, and investigations and treatment are comparable to that in the general population although there are some nuances. Cancer patients are at a higher risk of arrhythmogenic causes of palpitations and non-arrhythmogenic causes of palpitations. This review will appraise the literature with regards to the development and management of palpitations in the cancer patient.

Keywords

Cardio-oncology, palpitations, arrhythmia, chemotherapy, atrial fibrillation, prolonged QTc, oncology Disclosure: GL reports consultancy and speaker fees from Bayer, Bayer/Janssen, BMS/Pfizer, Biotronik, Medtronic, Boehringer Ingelheim, Microlife, Roche and DaiichiSankyo outside the submitted work. No fees are received personally. HE has no conflicts of interest to declare. Received: 24 August 2021 Accepted: 27 September 2021 Citation: European Cardiology Review 2021;16:e45. DOI: https://doi.org/10.15420/ecr.2021.44 Correspondence: Gregory YH Lip, Liverpool Centre for Cardiovascular Science, University of Liverpool and Liverpool Heart and Chest Hospital, Thomas Drive, Liverpool L14 3PE, UK E: gregory.lip@liverpool.ac.uk Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Cancer and cardiovascular disease (CVD) are among the leading causes of death worldwide. In recent decades, there has been remarkable progress in the detection and treatment of cancer and CVD that has translated to a significantly improved prognosis for both conditions.1,2 Unsurprisingly, these trends have resulted in a growing population with both CVD and cancer. The conditions frequently coexist and share multiple mutual risk factors. Furthermore, cancer treatments share various detrimental effects in common, especially upregulation of cardiovascular risk factors.3 In the cancer population, CVD is the second most common cause of morbidity and mortality, second only to recurrent malignancy.4 In fact, the risk of CVD in the cancer population is 800% higher than that of the general population and the relative risk of coronary artery disease is over 1,000% more in cancer survivors compared to their cancer-free siblings.4 The overall burden of CVD in the cancer population is likely to increase with an increasingly ageing population and a high lifetime risk of both conditions in the developed world. In response to the growing population of cancer patients and survivors with CVD the sub-speciality of cardio-oncology was developed to optimise care. Cardio-oncology is a relatively new sub-specialty within cardiology focusing on the optimal diagnosis, prevention and treatment of the cardiovascular consequences of cancer and its treatment. The world’s first cardio-oncology unit was built in the US in the MD Anderson Center in 2000. The international cardio-oncology society was created in 2009 and the first dedicated cardio-oncology service was started in the UK at the Royal Brompton Hospital in 2011.5,6 In a 2016 position document, the

European Society of Cardiology provided a breakdown of cardiovascular complications of cancer therapy into nine main categories:

• • • • • • • • •

left ventricular systolic dysfunction; arterial hypertension; pulmonary hypertension; valvular disease; cardiac arrhythmias; thromboembolic disease; peripheral vascular disease and stroke; coronary artery disease; and pericardial disease.

Palpitations are defined as a rapid pulsation or abnormally rapid or irregular beating of the heart. Patients often describe palpitations as a rapid fluttering in the chest, a skipped beat, or a pounding sensation in the chest.7 Palpitations are one of the most common presenting complaints when patients attend the emergency department or see their primary care provider or cardiologist.8 Palpitations are commonly benign and represent an abnormal awareness of one’s heartbeat. However, less commonly they represent abnormal heart rhythms. In the cancer population, palpitations are a frequent occurrence and investigations and treatment are comparable to that in the general population although with some nuances. The sensation of palpitation can arise from extrasystoles or tachyarrhythmias. Less commonly, bradycardias can also be implicated. In

Palpitations in Cardio-oncology Table 1: Broad Categorisation of the Aetiology of Palpitations

being more likely to suffer palpitations due to anxiety and stress from dealing with cancer and its treatment.

Aetiology of Palpitations

Clinical Work-up

Cardiac causes of palpitations • AF • Atrial flutter • Sinus tachycardia • Normal sinus rhythm • Premature atrial contractions • Sick sinus syndrome • Supraventricular tachycardia • Complete heart block • Ventricular tachycardia • Non-sustained ventricular tachycardia • Premature ventricular contractions • Torsades de pointes • VF

The diagnosis of palpitations can be challenging for a variety of reasons, and their transient nature is a large contributing factor. Work-up can often be fruitless and patients are frequently left without a probable diagnosis and are not given any treatment.10 This means a large proportion of patients continue to suffer recurrences of palpitations, which can be a cause of morbidity and reduced quality of life. The current investigation process for palpitations is often guided by the treating clinician’s practice. There is little in the literature that could be used as a specific guidelines/ policy document to guide practice.11 Clinical work-up will usually incorporate a combination of history, examination and subsequent investigation as required.

History

Anxiety disorders • Panic attacks • Generalised anxiety • Somatisation Miscellaneous causes • Anaemia • Caffeine • Alcohol • Drug toxicity (such as amphetamines or theophylline) • Thyroid disorders • Phaeochromocytoma • Electrolyte abnormalities No identifiable cause found Cancer patient specific • Cardiac myxomas • Rhabdomyomas • Chemotherapy (ibrutinib, arsenic trioxide) • Post-surgical

patients who describe palpitations as a brief extra strong beat in the chest, it is thought that this is induced ventricular/atrial extrasystoles. In rapid persistent palpitations, it is thought that supraventricular tachycardias are implicated. This review will appraise the literature with regards to the development and management of palpitations in people with cancer. Specifically, this article will focus on the differential diagnosis, clinical approach, investigations and management of palpitations.

Diagnosis and Investigations Aetiology/Differential Diagnosis of Palpitations

Palpitations can be divided into four categories for the purpose of this discussion:

• Cardiac causes. • Anxiety disorders. • Miscellaneous causes, such as medications/thyrotoxicosis, caffeine and anaemia.

• Unknown causes (16% of scenarios).9 Cardiac arrhythmic causes of palpitations are the most worrying for patients and they can be life-threatening. Table 1 demonstrates the breakdown and subcategories of palpitations. Nuances do exist in the cancer population, where patients are more likely to suffer cardiac palpitations due to cancer or complications of its treatment, as well as

A good clinical history remains at the core of assessment and can help delineate high-risk from low-risk patients and it can guide investigations depending on the risk profile. A good history can provide more clues towards the diagnosis than the examination because palpitations have often spontaneously ceased by the time of the assessment. The initial clinical assessment is often used to paint a clinical risk profile of a patient and estimate the underlying likelihood of serious causes of arrhythmias. The pre-test probability is the single most important tool in building a risk profile for patients. In one study among patients with cardiac disease, palpitations were attributed to an arrhythmogenic focus 91% of the time.12 Therefore, the complaint of palpitations should be taken more seriously in patients with pre-existing cardiac disease. In a systematic review, the strongest predictive factors for significant cardiac arrhythmia were a known history of cardiac disease (likelihood ratio [LR] 2.03; 95% CI [1.33–3.11]), and palpitations affected by sleeping (LR 2.29; 95% CI [1.33–3.94]) or while at work (LR 2.17; 95% CI [1.19– 3.96]). Strongly negative predictive factors included palpitations lasting less than 5 minutes (LR 0.38; 95% CI [0.22–0.63]) and a known history of panic disorder (LR 0.26; 95% CI [0.07–1.01]).13 It is vital for the clinician to establish duration and frequency of provoking/ relieving factors and it may be useful to allow the patient to tap or clap out their perceived palpitation. Table 2 demonstrates the salient points in a palpitation’s history. It is important to search for red flags, such as syncope, exercise-induced palpitations or a family history of sudden death. It is important to elucidate what medication the patient is on as some chemotherapeutic agents are heavily implicated as arrhythmogenic substrates.

Examination

The role of the examination is limited as frequently it is performed when the patient is asymptomatic and there are no rhythm abnormalities. The examination should focus on any possible cardiac or systemic illness that may be implicated in palpitations. A good examination should look for evidence of cardiac disease in the form of signs of heart failure, an irregular pulse or valvular disease. Signs of non-cardiac causes of palpitations can also be elicited in the form of tremors/goitre (thyrotoxicosis) or pallor (anaemia). The usefulness of these clinical signs is unproven; however, as the data are largely limited to anecdotal evidence and there are currently no data evaluating the presence of these signs with arrhythmia. The only sign with good evidence is the presence of resting bradycardia (<60 BPM; LR 3.00; 95% CI [1.27–7.08]).14 While necessary during work-up, it is well recognised that clinical

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Palpitations in Cardio-oncology examination alone is not sufficient to accurately exclude clinically significant arrhythmias in most patients.

Clinical Investigations

There is a similar set of investigations that all oncology patients presenting with palpitations should undergo, which includes:

• Full blood count, urea and electrolytes (including magnesium and calcium) and thyroid function tests.

• Echocardiogram to identify structural heart disease that increases the index of suspicion for cardiac arrhythmia. • 12-lead ECG with subsequent ambulatory monitoring dependent on the frequency of symptoms.

In the general population the above may be more than sufficient to reassure both the patient and the clinician regarding the benign nature of palpitations. However, the cancer population is deemed to be at high risk of CVD and therefore aggressive investigation is advised. It is advisable to undertake ambulatory monitoring tailored to the patient’s symptom burden and preferences. Ambulatory monitoring can be diagnostic when it establishes a correlation between palpitations and an ECG recording.15 In patients who experience asymptomatic arrhythmias the role of ambulatory monitoring is more tenuous in diagnosing palpitations.16 Ambulatory monitoring is available in five formats:

• Holter monitors that are attached to patients for a limited period of a few days.

• External loop recorders and event recorders that can be worn for a

prolonged period and are triggered by users when palpitations are experienced. • Implantable loop recorders (ILR) that are placed subcutaneously for prolonged periods of time. • Newer ambulatory monitoring devices can offer ambulatory monitoring without the wiring required in normal ambulatory monitoring.17 • Emerging technologies, such as smartwatches with ECG monitoring, which can reliably screen for asymptomatic AF.18,19 However, their role in the investigation of other arrhythmias is much less clear. If the smartwatch uses photoplethysmography for detection, then subsequent confirmation with a formal ECG will be required before treatment.20 Table 3 demonstrates the choices in ambulatory ECG monitoring. Ambulatory monitoring has inherent limitations, chiefly that it is not possible to always make a precise diagnosis, especially when using single-lead devices. It may cause difficulty when deciding if the witnessed rhythm is a supraventricular rhythm with aberrant conduction or a ventricular tachycardia. Furthermore, ambulatory monitoring requires the patient to experience a recurrence of symptoms so that the arrhythmia is captured. This can delay the diagnosis and leaves the patient at risk of malignant rhythms. Rarely, electrophysiology testing can be performed to enable a detailed analysis of the underlying cause of a cardiac arrhythmia as well as its originating site. However, these are only indicated in patients with a high pre-test probability of a serious cardiac arrhythmia.7,21 Electrophysiology studies can correctly identify the type of arrhythmia responsible for palpitations and enables simultaneous ablation in the same session. This is usually used in high-risk patients with significant heart disease and

Table 2. Taking a History When Investigating a Patient with Palpitations What to ask about the palpitations themselves What do you mean by palpitations? How often do you get palpitations? Does anything bring on your palpitations and does anything get rid of them? When do your palpitations come on? What is the relationship of your palpitations to sleep? Or exercise? Have you ever suffered with shortness of breath/syncope/presyncope with your palpitations? Questions about the past medical history/family history/social history What medical conditions do you have? Is there a family history of sudden cardiac death? Do you consume caffeinated drinks? Do you consume alcohol? What medications are you taking? What chemotherapeutic agents are you on? Do you take any recreational drugs? Questions about the patient’s mental health How is your mood? Have you ever suffered from panic disorders? Have you ever felt anxious without a known trigger? Do you find that your palpitations are preceded by anxiety or is it your palpitations that cause anxiety?

palpitations associated with syncope as the risk of adverse events from untreated events is unacceptably high. This high-risk cohort of patients can be directly referred for electrophysiology studies without ambulatory ECG monitoring.22,23

Special Situations in Cardio-oncology Palpitations Due to Psychosomatic Disorders

Anxiety and panic disorders are a frequent cause of palpitations.8 These disorders have been implicated in sinus tachycardia and can modulate increased awareness of one’s own heartbeat. Furthermore, it is known that intense emotions can produce arrhythmias secondary to increased adrenergic activation.24,25 Psychosomatic disorders are particularly relevant in cardio-oncology as it is known that patients suffering with cancer have much higher rates of anxiety, depression and panic disorders.26 This may act as a substrate for palpitations in this group. However, it is important to note that both psychosomatic and nonpsychosomatic palpitations are likely to exist at higher rates in the cardiooncology population as compared to the general population. This is because cardio-oncology patients are likely to suffer from higher rates of anxiety and higher rates of cardiac disease secondary to their age and the chemotherapeutic agents used in their treatment.27–29 Furthermore, cardiac arrhythmias and psychosomatic disorders are not mutually exclusive and can frequently coexist.30 It is also important to note that in one study looking at patients with arrhythmogenic disorders, about 66% were previously diagnosed as having psychosomatic palpitations.31 In the oncology population we advise that this diagnosis should only be reached if the patient has a benign history with a normal echocardiogram, a 12‑lead ECG and ambulatory monitoring.

Palpitations Due to Chemotherapeutic Agents

Several chemotherapeutic agents have been implicated in causing arrhythmias. This topic has recently seen several reviews and awareness is increasing.27,32,33 This section will briefly cover the most important implicated agents and their respective arrhythmias. Ibrutinib is a Bruton’s kinase (BTK) inhibitor that is an effective and welltolerated treatment for a variety of B-cell lymphomas. Ibrutinib has

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Palpitations in Cardio-oncology Table 3. Comparison of Various Methods of ECG Monitoring Investigation

Frequency of Symptoms for Investigation to be Useful in Yield

Advantages

Disadvantages

12-lead ECG

Current

Easily available

Low yield if patient is asymptomatic at the time of the ECG

24–120-hour Holter monitor

Daily/every few days

Easily available and relatively cheap

Low yield for patients who do not get frequent symptoms every day

Loop recorder

Short duration of weeks

Higher yield than Holter monitor and generally more cost-effective

Patient triggered meaning that asymptomatic arrhythmias can be missed. Patient discomfort

Implantable loop recorder

Months to years

High-yield long-term monitoring

Expensive Involves a procedure to insert internally

Smartwatches

Months to years

Long-term monitoring

Cost to patient Not validated in arrhythmias other than AF

demonstrated excellent results in chronic lymphocytic leukaemia, small lymphocytic lymphoma, mantle cell lymphoma and marginal zone lymphoma.34 Although generally well tolerated, ibrutinib is estimated to cause AF in about 6–16% of patients.35 This frequently occurs a few months into treatment with over 75% of cases reported in the first year. AF can often be a therapy-limiting side-effect and is the most common reason for patients stopping therapy.36 Therefore, it is prudent in patients presenting with palpitations who are on BTK inhibitors to investigate thoroughly for AF with prolonged ambulatory monitoring. Early referral to cardio-oncology is advised as treatment is more complex and requires joint decision-making on the need for rate/rhythm control and choice of anticoagulation. This cohort has increased risks of bleeding and ibrutinib is known to interact with a variety of medications used in the management of AF.37 We advise a rate control strategy in the first instance unless compelling reasons for rhythm control exist. It is advised to use a direct oral anticoagulant (DOAC) as the choice of anticoagulation.38 Cardio-oncology can also facilitate the use of lower doses of DOACs in patients at high risk of bleeding or a reduced dose of BTK inhibitors to reduce the burden of AF in conjunction with oncology and a multidisciplinary team approach.39 Arsenic trioxide is a potent agent used in the treatment of some leukaemias and myelomas. It is classically implicated in QTc prolongation in 26–93% of patients with rare life-threatening ventricular arrhythmias reported.40–42 This effect is largely transient and occurs 1–5 weeks after infusion and resolves about 8 weeks later.43 In this time patients are at risk of the consequences of prolonged QTc, including torsades de points (TdP), fatal ventricular arrhythmias and sudden cardiac death. The severity of the QTc prolongation can be variable and is related to electrolyte abnormalities and other agents known to prolong the QTc.40 Overall, it is estimated that about one-third of patients experience QTc prolongation >60 ms.40 In this cohort of patients cardio-oncology advice should be sought and close monitoring undertaken in the form of baseline and weekly ECG monitoring.44

Management

The management of palpitations in cardio-oncology is predicated on the underlying aetiology – cardiac arrhythmias, structural heart disease, chemotherapy-induced, anxiety disorders or systemic disorders – and its implicated prognosis. If a definitive aetiology is found and a curative therapy exists, such as ablation for supraventricular arrhythmias, this should be the treatment of choice.45 In the vast majority of benign arrhythmias, such as atrial/ventricular premature/delayed beats, it is advisable to undertake lifestyle interventions prior to pharmacological

interventions. It is well recognised that several lifestyle choices can reduce the risk of palpitations and arrhythmias, such as a reduced intake of caffeine, alcohol and recreational drugs. Furthermore, it is well recognised that a lack of sleep and lifestyle stress are linked to palpitations. Furthermore, in the absence of a sinister cause of palpitations, reassurance from a clinician can reduce the overall symptom burden. Overall, oncology patients with palpitations benefit from the same preventive measures that are recommended to the general population.46–48 Another consideration is the prognosis of the underlying cancer. In patients with a good prognosis, it would be reasonable to pursue all treatment strategies and investigations, while in patients with a prognosis that is measured in weeks or months, the value that will be added by some treatment strategies, such as anticoagulation for AF, may be questionable. The question of how to treat and investigate a patient with palpitations should always be preceded by the prognostic implications of the underlying cancer. A referral to cardio-oncology is always warranted in the context of a suspected chemotherapy-induced arrhythmia as cardio-oncologists can help facilitate better care for patients in liaison with oncology and the multidisciplinary team. Cardio-oncologists can facilitate prechemotherapy prophylactic antiarrhythmic therapy, or after discussion with oncology can facilitate reduced-dose chemotherapy regimens. AF is the most common cardiac arrhythmias in the cancer patient population (2–16% of patients during treatment) and management requires similar decisions as those made in the non-cancer population with regards to rate and rhythm control.49,50 However, there exists certain nuances in this population that need to be considered in the decision-making process. Anti-thrombotic therapy is particularly challenging because cancer can result in both a pro-thrombotic and pro-haemorrhagic state and an unpredictable anticoagulation response.51 This is highly dependent on the cancer type as the differential risks conferred by various cancers can be vastly different. Furthermore, the normal risk scores that can be used, such as CHA2DS2-VASc (congestive heart failure or left ventricular dysfunction, hypertension, age ≥75 years [doubled], diabetes, stroke [doubled] – vascular disease, age 65–74 years, sex [female]) and HASBLED (hypertension, abnormal renal/liver function [1 point each], stroke, bleeding history or predisposition, labile INR, elderly [>65 years], drugs/ alcohol concomitantly [1 point each]) have not been validated in the cancer population. Therefore, in the absence of evidence, an individualised approach is suggested and the decision should not purely hinge on risk assessment scores.52,53

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Palpitations in Cardio-oncology Once a decision to anticoagulate is made, the choice of agent is more nuanced than in the general population. Treatment with warfarin is more complex as efficacy and safety is dependent on the international normalised ratio (INR) and this can be subject to interactions with chemotherapeutic agents. Low molecular weight heparins (LMWH) are often used in the treatment of thromboembolism in this patient group. However, their longterm usefulness in AF is limited by the inconvenience of their need to be injected once a day. DOACs are becoming the de facto treatment of AF in the non-cancer population.20 The evidence base is more scarce in the cancer population. This is because many pivotal trials excluded patients with limited life expectancies and the evidence base is derived from observational studies. In a landmark study by Shah et al. of over 16,000 patients with AF and cancer, DOAC users experienced lower or similar rates of bleeding and stroke compared to those on warfarin and a lower rate of incident venous thromboembolism.54 An expert position paper by the Spanish cardio-oncology society recommends that DOACs should be used as a first-line choice in the treatment of AF in the cancer population.50 AF catheter ablation may be used in a high selective population where a rate/rhythm control strategy has failed and the patient has a high burden of symptoms and/or the chemotherapeutic agents used have a high likelihood of interaction with anticoagulation. There are currently very limited data on the safety and efficacy profile of catheter ablation of AF in 1. Quaresma M, Coleman MP, Rachet B. 40-year trends in an index of survival for all cancers combined and survival adjusted for age and sex for each cancer in England and Wales, 1971–2011: a population-based study. Lancet 2015;385:1206–18. https://doi.org/10.1016/S01406736(14)61396-9; PMID: 25479696. 2. Roth GA, Huffman MD, Moran AE, et al. Global and regional patterns in cardiovascular mortality from 1990 to 2013. Circulation 2015;132:1667–78. https://doi.org/10.1161/ CIRCULATIONAHA.114.008720; PMID: 26503749. 3. Ewer MS, Ewer SM. Cardiotoxicity of anticancer treatments. Nat Rev Cardiol 2015;12:547–8. https://doi.org/10.1038/ nrcardio.2015.65; PMID: 25962976. 4. Oeffinger KC, Mertens AC, Sklar CA, et al. Chronic health conditions in adult survivors of childhood cancer. N Engl J Med 2006;355:1572–82. https://doi.org/10.1056/ NEJMsa060185; PMID: 17035650. 5. Lenihan DJ, Cardinale D, Cipolla CM. The compelling need for a cardiology and oncology partnership and the birth of the International CardiOncology Society. Prog Cardiovasc Dis 2010;53:88–93. https://doi.org/10.1016/j.pcad.2010.06.002; PMID: 20728695. 6. Pareek N, Cevallos J, Moliner P, et al. Activity and outcomes of a cardio-oncology service in the United Kingdom-a fiveyear experience. Eur J Heart Fail 2018;20:1721–31. https://doi. org/10.1002/ejhf.1292; PMID: 30191649. 7. Brugada P, Gürsoy S, Brugada J, et al. Investigation of palpitations. Lancet 1993;341:1254–8. https://doi. org/10.1016/0140-6736(93)91155-F; PMID: 8098401. 8. Mayou R. Chest pain, palpitations and panic. J Psychosom Res 1998;44:53–70. https://doi.org/10.1016/S00223999(97)00209-2; PMID: 9483464. 9. Probst MA, Mower WR, Kanzaria HK, et al. Analysis of emergency department visits for palpitations (from the National Hospital Ambulatory Medical Care Survey). Am J Cardiol 2014;113:1685–90. https://doi.org/10.1016/j. amjcard.2014.02.020; PMID: 24698469. 10. Giada F, Raviele A. Diagnostic management of patients with palpitations of unknown origin. Ital Heart J 2004;5:581–6. PMID: 15554028. 11. Raviele A, Giada F, Bergfeldt L, et al. Management of patients with palpitations: a position paper from the European Heart Rhythm Association. Europace 2011;13:920– 34. https://doi.org/10.1093/europace/eur130; PMID: 21697315. 12. Weber BE, Kapoor WN. Evaluation and outcomes of patients with palpitations. Am J Med 1996;100:138–48. https://doi. org/10.1016/S0002-9343(97)89451-X; PMID: 8629647. 13. Thavendiranathan P, Bagai A, Khoo C, et al. Does this patient with palpitations have a cardiac arrhythmia? JAMA 2009;302:2135–43. https://doi.org/10.1001/jama.2009.1673; PMID: 19920238.

the cancer population; however, what limited data exist suggests a higher propensity for bleeding complications.55 A prolonged QTc is more commonly seen in the cancer population due to multiple risk factors including but not limited to advancing age, electrolyte abnormalities and chemotherapeutic agents. A prolonged QTc can lead to TdP, which may be experienced as palpitations by the patient. The duration of the QTc should be controlled before, during and after cancer treatment. A full list of QT-prolonging drugs can be found at Credible Meds (www.crediblemeds.org). The management of prolonged QTc is dependent on correcting the reversible factors (such as electrolyte abnormalities or QT-prolonging drugs). Cardiologists looking after cancer patients should actively rule out long QTc and TdP as a cause of palpitations.

Conclusion

Palpitations are a frequent cause of morbidity and rarely mortality in the cancer population. Palpitations are one of the most common presenting complaints to healthcare providers and are more common in the cancer population where they are under-recognised and under-treated. Therefore, it is essential for the general cardiologist to recognise the nuances of diagnosing and managing palpitations in the oncology population and to know when to refer to their local cardio-oncologist.

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Palpitations in Cardio-oncology 35. Brown JR, Moslehi J, O’Brien S, et al. Characterization of atrial fibrillation adverse events reported in ibrutinib randomized controlled registration trials. Haematologica 2017;102:1796–805. https://doi.org/10.3324/ haematol.2017.171041; PMID: 28751558. 36. Mato AR, Nabhan C, Barr PM, et al. Outcomes of CLL patients treated with sequential kinase inhibitor therapy: a real world experience. Blood 2016;128:2199–205. https://doi. org/10.1182/blood-2016-05-716977; PMID: 27601462. 37. Thorp BC, Badoux X. Atrial fibrillation as a complication of ibrutinib therapy: clinical features and challenges of management. Leuk Lymphoma 2018;59:311–20. https://doi. org/10.1080/10428194.2017.1339874; PMID: 28629235. 38. Ganatra S, Sharma A, Shah S, et al. Ibrutinib-associated atrial fibrillation. JACC Clin Electrophysiol 2018;4:1491–500. https://doi.org/10.1016/j.jacep.2018.06.004; PMID: 30573111. 39. Essa H, Lodhi T, Dobson R, et al. How to manage atrial fibrillation secondary to ibrutinib. JACC CardiacOncol 2021;3:140–4. https://doi.org/10.1016/j.jaccao.2020.11.016; PMID: 34396314. 40. Barbey JT, Pezzullo JC, Soignet SL. Effect of arsenic trioxide on QT interval in patients with advanced malignancies. J Clin Oncol 2003;21:3609–15. https://doi.org/10.1200/ JCO.2003.10.009; PMID: 14512391. 41. Ohnishi K, Yoshida H, Shigeno K, et al. Prolongation of the QT interval and ventricular tachycardia in patients treated with arsenic trioxide for acute promyelocytic leukemia. Ann Intern Med 2000;133:881–5. https://doi.org/10.7326/00034819-133-11-200012050-00012; PMID: 11103058. 42. Siu CW, Au WY, Yung C, et al. Effects of oral arsenic trioxide therapy on QT intervals in patients with acute promyelocytic leukemia: implications for long-term cardiac safety. Blood 2006;108:103–6. https://doi.org/10.1182/blood-2006-010054; PMID: 16514059.

43. Soignet SL, Frankel SR, Douer D, et al. United States multicenter study of arsenic trioxide in relapsed acute promyelocytic leukemia. J Clin Oncol 2001;19:3852–60. https://doi.org/10.1200/JCO.2001.19.18.3852; PMID:11559723. 44. Westervelt P, Brown RA, Adkins DR, et al. Sudden death among patients with acute promyelocytic leukemia treated with arsenic trioxide. Blood 2001;98:266–71. https://doi. org/10.1182/blood.V98.2.266; PMID: 11435292. 45. Macías Gallego A, Díaz-Infante E, García-Bolao I. Spanish Catheter Ablation Registry. 8th official report of the Spanish Society of Cardiology Working Group on Electrophysiology and Arrhythmias (2008). Rev Esp Cardiol 2009;62:1276–85. https://doi.org/10.1016/S1885-5857(09)73355-9; PMID: 19889339. 46. Graham I, Atar D, Borch-Johnsen K, et al. European guidelines on cardiovascular disease prevention in clinical practice: executive summary: Fourth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice. Eur Heart J 2007;28:2375–414. https://doi.org/10.1093/eurheartj/ ehm316; PMID: 17726041. 47. Jouven X, Zureik M, Desnos M, et al. Long-term outcome in asymptomatic men with exercise-induced premature ventricular depolarizations. N Engl J Med 2000;343:826–33. https://doi.org/10.1056/NEJM200009213431201; PMID: 10995861. 48. Binici Z, Intzilakis T, Nielsen OW, et al. Excessive supraventricular ectopic activity and increased risk of atrial fibrillation and stroke. Circulation 2010;121:1904–11. https:// doi.org/10.1161/CIRCULATIONAHA.109.874982; PMID: 20404258. 49. Farmakis D, Parissis J, Filippatos G. Insights into oncocardiology: atrial fibrillation in cancer. J Am Coll Cardiol 2014;63:945–53. https://doi.org/10.1016/j.jacc.2013.11.026;

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PMID: 24361314. 50. López-Fernández T, Martín-García A, Roldán Rabadán I, et al. Atrial fibrillation in active cancer patients: expert position paper and recommendations. Rev Esp Cardiol (Engl Ed 2019;72:749–59. https://doi.org/10.1016/j.rec.2019.03.019; PMID: 31405794. 51. Lee AY. Deep vein thrombosis and cancer: survival, recurrence, and anticoagulant choices. Dis Mon 2005;51:150–7. https://doi.org/10.1016/j. disamonth.2005.03.010; PMID: 15900267. 52. Zamorano JL, Lancellotti P, Rodriguez Muñoz D, et al. 2016 ESC position paper on cancer treatments and cardiovascular toxicity developed under the auspices of the ESC Committee for Practice Guidelines: the Task Force for cancer treatments and cardiovascular toxicity of the European Society of Cardiology (ESC). Eur Heart J 2016;37:2768–801. https://doi.org/10.1093/eurheartj/ehw211; PMID: 27567406. 53. Steffel J, Verhamme P, Potpara TS, et al. The 2018 European Heart Rhythm Association Practical Guide on the use of nonvitamin K antagonist oral anticoagulants in patients with atrial fibrillation. Eur Heart J 2018;39:1330–93. https://doi. org/10.1093/eurheartj/ehy136; PMID: 29562325. 54. Shah S, Norby FL, Datta YH, et al. Comparative effectiveness of direct oral anticoagulants and warfarin in patients with cancer and atrial fibrillation. Blood Adv 2018;2:200–9. https://doi.org/10.1182/ bloodadvances.2017010694; PMID: 29378726. 55. Giustozzi M, Ali H, Reboldi G, et al. Safety of catheter ablation of atrial fibrillation in cancer survivors. J Interv Card Electrophysiol 2021;60:419–26. https://doi.org/10.1007/ s10840-020-00745-7; PMID: 32377917.

Microvascular Angina

Microvascular Angina: Diagnosis and Management Haider Aldiwani ,1,2 Suzan Mahdai ,2 Ghaith Alhatemi

and C Noel Bairey Merz

1. Barbra Streisand Women’s Heart Center, Cedars-Sinai Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California, US; 2. Scripps Health Institution Chula Vista Hospital, Department of Internal Medicine, San Diego, US; 3. St Mary Mercy Hospital, Department of Internal Medicine, Livonia, Michigan, US

Abstract

Recognition of suspected ischaemia with no obstructive coronary artery disease – termed INOCA – has increased over the past decades, with a key contributor being microvascular angina. Patients with microvascular angina are at higher risk for major adverse cardiac events including MI, stroke, heart failure with preserved ejection fraction and death but to date there are no clear evidence-based guidelines for diagnosis and treatment. Recently, the Coronary Vasomotion Disorders International Study Group proposed standardised criteria for diagnosis of microvascular angina using invasive and non-invasive approaches. The management strategy for remains empirical, largely due to the lack of high-levelevidence-based guidelines and clinical trials. In this review, the authors will illustrate the updated approach to diagnosis of microvascular angina and address evidence-based pharmacological and non-pharmacological treatments for patients with the condition.

Keywords

Microvascular angina, coronary microvascular dysfunction, coronary function test, diagnosis, management Disclosure: CNBM is on the board of directors for iRhythm, receives fees paid through CSMC from Abbott Diagnostics and Sanofi; and is on the European Cardiology Review editorial board; this did not influence peer review. This work is solely the responsibility of the authors and does not necessarily represent the official views of the National Heart, Lung, and Blood Institute, the National Institutes of Health or the US Department of Health and Human Services. All other authors have no conflicts of interest to declare. Funding: This work was supported by contracts from the National Heart, Lung and Blood Institutes nos. N01-HV-68161, N01-HV-68162, N01-HV-68163, N01-HV-68164, grants U0164829, U01 HL649141, U01 HL649241, K23 HL105787, K23 HL125941, K23 HL127262, K23HL151867 T32 HL69751, R01 HL090957, 1R03 AG032631, R01 HL146158, R01HL124649, PR150224P1 (CDMRP-DoD) and U54 AG065141; GCRC grant MO1-RR00425 from the National Center for Research Resources, the National Center for Advancing Translational Sciences grant UL1TR000124; and grants from the Gustavus and Louis Pfeiffer Research Foundation, Danville, NJ; the Women’s Guild of CedarsSinai Medical Center, Los Angeles, CA; the Ladies Hospital Aid Society of Western Pennsylvania, Pittsburgh, PA; QMED, Inc, Laurence Harbor, NJ; the Edythe L Broad and Constance Austin Women’s Heart Research Fellowships, Cedars-Sinai Medical Center, Los Angeles, CA; the Barbra Streisand Women’s Cardiovascular Research and Education Program, Cedars-Sinai Medical Center, Los Angeles, CA; the Society for Women’s Health Research, Washington, DC; the Linda Joy Pollin Women’s Heart Health Program, the Erika Glazer Women’s Heart Health Project and the Adelson Family Foundation, Cedars-Sinai Medical Center, Los Angeles, CA, US. Received: 21 April 2021 Accepted: 16 July 2021 Citation: European Cardiology Review 2021;16:e46. DOI: https://doi.org/10.15420/ecr.2021.15 Correspondence: C Noel Bairey Merz, Barbra Streisand Women’s Heart Center, Smidt Heart Institute, Cedars-Sinai Medical Center, 127 S San Vicente Blvd, Suite A3600, Los Angeles, CA 90048, US. E: merz@cshs.org Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

The recognition of suspected ischaemia with no obstructive coronary artery disease (INOCA) has increased over the past decades, with a key contributor being microvascular angina (MVA).1 Evidence of MVA was previously thought to be benign.2–4 Previous studies have demonstrated that patients with suspected MVA are often found to have coronary microvascular dysfunction (CMD) and are at higher risk of developing major adverse cardiac events (MACE), including MI, stroke and heart failure with preserved ejection fraction (HFpEF).5–7 Data from the Women’s Ischaemic Syndrome Evaluation (WISE) suggest there may be at least 3–4 million women and men with vasomotion dysfunction.8 The prevalence of MVA appears to have increased over the past several years because of increased diagnostic imaging, with a recent study reporting that of 400,000 individuals undergoing diagnostic angiography for suspected coronary artery disease (CAD), over 50% were found to have either no CAD or non-obstructive CAD.9–11 Recent studies also showed that CMD is identified in four in five patients with suspected MVA

or vasospastic angina.12–14 Anatomically, the coronary vasculature is classified into large calibre vessels (≥500 μm; the epicardial coronary arteries) and smaller vessels (<500 μm; the arterioles that feed the capillaries). The term INOCA encompasses a large number of clinical scenarios characterised by reduced coronary flow reserve (CFR) in the absence of anatomical obstructive epicardial disease.10,11,15

Pathophysiology

The pathophysiological mechanism contributing to MVA is multifactorial. It was previously described by Camici and Crea as CMD with no obstructive CAD or myocardial disease, CMD with the presence of myocardial disease, CMD with the presence of obstructive CAD or iatrogenic.16 Early studies in patients with CMD and no CAD (formerly known as cardiac syndrome X) provided evidence of reduced endothelial-dependent (e.g. acetylcholine) and non-endothelial-dependent (e.g. nitroglycerin) coronary vasodilation as well as metabolic evidence of myocardial ischaemia.17,18 Maseri et al. proposed that these patients might have focal epicardial or microvascular

Diagnosis and Management of Microvascular Angina ischaemia scattered throughout the myocardium, therefore CMD with no CAD can be defined as epicardial, microvascular endothelial or nonendothelial dysfunction leading to reduced myocardial perfusion, most often detected by reduced CFR.1,19 Additionally, the data from WISE-CVD showed that myocardial scarring was prevalent (8%) in women with MVA and vasospastic angina with an added annual incidence of 1%.20 Recently, Rahman et al. physiologically described two endotypes of CMD – functional and structural.21 In structural CMD, the systemic endothelial dilatory function leads to systemic hypertension and increased myocardial work, whereas coronary blood flow augmentation is impaired and associated with inefficient cardiac-coronary coupling.21 The functional CMD endotype is related to inefficient cardiac-coronary coupling during peak exercise and during rest leads to higher myocardial oxygen demand in the setting of exhausted vasodilatory reserve.21 CMD with no obstructive CAD or myocardial disease represent the functional aspect of the classical CAD risk factors such as smoking, hypertension, hyperlipidaemia, diabetes and others.16 Ageing can result in CMD by increasing arterial wall stiffness, medial thickening and lumen enlargement. Over time, these changes may lead to increased pulse pressure and hypertrophy of arteries, which can to subsequently result in endothelial dysfunction and subendocardial hypoperfusion.22 Cigarette smoking is a known risk factor for CAD and impairs endothelial-dependent vasodilation in chronic smokers.23,24 Uncontrolled hypertension is associated with remodelling of the coronary arteries and can lead to arteriolar thickening and reduced myocardial perfusion.25 Diabetes and chronic hyperglycaemia reduce endothelial-dependent and nonendothelial-dependent coronary vasodilation.19,26 Reduced CFR has been documented in asymptomatic patients with hypercholesterolaemia and non-obstructive CAD.27 Additionally, data from the WISE study showed that myocardial-ischaemia-related steatosis appears to be linked mechanistically to impaired left-ventricular relaxation in women with CMD evidenced by magnetic resonance spectroscopy.28

Predictors and Adverse Outcomes

Similar to obstructive CAD, non-obstructive CAD risk factors including age, hypertension, diabetes and smoking are associated with increased mortality.29 Data from the WISE study showed that abnormal coronary function testing (CFT) used to diagnose women with MVA predicted adverse outcomes, including cardiac-related deaths, non-fatal MI, nonfatal stroke and hospitalisations related to heart failure.7 CFR <2.32 best predicted adverse outcomes in women with MVA, with a 5-year MACE rate of 27% versus 9.3% for those with a CFR >2.32 (p=0.01).7 Upon longerterm follow-up (median 9.7 years), CFR continued to be a predictor of increased MACE (HR 1.06; 95% CI [1.01–1.12]; p=0.02).30 Similar findings were observed in a previous study and summarised by Bairey Merz et al.1 Furthermore, Seitz et al. showed that long-term follow-up in patients with epicardial or microvascular spasm in the absence of obstructive CAD was associated with 7.5% cardiac and non-cardiac-related death, 1.4% nonfatal MI and 2.2% stroke over a median of 7.2 years.31 Non-invasive testing in patients with MVA also predicted MACE and showed consistent results with invasive testing. A recent report from the iPOWER study showed that echocardiographyderived coronary flow velocity reserve (CFVR) of 2.33 predicted MACE including non-fatal MI and heart failure (HR 1.07; 95% CI [1.03–1.11] per 0.1 unit decrease; p<0.001) over a median of 4.5 years follow-up.32 Zhou et al. showed that stress perfusion cardiac magnetic resonance (CMR)-derived myocardial perfusion reserve index (MPRI) <1.47 predicted MACE including all-cause death, acute coronary syndrome, epicardial CAD development,

heart failure hospitalisation and non-fatal stroke (HR 3.14; 95% CI [1.58– 6.25]; p=0.001) over a median of 5.5 years follow-up.33 Additionally, Murthy et al. showed that cardiac-PET-derived CFR <2.0 predicted MACE including cardiac death, MI, late revascularisation or heart failure hospitalisation at 3 years compared to patients with higher CFR.34 A meta-analysis by Gdoski et al. of patients with CMD detected through invasive or non-invasive testing showed that CMD patients had an OR of 5.16 (95% CI [2.81–9.47]; p<0.001) to develop MACE compared to patients without CMD.35 Endpoints were all-cause mortality and MACE including cardiac or cardiovascular death, nonfatal MI, cardiac hospitalisation or coronary revascularisation.35

Diagnosis

The Coronary Vasomotion Disorders International Study Group proposed standardised criteria for diagnosis of MVA including the following: symptoms suggestive of ischaemia in the absence of epicardial CAD (>50% diameter reduction or fractional flow reserve [FFR] <0.80), objective evidence of myocardial ischaemia and evidence of vasomotor dysfunction (abnormal index of microvascular resistance [IMR], CFR or microvascular spasm to acetylcholine).13,15

Symptoms

Patients with MVA can present with exertional retrosternal chest pain/ pressure or discomfort or have exertional dyspnoea.15 Symptoms may also develop during exercise, after exercise or even at rest and are relatively less likely to be relieved by nitrates compared with obstructive CAD.15,36 Duration of symptoms are variable, tend to be prolonged and may differ in nature, i.e. stabbing pain, jaw pain or back pain.15 CMD can occur in both men and women but recent reports and studies indicate that it is more prevalent in women (especially post-menopause).15 Although symptoms can be the initial presentation in patients with MVA, the results from the Cardiac Autonomic Nervous System study showed a high prevalence of silent ischaemia in women with CMD.37 In total, 39% of women with CMD had a total of 26 silent ischaemia episodes versus no episodes in the reference group (p=0.002). Among these women, 93% had silent ischaemia documented by ambulatory ECG tracing.37 The long-term prognosis of silent ischaemia in women with MVA is yet to be elucidated.

Evidence of Myocardial Ischaemia

Current guidelines recommend that patients with stable angina with an intermediate pre-test probability to have obstructive CAD should have non-invasive diagnostic testing for detection of myocardial ischaemia.15,38,39 Patients with stable angina can have evidence of myocardial ischaemia through rest/stress ECG and/or non-invasive imaging by reduced myocardial perfusion with single photon emission CT, PET or cardiac rest/ stress magnetic resonance or testing cardiac function using stress echocardiography. Patients with MVA can demonstrate ST-segment changes suggestive of myocardial ischaemia and may exhibit reduced perfusion on other non-invasive testing, while only a minority of patients demonstrate wall motion abnormalities.15,40

Absence of Obstructive or Flow‑limiting Coronary Artery Stenosis

The absence of obstructive or flow-limiting CAD is necessary to diagnose MVA. Anatomically coronary arteries can be classified to no CAD (mild) with <20% stenosis, non-obstructive CAD (moderate) with ≥20% but <50% and obstructive CAD (severe) with ≥50% in any epicardial coronary artery using coronary angiography.15,41 Limiting flow to the coronary arteries can be defined as FFR <0.8.15 Anatomical illustration of the absence of

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Diagnosis and Management of Microvascular Angina Table 1: Invasive and Non-invasive Testing Approaches to Diagnose Microvascular Angina Non-invasive Testing Transthoracic Doppler, contrast echocardiography

Cardiac PET

Advantages

Disadvantages

• Easy to perform • Minimal risk • No radiation • Relatively inexpensive • The most validated non-invasive tool to diagnose CMD • Carries a prognostication value • Accurate perfusion quantification • Less likely to be affected by renal function • Adding CT can allow anatomic assessment of the coronary

• Operator-dependent • Difficult imaging and poor image quality • Limited validation and poor correlation with PET • Radiation exposure • Expensive • Not widely available • Less spatial and temporal resolution compared to CT and CMR

arteries

CMR

Cardiac CT

• Not haematocrit-dependent • Standard post-processing • Validated against invasive measurements and cardiac PET • Myocardial perfusion semi-quantification • No radiation exposure • Excellent spatial and temporal resolution • Allows tissue characterisation with the same study

• Anatomic coronary data and perfusion data can be obtained in the same study

• Good spatial and temporal resolution compared to cardiac PET

• Expensive • Limited prognostication data • Complex post processing • Not widely available • Requires frequent breath holds and longer exam duration • Haematocrit-dependent • Limited in patients with MRI non-compatible devices • Limited in renal failure • High radiation exposure • Higher risk for contrast-induced nephropathy • Limited in renal failure • Post-processing is complex • Haematocrit-dependent • Limited validation in patients with MVA • Iodinated contrast can cause coronary vasodilation and overestimate myocardial perfusion

Invasive Testing Coronary function test

• Confirmatory test to diagnose CMD • Accurately identifies different pathways contributing to MVA including CFR, CBF and coronary artery diameter change

• Provides assessment of other haemodynamic measures such as LVEDP and assesses degree of coronary artery stenosis

• Radiation exposure • Not widely available • Risk of contrast-induced nephropathy in patients with renal failure • Requires complex preparation and hospitalisation

• Carries a prognostication value • Standardised protocol

CBF = coronary blood flow; CFR = coronary flow reserve; CMD = coronary microvascular dysfunction; CMR = cardiac magnetic resonance; LVEDP = left ventricular end diastolic pressure; MVA = microvascular angina.

obstructive CAD may be insufficient in certain instances such as diffused non-obstructive CAD, so it is necessary to demonstrate if there is any haemodynamically flow-limiting lesion of the epicardial coronaries using FFR defined as <0.8.15 Coronary CT angiography is a useful tool to exclude obstructive CAD epicardial disease defined as <50% stenosis and CTderived FFR is an emerging promising tool to measure FFR but not yet proven for use in routine practice.15,42

Non-invasive Testing

The presence of symptoms of angina or angina-like symptoms and evidence of myocardial ischaemia is sufficient evidence to consider MVA in the absence of obstructive CAD. Further details regarding imaging use are described in Table 1.36,43

Contrast and Doppler Transthoracic Echocardiography

Contrast or Doppler echocardiography can be used in the evaluation of CMD. They are considered safe, albeit operator-dependent and as yet

lacking reproducibility and validity. 43 In one study, patients with symptoms of angina and no obstructive CAD diagnosed by coronary angiography, CFVR was assessed using Doppler of the left anterior descending coronary artery at rest and after dipyridamole use.44 Twenty-six per cent of patients had CFVR <2 with greater physical limitation and disease perception scores on the Seattle Angina Questionnaire.1,44 The CEVENT study used Doppler-derived coronary flow reserve (TDE-CFR).45 In brief, a basic transthoracic echocardiography protocol was performed and the mid to distal part of the left anterior descending coronary artery was identified using colour Doppler in the interventricular sulcus in a modified two-chamber view.45 Pulsed Doppler was used to sample flow velocity signals at rest and during adenosine infusion. Mean diastolic flow velocity at baseline and during peak hyperaemia was measured by manual tracing of the diastolic Doppler flow signals.45 CFR was calculated as the ratio between the hyperaemic and baseline flow velocity values.45 A CFR ratio of ≤2 was considered reduced. Recently, CFVR has demonstrated a prognostic value, with data from the iPOWER study showing that CFVR <2.3 predicted MACE and heart failure hospitalisation.32 Furthermore, Gan

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Diagnosis and Management of Microvascular Angina Figure 1: Coronary Function Test Preparation and Protocol Review indications for invasive coronary function testing

Preparation

• Long-acting calcium channel blockers

Record LVEDP

• • • Withhold for • 24 h •

Caffeine Long-acting nitrates Short-acting calcium channel blockers α-blockers β-blockers

Protocol

Withhold for 48 h

Assess for increased cardiac sensitivity (e.g. chest pain with contrast infusion or catheter movement

Administer intravenous heparin (70 U/kg) Advance Doppler flow wire (0.014") pressure and flow system to proximal-mid LAD artery Confirm adequate CBF velocity signal

Withhold for 4h

• Sublingual nitroglycerin

Infuse provocative agents (using doses in Figure 2) Recordings and calculations

Chest symptoms thought to be angina or equivalent Evidence of ischaemia Confirmation of CAD (stenosis >50%); use FFR if borderline

12-lead ECG, repeated with chest pain or ischaemic ECG changes APV at baseline and after each provocative agent Haemodynamic variables (HR, BP) Coronary angiogram for coronary artery diameter measured 5 mm distal to tip of Doppler guide wire CFR = average peak velocity/ average baseline velocity CBF = π(coronary artery diameter/2)2(APV/2) CBF change = (peak CBF−baseline CBF)/(baseline CBF)

APV = arterial pulse velocity; BP = blood pressure; CAD = coronary artery disease; CBF = coronary blood flow; FFR = fractional flow reserve; HR = heart rate; LAD = left anterior descending; LVEDP = left ventricular end diastolic pressure. Source: Merz et al. 2017.111 Adapted with permission from Wolters Kluwer Health.

et al. showed that TDE-CFR value of ≤2.0 was an independent predictor of MACE (HR 4.63; 95% CI [2.78–7.69]; p<0.001) over a median of 4.5 years follow-up.45

Cardiac PET

Cardiac PET is the most validated, reliable and accurate non-invasive method in diagnosing CMD in patients with suspected MVA, although it is costly and with limited use in certain institutions.1,36,43 PET-derived myocardial perfusion measurement is based on myocardial flow (MBF) quantification in millilitres per minute per gram using intravenous positronemitting tracers such as 13N-ammonia, 82rubidium, 18F-flurpiridaz and 15 O-water.36,46 PET-derived myocardial perfusion imaging in conjunction with tracer-kinetic modelling allows accurate assessment of rest and post hyperaemic flow using adenosine, dobutamine, or dipyridamole and enables the determination of CFR through quantification of MBF and further characterisation of CMD.1,36,46 Furthermore, PET-derived CFR carries a prognostic value. In a study by Taqueti et al., CFR was an independent predictor for MACE including non-fatal MI and HFpEF hospitalisations (CFR < 2 had HR 2.38; 95% [CI 1.21–4.67]; p=0.01 for MACE and HR 2.47; 95% CI [1.09–5.62]; p=0.03 for HFpEF hospitalisation) after adjusting for age and history of AF.47 CFR was also found to be associated with impaired left ventricular myocardial relaxation or elevated filling pressures among patients with no obstructive CAD and minimally elevated troponin levels.48 Among patients with resistant hypertension, cardiac PET derived myocardial perfusion reserve was a predictor for diastolic dysfunction and cardiovascular adverse outcomes.49

Cardiac MRI

The assessment of CMD using CMR is validated against invasive tests and cardiac PET and does not involve radiation exposure.36,43,50 Myocardial perfusion assessment using rest/post-vasodilator stress (adenosine)

allows semi-quantification of MPRI to evaluate CMD.36,50 Data from WISECVD showed that an MPRI of ≤1.84 predicted invasive CFT abnormality with a sensitivity of 73% and specificity of 74% using 1.5T magnet and CAAS MRV 3.4 as a post-processing software.50 In addition to its role in diagnosing CMD, CMR has greater spatial and temporal resolution compared to cardiac PET, although it is expensive, is not widely available and prognostic data are limited.36,43 Recently, an automated pixel-wise perfusion mapping technique was used to detect significant CAD lesion compared to invasive testing FFR, CMD defined by IMR, and to differentiate MVA from multivessel coronary disease. MBF ≤1.94 ml/g/min accurately detected obstructive CAD on a regional basis (area under the curve [AUC] 0.90; p <0.001).51 In patients without regional perfusion defects, global stress MBF <1.82 ml/g/min accurately detected CMD (AUC 0.94; p<0.001).51

CT Perfusion

CT perfusion has the potential to diagnose CMD and can simultaneously assess for CAD on the same study.36,43 Dynamic first-pass vasodilator stress and rest perfusion imaging allows perfusion quantification.36,43 Recent work by Rossi et al. used adenosine-stress dynamic CT myocardial perfusion imaging, and semiquantitative perfusion parameters, such as blood flow, were calculated by parametric deconvolution for each myocardial voxel.52 Semiquantitative perfusion predicted subendocardial myocardial ischaemia (AUC 0.87). CT perfusion also provides greater spatial and temporal resolution compared to cardiac PET.36,43 The perfusion quantification requires repeated imaging and exposes patients to high radiation doses and the need for iodinated contrast can be associated with higher risk of renal injury.36,43 Although CT perfusion has a potential to diagnose CMD, its validation is limited in patients with MVA and it is not regularly used to diagnose CMD.43

Invasive Testing

Coronary angiography can accurately exclude obstructive CAD defined as (<50% stenosis in epicardial artery or an FFR of >0.8). CFT is a standardised

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Diagnosis and Management of Microvascular Angina invasive test to diagnose and confirm different pathways of CMD.1,15,36,43 It is the confirmatory test to identify certain pathways and phenotypes in patients with suspected MVA.15,36,43 The coronary microcirculation is modulated further by physical and neural factors.53 CFT is performed by infusing vasoactive substances through a guiding catheter placed in the left main coronary artery, then a Doppler guide wire is positioned in the proximal left anterior descending coronary artery.53 Another approach is through using a thermodilution wire that can be positioned in the distal third of the targeted coronary artery.54–56 CMD pathway identification is performed through measurements of coronary blood flow (CBF) and the change in epicardial coronary artery diameter with 1) endotheliumdependent probes–acetylcholine), bradykinin, substance-P, l-NGmonomethyl arginine citrate, and shear stress – and predominantly, 2) endothelium-independent probes, adenosine and sodium nitroprusside. The CFT preparation and protocol along with calculation of CFR and CBF are illustrated in Figure 1. Graded infusion of different vasoactive substances including adenosine, acetylcholine and nitroglycerin are illustrated in Figure 2. After injecting the vasoactive substances, one or more pathway dysfunctions can be identified as shown in Figure 2 with interpretation. Because acetylcholine requires certain infusion concentrations and safety precautions, the infusion rate and concentrations of acetylcholine are standardised as shown in Table 2. Data from WISE-CVD also showed a good correlation between acetylcholine and cold pressor test to evaluate coronary artery diameter changes in women with MVA.57 Using the above protocol, four pathways contributing to CMD are being tested (Figure 2).7,53,58 A CFR ≤2.5 in response to adenosine is considered abnormal.7,53,58 Endothelial-dependent microvascular function using intermediate dose of acetylcholine to calculate CBF increase.53 CBF <50% increase in response to the highest dose of acetylcholine was considered abnormal.53 Endothelial-dependent macrovascular coronary function was defined as coronary artery dilation >5% in response to the acetylcholine infusion.53 Non-endothelial-dependent macrovascular function using a single dose of nitroglycerin.53 A diameter increase <20% was considered abnormal.53 Excellent safety data from previous reports were published with <1% adverse events and no deaths.53,59 Other methods used to identify CMD include calculating the IMR, which is calculated as the product of distal coronary pressure at maximal hyperaemia multiplied by the hyperaemic mean transit time.60 The normal range of IMR is considered to be <25.54 Another method for assessment of CMD is by semiquantitative analysis by calculating the thrombolysis in myocardial infarction (TIMI) frame count.54 In patients with suspected MVA the corrected TIMI frame count >25 (images acquired at 30 frames/second) suggests CMD.54 Advantages and limitations of invasive testing illustrated in Table 1.

Criteria for Diagnosis

Recently, Kunadian et al. described that INOCA is explained by the mismatch between blood supply and myocardial oxygen demands, which can be caused by CMD and/or epicardial vasospastic angina.55 Definitive MVA is only diagnosed if all four criteria are present including presence of symptoms, absence of obstructive/flow limiting coronary stenosis, objective evidence of myocardial ischaemia on non-invasive testing and evidence of CMD on CFT (Figure 3).15 Suspected MVA is diagnosed if the following criteria are present: symptoms; absence of obstructive/flow limiting coronary stenosis; and at least one of the following: objective evidence of myocardial ischaemia on non-invasive testing; or coronary microvascular spasm, defined as reproducibility of symptoms with ECG changes suggestive of ischaemia but no epicardial spasm during CFT (Figure 3).13,15

Figure 2: CMD Pathway Definitions on Administration of Different Vasoactive Substances Pathway identification CMD pathway

Microvascular dysfunction

Macrovascular dysfunction

Nonendothelium- CFR in response to ADO <2.5 dependent

Change in coronary artery diameter in response to NTG <20%

Endothelium- Change in CBF in response to ACH <50% dependent

Change in coronary artery diameter in response to ACH ≤0%

Coronary spasm

Angina + ECG changes Change in coronary artery diameter in response to ACH <90%

ADO

18 μg

36 μg

ACH

0.364 μg

36.4 μg

108 μg

NTG

200 μg

ACH = acetylcholine; ADO = adenosine; CBF= coronary blood flow; CFR = coronary flow reserve; CMD = coronary microvascular dysfunction; NTG = nitroglycerin. Source: Merz et al. 2017.111 Reproduced with permission from Wolters Kluwer Health.

Table 2: Intracoronary Acetylcholine Concentration and Infusion Prepared Concentration, mol/l (μg/ml)

Infusion Rate (ml/h)

Infusion Duration (min)

Infused Dose (μg)

10−6 (0.182)

0.364

10−4 (18.2)

36.4

120

108

10 (18.2) −4

111

Source: Merz et al. 2017. Reproduced with permission from Wolters Kluwer Health.

Management

Due to the lack of large randomised clinical trials addressing the treatment of MVA there are no definitive guidelines for treatment. The Japanese Circulation Society provided a low level of evidence for treatment of vasospastic angina, and US guidelines currently do not specifically address angina and CMD management.38,61–63 The European Society of Cardiology guidelines for diagnosis and management of chronic coronary syndromes, published in 2019, recommended testing for suspected MVA using a guidewire-based CFR and/or IMR as a Class IIa recommendation with level B evidence.62,64 Furthermore, the guidelines proposed the use of transthoracic Doppler echocardiography, CMR or cardiac PET as non-invasive test for assessment of CFR (Class IIb recommendation with level B evidence).62,64 The guidelines also recommended that the treatment should address the mechanism or pathway dysfunction contributing to MVA.62 In patients with abnormal CFR <2.0 or IMR ≥25 units and a negative acetylcholine provocation test, β-blockers, angiotensin-converting enzyme inhibitors (ACE-I), and statins, along with lifestyle changes and weight loss, are indicated.62 Microvascular spasm can also be treated like vasospastic angina.62 The effectiveness of a tailored treatment strategy was based on the findings from the CORMICA trial, which randomised 151 patients to a stratified medical treatment (based on the results of CFR, IMR, and acetylcholine testing) versus a usual treatment group (including a sham interventional diagnostic procedure).13,62,65 After 1 year of follow up there was a significant difference in angina scores estimated using Seattle

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Diagnosis and Management of Microvascular Angina Figure 3: COVADIS Criteria to Diagnose Patients with Microvascular Angina Clinical criteria for suspecting MVA

1. Symptoms of myocardial ischaemia

A: Effort and or rest angina B: Angina equivalents (i.e. shortness of breath)

2. Absence of obstructive CAD (<50% diameter reduction or FFR >0.80 by

3. Objective evidence of myocardial ischaemia

A: Coronary CTA B: Invasive coronary angiography

A: Ischaemic ECG changes during an episode of chest pain B: Stress-induced chest pain and or ischaemic ECG changes in the presence or absence of transient/ reversible abnormal myocardial/ perfusion and/or wall motion abnormality.

Definitive MVA is only diagnosed if all four criteria are present for a diagnosis of microvascular angina. Suspected MVA is diagnosed if symptoms of ischaemia are present (criteria 1) with no obstructive CAD (criteria 2) but only (a) objective evidence of myocardial ischaemia (criteria 3), or (b) evidence of impaired coronary microvascular function (criteria 4) alone.

4. Evidence of impaired coronary microvascular function

A: Impaired CFR (cutoff value depending on methodology used between ≤2.0 and 2.5) B: Coronary microvascular spasm, defined as reproduction of symptoms, ischaemic ECG shifts but no epicardial spasm during acetylcholine testing C: Abnormal coronary microvascular resistance indices (e.g. IMR >25) D: Coronary slow flow phenomenon, defined as TIMI frame count >25

CAD = coronary artery disease; CFR = coronary flow reserve; COVADIS = Coronary Vasomotion Disorders International Study Group; CTA = CT angiography; FFR = fractional flow reserve; IMR = index of microvascular resistance; MVA = microvascular angina; TIMI = thrombolysis in myocardial infarction. Source: Ong et al. 2018.15 Adapted with permission from Elsevier.

Angina Questionnaire favouring patients assigned to the stratified medical treatment arm.13,62,65

Pharmacological Therapy

Statins, Angiotensin Converting Enzyme Inhibitors and Aspirin (Anti-atherosclerotic Therapy)

Statins, ACE-I and aspirin have anti-atherosclerotic and anti-thrombotic effects, can counteract oxidative stress on cellular level, have antiinflammatory effects and can improve both endothelial and microvascular function.66,67 These agents are known to improve angina and myocardial perfusion. Statins In previous clinical trials using intravascular ultrasound (IVUS), statins have been shown to alter the progression and even promote the regression of atherosclerosis and improve vascular endothelial function.68,69 In addition to their cholesterol-lowering properties, statins have powerful antiinflammatory effects.70 In two pilot studies, atorvastatin improved CFR at 2 and 6 months.71,72 A recent systematic review and meta-analysis of randomised controlled trials assessing the effect of statins on coronary and peripheral endothelial function showed treatment with statins was associated with a significant improvement in endothelial function with a standardised mean difference of 0.66 (95% CI [0.46–0.85]; p<0.001).73 Angiotensin Converting Enzyme Inhibitors Data from the WISE study showed that after 16 weeks, treatment of women with MVA (CFR <3.0) with quinapril 80 mg/day was significantly associated with improvement of angina symptoms and CFR compared with the placebo group.74 Consistent with the WISE and the WISE-CVD studies, another study showed improvement in CFR, plasma nitrite and exercise duration after 8 weeks with enalapril 5 mg twice daily compared with the placebo group.75 Furthermore, in patients with hypertensive disease who were treated for 12 weeks with cilazapril, cardiac PET showed 42% improvement in their CFR.76 Studies have shown that the benefits of ACE-I are not limited to the objective measurements of CFT, endothelial function and symptoms but extend to improvement in other circulating biomarkers.64,77

Antiplatelet Agents In an IVUS study, coronary atherosclerosis was detected in most patients with microvascular dysfunction.78 Thus, thromboxane A2 (TXA2) inhibitors (low-dose aspirin and P2Y12 platelet inhibitors) are likely helpful in preventing adverse outcomes in patients with MVA. The proposed mechanism is that TXA2 can cause arterial vasoconstriction, platelet aggregation, and vascular injury. Therefore, inhibition of TXA2 pathway may prevent further microvascular damage.1

β-blockers, Calcium Channel Blockers and Nitrates (Anti-anginal Therapy)

β-blockers Certain β-blockers, including atenolol carvedilol and nebivolol, have been evaluated in small clinical studies,.79–81 Intracoronary nebivolol was associated with a significant increase in CFR as well as a decrease in collateral flow index, a finding that is parallel to reduction in myocardial oxygen consumption.81 β-blockers increase diastolic coronary filling time and reduce myocardial oxygen consumption. Calcium Channel Blockers Calcium channel blockers are widely used in vasospastic angina and have the effect of improving vasodilatory response, further episodes of vasospasm and reducing cardiac afterload.1 Although calcium channel blockers have a predominant vasodilatory effect on the epicardial arteries, one study demonstrated that intracoronary diltiazem administration did not improve CFR in patients with MVA.82 In another study, amlodipine did not improve anginal chest pain episodes.79 On the other hand, in patients with impaired vasodilator reserve, verapamil and long-acting nifedipine have been reported to be associated with improved symptoms and exercise tolerance.83 Nitrates Nitrates can ameliorate anginal pain through venodilation to reduce preload. They may also have some coronary vasodilatory effect, but this effect is greater in patients with obstructive CAD compared to MVA.1,15 Generally, patients with MVA do not have rapid or sufficient symptom relief in response to sublingual nitroglycerin.15 Kanatsuka et al.

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Diagnosis and Management of Microvascular Angina demonstrated that steady-state infusion of nitroglycerin selectively dilates coronary arterial vessels >200 μm.84 This selectivity may explain the inefficient relief of angina symptoms in patients with MVA.

Other Strategies

Ranolazine Ranolazine inhibits late sodium current and reduces intracellular calcium levels in cardiac myocytes, hence improving ventricle relaxation and oxygen consumption.85 Variable results on symptoms and CFR have been reported in pilot studies.86,87 In one large randomised cross-over clinical trial of ranolazine and placebo, there was no difference in symptoms and myocardial perfusion reserve as measured by CMR.88 However, when stratified by baseline CFR, those with reduced CFR showed improvement with ranolazine.89 Ivabradine Ivabradine reduces heart rate via its blocking effect on the If channels in the sinoatrial node.15,64 In patients with stable CAD, it is found to improve CFR.90 Another study showed improvement of angina symptoms but no effect on coronary microvascular function, suggesting the improvement may be attributed to the effect of decreased heart rate.87 Given the previous evidence, ivabradine may play a role in the treatment of MVA. Low-dose Tricyclic Antidepressants (Abnormal Cardiac Nociception) Abnormal cardiac nociception is a condition primarily studied in women with suspected MVA and characterised by abnormal cardiac pain perception.91 Tricyclic antidepressants can modulate norepinephrine uptake and anticholinergic effects, which may induce analgesia. Aminophylline Aminophylline is a nonselective adenosine-receptor antagonist and blocks the mediation of nociception. The suggested mechanism to improve symptoms in patients with CMD is by attenuating the excess dilation of the microvasculature in relatively well-perfused areas, thus shunting blood to a poorly perfused areas.1 Imipramine has also been studied, and shown to reduce frequency of symptoms, albeit with no significant improvement in quality of life.92 Mineralocorticoid Inhibitors Mineralocorticoid inhibitors although it is one of potential therapies for CMD but it provided no additional of anginal improvement when combined with ACE-I in previous randomised clinical trial.93 Phosphodiesterase Inhibitors The effect of the phosphodiesterase (PDE) type 3 inhibitor cilostazol has been assessed in patients with coronary vasospasm.64 In one study in patients with coronary vasospasm refractory to calcium channel blockers and nitrates, the addition of cilostazol appeared effective.94 The PDE type 5 inhibitor sildenafil has demonstrated acute increases in CFR, especially in women with MVA with CFR <2.5.95 Rho-kinase Inhibitors Rho-kinase plays an important role in coronary vasospasm.96 Fasudil has been found to be effective in preventing acetylcholine induced coronary spasm.97 Intracoronary fasudil is effective not only in patients with

epicardial coronary spasm but also approximately two-thirds of those with MVA.98 L-arginine L-arginine is a precursor of nitric oxide. L-arginine supplementation has been shown to improve both symptoms and endothelial function, but increases the risk of MI in patients with obstructive CAD.99 Glycaemic Active Agents Sodium–glucose co-transporter (SGLT) 1 and 2 inhibitors improve cardiovascular outcomes in studies of patients with diabetes. Inhibition of the endothelial SGLT2 improves hyperglycaemia-induced vascular dysfunction in vitro.100 Any benefit on CMD and outcome in patients with diabetes with MVA has not yet been demonstrated. Metformin is an insulin sensitiser and may improve endothelial function in nondiabetic women with suspected MVA.101 Endothelin Receptor Antagonists Endothelin (ET)-1 contributes to coronary endothelial dysfunction and may increase atherosclerosis risk factor burden.102,103 ET-1 is a small peptide produced primarily in the endothelium that is a potent constrictor of human blood vessels.104 ET-1 is mediated by two receptors: ETA and ETB ETA activation by ET-1 mediates coronary vasoconstriction.104 In a randomised clinical trial evaluating the ET receptor antagonist atrasentan in patients with CMD, microvascular coronary endothelial function after 6 months was improved.105 The CORMICA investigators found that peripheral arterioles from patients with MVA showed enhanced constriction to ET-1 compared with reference controls, which may be a target for future therapies.106 The on-going clinical trial PRIZE aims to test efficacy of the potent ET inhibitor zibotentan as an adjunct therapy in patients with MVA.104

Non-pharmacological Therapy

Exercise training is beneficial in stimulating nitric oxide pathways, which can result in exercise capacity with less anginal pain.107 Spinal cord stimulation improves anginal pain perception, and increases exercise tolerance.108,109 Enhanced external counter pulsation uses pneumatic cuffs applied to a patient’s legs with simultaneous inflation and deflation synchronised to the cardiac cycle to improve haemodynamics.110

Future Directions

Continued work is needed to refine diagnostic and management strategies for MVA and CMD. On-going trials are exploring whether the intensive treatment of coronary atherosclerosis with high-intensity statins, ACE-I or angiotensin receptor blockers (ARBs) and low-dose aspirin improves angina and ischaemia. The WARRIOR trial (NCT03417388) is testing if such treatment translates to improved outcomes, while the MINOCA-BAT study (NCT03686696) is evaluating a β-blocker and ACE/ ARB intervention on MACE.

Conclusion

Recognition of suspected INOCA has increased over the past decades, with a key contributor being MVA. Patients with MVA are at higher risk for MACE including MI, stroke, HFpEF and death. Guidelines for diagnosis and management of patients with MVA are still evolving. However, on-going clinical trials are testing strategies that will inform the management of patients with MVA.

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Women and Heart Disease

The Female Athlete’s Heart: Overview and Management of Cardiovascular Diseases Silvia Castelletti

and Sabiha Gati

2,3

1. Cardiomyopathy Unit and Center for Cardiac Arrhythmias of Genetic Origin, Department of Cardiovascular, Neural and Metabolic Science, Istituto Auxologico Italiano IRCCS, Milan, Italy; 2. National Heart and Lung Institute, Imperial College London, UK; 3. Department of Cardiology, Royal Brompton Hospital, London, UK

Abstract

The number of female athletes taking part in elite and amateur sport is ever increasing. In contrast with male athletes, few studies have focused on cardiovascular adaptations to exercise in women, the effects of lifelong exercise on heart muscle and electrical tissue, the risk of exerciserelated sudden cardiac death and the management of cardiovascular disease. Women have a lower prevalence of large QRS complexes, repolarisation changes including inferior and lateral T-wave inversion, and cardiac dimensions exceeding predicted limits compared with men. The risk of exercise-related sudden cardiac death is significantly lower in women than men. Also, women who have engaged in lifelong exercise do not have a higher prevalence of AF, coronary artery calcification or myocardial fibrosis than their sedentary counterparts. Apart from providing an overview of the existing literature relating to cardiac adaptations, this review explores possible reasons for the sex differences and focuses on the management of cardiovascular disorders that affect female athletes.

Keywords

Athlete, athlete’s heart, arrhythmias, cardiomyopathy, COVID-19, ECG, female, mitral valve prolapse, sudden death Disclosure: The authors have no conflicts of interest to declare. Received: 11 June 2021 Accepted: 15 September 2021 Citation: European Cardiology Review 2021;16:e47. DOI: https://doi.org/10.15420/ecr.2021.29 Correspondence: Sabiha Gati, Royal Brompton Hospital, Sydney St, London SW3 6NP, UK. E: s.gati@rbht.nhs.uk Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

There has been a momentous rise in the number of female athletes competing in the Olympics and the highest ranks of sports, yet women remain understudied. It is vital to recognise the impact of intensive exercise on the female athlete’s heart. It is well known that regular intensive exercise is associated with several electrical and cardiac structural manifestations that lead to a larger stroke volume to generate and deliver an increased cardiac output for prolonged periods.1,2 The chromosomal variation between men and women results in several differences, including physiological, psychological and biochemical variations, that will influence their cardiovascular adaptation to exercise. Women are generally smaller, with a lower lean body mass, higher circulating oestrogens and lower androgen levels to produce the power and momentum for sports.3 This review will focus on the management of cardiovascular disorders in female athletes.

The Female Athlete’s Heart

Although female athletes develop similar qualitative cardiac structural changes to their male athletic counterparts, these appear to be on a smaller scale. A principal study performed in female athletes by Pelliccia et al. compared predominantly 600 white women with 66 sedentary controls.4 The women

in this study were relatively young, with a mean age of 21 years, an exercise history of more than 9 years and participated in 27 sporting disciplines, including swimming, roller skating, track events and gymnastics. The research found that compared with controls, female athletes had a 6% thicker left ventricle (LV) wall and a 14% greater LV cavity size (LV end-diastolic, 49 ± 4 mm versus 46 ± 3 mm; p<0.001). In absolute terms, 8% of women had an enlarged LV cavity (>54 mm) and 1% had a LV cavity of >60 mm that could be comparable to a dilated cardiomyopathy. In comparison to male athletes, women had smaller absolute LV cavity dimensions, with 48% of men achieving a LV enddiastolic dimension of >54 mm. Irrespective of sex, determinants of cardiac size include age, ethnicity and sporting discipline with the largest dimensions identified in those who engage in endurance sport.5 Right ventricle (RV) dilatation occurs in response to increased cardiac preload and is often identified in endurance athletes. RV size parallels changes found in the LV and physiologically these should be symmetrical without differences in the RV:LV ratio.6–8 Female athletes generally have smaller absolute RV dimensions than male athletes but, when indexed to body surface area, female athletes have larger RV dimensions.8 Female athletes generally do not achieve a LV wall thickness >11 mm, but are able to develop a large LV cavity size.9 Recently, female athletes’ hearts were evaluated with LV geometry, which takes into account the LV mass and relative LV wall thickness (ratio of LV wall thickness to cavity

CVD in Female Athletes size).10 Normal geometry is defined as a normal LV mass and relative wall thickness <0.42; concentric remodelling is defined as a normal LV mass and increased relative wall thickness (>0.42); concentric LV hypertrophy is defined as an increased LV mass and a relative wall thickness; and eccentric LV hypertrophy is defined as an increased LV mass and normal relative wall thickness.11 Finocchiaro et al.10 studied LV geometry in 1,083 young adult athletes including 443 women competing in several sports. They identified that 22% of female athletes showed abnormal geometry with a higher prevalence of eccentric LV hypertrophy in those engaging in endurance sports. In contrast, male athletes are more likely to develop concentric hypertrophy (9% versus 3%; p<0.001). None of the women exhibited a relative LV wall thickness of >0.48, which suggests that female hearts adapt by increasing their LV cavity size. This parameter may be used to differentiate abnormal LV hypertrophy from physiological changes rather than absolute LV wall thickness measurements. Furthermore, Rawlins et al. assessed how ethnic differences affect cardiac adaptations in 400 female athletes.12 The authors demonstrated a greater LV wall thickness (9.2 ± 1.2 mm versus 8.6 ± 1.2 mm; p<0.001) and LV mass (187 ± 42 g versus 172 ± 42 g; p<0.008) in black compared with white female athletes. Eight black female athletes (3%) exhibited a LV wall thickness >11 mm (12–13 mm), but none of the white female athletes did. All female athletes demonstrated normal indices of systolic and diastolic function. Therefore, a LV wall thickness of >13mm in a black female athlete is rare and warrants further evaluation. Left atrial enlargement occurs in correlation with LV dilatation secondary to high preload imposed on all four chambers with intensive endurance exercise.13 Female athletes have a greater absolute and indexed atrial volumes compared with controls. An indexed left atrial volume of 22– 33 mm/m2 has been suggested in women.14

The Female Athlete’s ECG

The athlete’s ECG reflects changes in vagal tone and cardiac dimensions. Women generally show smaller quantitative changes with a lower prevalence for voltage criteria for biventricular hypertrophy, and shorter PR interval and QRS duration.10 Women have different patterns of T-wave inversion from male athletes. Minor anterior precordial T-wave inversion is more common in women, particularly when limited to leads V1–V3, and has not been associated with underlying structural heart disease.10,15,16 The current international recommendations on ECG interpretations in athletes suggest T-wave inversion in leads V1–V2 in women does not warrant further evaluation in the absence of symptoms or a family history of cardiomyopathy.17 In contrast, T-wave inversion in the lateral and inferior leads in female athletes is rare and should raise concerns of pathological LV hypertrophy. Women in general have a longer corrected QT interval than men. Based on international recommendations, a QTc >480 ms warrant further evaluation for long QT syndrome in female athletes.17

Cardiovascular Diseases in Female Athletes Cardiomyopathies Dilated Cardiomyopathy

Dilated cardiomyopathy (DCM) is defined as LV or biventricular systolic impairment with or without cavity enlargement that is not explained by coronary disease or abnormal loading conditions.18 It has several causes including genetic predisposition, myocarditis, tachycardia-induced or

ventricular premature beat-induced cardiomyopathy, drugs, toxins, peripartum cardiomyopathy and, occasionally, the cumulative effects of more than one aetiology.18 The clinical spectrum of DCM may vary from a phenotype with the absence of symptoms, isolated LV dilatation and normal or low-normal systolic function to overt disease with significant systolic dysfunction. Some athletes engaging in endurance sport, such as long-distance running, swimming and rowing, may exhibit large cardiac dimensions that overlap with those observed in patients with DCM. The differentiation between cardiac pathology and physiological adaptation is fundamental to prevent a wrong diagnosis and fatal consequences. A dilated left ventricle of >60 mm consistent with a DCM is identified in only 1% of female athletes.4 These women should be evaluated thoroughly with a detailed clinical history, including any relevant family history of cardiomyopathy. They should be investigated with cardiovascular MRI to exclude myocardial fibrosis, prolonged ECG analysis for significant arrhythmias and exercise echocardiography for their haemodynamic response to exercise, to assess for presence of exercise-induced symptoms or arrhythmias and to evaluate for a contractile reserve of >11% to exclude cardiac pathology. In general, symptomatic women with DCM should abstain from most competitive and leisure sports associated with moderate or high-intensity exercise.19 A select group of female athletes with DCM who have mildly impaired LV ejection fraction of 45–50% without high-risk markers or arrhythmias may participate in most competitive sport.19 Annual follow-up is recommended for females with DCM who exercise regularly (Figure 1).

Hypertrophic Cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is diagnosed in the presence of an unexplained increase in LV thickness to ≥15 mm in end-diastole in any myocardial segment.20 HCM may also be considered in women with a LV wall thickness of ≥13 mm in the presence of a positive genetic test or family history of HCM.20 Women and men should be equally affected given the autosomal dominance of this disease; however, this is not reflected in the literature. Although there may be a lack of awareness of cardiovascular disease (CVD) in women, it is possible that hormonal influences and genetics play a role. Oestrogens have a protective role as women usually have an older age of onset, a lower LV mass and a secondary hypertrophic response. Female athletes rarely succumb to sudden cardiac death (SCD) from HCM. In the US National Registry, women accounted for only 3% of 302 individuals who died of HCM.21 This observation is relevant to the prescription of competitive sports and intensive exercise in this cohort. White female athletes rarely exceed a LV wall thickness >11 mm and around 3% of black female athletes will have a LV wall thickness between 12 mm and 13 mm.9,12 Therefore, a LV wall thickness of 12 mm in a female athlete may fall into a grey zone depending on body size, sporting discipline and ethnicity, and may potentially raise concern for pathology, such as HCM. A systematic approach is required when assessing women with HCM or the suspicion of pathological HCM who request exercise advice. The baseline evaluation should include a comprehensive personal and family history, assessment of the severity of the HCM phenotype and the presence of conventional risk factors for SCD. Evidence has been evolving over the past two decades that exercise is beneficial with low rates of

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CVD in Female Athletes Figure 1: Adaptations and Exercise with Cardiovascular Diseases Female athlete’s heart Increased LVED/BSA; eccentric hypertrophy Decreased LVWT/LV mass; low/none calcium score No myocardial scar; reduced risk of arrhythmias

Hypertrophic cardiomyopathy Participation in highintensity exercise may be considered in those with low-risk markers for sudden cardiac death

Dilated cardiomyopathy Regardless of ejection fraction, in the absence of limiting symptoms and complex arrhythmias, participation in low-to-moderate intensity exercise should be considered

Coronary artery disease Women at a low risk of exercise-induced adverse events may participate in all sports

Arrhythmogenic cardiomyopathy Participation in low-intensity exercise for 50 minutes per week should be considered

AF Regular physical activity is recommended to prevent AF Long QT syndrome Exercising women with long QT syndrome should avoid QT-prolonging drugs

Myocarditis Return to exercise should be considered after 3–6 months in the absence of symptoms, ongoing inflammation, complex arrhythmia and a normal LV systolic function

Cardiac adaptations to exercise and eligibility for physical activity in specific cardiovascular diseases in female athletes. BSA = body surface area; LV = left ventricle; LVED = left ventricular end-diastolic volume; LVWT = left ventricular wall thickness.

adverse events in adults with mild phenotypes of HCM.22 A more liberal approach to competitive sports participation and intensive exercise has been adopted in individuals with morphologically mild HCM and a low 5-year HCM risk of sudden cardiac death score of <4% (Figure 1).23

Arrhythmogenic Cardiomyopathy

Arrhythmogenic cardiomyopathy (AC) is defined by the presence of fibrofatty replacement and myocardial fibrosis of both or individual ventricles and life-threatening ventricular arrhythmias. It is also recognised that intensive exercise and endurance sport in individuals with AC accelerates the phenotype.24 AC is an autosomal dominant disease with an equal number of men and women genetically affected. However, several large studies have shown women are less phenotypically affected than the men, possibly owing to different levels of participation in competitive sport and/or endocrine influences.25–29 Studies in mice suggest androgen levels contribute to the advancement of the disease process. The androgen receptors in the heart are upregulated with exercise, which may be a contributory factor for the disease progression, and female athletes usually have a lower number of androgen receptors in their hearts than men.30 One-third of athletes will exceed the cut-off values in RV dimensions for the minor criteria defining AC. Consequently, in female athletes with a disproportionate ratio of right to ventricular end-diastolic volume (RVEDV:LVEDV) of >1.3 should undergo a detailed evaluation in the presence of symptoms and/or relevant family history of cardiomyopathy.6 It is also recognised that intensive exercise and endurance sport in individuals with AC exacerbates the phenotype. A cautious approach is

therefore recommended in people with AC, including those who are genotype positive but phenotype negative. Participation in low to moderate intensity recreational exercise may be considered for individuals without a history of cardiac arrest, ventricular arrhythmias or unexplained syncope with minimal structural cardiac abnormalities or <500 premature ventricular complexes in 24 hours (Figure 1).19

Myocarditis

Myocarditis is a non-ischaemic inflammatory myocardial disease that may cause cardiac dysfunction and complex arrhythmias. In the developed world, viral myocarditis is the most common aetiology.31,32 The precise incidence and prevalence of myocarditis is unknown. It accounts for 5–15% of SCD in young athletic individuals.33–37 Daily exercise in mice models infected with the coxsackie virus was associated with increased predisposition to fulminant myocarditis and sudden death.38 Testosterone levels are associated with increase fibrosis and heart failure.39 SCD during sports from myocarditis appears to be more prevalent in men than women, which may be linked to the testosterone-related inflammatory response.33,34 The clinical presentation of myocarditis is heterogenous and patients may initially present with coryzal symptoms. Athletic individuals may exhibit non-specific symptoms of general malaise, fatigue or diarrhoea.40 At the other extreme, individuals can present with fatal arrhythmias and cardiogenic shock. Almost 50% of people with myocarditis will demonstrate full resolution of LV dysfunction within 30 days but 12–25% will progress to fulminant heart failure that is an adverse prognostic marker in the long term.33,41

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CVD in Female Athletes Figure 2: Myocarditis: Management and Physical Activity Suspicion of myocarditis

CMR compatible with myocarditis

Evidence of ongoing inflammation, impaired LV

Restriction from competitive sport or intensive exercise for 3–6 months

Repeat CMR in 3–6 months

Extensive LGE and LV impairment

Stable or declining LGE and normal LV

Normal CMR

Abstain from high-intensity exercise

Case-by-case decision-making surveillance

Can compete in all sport

Management and exercise guidance for athletes with suspicion of myocarditis. CMR = cardiovascular magnetic resonance; LGE = late gadolinium enhancement; LV = left ventricle.

Currently, there is no single clinical or imaging marker to confirm the diagnosis of myocarditis with certainty. In the current era, cardiovascular MRI is the most useful diagnostic and prognostic test with an excellent sensitivity and specificity for detecting myocardial hyperaemia, inflammation, oedema and/or focal fibrosis.42 The extent (>10% increase) and distribution (anteroseptal) of myocardial fibrosis are important predictors of cardiovascular events that should be assessed during clinical follow-up.43–45 Intensive exercise should be avoided in individuals with myocarditis. Women with active myocarditis should not engage in sport for 3–6 months and should return to intensive exercise only when LV function is normal and no complex ventricular arrhythmias are seen on an exercise stress test (Figures 1 and 2).19

Coronavirus Disease 2019

Athletic individuals infected with severe acute respiratory syndrome coronavirus 2 may be at risk of a subclinical myocarditis and may remain asymptomatic or develop mild symptoms.46 Women appear to be less severely affected by coronavirus disease 2019 (COVID-19) than men and have a lower prevalence of cardiovascular injury.47,48 It is likely that levels of ACE2 expression and sex hormones regulate these changes and control systemic inflammation.49–51 Athletes who test positive for COVID-19 and exhibit isolated cardiac symptoms are required to refrain from high-intensity physical activity and sport for at least 7–14 days since they are symptom free.52,53 Following resolution of symptoms, athletes with a negative COVID-19 test should undertake cardiac testing including a high-sensitive troponin test, an ECG and echocardiogram to exclude cardiac involvement.52,53 Abnormalities specifically relating to myocarditis warrant a 3–6 month sports restriction.

More recently, rare cases of myocardial and pericardial inflammation following COVID-19 vaccination have been reported.54,55 The Centers for Disease Control and Prevention reported an incidence of 4.8 cases per 1 million between COVID-19 mRNA vaccines and myocarditis, particularly in young men within a few days of the second vaccination.56 Pericarditis tended to affect older patients after the first or second dose. Women also experience post-vaccination cardiac inflammation but to a lesser degree.54 The recommendations for the management of exercising after COVID-19 are likely to evolve over time as long-term data are acquired in this highly infectious virus.

Hypertension

Hypertension is common in the global population, affecting around onethird of people. Exercise is an effective treatment strategy for hypertension but conversely, exercise-induced hypertension may equally increase the risk of cardiovascular events. The precise prevalence of hypertension in female athletes is unknown as definitions in the literature vary but it is likely to be similar to that identified in the general population.57 There is also a lack of consensus in the definition and threshold for abnormalities in exercise-induced hypertension, which carries an elevated cardiovascular risk as it is linked with subclinical hypertension.58,59 Determining factors for hypertension include older age, drugs (i.e. anabolic steroids and nonsteroidal anti-inflammatory drugs), sporting discipline and the intensity of sport. Few studies in the literature have evaluated sex differences in hypertension.60–63 Female athletes appear to have a lower prevalence of hypertension and lower systolic and diastolic values compared to male athletes in both low and high bodyweight classes.60,61,63 There are no significant differences between various sports although higher blood

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CVD in Female Athletes pressure (BP) readings have been detected in endurance (including swimming, triathlons and pentathlons) and artistic sports.60

MVP is more prevalent in women and the most common structural postmortem cardiac abnormality identified.71–72

Only one study has reported higher BP values in female than male athletes (13% versus 7%) but this difference was likely due to a wide variation in age.62 The study included athletes aged 13–77 years, but men were predominantly younger than 35 years. Of the hypertensive women, 92% were aged >35 years, while 73% of the hypertensive men were >35 years old. Out-of-office BP recordings should be performed in all athletes with BP >140/80 mmHg on physical examination as there is a high prevalence of white-coat syndrome. Hypertensive individuals should participate in at least 30 mins of moderate-intensive dynamic aerobic exercise 5–7 days per week to reduce systolic and diastolic BP of 7 and 5 mmHg, respectively.

Features of increased arrhythmic risk include: female sex; personal history of syncope; family history of SCD or MVP; T-wave inversion, ST-segment elevation, long QTc on ECG; bi-leaflet prolapse; the Pickelhaube sign (high velocity systolic signal with tissue Doppler imaging S-wave >16 cm/s, resembling the pickelhaube spiked helmet); mitral annulus disjunction; complex ventricular arrhythmias on ECG monitoring or exercising testing; and presence of fibrosis on CMR.73–74

Ischaemic Heart Disease

Atherosclerotic coronary artery disease (CAD) is a potentially fatal condition affecting predominantly mature athletes. It is more common in men with a 9:1 ratio for SCD among competitive athletes and is even higher among recreational athletes with prevalence ratio of 20:1.64 Although hormonal influences cannot be disregarded, the likely explanation for this sex difference is the engagement in lower-intensity sports and participation rates in sports among women.65 The majority of studies evaluating CAD have been conducted in male runners. There are few data in female cohorts, demonstrating a low prevalence of CAD.65–67 A study on 152 master athletes, 30% of them women, found no differences in the plaque prevalence and composition compared with sedentary women.65 Similar results had been reported in the same year in a smaller study on 26 female marathon runners; athletes had coronary artery calcium (CAC) counts and calcified plaque volumes comparable to sedentary individuals.66 Another large study on 9,501 women failed to demonstrate an association of high-intensity exercise and high coronary artery calcification scores.67 In athletes with established CAD, there is a potentially increased risk of MI during vigorous physical activity. Therefore, the management of such individuals should focus on risk stratification for recurring events, arrhythmias and inducible ischaemia. Additional evaluation for symptoms of ischaemia, LV ejection fraction <50% and reduced exercise capacity is also warranted. Athletes with any of these high-risk features should be advised to confine themselves to low- and moderate-intensity exercise once symptoms have settled or following a period of 12 months after MI or coronary revascularisation (Figure 1).

Spontaneous Coronary Artery Dissection

Spontaneous coronary artery dissection (SCAD), although rare, is a frequent cause of acute coronary syndrome in low-cardiovascular risk, middle-aged women.68,69 SCAD is defined as non-iatrogenic separation of the coronary arterial wall with or without intimal tear by intramural haemorrhage and can be triggered by physical, emotional and hormonal stressors.70 Spontaneous healing is recommended as the first-line therapy. Data on the risk of exercise triggering coronary dissection are rare so a cautious approach to exercise is generally recommended. Individual assessment for symptoms and inducible myocardial ischaemia is advised before recommencing leisure sport or competitive exercise.19

Mitral Valve Prolapse

Mitral valve prolapse (MVP) is characterised by fibromyxomatous changes of the mitral valve tissue with a >2 mm extension into the left atrial cavity.

The effect of high-intensity exercise on the risk of SCD remains uncertain. In an 8 ± 2 years’ follow-up study on 215 athletes with MVP, no cases of SCD were registered.75 Other adverse events occurred at a rate of 0.5% per annum, mainly in older athletes, with none occurring in athletes with isolated MVP or mild mitral regurgitation.75 Asymptomatic female athletes with MVP and mild or moderate mitral regurgitation can participate in all competitive and recreational sports in the absence of the aforementioned risk markers. In the presence of symptoms or high-risk features, the general advice is to restrict to lowintensity aerobic exercise.22

Arrhythmias

Sex differences in electrophysiological changes are well known. Women have greater sinoatrial node automaticity, atrioventricular node function, infra-Hisian conduction and longer ventricular action potential duration, which may influence the prevalence of arrhythmias in female athletes. However, the vast majority of studies have focused mainly on male athletic populations and sub-data analyses are limited as they are largely underpowered. Female athletes appear to be at lower risk of bradyarrhythmias and accessory pathways than male athletes, including a higher degree of atrioventricular block.76–78 In contrast, atrioventricular nodal re-entry tachycardias appear to be more prevalent in women.19,76,78

AF is the most common arrhythmia in the general population and is associated with a high risk of heart failure, stroke and mortality. Several studies have revealed a J-shaped relationship between exercise, the risk of developing AF and endurance exercise. The risk of AF is generally reduced at low to moderate intensity exercise (Figure 1).79–81 However, regular vigorous exercise may result in AF in some individuals.78,82–86 Mature endurance athletes generally have a fivefold increased risk of AF.87 However, it remains controversial whether sex-specific differences exist in relation to the risk of AF and long-term endurance exercise.88 The vast majority of data focus on male athletes and a number of studies have failed to prove any increased risk of AF in female athletes.89–91 A meta-analysis that included 103,298 mature female athletes (aged 54–63 years) demonstrated an 8.7% lower risk of AF with moderate-intensity exercise with a further reduction to 28% in women exercising at a high intensity.91 However, female endurance athletes who engaged in very high intensity exercise were underrepresented in this analysis. In contrast the Norwegian Tromsø Study followed 20,484 subjects, half of them women, for an average of 20 years.88 Healthcare records were intermittently reviewed prospectively to identify cases of AF. Intense endurance training was associated with a twofold increased risk of AF in

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CVD in Female Athletes women aged >40 years. However, moderate-intensity exercise was associated with a significantly lower risk of AF over the 20-year follow-up period. A more recent study of 402,406 individuals (52.5% women) aged 40–69 years with 2.8 million person-years of follow-up reported a number of points pertaining to women.79 Physical activity of >500 metabolic equivalent-minutes per week (MET-min/wk) was associated with reduced risk of AF, which was more pronounced in women than men. In women, incident AF declined with physical activity of up to 5,000 MET-min/wk compared with men who demonstrated a moderate decline. Female athletes who develop AF without a substantial cumulative effect of exercise should be evaluated for typical causes of AF such as thyrotoxicosis, valvular heart disease, alcohol abuse, hypertension and ischaemic heart disease. AF ablation is recommended in exercising individuals with recurrent symptomatic AF and/or those who do not want drug therapy because of its impact on athletic performance.19 The athlete should also be counselled on the effect of long-lasting intensive exercise on AF recurrence. Direct bodily contact sports are not recommended in athletes with AF who are anticoagulated.19

Long QT Syndrome

Long QT syndrome (LQTS) is a genetic cardiac disorder characterised by a prolonged QT interval on the ECG and is associated with the increased risk of life-threatening arrhythmias, particularly stress-induced torsades de pointes.92 Healthy women have longer QT intervals than men, which appears in the post-pubertal phase, owing to a longer ventricular action potential. Recently published clinical observations demonstrated that exercise could induce repolarisation prolongation and suggest LQTS.93 Differences in cardiac repolarisation in women and men have also been reported in LQTS.94 Therefore, the upper limits of normal corrected QT are higher in female athletes than in men (480 ms versus 470 ms in female and male athletes, respectively).77 Women are more likely to be affected by LQTS, despite the equal sex distribution of the disease genotype. They are also at a higher risk of arrhythmias in response to QT-prolonging drugs and electrolyte imbalances than men. Female sex also appears to be an independent risk marker for cardiac events in LQTS.95 Although the data are scarce, given the sex differences, these finding supports the theory that sex hormones most likely regulate cardiac repolarisation. In the setting of competitive sport, establishing arrhythmic risk can be difficult, particularly in individuals who are genotype positive and phenotype negative. Some studies have reported a lower incidence of arrhythmic events in affected individuals competing in sports but these studies were limited by younger age, participation in low-intensity sports inclusion and their retrospective nature.96–98 In the general adult population, the major risk predictors include a history of cardiac events, QTc values, being a paediatric male or adult female individual as well as the pathogenic mutation in the QT genes.98 It is recommended that all exercising individuals with LQTS with symptoms or prolonged QTc are treated with β-blocker therapy. Individuals should

also be advised to avoid QT-prolonging drugs and electrolyte imbalance. Ventricular arrhythmias in LQTS are adrenergically driven; therefore, highintensity exercise is prohibited even while on beta-blockers in people with a QTc >500 ms or genetically confirmed LQTS with a QTc³ of 480 ms in women. In individuals who are genotype positive and phenotype negative, the European recommendations advise on shared decision making with the athlete in question (Figure 1).19

Veteran Female Athletes

The number of veteran athletes aged 40 years and above engaging in endurance sports including triathlon and marathons has continued to increase with time. There has been a surge in the number of recreational female athletes in this age category. In parallel, there is emergent evidence that chronic exposure to large amounts of endurance exercise may predispose athletes to AF, myocardial fibrosis and increased CAC.65,99–102 Consequently, in some individuals, life-long exercise may be detrimental to an otherwise normal cardiac structure and function. Unfortunately, enrolment of women has been slow in studies evaluating the effects of long-term exercise on the heart to further our understanding of sex differences on cardiac maladaptation. Arrhythmias, myocardial fibrosis, high CAC and atherosclerotic plaque burden appear to be less prevalent in women suggesting oestrogen may play a role in preserving cardiac health.65 A large meta-analysis including 149,000 women demonstrated that longterm vigorous exercise was associated with a 28% reduced risk of AF in female athletes. 79,91 Studies investigating myocardial fibrosis have predominantly focussed on male athletes. In a study, otherwise healthy long-term triathletes of whom one-third were female were investigated with cardiovascular MRI.103 None of the female athletes had myocardial fibrosis compared to 17% of male athletes correlating with a higher peak exercise BP and the number of hours of training. Female athletes generally have a lower peak exercise BP that may account for the difference. A study by Merghani et al.104 evaluated 170 veteran athletes aged 54 ± 8.5 years, of whom 29% were female, and 132 controls of a similar age, sex and low-risk coronary score for coronary disease. There was a higher prevalence of AF, coronary plaques, myocardial fibrosis and ventricular tachycardia limited to male athletes in comparison with healthy controls. None of the female veteran athletes exhibited adverse cardiac remodelling. Female athletes had a similar burden of coronary disease as sedentary women. The absence of coronary disease in female veteran athletes suggests their genetic and hormonal make-up may hold back adverse arrhythmogenic remodelling.

Sudden Cardiac Death

There is a significantly lower prevalence of exercise-related SCD in women with a ratio of 3:1–10:1, and this also holds true for older recreational athletes, where the men are 20-fold more likely to die of SCD than female athletes.19 There also appear to be sex differences relating to diseases that predispose people to SCD. Female athletes rarely succumb to HCM according to the US National Registry, which is probably due to fewer ventricular arrhythmic events from a reduced volume and intensity of exercise in women.21 However, hormonal and metabolic factors may also play a protective role in reducing the arrhythmic risk during intensive exercise.

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CVD in Female Athletes In contrast, a different situation exists in women with MVP. In the Italian pathology registry of 650 SCDs, 7% of deaths were attributed to MVP and, of these, the majority (60%) were in women.105 The vast majority of SCD in female athletes are associated with sudden arrhythmic death syndrome where structurally normal hearts are identified on post-mortem analysis.33

Conclusion

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have a lower prevalence of concentric LVH and cardiac dimensions exceeding predicted upper limits. In contrast with men, female endurance athletes do not show a higher prevalence of AF and raised CAC, according to current data. SCD during sport is significantly less common in women than men and is mainly secondary to electrical disease rather than structural abnormalities. There are still major gaps in our knowledge relating to several CVDs beyond the scope of this review. Further large studies are required in female athletes with a variety of cardiovascular conditions to understand the disease process in our sex.

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fibrillation in vigorously exercising middle aged men: casecontrol study. BMJ 1998;316:1784–5. https://doi.org/10.1136/ bmj.316.7147.1784; PMID: 9624065. 84. Claessen G, Colyn E, La Gerche A, et al. Long-term endurance sport is a risk factor for development of lone atrial flutter. Heart 2011;97:918–22. https://doi.org/10.1136/ hrt.2010.216150; PMID: 21398696. 85. Grimsmo J, Grundvold I, Maehlum S, Arnesen H. High prevalence of atrial fibrillation in long-term endurance cross-country skiers: echocardiographic findings and possible predictors – a 28–30 years follow-up study. Eur J Cardiovasc Prev Rehabil 2010;17:100–5. https://doi. org/10.1097/HJR.0b013e32833226be; PMID: 20065854. 86. Molina L, Mont L, Marrugat J, et al. Long-term endurance sport practice increases the incidence of lone atrial fibrillation in men: a follow-up study. Europace 2008;10:618– 23. https://doi.org/10.1093/europace/eun071; PMID: 18390875. 87. Abdulla J, Nielsen JR. Is the risk of atrial fibrillation higher in athletes than in the general population? A systematic review and meta-analysis. Europace 2009;11:1156–9. https://doi. org/10.1093/europace/eup197; PMID: 19633305. 88. Morseth B, Graff-Iversen S, Jacobsen BK, et al. Physical activity, resting heart rate, and atrial fibrillation: the Tromsø Study. Eur Heart J 2016;37:2307–13. https://doi.org/10.1093/ eurheartj/ehw059; PMID: 26966149. 89. Wilhelm M, Roten L, Tanner H, et al. Gender differences of atrial and ventricular remodeling and autonomic tone in nonelite athletes. Am J Cardiol 2011;108:1489–95. https://doi. org/10.1016/j.amjcard.2011.06.073; PMID: 21864814. 90. Everett BM, Conen D, Buring JE, et al. Physical activity and the risk of incident atrial fibrillation in women. Circ Cardiovasc Qual Outcomes 2011;4:321–7. https://doi.org/10.1161/ CIRCOUTCOMES.110.951442; PMID: 21487092. 91. Mohanty S, Mohanty P, Tamaki M, et al. Differential association of exercise intensity with risk of atrial fibrillation in men and women: evidence from a meta-analysis. J Cardiovasc Electrophysiol 2016;27:1021–9. https://doi. org/10.1111/jce.13023; PMID: 27245609. 92. Priori SG, Wilde AA, Horie M, et al. Executive summary: HRS/ EHRA/APHRS expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes. Heart Rhythm 2013;10:e85–108. https://doi.org/10.1016/j.hrthm.2013.07.021; PMID: 23916535. 93. Dagradi F, Spazzolini C, Castelletti S, et al. Exercise traininginduced repolarization abnormalities masquerading as congenital long QT syndrome. Circulation 2020;142:2405–15. https://doi.org/10.1161/CIRCULATIONAHA.120.048916; PMID: 33073610. 94. Locati EH, Zareba W, Moss AJ, et al. Age- and sex-related differences in clinical manifestations in patients with congenital long-QT syndrome: findings from the International LQTS Registry. Circulation 1998;97:2237–44. https://doi.org/10.1161/01.CIR.97.22.2237; PMID: 9631873. 95. Makkar RR, Fromm BS, Steinman RT, et al. Female gender as a risk factor for torsades de pointes associated with cardiovascular drugs. JAMA 1993;270:2590–7. https://doi. org/10.1001/jama.1993.03510210076031; PMID: 8230644. 96. Johnson JN, Ackerman MJ. Return to play? Athletes with congenital long QT syndrome. Br J Sports Med 2013;47:28– 33. https://doi.org/10.1136/bjsports-2012-091751; PMID: 23193325. 97. Chambers KD, Beausejour Ladouceur V, Alexander ME, et al. Cardiac events during competitive, recreational, and daily activities in children and adolescents with long QT syndrome. J Am Heart Assoc 2017;6:e005445. https://doi. org/10.1161/JAHA.116.005445; PMID: 28935680. 98. Aziz PF, Sweeten T, Vogel RL, et al. Sports participation in genotype positive children with long QT syndrome. JACC Clin Electrophysiol 2015;1:62–70. https://doi.org/10.1016/j. jacep.2015.03.006; PMID: 26301263. 99. D’Silva A, Sharma S. Management of mature athletes with cardiovascular conditions. Heart 2018;104:1125–34. https:// doi.org/10.1136/heartjnl-2016-310744; PMID: 29032360. 100. Erbel R, Mohlenkamp S, Moebus S, et al. Coronary risk stratification, discrimination, and reclassification improvement based on quantification of subclinical coronary atherosclerosis: the Heinz Nixdorf Recall study. J Am Coll Cardiol 2010;56:1397–406. https://doi.org/10.1016/j. jacc.2010.06.030; PMID: 20946997. 101. Dores H, de Araújo Gonçalves P, Monge J, et al. Subclinical coronary artery disease in veteran athletes: is a new preparticipation methodology required? Br J Sports Med 2020;54:349–53. https://doi.org/10.1136/ bjsports-2018-099840; PMID: 3041342. 102. Aengevaeren VL, Eijsvogels TMH. Coronary atherosclerosis in middle-aged athletes: current insights, burning questions, and future perspectives. Clin Cardiol 2020;43:863–71. https:// doi.org/10.1002/clc.23340; PMID: 32031291. 103. Tahir E, Starekova J, Muellerleile K, et al. Myocardial fibrosis

CVD in Female Athletes in competitive triathletes detected by contrast-enhanced CMR correlates with exercise-induced hypertension and competition history. JACC Cardiovasc Imaging 2018;11:1260– 70. https://doi.org/10.1016/j.jcmg.2017.09.016; PMID: 29248656.

104. Merghani A, Maestini V, Rosmini S, et al. Prevalence of subclinical coronary artery disease in masters endurance athletes with a low atherosclerotic risk profile. Circulation 2017;136:126–37. https://doi.org/10.1161/ CIRCULATIONAHA.116.026964; PMID: 28465287.

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105. Basso C, Perazzolo Marra M, Rizzo S, et al. Arrhythmic mitral valve prolapse and sudden cardiac death. Circulation 2015;132:556–66. https://doi.org/10.1161/ CIRCULATIONAHA.115.016291; PMID: 26160859.

CVD in CKD Patients

Coronary Artery Disease in Chronic Kidney Disease: Need for a Heart–Kidney Team-Based Approach Gautam R Shroff ,1 Michelle D Carlson

and Roy O Mathew

1. Division of Cardiology, Department of Medicine, Hennepin Healthcare & University of Minnesota Medical School, Minneapolis, MN, US; 2. Division of Nephrology, Department of Medicine, Columbia VA Health Care System, Columbia, SC, US

Abstract

Chronic kidney disease and coronary artery disease are co-prevalent conditions with unique epidemiological and pathophysiological features, that culminate in high rates of major adverse cardiovascular outcomes, including all-cause mortality. This review outlines a summary of the literature, and nuances pertaining to non-invasive risk assessment of this population, medical management options for coronary heart disease and coronary revascularisation. A collaborative heart–kidney team-based approach is imperative for critical management decisions for this patient population, especially coronary revascularisation; this review outlines specific periprocedural considerations pertaining to coronary revascularisation, and provides a proposed algorithm for approaching revascularisation choices in patients with end-stage kidney disease based on available literature.

Keywords

Chronic kidney disease, end-stage kidney disease, non-invasive imaging, coronary artery disease, coronary artery bypass surgery, percutaneous coronary intervention, dialysis Disclosure: The authors have no conflicts of interest to declare. Received: 26 June 2021 Accepted: 19 October 2021 Citation: European Cardiology Review 2021;16:e48. DOI: https://doi.org/10.15420/ecr.2021.30 Correspondence: Gautam R Shroff, Division of Cardiology, Hennepin Healthcare, O5, 701 Park Avenue S, Minneapolis, MN 55415, US. E: shrof010@umn.edu Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Chronic kidney disease (CKD) and cardiovascular disease (CVD) are coprevalent conditions with distinct epidemiological characteristics. Nearly 15% of the adult population in the US is affected by CKD, whereas endstage kidney disease (ESKD) affects a smaller population; in the year 2018, ~554,038 patients were estimated to receive dialysis, and 229,887 patients had a functional kidney transplant in the US.1 The burden of CVD is nearly twofold higher among individuals with CKD versus without CKD (66% versus 32%).2 Among ESKD patients on dialysis, prevalent CVD is estimated to be a staggering 77%, with that of coronary artery disease (CAD) about 44%.1 The presence of CKD is associated with worse CVD outcomes. In an ambulatory population of 1.1 million adults, worsening kidney function was demonstrated to have a graded and independent association with all-cause mortality and CVD events.3 Similarly, in a collaborative meta-analysis, CKD was an independent predictor of allcause and CVD mortality.4 The presence of CKD adversely impacts survival following any CVD event. Estimated 2-year adjusted survival following acute MI is ~87% without CKD, ~75% in CKD stages 4–5, ~53% in dialysis and ~77% in kidney transplant recipients.1

Clinical Presentation and Outcomes

Patients with CKD have a greater likelihood of acute rather than stable presentations with CAD.5 Importantly, patients with advanced CKD/ESKD are less likely to experience chest pain or have diagnostic electrocardiographic findings.6–8 It has also been demonstrated that inhospital mortality with acute MI is exponentially higher in the presence of CKD compared with the absence of CKD.6,8–10 Multiple potential

aetiopathogenic factors have been postulated to be contributory. Atypical clinical presentations in AMI may be a potentially contributory factor, and it has also been consistently demonstrated that patients with CKD receive fewer evidence-based therapies, including reperfusion/revascularisation therapies.9,10 Although it is problematic to derive any causal conclusions from associations from observational data, there has been concern raised about potential therapeutic nihilism or ‘renalism’ in this population. Based on data from contemporary studies, reassuringly, mortality from AMI has been declining in CKD/ESKD.11,12

Pathophysiology: What is Unique?

Understanding the unique aspects of CAD in CKD is important for identifying specific targets in this high-risk population. Autopsy studies in patients with advanced CKD and on dialysis identified more calcified and extensive atherosclerotic lesions. Invasive coronary angiography (ICA) data demonstrate fourfold higher relative risk of having multivessel CAD among patients with moderate-to-severe CKD, as compared with those with mild/no renal insufficiency, after controlling for the effect of diabetes.13 Patients with CKD, who underwent ICA prior to and during AMI, had a greater number of coronary plaques, specifically with >50% stenosis.14 There were also many similarities between characteristics of coronary plaques progressing to AMI in patients with and without CKD, demonstrating that degree of stenosis is not the only defining characteristic of coronary atherosclerosis in CKD. This suggests that although traditional pathophysiology is in play, it does not fully explain the heightened risk for CVD events, including AMI, experienced by patients with advanced CKD.

CAD in CKD It is likely that there is a reciprocal relationship between coronary atherosclerotic process and renal function: the presence of atherosclerotic CAD has been demonstrated to be associated with worsening kidney function and vice versa.15,16 Much of the contribution of CKD to atherosclerosis progression lies in the heightened inflammatory milieu associated with decreasing renal function that may enhance the atherosclerotic process independent of traditional risk factors.17 This inflammatory phenotype of the endothelium was similarly observed in vascular tissue from children with CKD requiring dialysis therapy.18 Sanchis et al. proposed the terminology ‘inflammaging’ to conceptualise the process of premature vascular senescence due to dysregulated metabolism promoting oxidative DNA damage and pro-inflammatory substrate.18

and single-photon emission CT myocardial perfusion imaging were employed. In general, these studies demonstrated prognostic utility in risk prediction of adverse CV outcomes and mortality in CKD/ESKD.31–36 However, their diagnostic accuracy (sensitivity/specificity) to predict obstructive CAD is suboptimal in this population relative to the general population.37 This was most recently demonstrated by the low prevalence of obstructive CAD in the invasive arm in the ISCHEMIA-CKD trial, despite the inclusion criteria of moderate/severe ischaemia on cardiac stress testing.38 Several factors can be postulated to adversely impact test accuracy due to various factors, including higher prevalence of obstructive CAD, significant left ventricular hypertrophy, endothelial dysfunction and reduced coronary flow reserve.

Another component of coronary atherosclerosis that has become a useful diagnostic tool is calcification. Coronary artery calcification (CAC) in the general population correlates very well with sites of atherosclerotic plaque. Patients with CKD demonstrate greater degrees of plaque calcification, as well as premature and progressive vascular calcification. A recent metaanalysis of 47 studies in patients with various stages of CKD and kidney transplantation identified a pooled prevalence of CAC across CKD stages of ~60%, with a nearly two- to fourfold associated increase in all-cause and CV mortality.19 The calcification process is promoted in CKD for a number of reasons, including enhanced exposure to the substrates of calcium and phosphorus in the setting of metabolic bone disorders, as well as an imbalance favouring calcification promoters (e.g. receptor activator of nuclear factor-κB, and receptor activator of nuclear factor-κB ligand) over inhibitors (e.g. klotho, osteoprotegerin and fetuin A).20,21 CKD is characterised by extensive vascular calcification involving not just the tunica intima, but also extending into the tunica media.22 In addition, vitamin K metabolism is deranged in CKD, leading to further reductions in inhibitors of vascular calcification (e.g. matrix GLA protein).23 This is compounded when vitamin K antagonists (e.g. warfarin) are used in advanced CKD patients. Use of vitamin K antagonists have been associated with greater valvular and vascular calcifications in CKD patients.24,25

Coronary CT angiography has been shown to be a strong predictor of future events in the population of subjects without renal disease, but has traditionally been used with trepidation in CKD/ESKD patients, for concern that the high burden of CAC may confound assessment, as well as the risk of contrast nephropathy.39–41 In a study evaluating individuals undergoing coronary CT angiography (n=1,541), CKD remained a strong, independent predictor of all-cause mortality, CV mortality and MI; however, increased risk of CV mortality in CKD patients was driven by non-coronary CV deaths.42 These findings suggest that CV mortality in individuals with advanced CKD is not driven solely by obstructive CAD, but rather nonatherosclerotic CV events (e.g. heart failure and arrhythmias). This observation has important implications pertaining to the predictive capabilities of non-invasive stress testing (which evaluate for obstructive CAD) in predicting CV events in CKD – which cannot be completely predicted by non-invasive (or invasive) testing. CAC may also be considered to guide primary prevention among those with asymptomatic CKD without known CVD.43 Finally, assessment of coronary flow reserve by PET reflects not just epicardial stenosis, but also diffuse atherosclerosis and microvascular dysfunction, and has been shown to have prognostic utility in this population.44,45

The high incidence of non-ST-elevation MI and the prevalence of heart failure with preserved ejection fraction/diastolic dysfunction in CKD suggests a unique process distinct from the typical coronary atherosclerotic plaque rupture with subsequent myocardial wall injury and progressive systolic dysfunction seen in the general population. Aside from the larger coronary vessels, the microcirculation perfusing the myocardium is being examined as an important contributor of such myocardial dysfunction. Microcirculation dysfunction – evaluated as poor coronary flow reserve and overall capillary density – is impaired in CKD.26,27 Contributing factors include left ventricular hypertrophy associated with long-standing hypertension, which is common in CKD. Finally, the complex interplay of pathophysiological dysregulation between the heart and the kidneys is increasingly well-recognised and referred to as cardiorenal syndromes. To encompass the wider spectrum of bidirectional dysregulation, two major phenotypic categories have been proposed: cardiorenal and renocardiac syndromes.28 In composite, five distinct phenotypic subtypes have been described in the literature contingent upon acuity of presentation, as well as the sequence of organ involvement.28

Non-invasive Evaluation for Stable Coronary Artery Disease

In light of the high burden of CVD and CV mortality among individuals with CKD/ESKD, what is the ability of non-invasive testing to augment prognostic data?29,30 Traditionally, dobutamine stress echocardiography

Special Considerations: Kidney Transplant Evaluation

The preponderance of data regarding non-invasive evaluation in CKD/ ESKD patients is based in the pre-renal transplant population, where the goal of non-invasive evaluation is to decrease the risk of cardiac morbidity/mortality post-transplant in mostly asymptomatic patients. There have been a multitude of small studies comparing different stress testing modalities for obstructive CAD prior to renal transplant. In a systematic review and meta-analysis, non-invasive imaging and ICA had similar predictive accuracy to identify future adverse CV events in advanced CKD; and a significant proportion of transplant candidates experienced adverse events despite prior negative stress tests.46 Again, these findings highlight the importance of contribution of non-coronary CV events as a contributor towards all-cause and CV mortality in this population. As in the general CKD population, coronary CT angiography has also been evaluated and found to have value in pre-transplant evaluation.47,48 Interestingly, post hoc analysis of the ISCHEMIA-CKD trial has brought into question the role of routine revascularisation in kidney transplant candidates, which may, in turn, impact patterns of upstream non-invasive testing.49 The ongoing and eagerly anticipated CARSK trial will address whether eliminating screening tests for occult CAD in those wait-listed for kidney transplantation is non-inferior to regular screening for the prevention of major CV events.50 However, by virtue of its design, this trial will only address management of wait-listed individuals and not the upstream question of whether/in whom/which initial non-invasive CV testing should be performed in this population.

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CAD in CKD Medical Management of Coronary Artery Disease

disease in persons with CKD.64 Newer antidiabetes drugs that have CV benefits in the overall population are now being investigated in CKD patients. The DAPA-CKD trial enrolled patients with an estimated glomerular filtration rate (eGFR) of 25–75 ml/min/1.73 m2, and showed that compared with placebo, dapagliflozin decreased the risk of the primary outcome of decline in eGFR, ESKD, renal death or CV death, as well as the risk of the pre-specified secondary endpoint of death from CV cause and hospitalisation for heart failure.65 A pre-specified analysis of the trial showed that the decrease in all-cause mortality in the trial was driven by a lower incidence of non-CV death from infection/malignancy rather than a lower risk of CV mortality; the study was underpowered to detect a difference in the risk of non-fatal MI.66 As a group, the sodium–glucose cotransporter 2 (SGLT2) inhibitors have demonstrated marked reduction in CV events extending to eGFR values as low as 30 ml/min/1.73 m2.67 These agents are a promising new addition to the armamentarium for reducing overall CV risk (albeit not CAD alone) in CKD.

When considering dual-antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI), a meta-analysis of five trials involving 1,902 participants with moderate CKD showed that a short duration of DAPT (≤6 months) and an extended duration of DAPT (≥30 months) have a similar incidence of the combined endpoint of all-cause mortality, MI, stroke and stent thrombosis when compared with a 12-month DAPT duration.53 The risk of major bleeding was also similar. The recent ESC guidelines for the management of ACS remind us that there continues to be insufficient evidence to assess the safety and efficacy of P2Y12 receptor inhibitors in stage 5 CKD/ESKD, although DAPT is routinely prescribed in these patients following PCI.54 There is a growing body of data regarding the use of direct oral anticoagulants for secondary prevention of CV disease. The benefit of rivaroxaban and aspirin was superior to aspirin alone in CKD; however, the risk of major bleeding was higher.55 As always, the dual risks of bleeding and thrombosis make it precarious navigating the narrow route of safety between Scylla and Charybdis with direct oral anticoagulants.56

Impact of AF

Statins form the mainstay of management of CAD in the general population, but their use in the CKD population is more controversial. The SHARP trial enrolled 9,270 patients with CKD without known CAD, and demonstrated reduction in major adverse cardiac events with a combination of simvastatin 20 mg and ezetimibe 10 mg daily.57 In the ESKD population on dialysis, the results of the 4D and AURORA trials highlighted no benefit in reduction of major adverse cardiac events with use of statins.58,59 A subsequent meta-analysis by the Cholesterol Treatment Trialist’s group demonstrated that despite a waning effect of therapies that lower LDL cholesterol (statins, ezetimibe) on clinical outcomes in ESKD compared with earlier stages of CKD, the overall treatment interaction by CKD stage was not significant.60 This observation suggests their potential beneficial role in all stages of CKD. The treatment of hypertension is beneficial in reducing CV events in CKD patients; intensive blood pressure control compared with standard blood pressure control in CKD patients without diabetes showed a strong trend (albeit non-statistically significant) towards the reduction of major adverse cardiac events.61 As in this instance, unfortunately, most evidence in CKD patients is based on subgroup analysis and is often underpowered or of low statistical quality.62 The optimal target blood pressure and most efficacious antihypertensive agent in decreasing CV risk in persons with CKD has not yet been established, especially in ESKD.63

Potential Role of Renal Therapeutics

Data to guide medical management of CAD in advanced CKD/ESKD patients is limited, as this group has been excluded from most clinical trials.51 This is particularly the case when it comes to anti-thrombotic agents: although at increased risk for thrombotic events, they are paradoxically at increased risk for bleeding complications as well, and, therefore, particularly prone to exclusion. Based on the pathophysiology at play, antiplatelet and anticoagulant drugs may have different effects and efficacies in CKD compared with those without CKD. In a metaanalysis of antiplatelet agents in CKD, among individuals with acute coronary syndrome (ACS; n=9,969), antiplatelet agents compared with standard care had no significant effect on all-cause/CV mortality/MI, but were associated with serious bleeding.52 In a stable group of patients (n=11,701), antiplatelet agents decreased the risk of MI while increasing the risk of minor bleeding, with uncertain effects on major bleeding and mortality.

Diabetes is a strong risk factor for CV disease, but there is insufficient data to suggest that management of diabetes can decrease the risk of CV

AF is prevalent in CKD patients, and a further complicating factor in the selection of appropriate antiplatelet and anticoagulant agents. CKD itself is a risk factor both for AF and stroke, and patients with CKD are paradoxically at an increased risk for bleeding with or without anticoagulation.68 In general, direct oral anticoagulants are non-inferior to warfarin, with a lower risk of bleeding in CKD. There are insufficient prospective data to guide anticoagulation selection in patients with CKD, although apixaban is increasingly used based on pharmacokinetic data/ retrospective analyses, especially in ESKD.68,69 There are no randomised data to guide the selection of combination antiplatelet and anticoagulant therapies following PCI in CKD patients with AF, but given the increased risk of bleeding associated with advanced CKD, ‘triple therapy’ in general should be avoided. A reasonable proposed approach is to employ clopidogrel and oral anticoagulation (without aspirin) for 12 months, followed by oral anticoagulation alone.70 However, careful individualisation by the clinician is necessary based on many different variables. Complications of reduced eGFR that deserve attention for minimising the risk of CAD events include CKD-mineral bone disease (MBD), anaemia and reduced GFR itself. CKD-MBD is associated with accelerated calcification of the arterial system, including the coronary arteries.40,71 However, the effects of management of CKD-MBD on CAD events have been mixed. Most randomised trials of management of various components of CKDMBD (parathyroid hormone reduction or phosphorus reduction) have not demonstrated a reduction in mortality or ACS. In the EVOLVE trial, treatment with the calcimimetic, cinacalcet, did not reduce the incidence of death, MI or unstable angina.72 In secondary analysis of treatment effect on subtypes of causes of death (overall CV and sudden death), there was evidence of benefit from treatment with cinacalcet.73 Despite the post hoc nature of the analysis, the benefits of reduction of parathyroid hormone appear to be towards non-atherosclerotic events. Reduction in phosphate intake is an important component of CKD-MBD management. This is primarily accomplished by the ingestion of phosphate binders with meals (as dietary phosphate restriction is notoriously difficult to achieve). These binders have primarily been calcium-based or noncalcium-based (aluminium-based binders are no longer used). There have been concerns of increased non-skeletal calcification with prolonged use of calcium-based binders, so several studies have examined the relative benefit of non-calcium binders to calcium-based binders.74,75 Both studies revealed a marginal benefit with non-calcium binders (specifically

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CAD in CKD Table 1: Revascularisation with Coronary Artery Bypass Graft Versus Percutaneous Coronary Intervention in Chronic Kidney Disease and End-stage Kidney Disease Study

Population Studied and Numbers

Outcomes

Chronic Kidney Disease

Chang et al. 2013109

• Patients undergoing CABG (n=4,547) or PCI (n=8,620) • CKD patients using the 5% Medicare sample • 2001–2007 • 22,361 patients from large integrated healthcare system in

Bangalore et al. 2015110

• 11,305 patients from New York state registry undergoing

Charytan et al. 2012108

Mortality: CABG versus PCI • Short-term (3 months): adjusted HR 1.25; 95% CI [1.12–1.40] • Long-term (6 months onward): adjusted HR 0.61; 95% CI [0.55–0.69] Mortality: CABG versus PCI • HR 0.73; 95% CI [0.56–0.95] for eGFR 45–59 ml/min/1.73 m2 • HR 0.87; 95% CI [0.67–1.14] for eGFR <45 ml/min/1.73 m2

north California • 1996–2008 • 8,172 patients included in propensity matched analysis

Mortality: PCI versus CABG revascularisation • Short-term: • 2008–2011 HR 0.55; 95% CI [0.35–0.87] • Long-term: • CKD (eGFR <60 ml/min/1.73 m2) • Multivessel CAD, severe stenosis >70% in at least two major epicardial HR 1.07; 95% CI [0.92–1.24] vessels • PCI with implantation of everolimus-eluting stents

End-stage Kidney Disease Chang et al. 2012111

Shroff et al. 201392

• 21,981 dialysis patients from the United States Renal Data System • Multivessel coronary disease undergoing CABG versus PCI • 1997–2009 • 23,033 dialysis patients from the United States Renal Data System undergoing coronary revascularisation • 2004–2009 • 6,178 CABG, 5,011 bare metal stents, 11,844 drug-eluting stents

CABG versus PCI • Mortality: HR 0.87; 95% CI [0.84–0.90] • Mortality and MI: HR 0.88; 95% CI [0.86–0.91]

• In-hospital mortality: 8.2% CABG versus 2.7% PCI with drug-eluting stents • Long-term mortality CABG (with internal mammary grafts) versus PCI (HR 0.83; p<0.0001).

Summary of representative data from large observational studies evaluating revascularisation with coronary artery bypass graft versus percutaneous coronary intervention in chronic kidney disease and end-stage kidney disease. CABG = coronary artery bypass graft; CAD = coronary artery disease; CKD = chronic kidney disease; eGFR = estimated glomerular filtration rate; PCI = percutaneous coronary intervention.

sevelamer) for all-cause mortality, but not for specific CV events. In contrast, specific serum phosphorus targets have recently been demonstrated to reduce CAC in patients on haemodialysis. However, longer-term studies are required to determine if this would result in clinical endpoint improvement. Despite limited evidence for control of metabolic parameters of renal disease and modification in coronary disease risk, there are some recent findings that deserve mention. More recently, Isaka et al. examined optimal phosphate level control in patients on haemodialysis in a 2 × 2 factorial design prospective randomised trial.75 Targeting a strict phosphate control of <4.5 mg/dl over the course of 12 months was associated with a slower progression of CAC, as compared with liberal control (5–6 mg/dl), but the type of phosphate binder used was not significantly associated with change in CAC. Finally, a recently developed chelating agent (SN472) was demonstrated to slow the progression of CAC in haemodialysis patients with elevated CAC, although this is still in early stages of a clinical trial.77 Anaemia is another common complication of CKD. The coexistence of anaemia and CKD has been associated with increased risk of fatal and non-fatal MI, as well as worse clinical outcomes following PCI.78–80 No randomised controlled trial has demonstrated a benefit of correcting anaemia on clinical outcomes (all-cause mortality or CV events) in nondialysis and dialysis-requiring CKD.81–83 The benefits of the novel hypoxiainducible factor inhibitors for the treatment of anaemia of CKD on cardiovascular outcomes is yet to be determined. Ultimately, correction of uraemia is required to reverse the overwhelming effects on the CV system. Currently, this is best accomplished via kidney transplantation.

Studies have demonstrated the consistent reduction in mortality and CV events following kidney transplantation, as opposed to staying on dialysis.84

Coronary Revascularisation

A randomised study of historical importance by Manske et al. first addressed the vexing issue of revascularisation in 151 insulin-dependent diabetic patients with CKD who underwent coronary angiography for renal transplantation evaluation.85 In this small cohort of 26 patients who were randomised to medical therapy (calcium channel blocker plus aspirin) versus revascularisation, a significant survival benefit was noted with revascularisation compared with medical therapy. Since then, but prior to the publication of ISCHEMIA-CKD, a plethora of observational registries have compared the best modality for revascularisation in CKD/ ESKD. In general, in this high-risk population, coronary artery bypass graft (CABG) is associated with higher in-hospital and short-term mortality rates than PCI, whereas in the long-term, CABG is associated with improved survival. A summary of published observational evidence pertaining to outcomes with surgical versus percutaneous revascularisation in CKD/ ESKD is presented in Table 1. Several large systemic meta-analyses have also been performed to further consolidate data obtained from registries. These meta-analyses have consistently shown a survival advantage of CABG compared with PCI in long-term follow-up among patients with moderate and severe CKD.86–88 Several special considerations deserve specific mention. The context of revascularisation needs to be factored into decision-making, but in general, there is a dearth of specific information in this regard. In ESKD patients on dialysis, it was shown that CABG (versus PCI) was associated

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CAD in CKD with higher long-term survival in the context of ACS, but had equivalent outcomes in the absence of ACS.89 Similarly, a study of Medicare beneficiaries evaluated the comparative effectiveness of different revascularisation modalities among 34,385 individuals with CKD.90 In high-risk patients (those presenting with ACS), revascularisation with CABG and PCI relative to medical therapy were associated with lower hazards of mortality, but not in low-risk patients. Finally, among 13,085 patients on dialysis undergoing CABG, off-pump CABG was associated with a lower risk of in-hospital mortality from any cause (HR 0.92; 95% CI [0.86–0.99]).91 However, the survival difference was no longer significant after 2 years, suggesting that the choice of surgical technique should be deferred to the local expertise and preference of the surgeon. Ultimately, only a randomised clinical trial would be able to accurately discern differences in outcomes between CABG versus PCI in CKD/ESKD patients. ISCHEMIA-CKD is the largest randomised clinical trial to date examining the optimal therapy for chronic CAD in patients with CKD stages G4–5D.38 There was no benefit to an early invasive strategy of coronary revascularisation combined with optimised guideline-directed medical therapy (GDMT) compared with GDMT alone (with revascularisation reserved for GDMT failure). Several important points can be garnered from this significant clinical trial. The paradigm of non-invasive testing to identify clinically important coronary stenosis in a largely asymptomatic population requires re-evaluation. Just over half of those who underwent ICA were identified as having lesions that were amenable to intervention, despite meeting the entry criteria of moderate or severe ischaemia on non-invasive stress testing, revealing a disconnect between stress testing and ICA results. Also, GDMT was well-tolerated, and goals were achievable; maximising current risk reduction strategies may maximise benefits among patients with longer life-expectancy or candidates for transplantation. ISCHEMIA-CKD has revealed the importance of specific hypothesis testing of CV treatment strategies in this high-risk population.

Proposed Clinical Approach to Periprocedural Management in Patients Needing Coronary Revascularisation

Due to the high-risk nature of this population, coronary revascularisation requires meticulous planning to reduce attendant risks of CV and renal decompensation. We recommend a heart–kidney team-based approach with careful consideration of the following variables.

Choice of Coronary Artery Bypass Graft Versus Percutaneous Coronary Intervention

that the use of internal mammary artery grafts has been consistently shown to independently confer a survival advantage among ESKD patients undergoing surgical revascularisation.91,92 Third, among patients with CKD, additional input from the nephrologist is extremely valuable. Particularly among dialysis patients, nephrologists typically have a long-standing, continuity relationship with the patient, and can provide very meaningful input pertaining to outlook/preferences, long-term prognosis, and nuances regarding dialysis access and metabolic management. Fourth, apart from the usual consideration pertaining to coronary anatomy and LV dysfunction, specific considerations of importance in patients with CKD include manifestations of deranged calcium/phosphorus/parathyroid metabolism, such as accompanying haemodynamically significant valvular disease (mitral annular calcification causing mitral stenosis/calcific aortic stenosis) or the presence of a ‘porcelain’ aorta. These factors could specifically impact the choice of a surgical versus percutaneous approach to coronary revascularisation. Fifth, regarding the bleeding risk, short-term bleeding risk is increased in patients with CKD.93 More recently, a lower risk of transfusion requirement with a transradial versus transfemoral approach has been shown among patients with CKD.94 Relaying the risks of bleeding with anticoagulation related to the acute procedure, as well as long-term anticoagulation if PCI is required, is important during shared decision-making. Ensuring appropriate monitoring and minimising important drug–drug interactions that can enhance bleeding (e.g. non-steroidal anti-inflammatory agents with antiplatelet drugs) are critical to minimising bleeding risk over the long term. Further studies on minimising duration of antiplatelet therapy post-PCI may also further lower bleeding risk in the CKD population. Sixth, radial access for PCI, as mentioned, has relative merits in terms of lower risk of dialysis, and lower postprocedural transfusion requirements.94 However, a subset of patients with CKD stage G5D will require the radial artery (typically of the non-dominant arm; dependent on the suitability of the veins) for radiocephalic arteriovenous fistula creation. Whether the use of the radial artery approach affects its future usability as an inflow or the survival of an existing radiocephalic fistula should merit specific discussion. These outcomes should be tracked in future studies.

Assessing and Mitigating the Risk of Acute Kidney Injury

First, a typical ‘heart team’ approach comprises input from interventional cardiology and cardiac surgeons for these considerations, but a ‘heart– kidney’ team approach is necessitated in this population to individualise the decision after careful deliberation of the trade-offs involved. We suggest using a ‘shared decision-making’ construct with the patient, including a detailed, carefully weighed discussion of short-term/inhospital mortality versus long-term risks/benefits of CABG versus PCI in a shared decision-making format with participation of the cardiologist and nephrologist, while actively factoring in the patient’s preferences. The baseline high competing risk of all-cause mortality with worsening CKD/ ESKD needs to be reconciled.

Acute kidney injury (AKI) can occur due to many different contributors in patients with concomitant CAD and CKD, including haemodynamic perturbations from congestion and low cardiac output/cardiogenic shock, cardiopulmonary pump run and inflammatory milieu of the membrane, use of intra-aortic balloon pump and extracorporeal support, atheroembolic phenomenon, and so on. The importance of mitigation of AKI risk is not limited to the acute hospitalisation or periprocedural period. There is a real risk of new/progressive CKD in patients who suffer AKI – this been demonstrated among patients undergoing ICA with subsequent contrast-associated AKI.95,96 Several validated risk calculators are easily available to prospectively assess the risk of AKI following PCI/CABG.97,98 Such risk calculators can provide clinicians guidance pertaining to estimated risk, to best plan management strategies.

Second, in patients with ESKD on haemodialysis, we propose an algorithmic approach outlined in Figure 1 that encapsulates the main tenets of learnings from observational evidence. It does bear emphasis

Meersch et al. demonstrated in a single-centre trial that implementation of a ‘KDIGO-bundle’ versus standard care in high-risk patients undergoing CABG reduced the risk of AKI significantly (55% versus 72%, p<0.004).99

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CAD in CKD Figure 1: Algorithmic Approach to Coronary Revascularisation in End-stage Kidney Disease Severe obstructive CAD on coronary angiography in ESKD Guideline-driven medical therapy optimised Clinical need to pursue coronary revascularisation

Multivessel obstructive CAD

Single-vessel CAD amenable to PCI

Heart–kidney team approach with multidisciplinary discussion between patient, nephrology, interventional cardiology and cardiothoracic surgery about risks versus benefits. Assessment of short-term versus long-term risks of procedural intervention relative to competing risk of mortality depending on comorbidities, dialysis vintage etc.

Discussion between patient, nephrology and interventional cardiology about risks of bleeding/stent thrombosis and procedural complications versus putative procedural success and need for long-term revascularisation

PCI with newgeneration drug-eluting stent preferred to bare metal stent

High short-term risks and comorbidity profile adversely impacting survival if CABG pursued

Acceptable short-term risks and favourable comorbidity profile from surgical perspective

Use of IMA technically not feasible or coronary anatomy not conducive to using IMA

Use of IMA technically feasible and anatomy conducive for IMA use

Reconsider risks versus benefits of PCI versus CABG based on local expertise

Pursue CABG, but consider ramifications of subclavian steal if left UE AV fistula

A proposal for an algorithmic approach to coronary revascularisation in end-stage kidney disease. AVF = arteriovenous fistula; CABG = coronary artery bypass graft; ESKD = end-stage kidney disease; IMA = internal mammary artery; PCI = percutaneous coronary intervention; UE = upper extremity.

This ‘KDIGO-bundle’ includes avoiding nephrotoxic agents, discontinuing angiotensin-converting enzyme inhibitors/angiotensin II antagonists for the preceding 48 hours, close monitoring of creatinine/urine output, avoiding hyperglycaemia and radiocontrast agents, and close monitoring to optimise volume status/haemodynamic parameters.100 Furthermore, this study demonstrated the salutary role of urinary biomarkers in the early detection of AKI. Using biomarkers to assess high-risk postoperative patients can aid in implementing early risk mitigating measures (e.g. optimisation of volume and haemodynamic status, assuring appropriate antibiotic levels and minimising the use of potentially nephrotoxic agents).

Risk of Contrast-induced Acute Kidney Injury

Among patients with pre-dialysis CKD, careful prospective assessment of the risk of contrast-induced (CI) AKI is paramount. Limiting the use of iodinated contrast medium to the smallest possible volume, including consideration of ‘staged’ procedures requiring high volumes of contrast. It is increasingly recognised that risks associated with iodinated contrast medium are often overestimated.101 An individualised approach guided by left ventricular end-diastolic pressure has been shown to lead to a substantial reduction in CI-AKI.102 Also, among patients at high-risk for AKI, there was no benefit to intravenous sodium bicarbonate compared with normal saline, or of oral

acetylcysteine compared with placebo in preventing of CI-AKI.103 This finding was further substantiated specifically among patients with CKD.104 Thus, hydration with intravenous normal saline or orally remains the cornerstone intervention for preventing CI-AKI.

Avoiding Nephrotoxic Agents

Apart from iodinated contrast medium, there are several nephrotoxic agents that could contribute to AKI in the context of coronary revascularisation. It is prudent to avoid the ‘triple whammy’ of renin– angiotensin aldosterone blockers, diuretics and non-steroidal inflammatory agents.101 It is further recommend to include a clinical pharmacist in the team for drug stewardship.

Dialysis Management

Occasionally renal replacement therapy (RRT) becomes necessary in the context of AKI in CKD. The KDIGO group has provided detailed guiding principles for the use of RRT in the context of AKI, including vascular access, dialysis prescription and management of anticoagulation including in the setting of extracorporeal support. It is important to highlight that typically, in haemodynamically unstable situations continuous rather than intermittent RRT is recommended; but the selection of modalities is dependent upon several clinical variables and requires careful planning by the heart–kidney team. Perioperative risks of patients

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CAD in CKD with CKD 5D (on chronic dialysis) are exceedingly high, necessitating astute perioperative planning of dialysis.

Goal-directed Fluid Therapy and Haemodynamic Management

For patients on chronic peritoneal dialysis (PD), it is preferred to continue PD post-CABG, since survival is comparable to haemodialysis.105 Furthermore, haemodynamic stability with PD is better than intermittent haemodialysis, and thus PD can be considered even in haemodynamically unstable patients post-CABG.106 However, fluid and metabolic needs may sometimes overwhelm the clearance capabilities of the peritoneal membrane limiting PD. In particular, among patients undergoing high-risk CABG, if haemodynamically unstable or continuous RRT is expected postprocedure, clinicians should be aware that an arteriovenous fistula/ graft may not be able to provide continuous dialysis, and PD may not be adequate in cases of marked hyperkalaemia. An intentional preprocedural discussion with the patient and the nephrologist regarding post-CABG dialysis modality, and any anticipated need for temporary dialysis access placement, may circumvent the need for hurried access placement postprocedure.

Conclusion

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A goal-directed fluid management strategy is suggested rather than an informal approach to fluid management to preventing AKI, which can be critical among patients undergoing complex coronary revascularisation.97 The use of pulmonary artery catheters to assess volume status and cardiac output may be helpful in selected subsets of patients with severe ventricular dysfunction, accompanying valvular disease and significant pulmonary hypertension.107 Patients with CKD/ESKD and concomitant CAD constitute a high-risk population with unique epidemiological and pathophysiological characteristics, as well as nuances pertaining to non-invasive risk assessment, medical management and coronary revascularisation. A collaborative heart–kidney team-based approach is imperative for critical management decisions for this patient population, especially when pursuing coronary revascularisation.

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Aortic Valve Stenosis

Coronary Artery Disease in Patients with Aortic Stenosis and Transcatheter Aortic Valve Implantation: Implications for Management Antonio FB de Azevedo Filho ,1 Tarso AD Accorsi

1,2

and Henrique B Ribeiro

2,3

1. Department of Valvular Heart Disease, Heart Institute (InCor), University of São Paulo, São Paulo, Brazil; 2. Samaritano Paulista Hospital, São Paulo, Brazil; 3. Interventional Cardiology Department, Heart Institute (InCor), University of São Paulo, São Paulo, Brazil

Abstract

Aortic valve stenosis (AS) is the most common valvular heart disease among elderly patients. Since the pathophysiology of degenerative AS shares common pathways with atherosclerotic disease, the severity of AS in the elderly population is often concurrent to the presence of coronary artery disease (CAD). Although surgical aortic valve replacement has been the standard treatment for severe AS, the high operative morbidity and mortality in complex and fragile patients was the trigger to develop less invasive techniques. Transcatheter aortic valve implantation (TAVI) has been posed as the standard of care for elderly patients with severe AS with various risk profiles, which has meant that the concomitant management of CAD has become a crucial issue in such patients. Given the lack of randomised controlled trials evaluating the management of CAD in TAVI patients, most of the recommendations are based on retrospective cohort studies so that the Heart Team approach – together with an assessment of multiple parameters including symptoms and clinical characteristics, invasive and non-invasive ischaemic burden and anatomy – are crucial for the proper management of these patients. This article provides a review of current knowledge about assessment and therapeutic approaches for CAD and severe AS in patients undergoing TAVI.

Keywords

Coronary artery disease, transcatheter aortic valve implantation, percutaneous coronary intervention Disclosure: The authors have no conflicts of interest to declare. Received: 11 June 2021 Accepted: 16 August 2021 Citation: European Cardiology Review 2021;16:e49. DOI: https://doi.org/10.15420/ecr.2021.27 Correspondence: Henrique Barbosa Ribeiro, Heart Institute of São Paulo (InCor), University of São Paulo Brazil, Av Dr Enéas de Carvalho Aguiar 44, 05403-900 São Paulo, Brazil. E: henrique.ribeiro@hc.fm.usp.br Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Coronary Artery Disease in Patients with Aortic Stenosis

Aortic stenosis (AS) is the most prevalent valve disease in the elderly population, and it is frequently associated with concomitant coronary artery disease (CAD).1,2 The prevalence of CAD in patients with severe AS varies between 15–80% and it is found in about 30% of patients undergoing surgical aortic valve replacement (SAVR).3,4 The degenerative form of heart valve disease and the progression of atherosclerotic disease are similar and share common pathways.5 Epidemiological and histopathological data suggest that degenerative calcific valve heart disease is an active disease process linked to atherosclerosis and elastocalcinosis pathophysiology.1,5 Among patients undergoing transcatheter aortic valve implantation (TAVI), CAD prevalence occurs in 44–81% of patients (Figure 1), many of whom exhibit multivessel disease.6,7 In a recent meta-analysis including 4,000 patients undergoing TAVI with CAD, the mean syntax score (SS) was 14, with the involvement of the left main and left anterior descending artery was 11% and 50% of patients, respectively.8 Observational studies have suggested that there is a reduction of CAD prevalence in low- and intermediate-risk patients when compared to high-risk and inoperable patients.9–15 However, among the whole

spectrum of TAVI patients, including those at lower risk, the future development of symptomatic CAD may pose challenges related to coronary access.

Coronary Artery Disease in TAVI Patients

There are many contradictory results reported by observational studies evaluating the clinical outcomes of CAD in patients undergoing TAVI. A systematic review of 15 studies including 8,013 patients undergoing TAVI suggested no significant differences in overall 30-day mortality rates comparing patients with or without CAD. Nonetheless, at 1-year follow-up there was a significant increase in mortality among CAD patients (95% CI [1.07–1.36]; p=0.002).16 D’Ascenzo et al. suggested the risk of death after TAVI may closely convey the complexity of CAD.8 The 1-year mortality rate seems to be higher in patients with an SS >22 and lower in those with an SS <8. Discrepancies across studies might be explained by the heterogeneity of the definitions used and inclusion criteria. For example, there are different definitions of significant CAD, which may induce positive or negative clinical outcomes depending on severity of coronary lesions, including a lack of objective haemodynamic assessment with fractional flow reserve (FFR) or instantaneous wave-free ratio (iFR), which are rarely used.17 These aspects may also underestimate the completeness of revascularisation

Management of Coronary Disease in TAVI Patients Figure 1: Incidence of Coronary Artery Disease in Patients Undergoing Transcatheter Aortic Valve Implantation from the Main Studies in the Field 100% 90% 80%

81.80%

75.40%

74.90% 67.60%

Incidence (%)

70%

67.40%

65.50% 62.60%

60%

57.60%

50%

48.30%

47.90%

47.60%

Italian Registry (n=663)

FRANCE 2 (n=3,195)

UK Registry (n=870)

44.30%

40% 30% 20% 10% 0%

CoreValue US Pivotal Trail ER (n=489)

CoreValue US Pivotal Trail ER TAVR (n=390)

PARTNER A TAVR (n=348)

PARTNER B TAVR (n=179)

PARTNER IIB PARTNER IIB Sapien Sapien XT (n=276) (n=284)

Figure 2: Proposed Algorithm for a Hybrid iFR-FFR Strategy for the Management of Coronary Artery Disease in Patients Undergoing TAVI Angiographic intermediate coronary stenosis Pre-TAVI pressure-wire interrogation

iFR <0.83

iFR 0.83–0.93

iFR >0.93

Treatment

Perform TAVI

Defer

Post-TAVI FFR measurement

FFR ≤0.8

FFR ≥0.8

Treatment

Defer

ADVANCE (n=1,015)

SOURCE XT (n=2,688)

who underwent angio-guided PCI (91.4% versus 68.1%, respectively; HR 0.3; 95% CI [0.1–0.6]; p=0.001).24 The limitation of FFR use may be the modified coronary flow reserve as a consequence of the left ventricular hypertrophy that is common in AS, resulting in an underestimate of coronary stenosis severity.20 Yet, coronary flow during the wave-free period of diastole has been shown not to change post-TAVI, suggesting that iFR would be less influenced by the effect of the stenotic aortic valve, and would also not need the administration of a vasodilator. It is important to remember that the common threshold of 0.89 for determining lesion severity may not be valid in this population.25 Scarsini et al. proposed a hybrid strategy using FFR only when iFR values were between 0.83 and 0.93, suggesting that 63% of the patients could be assessed without adenosine while maintaining 97% agreement with FFR lesion severity classification (Figure 2).22

Non-invasive Coronary Assessment

FFR = fractional flow reserve; iFR = instantaneous wave-free ratio; TAVI = transcatheter aortic valve implantation. Source: Scarsini et al. 2018.22 Reproduced with permission from Elsevier.

and therefore affect clinical outcomes. Likewise, differences among composite clinical endpoints and limited follow-up must also be considered.17

Coronary Artery Disease Assessment Invasive Coronary Assessment

SURTAVI (n=541)

Invasive coronary angiography (ICA) remains the standard method to determine the presence and severity of CAD. However, haemodynamic functional assessment of coronary lesions in TAVI candidates using FFR or iFR may be useful in the presence of a coronary lesion without evidence of ischaemia in the corresponding myocardial territory, once a discrepancy exists between ICA and functional evaluation.18,19 Therefore, the use of FFR is safe and well tolerated in those with severe AS, even using IV adenosine or intracoronary adenosine (Table 1).20–23 A recent study has shown that FFR-guided percutaneous coronary intervention (PCI) in patients with CAD undergoing TAVI yielded lower major adverse cardiac and cerebrovascular event-free survival compared with angiography-guided PCI (92.6% versus 82.0%, respectively; HR 0.4; 95% CI [0.2–1.0]; p=0.035).24 Also, deferred lesions based on FFR presented better outcomes compared with patients

Several studies have compared the performance of CT angiography (CTA) with ICA for the detection of significant coronary stenosis during the preTAVI work-up. These studies confirmed a good CTA performance in terms of negative predictive value (NPV), but with a relatively poor specificity (Table 2).26–33 Chieffo et al. showed the feasibility of CTA as a gatekeeper for ICA, with ICA performed in only 24% of TAVI candidates.34 Van Boogert et al. suggested CTA sensitivity, specificity, positive predictive value (PPV) and NPVs of 95, 65, 71 and 94% respectively, for detecting significant stenosis.35,36 Likewise, a recent study including 127 patients compared CTA with ICA images, and an excellent NPV for significant CAD as determined by stenosis ≥50% (97.5%) and for severe CAD with stenosis ≥70% (96.3%) were detected, suggesting a good CTA performance for ruling out CAD pre-TAVI procedure.35 Van den Boogert et al. used the DEPICT CTA database to demonstrate higher CTA diagnostic accuracy to rule out left main (LM) and proximal coronary stenosis in patients undergoing work-up for TAVI, with a sensitivity of 96.4% and NPV of 98.0% for a threshold of ≥50%, and a sensitivity of 96.7% and NPV of 99.0% for a threshold of ≥70% diameter stenosis.36 Therefore, CTA may become an important tool in the stratification of CAD among TAVI candidates, particularly with the increasing number of lower-risk patients.17

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Management of Coronary Disease in TAVI Patients Table 1: FFR and iFR use for Myocardial Ischaemia Assessment in TAVI Study

No. of Patients FFR/iFR Values Pre-TAVI (No. of Lesions)

FFR/iFR Values After TAVI

PCI Treatment After FFR

Follow-up

Stanojevic et al. 201623 72 (82 lesions)

FFR ≤0.80 (0.76 ± 0.03) FFR >0.80 (0.88 ± 0.04)

–

37 lesions (45.10%)

9 ± 14 months after TAVI: 4 ACS, no TVR or TLR

Pesarini et al. 201621

54 (133 lesions)

FFR (LAD) ≤0.80 (0.72 ± 0.12) FFR (LAD) >0.80 (0.88 ± 0.12)

FFR (LAD) ≤0.8 (0.69 ± 0.13) FFR (LAD) >0.8 (0.89 ± 0.13)

19 lesions (14.20%)

At 30 days: no sustained angina or hypotension, MI or heart failure

Scarsini et al. 201822

62 (141 lesions)

FFR 0.88 ± 0.09 iFR <0.83 (0.69 ± 0.11) iFR 0.83–0.93 (0.88 ± 0.11) iFR >0.93 (0.95 ± 0.11)

FFR 0.87 ± 0.08 iFR <0.83 (0.71 ± 0.13) iFR 0.83–0.93 (0.88 ± 0.10) iFR >0.93 (0.95 ± 0.10)

19 lesions (13.40%)

At 30 days: no death or new coronary revascularisation

Ahmad et al. 201820

28 (30 lesions)

FFR 0.87 ± 0.08 iFR 0.88 ± 0.09

FFR 0.85 ±0.09 iFR 0.88 ±0.09

–

Lunardi et al. 201924

94 (142 lesions)

FFR 0.87 ± 0.12

FFR 0.87 ±0.08

31 lesions (21.80%)

24.2 ± 17 months after TAVI: 16 death; 3 cardiac deaths; 4 AMI; 1 elective PCI; 1 stroke; 7 MACCE

AMI = acute MI; ACS = acute coronary syndrome; FFR = fractional flow reserve; iFR = instant wave-free ratio; LAD = left anterior descending; MACCE = major adverse coronary and cerebrovascular events; TAVI = transcatheter aortic valve implantation; TLR = target lesion revascularisation; TVR = target vessel revascularisation.

Table 2: Accuracy of CT Angiography for Coronary Artery Disease Assessment Pre-TAVI Study

Patients (n)

Significant Stenosis (%)

Sensitivity (%)

Specificity (%)

NPV (%)

PPV (%)

Pontone et al. 201132

>50%

Andreini et al. 201426

325

>50%

100

Hamdan et al. 2015

115

>50%

Harris et al. 2015

100

>50%

Opolski et al. 201531

475

>50%

Chieffo et al. 2015

491

>50%

–

Matsumoto et al. 201729

>50%

Strong et al. 2019

200

>50%

100

Meier et al. 2021

127

>50% >70%

81 43

88 98

97 96

44 56

NPV = negative predictive value; PPV = positive predictive value; TAVI = transcatheter aortic valve implantation.

Non-invasive methods for diagnosing ischaemic coronary lesions, such as FFR derived from computed tomography angiography (CT-FFR), use computational flow dynamics and provide both anatomical and functional information, ultimately improving the dynamic assessment of patients with CAD.37 In addition, there are promising clinical data with the selective use of CT-FFR in pre-TAVI patients. Michail et al. in the CAST-FFR study suggested a good correlation between diagnostic accuracy of CT-FFR versus conventional FFR in pre-TAVI assessment and an improved accuracy compared to CTA alone.38 Another non-invasive technology for diagnosis of CAD is the angiographybased quantitative flow ratio (QFR) software that uses the Thrombolysis in MI (TIMI) frame count of a single vessel in two orthogonal projections as the surrogate blood flow marker to calculate the translesional gradient ratio. Mejía-Rentería et al. demonstrated superior diagnostic performance of QFR compared to angiography based on FFR as a reference in assessing the functional relevance of coronary lesions in severe AS patients undergoing TAVI (AUC 0.88; 95% CI [0.82–0.93] versus 0.74; 95% CI [0.66–0.81], respectively; p=0.0002)..39 Particularly when the aortic valvular area (AVA) is ≥0.80 cm2, agreement between both methods was 91%, and it decreased to 79% when the AVA was between 0.60 and 0.80 cm, although coronary microvascular dysfunction probably affects the overall diagnostic performance of QFR.39,40

All these promising techniques have some limitations and larger prospective and randomised studies are still warranted.

Percutaneous Coronary Intervention in TAVI Patients

There is a lack of robust data and randomised clinical evidence on the indication for PCI in patients with significant CAD undergoing TAVI. In general, the decision to perform PCI before TAVI commonly relies on recommendations from stable CAD guidelines, including the presence of ischaemic symptoms and the anatomy of the coronary lesions. The American College of Cardiology has proposed a treatment algorithm considering a higher benefit of PCI in patients undergoing TAVI with proximal epicardial coronary stenosis >70% or left main stenosis >50%, patients’ symptoms or if CAD access in the future would be limited by TAVI (Figure 3).41 A previous systematic review of nine studies involving 3,858 participants showed that those patients who underwent PCI showed higher rates of major vascular complications and mortality at 30 days.7 Nonetheless, there were no differences in effect estimates for 30-day cardiovascular mortality, MI, acute kidney injury, stroke or mortality at 1 year.7 The only prospective and randomised controlled trial comparing elective preprocedure PCI versus no PCI in patients undergoing TAVI with significant

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Management of Coronary Disease in TAVI Patients Figure 3: Proposed Algorithm for the Management of Coronary Artery Disease in Patients Undergoing TAVI Pre-TAVR patient evaluation/coronary angiogram

Significant CAD

No significant CAD

Proximal endocardial vessel or left main stenosis Proceed with TAVR

Yes

Consider PCI prior to or at the time of TAVR if PCI risk is not prohibitive

Collectively, considering the absence of robust data and despite some apparently contradictory results, PCI seems to be safe before TAVI procedures in patients with severe CAD who are symptomatic (angina), or have acute coronary syndrome (ACS), or even have positive ischaemia tests (invasive or non-invasive), without a significant increase in the risk of complications with an improvement in the overall prognosis in selected cases after medium- to long-term follow-up.49

Concomitant Percutaneous Coronary Intervention and TAVI

Non-proximal or branch vessel stenosis with small area or myocardium at risk

Concern for patient’s symptoms coming from CAD?

Yes: consider PCI pre-TAVR

importance for those with previous chronic kidney disease (30–50% of the TAVI population), congestive heart failure, anaemia, AF, among other factors that together may also increase mortality.48

Reassess CAD after TAVR per AUC. If access to coronary will be limited by TAVR consider pre-TAVR PCI

AUC = area under the curve; CAD = coronary artery disease; PCI = percutaneous coronary intervention; TAVI = transcatheter aortic valve implantation; TAVR = transcatheter aortic valve replacement. Source: Ramee et al. 2016.41 Adapted with permission from Elsevier

CAD is the ACTIVATION trial.42 The study randomised 235 patients to the treatment of significant CAD by PCI (test arm) versus no PCI (control arm). Significant coronary disease was defined as ≥1 lesion of ≥70% severity in a major epicardial vessel or 50% in a vein graft or protected left main lesion.42 There were no differences in the primary endpoints of death or rehospitalisation at 1-year follow-up between the two treatment strategies. However, there was a higher rate of bleeding in the PCI group (44.5% versus 28.4%, p=0.02) in the first 30 days after the TAVI procedure.43 Likewise, Chakravarty et al. evaluated 204 patients with coexisting aortic valve disease and LM coronary disease undergoing TAVI in addition to PCI.44 This large case series demonstrated that even for LM disease in patients undergoing TAVI, it is feasible and safe to perform a planned LM PCI before or during TAVI procedures, with clinical outcomes comparable to that of isolated TAVI procedures.44 Another important aspect in such patients is the completeness of revascularisation when indicated. Using the residual SYNTAX score (rSS), a previous meta-analysis has shown that patients with a higher rSS have increased mortality after TAVI, suggesting the negative impact of incomplete coronary revascularisation.8,45 Although these findings are contradictory and should be evaluated in the context of the presence of ischaemia, it is important to provide complete revascularisation in such patients undergoing TAVI, at least in the main vessels/territories.46

Percutaneous Coronary Intervention Before TAVI

Patients may benefit from both therapeutic strategies, either staged versus simultaneous procedures. Some observational studies have suggested that PCI performed 30 days before TAVI may increase the risk of vascular and bleeding complications, probably associated with the additional vascular puncture.47 However, this strategy may reduce periprocedural MI as well as protecting patients at high-risk for developing contrast-induced nephropathy from dye overload. This is of greater

It is possible that simultaneous PCI and TAVI could be an adequate strategy for unstable patients with very elevated aortic gradients who are at high risk for coronary occlusion, such as ostial lesions, low LM height and valve-in-valve (VIV) implant.49 Several studies have suggested the safety of performing PCI and TAVI at the same time, probably due to lower vascular bleeding complications, as well as reducing procedure time and minimising the need for dual antiplatelet therapy (DAPT).50,51 Yang et al. compared concomitant versus staged PCI and TAVI through a systematic review of four studies including 209 patients and showed no differences in overall 30-day mortality between the groups, as well as renal failure, peri-procedural MI, life-threatening bleeding and major stroke.6 Ochiai et al. investigated the optimal timing for PCI comparing three strategies (PCI pre-TAVI versus PCI concomitant to TAVI versus PCI post-TAVI) and found no differences after 2-year follow-up in the composite of major adverse cardiac and cerebrovascular events (concomitant versus pre-TAVI, HR 0.92; 95% CI [0.52–1.66]; p=0.79; postversus pre-TAVI, HR 0.45; 95% CI [0.18– 1.16]; p=0.10).52 Therefore, the optimal timing of PCI and TAVI remains unclear and must be individualised for each patient (Table 3).

Percutaneous Coronary Intervention After TAVI

As the TAVI procedure become available to patients from all surgical risk categories, a longer life expectancy brings greater possibility of PCI after TAVI, as well as VIV procedures. However, there are a large number of technical difficulties for selective catheterisation of the coronary ostia when the TAVI bioprosthesis is in place and during VIV procedures where it might be unfeasible in approximately a third of patients.53,54 Optimising transcatheter aortic valve commissural alignment in native annulus may avoid coronary artery overlap and facilitate coronary access in the future, especially using certain types of self-expandable transcatheter bioprostheses (Evolut from Medtronic and ACURATE-neo from Boston Scientific).52–56 Redondo et al. developed a promising method for proper commissural alignment (ACURATE-neo bioprosthesis) to insert the delivery system with a patient-specific rotation based on CT data analysis, tested in 3D, printed in silico models and in vivo.56 The results suggested an important reduction in commissural misalignment and coronary artery overlap.56 Yudi et al. proposed a catheter selection algorithm depending on the type of bioprosthesis, the procedure (ICA or PCI), and the position of the transcatheter valve commissure with respect to the coronary ostium.57 Another study reported technical success in all 46 cases of PCI performed immediately after balloon-expandable TAVI within the same operative session.54

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Management of Coronary Disease in TAVI Patients Table 3: Timing Comparison of Percutaneous Coronary Intervention Strategies for Patients Undergoing TAVI PCI before TAVI

Simultaneous PCI and TAVI

Benefits

Risks

• Improves coronary flow pre-TAVI • Reduces periprocedural MI • Easier coronary access • Less contrast infusion • Less probability of CIN • Avoids additional vascular puncture (injury and bleeding) • Reduces hospitalisations and costs • Reduces haemodynamic deterioration for elevated or unstable

• Haemodynamic deterioration during PCI (elevated aortic gradients, ostial lesions)

• Vascular injury and bleeding (additional vascular puncture) • Increase in bleeding risk due to the need for DAPT • Increases volume of contrast infusion (risk of CIN) • Increases the procedure duration (X-ray exposure, operator fatigue)

aortic gradients

PCI after TAVI

• Reduces DAPT duration • Improves haemodynamic pre-PCI • Improves accuracy of functional assessment of CAD • Reduces bleeding risk (no previous DAPT)

• Ischaemia during TAVI • Difficult coronary cannulation

CAD = coronary artery disease; CIN = contrast-induced nephropathy; DAPT = dual antiplatelet therapy; PCI = percutaneous coronary intervention; TAVI = transcatheter aortic valve implantation.

Coronary Complications Post-TAVI

Coronary obstruction remains a rare but potentially life-threatening complication of TAVI and it usually occurs after valve implantation and more frequently in women and during VIV procedures.58–60 A low coronary ostium take off and shallow sinus of Valsalva are important risk factors during native aortic valve TAVI. In cases of VIV, the main risk factors relate to the type of surgical bioprosthesis (stented with externally mounted leaflets and stentless bioprosthesis) and a shorter virtual valve-tocoronary ostia distance.58–60 Persistent severe hypotension immediately after valve implantation, irrespective of the presence or absence of STsegment changes, should prompt the possibility of coronary obstruction, with the evaluation of new segmental abnormalities in the echocardiogram, as well as coronary ostia flow. PCI is a feasible and effective treatment in most cases, although the rates of additional haemodynamic support, conversion to open heart surgery or stent compression requiring the implantation of a second stent remain important challenges. Therefore, preventive measures may also be undertaken, such as using a guidewire, with or without a stent placement, in higher risk patients. Unplanned PCI following TAVI is not common and ACS is frequently related to an atherothrombotic mechanism, progression of CAD, or failure of a previous PCI. Stefanini et al.’s study, based on multicentre international registry data, reported PCI due to ACS after TAVI at a median time of 191 days.61 There was PCI success in 96.6%, and no significant differences between patients treated with balloon-expandable and self-expandable bioprostheses (100% versus 94.9%; p=0.150).61 However, considering a retrospective cohort study, statistical analysis limitations and significant biases may affect the conclusion. Another recent cohort of 779 patients reported an incidence of ~10% of an ACS at a median follow-up of ~2 years.62 Of note, a non–ST-segment elevation MI (NSTEMI) type 2 occurred in 36%, unstable angina in 35% and NSTEMI type 1 in 28%, yielding an all-cause mortality rate of 37% after a median follow-up of 21 months post-ACS.62 Other potential mechanisms for coronary events might be impaired flow dynamics and coronary hypoperfusion related to the TAVI bioprosthesis, a coronary embolism related to subclinical leaflet thrombosis in a bioprosthetic aortic valve thrombosis, a late valve migration occluding the coronary ostia and Kounis hypersensitivity-associated thrombotic syndrome.62–65

Dual Anti-platelet Therapy Timing

Medical therapy including antiplatelet therapy is often recommended for asymptomatic patients with ACS or stable CAD, with applicability for the

Figure 4: Algorithm for Oral Anticoagulation or Antiplatelet Therapy in Patients Undergoing TAVI and Recent Coronary Stenting C Yes OAC indication

UFH

OAC

PCI <3 months?

Yes UFH

TAVI

OAC

ASA

OAC

ASA OR

PCI <3 months? No

Pre-TAVI

ASA No

SAPT (No OAC indication)

Post-TAVI

ASA OR

1 to 6 months

lifelong

ASA = acetylsalicylic acid (75–100 mg/daily); C = clopidogrel (75 mg/daily); OAC = oral anticoagulation (vitamin K antagonists or direct oral anticoagulants); PCI = percutaneous coronary intervention; SAPT = single antiplatelet therapy; TAVI = transcatheter aortic valve implantation; UFH = unfractionated heparin. Data source: Ten Berg et al. 2021.55

TAVI population. Nonetheless, safety of DAPT is an important consideration for PCI in TAVI patients given the higher bleeding risk (HBR) profile that is generally seen among these patients. Although more potent antiplatelet therapy with ticagrelor and prasugrel may be considered for high-risk PCI, especially in patients with a recent ACS, there are no data evaluating its safety in such HBR patients, especially in the periprocedural timing of the TAVI procedure.18,19 Rodes-Cabau et al. suggested a tendency of DAPT (aspirin plus clopidogrel) to increase the incidence of death, MI, ischaemic stroke or transient ischaemic attack, or major or life-threatening bleeding events compared with single antiplatelet therapy (aspirin) at 3-month follow-up. The POPular TAVI trial showed similar results at 1-year follow-up in patients without indication for long-term oral anticoagulation.66,67 Thus, the combination of low-dose aspirin plus clopidogrel should be recommended after PCI with therapy duration between 3 to 6 months.18,19 However, after this period and for those patients without CAD undergoing TAVI, monotherapy either with low-dose aspirin or clopidogrel is recommended (Figure 4).55,68 Finally, among patients undergoing TAVI more than 35% have concomitant AF with an indication for oral anticoagulation (OAC) and without recent PCI

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Management of Coronary Disease in TAVI Patients or formal indication to receive antiplatelet therapy.69 OAC alone should be indicated in such circumstances (Figure 4).55,68 In patients with an indication for concomitant use of OAC and antiplatelet therapy, triple therapy (DAPT plus OAC) should be avoided, and only suggested for those patients with a very high thrombotic risk but restricted to a very short period of time (usually for 1 month after recent PCI), followed by clopidogrel alone plus OAC.70,71

Conclusion

CAD concomitant with severe AS in elderly patients undergoing TAVI is very common and therefore requires careful assessment and proper management of ischaemia. Although the standard evaluation of coronary 1. Pibarot P, Dumesnil JG. Improving assessment of aortic stenosis. J Am Coll Cardiol 2012;60:169–80. https://doi. org/10.1016/j.jacc.2011.11.078; PMID: 22789881. 2. Stewart BF, Siscovick D, Lind BK, et al. Clinical factors associated with calcific aortic valve disease. Cardiovascular Health Study. J Am Coll Cardiol 1997;29:630–4. https://doi. org/10.1016/S0735-1097(96)00563-3; PMID: 9060903. 3. Thalji NM, Suri RM, Daly RC, et al. Assessment of coronary artery disease risk in 5463 patients undergoing cardiac surgery: when is preoperative coronary angiography necessary? J Thorac Cardiovasc Surg 2013;146:1055–64.e1. https://doi.org/10.1016/j.jtcvs.2013.06.046; PMID: 24012061. 4. Malmberg M, Gunn J, Sipila J, et al. Comparison of longterm outcomes of patients having surgical aortic valve replacement with versus without simultaneous coronary artery bypass grafting. Am J Cardiol 2020;125:964–9. https:// doi.org/10.1016/j.amjcard.2019.12.015; PMID: 31948663. 5. Lerman DA, Prasad S, Alotti N. Calcific aortic valve disease: molecular mechanisms and therapeutic approaches. Eur Cardiol 2015;10:108–12. https://doi.org/10.15420/ ecr.2015.10.2.108; PMID: 27274771. 6. Yang Y, Huang FY, Huang BT, et al. The safety of concomitant transcatheter aortic valve replacement and percutaneous coronary intervention: a systematic review and meta-analysis. Medicine (Baltimore) 2017;96:e8919. https://doi.org/10.1097/MD.0000000000008919; PMID: 29310382. 7. Kotronias RA, Kwok CS, George S, et al. Transcatheter aortic valve implantation with or without percutaneous coronary artery revascularization strategy: a systematic review and meta-analysis. J Am Heart Assoc 2017;6 e005960. https://doi. org/10.1161/JAHA.117.005960; PMID: 28655733. 8. D’Ascenzo F, Verardi R, Visconti M, et al. Independent impact of extent of coronary artery disease and percutaneous revascularisation on 30-day and one-year mortality after TAVI: a meta-analysis of adjusted observational results. EuroIntervention 2018;14:e1169–77. https://doi.org/10.4244/EIJ-D-18-00098; PMID: 30082258. 9. Mack MJ, Leon MB, Thourani VH, et al. Transcatheter aorticvalve replacement with a balloon-expandable valve in lowrisk patients. N Engl J Med 2019;380:1695–705. https://doi. org/10.1056/NEJMoa1814052; PMID: 30883058. 10. Makkar RR, Thourani VH, Mack MJ, et al. Five-year outcomes of transcatheter or surgical aortic-valve replacement. N Engl J Med 2020;382:799–809. https://doi. org/10.1056/NEJMoa1910555; PMID: 31995682. 11. Popma JJ, Deeb GM, Yakubov SJ, et al. Transcatheter aorticvalve replacement with a self-expanding valve in low-risk patients. N Engl J Med 2019;380:1706–15. https://doi. org/10.1056/NEJMoa1816885; PMID: 30883053. 12. Popma JJ, Adams DH, Reardon MJ, et al. Transcatheter aortic valve replacement using a self-expanding bioprosthesis in patients with severe aortic stenosis at extreme risk for surgery. J Am Coll Cardiol 2014;63:1972–81. https://doi.org/10.1016/j.jacc.2014.02.556; PMID: 24657695. 13. Reardon MJ, Van Mieghem NM, Popma JJ, et al. Surgical or transcatheter aortic-valve replacement in intermediate-risk patients. N Engl J Med 2017;376:1321–31. https://doi. org/10.1056/NEJMoa1700456; PMID: 28304219. 14. Sengupta A, Zaid S, Kamioka N, et al. Mid-term outcomes of transcatheter aortic valve replacement in extremely large annuli with Edwards SAPIEN 3 valve. JACC Cardiovasc Interv 2020;13:210–6. https://doi.org/10.1016/j.jcin.2019.08.042; PMID: 31883715. 15. Van Mieghem NM, Popma JJ, Deeb GM, et al. Complete 2-year results confirm Bayesian analysis of the SURTAVI trial. JACC Cardiovasc Interv 2020;13:323–31. https://doi. org/10.1016/j.jcin.2019.10.043; PMID: 32029248. 16. Sankaramangalam K, Banerjee K, Kandregula K, et al.

anatomy is still invasive ICA, complementary haemodynamic functional methods such as FFR and iFR and non-invasive methods, such as CTA and FFR-CTA, may improve the diagnosis of ischaemia in such patients and decrease the probability of unnecessary PCI. Since the prognosis of pre-emptive PCI in patients undergoing TAVI with CAD is uncertain and the optimal timing for PCI is still controversial, an individualised approach should be based on the patient’s profile, characteristics, symptoms and preferences, as well as the anatomical feasibility of the procedure. Future studies with a larger number of patients are of utmost importance to better define the best treatment of patients with concomitant CAD undergoing TAVI.

Impact of coronary artery disease on 30-day and 1-year mortality in patients undergoing transcatheter aortic valve replacement: a meta-analysis. J Am Heart Assoc 2017;6:e006092. https://doi.org/10.1161/JAHA.117.006092; PMID: 29021275. 17. Faroux L, Guimaraes L, Wintzer-Wehekind J, et al. Coronary artery disease and transcatheter aortic valve replacement: JACC state-of-the-art review. J Am Coll Cardiol 2019;74:362– 72. https://doi.org/10.1016/j.jacc.2019.06.012; PMID: 31319919. 18. Fihn SD, Blankenship JC, Alexander KP, et al. 2014 ACC/ AHA/AATS/PCNA/SCAI/STS focused update of the guideline for the diagnosis and management of patients with stable ischemic heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines, and the American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. J Am Coll Cardiol 2014;64:1929–49. https://doi.org/10.1016/j. jacc.2014.07.017; PMID: 25077860. 19. Neumann FJ, Sousa-Uva M, Ahlsson A, et al. 2018 ESC/ EACTS Guidelines on myocardial revascularization. Eur Heart J 2019;40:87–165. https://doi.org/10.1093/eurheartj/ehy394; PMID: 30165437. 20. Ahmad Y, Gotberg M, Cook C, et al. Coronary hemodynamics in patients with severe aortic stenosis and coronary artery disease undergoing transcatheter aortic valve replacement: implications for clinical indices of coronary stenosis severity. JACC Cardiovasc Interv 2018;11:2019–31. https://doi.org/10.1016/j.jcin.2018.07.019; PMID: 30154062. 21. Pesarini G, Scarsini R, Zivelonghi C, et al. Functional assessment of coronary artery disease in patients undergoing transcatheter aortic valve implantation: influence of pressure overload on the evaluation of lesions severity. Circ Cardiovasc Interv 2016;9:e004088. https://doi. org/10.1161/CIRCINTERVENTIONS.116.004088; PMID: 27803040. 22. Scarsini R, Pesarini G, Lunardi M, et al. Observations from a real-time, iFR-FFR ‘hybrid approach’ in patients with severe aortic stenosis and coronary artery disease undergoing TAVI. Cardiovasc Revasc Med 2018;19:355–9. https://doi. org/10.1016/j.carrev.2017.09.019; PMID: 29113864. 23. Stanojevic D, Gunasekaran P, Tadros P, et al. Intravenous adenosine infusion is safe and well tolerated during coronary fractional flow reserve assessment in elderly patients with severe aortic stenosis. J Invasive Cardiol 2016;28:357–61. PMID: 27315577. 24. Lunardi M, Scarsini R, Venturi G, et al. Physiological versus angiographic guidance for myocardial revascularization in patients undergoing transcatheter aortic valve implantation. J Am Heart Assoc 2019;8:e012618. https://doi.org/10.1161/ JAHA.119.012618; PMID: 31718439. 25. Gotberg M, Cook CM, Sen S, et al. The evolving future of instantaneous wave-free ratio and fractional flow reserve. J Am Coll Cardiol 2017;70:1379–402. https://doi.org/10.1016/j. jacc.2017.07.770; PMID: 28882237. 26. Andreini D, Pontone G, Mushtaq S, et al. Diagnostic accuracy of multidetector computed tomography coronary angiography in 325 consecutive patients referred for transcatheter aortic valve replacement. Am Heart J 2014;168:332–9. https://doi.org/10.1016/j.ahj.2014.04.022; PMID: 25173545. 27. Hamdan A, Wellnhofer E, Konen E, et al. Coronary CT angiography for the detection of coronary artery stenosis in patients referred for transcatheter aortic valve replacement. J Cardiovasc Comput Tomogr 2015;9:31–41. https://doi. org/10.1016/j.jcct.2014.11.008; PMID: 25576406.

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28. Harris BS, De Cecco CN, Schoepf UJ, et al. Dual-source CT imaging to plan transcatheter aortic valve replacement: accuracy for diagnosis of obstructive coronary artery disease. Radiology 2015;275:80–8. https://doi.org/10.1148/ radiol.14140763; PMID: 25393848. 29. Matsumoto S, Yamada Y, Hashimoto M, et al. CT imaging before transcatheter aortic valve implantation (TAVI) using variable helical pitch scanning and its diagnostic performance for coronary artery disease. Eur Radiol 2017;27:1963–70. https://doi.org/10.1007/s00330-016-45474; PMID: 27562479. 30. Meier D, Depierre A, Topolsky A, et al. Computed tomography angiography for the diagnosis of coronary artery disease among patients undergoing transcatheter aortic valve implantation. J Cardiovasc Transl Res 2021. https://doi.org/10.1007/s12265-021-10099-8; PMID: 33543417; epub ahead of press. 31. Opolski MP, Kim WK, Liebetrau C, et al. Diagnostic accuracy of computed tomography angiography for the detection of coronary artery disease in patients referred for transcatheter aortic valve implantation. Clin Res Cardiol 2015;104:471–80. https://doi.org/10.1007/s00392-0140806-z; PMID: 25559245. 32. Pontone G, Andreini D, Bartorelli AL, et al. Feasibility and accuracy of a comprehensive multidetector computed tomography acquisition for patients referred for balloonexpandable transcatheter aortic valve implantation. Am Heart J 2011;161:1106–13. https://doi.org/10.1016/j.ahj.2011.03.003; PMID: 21641357. 33. Strong C, Ferreira A, Teles RC, et al. Diagnostic accuracy of computed tomography angiography for the exclusion of coronary artery disease in candidates for transcatheter aortic valve implantation. Sci Rep 2019;9:19942. https://doi. org/10.1038/s41598-019-56519-3; PMID: 31882777. 34. Chieffo A, Giustino G, Spagnolo P, et al. Routine screening of coronary artery disease with computed tomographic coronary angiography in place of invasive coronary angiography in patients undergoing transcatheter aortic valve replacement. Circ Cardiovasc Interv 2015;8:e002025. https://doi.org/10.1161/CIRCINTERVENTIONS.114.002025; PMID: 26160830. 35. van den Boogert TPW, Vendrik J, Claessen B, et al. CTCA for detection of significant coronary artery disease in routine TAVI work-up: a systematic review and meta-analysis. Neth Heart J 2018;26:591–9. https://doi.org/10.1007/s12471-0181149-6; PMID: 30178209. 36. van den Boogert TPW, Claessen B, Opolski MP, et al. DEtection of ProxImal Coronary stenosis in the work-up for Transcatheter aortic valve implantation using CTA (from the DEPICT CTA collaboration). Eur Radiol 2021. https://doi. org/10.1007/s00330-021-08095-2; PMID: 34132873; epub ahead of press. 37. Lu MT, Ferencik M, Roberts RS, et al. Noninvasive FFR derived from coronary CT angiography: management and outcomes in the PROMISE trial. JACC Cardiovasc Imaging 2017;10:1350–8. https://doi.org/10.1016/j.jcmg.2016.11.024; PMID: 28412436. 38. Michail M, Ihdayhid AR, Comella A, et al. Feasibility and validity of computed tomography-derived fractional flow reserve in patients with severe aortic stenosis: The CASTFFR study. Circ Cardiovasc Interv 2021;14:e009586. https:// doi.org/10.1161/CIRCINTERVENTIONS.120.009586; PMID: 33322917. 39. Mejia-Renteria H, Lee JM, Lauri F, et al. Influence of microcirculatory dysfunction on angiography-based functional assessment of coronary stenoses. JACC Cardiovasc Interv 2018;11:741–53. https://doi.org/10.1016/j. jcin.2018.02.014; PMID: 29673505. 40. Mejia-Renteria H, Nombela-Franco L, Paradis JM, et al.

Management of Coronary Disease in TAVI Patients Angiography-based quantitative flow ratio versus fractional flow reserve in patients with coronary artery disease and severe aortic stenosis. EuroIntervention 2020;16:e285–92. https://doi.org/10.4244/EIJ-D-19-01001; PMID: 32207408. 41. Ramee S, Anwaruddin S, Kumar G, et al. The rationale for performance of coronary angiography and stenting before transcatheter aortic valve replacement: from the Interventional Section Leadership Council of the American College of Cardiology. JACC Cardiovasc Interv 2016;9:2371–5. https://doi.org/10.1016/j.jcin.2016.09.024; PMID: 27931592. 42. Khawaja MZ, Wang D, Pocock S, et al. The percutaneous coronary intervention prior to transcatheter aortic valve implantation (ACTIVATION) trial: study protocol for a randomized controlled trial. Trials 2014;15:300. https://doi. org/10.1186/1745-6215-15-300; PMID: 25059340. 43. Patterson T, Clayton T, Dodd M, et al. ACTIVATION (PercutAneous Coronary inTervention prIor to transcatheter aortic VAlve implantaTION): a randomized clinical trial. JACC Cardiovasc Interv 2021;14:1965–74. https://doi.org/10.1016/j. jcin.2021.06.041; PMID: 34556269. 44. Chakravarty T, Sharma R, Abramowitz Y, et al. Outcomes in patients with transcatheter aortic valve replacement and left main stenting: the TAVR-LM registry. J Am Coll Cardiol 2016;67:951–60. https://doi.org/10.1016/j.jacc.2015.10.103; PMID: 26916485. 45. Witberg G, Zusman O, Codner P, et al. Impact of coronary artery revascularization completeness on outcomes of patients with coronary artery disease undergoing transcatheter aortic valve replacement: a meta-analysis of studies using the residual SYNTAX score (synergy between PCI with taxus and cardiac surgery). Circ Cardiovasc Interv 2018;11:e006000. https://doi.org/10.1161/ CIRCINTERVENTIONS.117.006000; PMID: 29870384. 46. Paradis JM, Fried J, Nazif T, et al. Aortic stenosis and coronary artery disease: what do we know? What don’t we know? A comprehensive review of the literature with proposed treatment algorithms. Eur Heart J 2014;35:2069– 82. https://doi.org/10.1093/eurheartj/ehu247; PMID: 24970334. 47. van Rosendael PJ, van der Kley F, Kamperidis V, et al. Timing of staged percutaneous coronary intervention before transcatheter aortic valve implantation. Am J Cardiol 2015;115:1726–32. https://doi.org/10.1016/j. amjcard.2015.03.019; PMID: 25890631. 48. Allende R, Webb JG, Munoz-Garcia AJ, et al. Advanced chronic kidney disease in patients undergoing transcatheter aortic valve implantation: insights on clinical outcomes and prognostic markers from a large cohort of patients. Eur Heart J 2014;35:2685–96. https://doi.org/10.1093/eurheartj/ehu175; PMID: 24796337. 49. Perez S, Thielhelm TP, Cohen MG. To revascularize or not before transcatheter aortic valve implantation? J Thorac Dis 2018;10:s3578–S87. https://doi.org/10.21037/jtd.2018.09.85; PMID: 30505538. 50. Barbanti M, Todaro D, Costa G, et al. Optimized screening of coronary artery disease with invasive coronary angiography and ad hoc percutaneous coronary intervention during transcatheter aortic valve replacement. Circ Cardiovasc Interv 2017;10:e005234. https://doi.org/10.1161/ CIRCINTERVENTIONS.117.005234; PMID: 28768757.

51. Penkalla A, Pasic M, Drews T, et al. Transcatheter aortic valve implantation combined with elective coronary artery stenting: a simultaneous approach. Eur J Cardiothorac Surg 2015;47:1083–9. https://doi.org/10.1093/ejcts/ezu339; PMID: 25217500. 52. Ochiai T, Yoon SH, Flint N, et al. Timing and outcomes of percutaneous coronary intervention in patients who underwent transcatheter aortic valve implantation. Am J Cardiol 2020;125:1361–8. https://doi.org/10.1016/j. amjcard.2020.01.043; PMID: 32106928. 53. Blumenstein J, Kim WK, Liebetrau C, et al. Challenges of coronary angiography and intervention in patients previously treated by TAVI. Clin Res Cardiol 2015;104:632–9. https://doi.org/10.1007/s00392-015-0824-5; PMID: 25720330. 54. Nai Fovino L, Scotti A, Massussi M, et al. Coronary angiography after transcatheter aortic valve replacement (TAVR) to evaluate the risk of coronary access impairment after TAVR-in-TAVR. J Am Heart Assoc 2020;9:e016446. https://doi.org/10.1161/JAHA.120.016446; PMID: 32578484. 55. Ten Berg J, Sibbing D, Rocca B, et al. Management of antithrombotic therapy in patients undergoing transcatheter aortic valve implantation: a consensus document of the ESC Working Group on Thrombosis and the European Association of Percutaneous Cardiovascular Interventions (EAPCI), in collaboration with the ESC Council on Valvular Heart Disease. Eur Heart J 2021;42:2265–9. https://doi. org/10.1093/eurheartj/ehab196; PMID: 33822924. 56. Redondo A, Valencia-Serrano F, Santos-Martinez S, et al. Accurate commissural alignment during ACURATE neo TAVI procedure. Proof of concept. Rev Esp Cardiol (Engl Ed) 2021. https://doi.org/10.1016/j.rec.2021.02.004; PMID: 33781722; epub ahead of press. 57. Yudi MB, Sharma SK, Tang GHL, Kini A. Coronary angiography and percutaneous coronary intervention after transcatheter aortic valve replacement. J Am Coll Cardiol 2018;71:1360–78. https://doi.org/10.1016/j.jacc.2018.01.057; PMID: 29566822. 58. Ribeiro HB, Nombela-Franco L, Urena M, et al. Coronary obstruction following transcatheter aortic valve implantation: a systematic review. JACC Cardiovasc Interv 2013;6:452–61. https://doi.org/10.1016/j.jcin.2012.11.014; PMID: 23602458. 59. Ribeiro HB, Rodes-Cabau J, Blanke P, et al. Incidence, predictors, and clinical outcomes of coronary obstruction following transcatheter aortic valve replacement for degenerative bioprosthetic surgical valves: insights from the VIVID registry. Eur Heart J 2018;39:687–95. https://doi. org/10.1093/eurheartj/ehx455; PMID: 29020413. 60. Ribeiro HB, Webb JG, Makkar RR, et al. Predictive factors, management, and clinical outcomes of coronary obstruction following transcatheter aortic valve implantation: insights from a large multicenter registry. J Am Coll Cardiol 2013;62:1552–62. https://doi.org/10.1016/j.jacc.2013.07.040; PMID: 23954337. 61. Stefanini GG, Cerrato E, Pivato CA, et al. Unplanned percutaneous coronary revascularization after TAVR: a multicenter international registry. JACC Cardiovasc Interv 2021;14:198–207. https://doi.org/10.1016/j.jcin.2020.10.031; PMID: 33478637. 62. Vilalta V, Asmarats L, Ferreira-Neto AN, et al. Incidence,

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clinical characteristics, and impact of acute coronary syndrome following transcatheter aortic valve replacement. JACC Cardiovasc Interv 2018;11:2523–33. https://doi. org/10.1016/j.jcin.2018.09.001; PMID: 30573061. 63. Lugomirski P, McArdle B, Alak A, et al. Late presentation of left main coronary artery impingement post-transcatheter aortic valve replacement. JACC Cardiovasc Interv 2015;8:e159–60. https://doi.org/10.1016/j.jcin.2015.03.033; PMID: 26315749. 64. Ramirez R, Ovakimyan O, Lasam G, Lafferty K. A very late presentation of a right coronary artery occlusion after transcatheter aortic valve replacement. Cardiol Res 2017;8:131–3. https://doi.org/10.14740/cr559w; PMID: 28725331. 65. Soufras GD, Hahalis G, Kounis NG. Thrombotic complications associated with transcatheter aortic valve implantation: the role of Kounis hypersensitivity-associated thrombotic syndrome. Cardiovasc Pathol 2014;23:383–4. https://doi. org/10.1016/j.carpath.2014.06.004; PMID: 25060387. 66. Rodes-Cabau J, Masson JB, Welsh RC, et al. Aspirin versus aspirin plus clopidogrel as antithrombotic treatment following transcatheter aortic valve replacement with a balloon-expandable valve: The ARTE (Aspirin Versus Aspirin + Clopidogrel Following Transcatheter Aortic Valve Implantation) randomized clinical trial. JACC Cardiovasc Interv 2017;10:1357–65. https://doi.org/10.1016/j.jcin.2017.04.014; PMID: 28527771. 67. Brouwer J, Nijenhuis VJ, Delewi R, et al. Aspirin with or without clopidogrel after transcatheter aortic-valve implantation. N Engl J Med 2020;383:1447–57. https://doi. org/10.1056/NEJMoa2017815; PMID: 32865376. 68. Otto CM, Nishimura RA, Bonow RO, et al. 2020 ACC/AHA guideline for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation 2021;143:e72–227. https://doi.org/10.1161/CIR.0000000000000932; PMID: 33332149. 69. Tarantini G, Mojoli M, Windecker S, et al. Prevalence and impact of atrial fibrillation in patients with severe aortic stenosis undergoing transcatheter aortic valve replacement: an analysis from the SOURCE XT prospective multicenter registry. JACC Cardiovasc Interv 2016;9:937–46. https://doi. org/10.1016/j.jcin.2016.01.037; PMID: 27085579. 70. Valgimigli M, Bueno H, Byrne RA, et al. 2017 ESC focused update on dual antiplatelet therapy in coronary artery disease developed in collaboration with EACTS: The Task Force for dual antiplatelet therapy in coronary artery disease of the European Society of Cardiology (ESC) and of the European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J 2018;39:213–60. https://doi.org/10.1093/ eurheartj/ehx419; PMID: 28886622. 71. Kuno T, Yokoyama Y, Briasoulis A, et al. Duration of antiplatelet therapy following transcatheter aortic valve replacement: systematic review and network meta-analysis. J Am Heart Assoc 2021;10:e019490. https://doi.org/10.1161/ JAHA.120.019490; PMID: 33870703.

Ischaemic Heart Disease

Relationship Between Exposure to Sulphur Dioxide Air Pollution, White Cell Inflammatory Biomarkers and Enzymatic Infarct Size in Patients With ST-segment Elevation Acute Coronary Syndromes Laura Díaz-Chirón ,1 Luis Negral ,2,3 Laura Megido ,3 Beatriz Suárez-Peña ,4 Alberto Domínguez-Rodríguez ,5,6,7 Sergio Rodríguez ,8,9 Pedro Abreu-Gonzalez ,10 Isaac Pascual ,11,12,13 César Moris 11,12,13 and Pablo Avanzas 11,12,13 1. Department of Cardiology, Valle del Nalón Hospital, Asturias, Spain; 2. Department of Chemical and Environmental Engineering, Technical University of Cartagena, Cartagena, Spain; 3. Department of Chemical and Environmental Engineering, Polytechnic School of Engineering, Gijón Campus, University of Oviedo, Gijón, Spain; 4. Department of Materials Science and Metallurgical Engineering, Polytechnic School of Engineering, Gijón Campus, University of Oviedo, Gijón, Spain; 5. Hospital Universitario de Canarias, Servicio de Cardiología, Tenerife, Spain; 6. Facultad de Ciencias de la Salud, Departamento de Enfermería, Universidad de La Laguna, Tenerife, Spain; 7. Universidad Europea de Canarias, Facultad de Ciencias de La Salud, La Orotava, Tenerife, Spain; 8. Estación Experimental De Zonas Áridas, EEZA CSIC, Almería, Spain; 9. Instituto de Productos Naturales de y Agrobiologia, IPNA CSIC, Tenerife, Spain; 10. Department of Physiology, Faculty of Medicine, University of La Laguna, San Cristóbal de La Laguna, Spain; 11. Hospital Universitario Central de Asturias, Department of Cardiology, Oviedo, Spain; 12. Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Spain; 13. Department of Medicine, University of Oviedo, Oviedo, Spain

Abstract

Aims: To analyse the relationship among air pollutants, markers of inflammation and infarct size in patients with acute coronary syndrome (ACS). Methods: This was a prospective analysis of consecutive patients admitted to hospital because of ACS. Cardiac biomarkers were drawn. The daily mean values of the air pollutants from the day before until 7 days before admission were analysed. The study population was stratified according to infarct size, based on median peak troponin value. Results: Patients were divided into two groups of 108 subjects each, according to median peak troponin value. Patients with extensive MIs had a higher neutrophil:lymphocyte ratio and leukocyte and neutrophil counts than patients with smaller MIs. In addition, they were exposed to higher concentrations of sulphur dioxide (9.7 ± 4.1 versus 8.4 ± 3.1 μg/m3; p=0.009) and lower concentrations of ozone (33.8 ± 13.7 versus 38.6 ± 14.5 μg/m3; p=0.014). Multivariate analysis showed that sulphur dioxide levels (OR 1.12; 95% CI [1.031–1.21]; p=0.007) and neutrophil/lymphocyte ratio (OR 1.08; 95% CI [1.011–1.17]; p=0.024) were independent predictors of infarct size. Conclusion: Patients with extensive MIs had higher white cell inflammatory levels and had been exposed to higher sulphur dioxide concentrations in the ambient air.

Keywords

Ambient air pollution, white cell inflammation, ST-segment elevation acute coronary syndrome, myocardial infarct size, troponin, neutrophil:lymphocyte ratio, sulphur dioxide Disclosure: PA is deputy editor of European Cardiology Review; this did not influence peer review. All other authors have no conflict of interests to declare. Trial registration: This is an observational, non-randomised study, so it has not been registered. Consent and ethics: Informed consent was obtained from patients and they consented to the submission of research to the journal. This study was carried out in accordance with the Code of Ethics of the World Medical Association (Declaration of Helsinki). Data availability statement: Authors elect not to share data. Received: 5 August 2021 Accepted: 26 August 2021 Citation: European Cardiology Review 2021;16:e50. DOI: https://doi.org/10.15420/ecr.2021.37 Correspondence: Pablo Avanzas, Department of Cardiology, Hospital Universitario Central de Asturias, Avenue of Rome s/n, 33011 Oviedo, Spain. E: avanzas@secardiologia.es Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Cardiovascular diseases are the leading cause of mortality throughout the world including Spain, mainly in the form of ischaemic heart disease.1–3 Acute coronary syndrome (ACS) is one of the most severe forms of presentation of ischaemic heart disease. Coronary atherosclerosis is the most frequent pathophysiological process underlying ACS, which is complicated by atherosclerotic plaque rupture or erosion.4 A range of factors have been reported to contribute to the development of ACS.5 The classic risk factors related to the development of cardiovascular diseases are smoking, arterial hypertension, dyslipidaemia

and diabetes. In addition, many epidemiological studies have found an association between environmental pollution exposure and harmful health effects, with an important increase in morbidity and mortality.6 The existing evidence indicates that most deaths caused by environmental pollution are attributable to cardiovascular diseases.7 This has led to the suggestion that environmental pollution constitutes a new modifiable cardiovascular risk factor.8 Air pollution consists of a complex mixture of compounds in the form of gases and particulate matter (PM), with evidence supporting PM as the

Air Pollution, Inflammatory Biomarkers and Infarct Size In STEMI Patients Figure 1: Pollution in Study Area

DU 2.50 1.50 1.00 0.75 0.50 0.25 0.00 -0.25 -0.50 Distribution of sulphur dioxide over western Europe detected from satellite (sensor OMI) according to Fioletov et al. shown in Dobson units (DU). The black arrow indicates the location of Asturias, the study region. Source: Fioletov et al. 2016.11 Adapted from Copernicus Publications under a Creative Commons (CC BY 3.0) licence.

main cause of cardiovascular morbidity and mortality.6 The precise mechanisms whereby the inhaled particles produce their adverse effects upon the cardiovascular system are not fully clear.9 After entering the body through the respiratory system, inhaled PM may trigger an inflammatory response at pulmonary level, with a secondary systemic inflammatory response that in turn exerts its cardiovascular effects.10 This study was carried out in Asturias in northern Spain, a region where coal burning and heavy industry have regularly been sources of sulphur dioxide and other pollutants. Satellites often detect high loads of sulphur dioxide over this region (Figure 1).11 Considering the pollution levels in the Asturias region, we hypothesise that exposure to ambient air pollution days before an acute MI could influence the observed white cell inflammatory response and the infarct size.12 Therefore, this study analyses the influence of exposure to environmental pollutants on the white cell inflammatory markers in patients with acute MI, evaluates whether such exposure influences infarct size and reviews current data in the literature.

Methods Study Population

A prospective study was carried out involving 236 patients consecutively admitted to Hospital Universitario Central de Asturias (HUCA) from 1 January 2014 to 31 December 2015 with a diagnosis of ST-segment elevation acute coronary syndrome (STEACS), with successful (final TIMI flow 3) primary angioplasty/percutaneous coronary intervention (PCI). STEACS was defined according to the European Society of Cardiology clinical practice guidelines as persistent chest pain or other symptoms indicating ischaemia and ST-segment elevation on at least two contiguous electrocardiographic leads.13 Twenty patients were excluded due to sepsis, surgery or trauma in the

previous 3 months, neoplasms, cirrhosis, chronic inflammatory or autoimmune diseases, active corticosteroid treatment, a life expectancy of less than one year or unsuccessful angioplasty (final TIMI flow 0, 1 or 2). The final cohort consisted of 216 patients.

Primary Angioplasty

Conventional coronary angiography was performed using radial or femoral artery access. The angiograms were evaluated based on the modified 17-segment model proposed by the American Heart Association, which includes the major coronary artery trunks and their main branches.14 An obstructive lesion was defined as a reduction of >70% in vessel diameter, except in the case of the left common trunk, where the percentage was defined as >50%. PCI was performed as established in the clinical practice guidelines.13

Study Variables

With regard to air pollutants and meteorological variables, we analysed daily mean values (24 hours) from the day before (lag 1) until 7 days before admission (lag 7) of each of the 216 patients admitted with ACS in the period 2014–2015. These mean values were calculated based on the data recorded in one of the four air quality monitoring stations in the municipality of Oviedo. Data were supplied by the local authorities (Consejería de Fomento, Ordenación del Territorio y Medio Ambiente). The selected station was Palacio de Deportes (43° 22' 03.1" N; 5° 49' 54.4" W), which is in an urban area. A nearby highway with heavy traffic clearly influenced the recordings. The access to the city through this highway was shut down for several days in December 2015 because of high concentrations of PM10 (particles ≤10 μm diameter that can be inhaled). For the air pollutants, we analysed the data for sulphur dioxide (SO2), nitric oxide (NO), nitrogen dioxide (NO2), carbon monoxide (CO), ozone (O3), benzene (C6H6), toluene (C7H8), xylene (C8H10) and PM. For meteorological variables, we recorded precipitation (in mm), temperature, pressure, relative humidity and wind speed.

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Air Pollution, Inflammatory Biomarkers and Infarct Size In STEMI Patients A number of clinical variables were compiled for the patients, including cardiovascular risk factors (age, smoking, arterial hypertension, hypercholesterolaemia and diabetes), sex, kidney disease and previous MI. For the laboratory test parameters, we recorded haemoglobin, leukocytes, neutrophils, lymphocytes and platelet counts from the first blood count made after symptom onset (generally upon patient arrival in hospital), as well as ultra-sensitive troponin T peak concentration.

Table 1: Patient Characteristics by Infarct Size Small Enzymatic Infarct Size (n=108)

Large Enzymatic Infarct Size (n=108)

p-value

Age, years

62 ± 12.8

66.2 ± 13.9

0.023

Male sex, n (%)

89 (82.4%)

87 (80.6%)

0.86

The following coronary angiographic data were recorded: culprit artery; number of diseased vessels; treatment of some vessel apart from the culprit artery; stent placement (or not); the number of stents placed; and final TIMI flow.

Previous MI, n (%)

20 (18.5%)

16 (15%)

0.6

PAD, n (%)

2 (1.9%)

6 (5.6%)

0.28

Renal failure, n (%)

2 (1.9%)

5 (4.6%)

0.44

Stroke, n (%)

2 (1.9%)

Primary Endpoint

Cardiovascular Risk Factors Hypertension, n (%)

42 (38.9%)

56 (51.9%)

0.07

Smoking, n (%)

68 (63%)

67 (62%)

Dyslipidaemia, n (%)

36 (33.3%)

46 (42.6%)

0.21

Diabetes, n (%)

22 (20.4%)

32 (29.6%)

0.16

Time from FMC to PCI, minutes

69 [101-54]

75 [59–111]

0.29

Successful reperfusion, n (%)

108 (100%)

Predischarge LVEF, %

55.4 ± 10.4

50.8 ± 12.8

0.005

Left main coronary artery, n (%) 6 (%)

9 (%)

0.61

LAD artery, n (%)

42 (%)

47 (%)

The relationship between air pollutants an myocardial infarct size was studied by an analysis of time series. Continuous variables were reported as the mean ± SD or as the median and interquartile range (IQR) in the absence of normal data distribution. Qualitative variables were reported as absolute values and percentages. Ambient air pollution values for each patient were calculated as 24-hour averages from the previous day up to 7 days before admission.

Circumflex artery, n (%)

11 (%)

12 (%)

Right coronary artery, n (%)

48 (%)

40 (%)

Vein graft, n (%)

1 (%)

0 (%)

For the purpose of the analysis, patients were divided into two groups of 108 according to infarct size, based on the median peak troponin value (2,991.5 ng/ml). The baseline characteristics of the two groups of patients were compared using the χ-squared test for categorical variables. Continuous quantitative variables with a normal distribution were compared using the Student’s t-test, while the nonparametric Mann– Whitney U-test or Kruskal–Wallis test was used in the absence of a normal distribution.

Patients were classified into two groups by enzymatic infarct size. FMC = first medical contact. LAD = left anterior descending; LVEF = left ventricle ejection fraction; PAD = peripheral arterial disease; PCI: percutaneous coronary intervention; STEACS = ST-elevation acute coronary syndrome.

A multivariate analysis was performed based on a regression model in which the dependent variable was infarct size and the independent variables were the parameters found to be significant (p<0.05) in the univariate analysis. The results were expressed using the OR and 95% CI. Statistical significance was considered for p<0.05 in all cases. The SPSS statistical package was used throughout.

Results

The primary endpoint of this study was to investigate the impact of the exposure to ambient air pollutants on white cell inflammatory markers in patients with acute MI, and evaluate whether such exposure influences infarct size. White cell inflammatory activity was assessed based on the neutrophil:lymphocyte ratio (NLR; absolute counts). Infarct size was analysed based on the median peak troponin value. For the purpose of the analysis, a large enzymatic infarct size was defined as infarction with peak troponin values above the median, while a small enzymatic infarct size was defined as infarction with peak troponin values below the median.

Statistical Analysis

A total of 236 patients were recruited, of whom 216 had data finally analysed after applying the exclusion criteria. The baseline characteristics of the two groups are shown in Table 1. There were significant differences between the two groups in terms of age and ventricular function at discharge. The patients with extensive infarcts were comparatively older and exhibited poorer ventricular function. There were no statistically significant differences between the

STEACS Presentation

Culprit Lesion

Coronary Artery Disease Extension One vessel disease, n (%)

61 (56.5%)

57 (52.8%)

Two vessel disease, n (%)

34 (31.5%)

Three vessel disease, n (%)

23 (12%)

17 (15.7%)

Table 2: Biochemical Results by Enzymatic Infarct Size Small Enzymatic Infarct Size (n=108)

Large Enzymatic Infarct Size (n=108)

p-value

Haemoglobin, mg/dl

14.8 ± 1.6

14.2 ± 2.2

0.019

Leukocytes, 10 /l

10.8 ± 3.4

12.5 ± 4.9

0.04

Neutrophils, 10 /l

6.9 ± 3.2

8.9 ± 4.5

<0.001

Lymphocytes, 109/l

2.9 ± 1.6

2.4 ± 1.5

0.029

Platelets, 10 /l

230 ± 72.7

236 ± 69.1

0.5

Troponin T, ng/ml

1,391 ± 888

7,767 ± 4,886

<0.001

NLR

3.8 ± 4.2

5.2 ± 4

0.015

NLR = neutrophil:lymphocyte ratio.

two groups in terms of the prevalence of cardiovascular risk factors, culprit lesion or the extent of coronary disease. The laboratory test parameters are reported in Table 2. Patients with larger MIs presented higher neutrophil:lymphocyte ratios, leukocyte

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Air Pollution, Inflammatory Biomarkers and Infarct Size In STEMI Patients Table 3: Meteorological Variables: Particulate and Gaseous Pollutant Levels

admitted due to STEACS treated with successful PCI. Patients with large enzymatic MIs presented with higher neutrophil:lymphocyte ratios.

Small Enzymatic Large Enzymatic p-value Infarct Size Infarct Size (n=108) (n=108) Meteorological Variables Wind speed (m/s)

2.2 ± 0.7

2.1 ± 0.6

0.15

Temperature (°C)

12.9 ± 4.2

13.4 ± 4.1

0.42

Relative humidity (%)

81 ± 7

81.5 ± 6.9

0.6

Pressure (hPa)

979.3 ± 5.9

979.1 ± 6.9

0.78

Precipitation (mm)

3.4 ± 3.6

2.8 ± 2.8

0.2

SO2 (μg/m3)

8.4 ± 3.1

9.7 ± 4.1

0.009

NO2 (μg/m3)

32.3 ± 9.1

34.2 ± 8.2

0.11

NO (μg/m3)

28.1 ± 24.4

32.2 ± 24.4

0.21

CO (mg/m )

0.3 ± 0.1

0.4 ± 0.1

0.25

O3 (μg/m )

38.6 ± 14.5

33.8 ± 13.7

0.014

C6H6 (μg/m )

0.6 ± 0.3

0.7 ± 0.3

0.57

C7H8 (μg/m3)

2.4 ± 1.4

2.6 ± 1.4

0.41

C8H10 (μg/m3)

1.4 ± 0.8

1.5 ± 0.8

0.38

28.6 ± 8.8

31.2 ± 8

0.16

Gaseous Pollutants

Particulate Matter PM10 (μg/m3)

Data on atmospheric pollution in ambient air and meteorological variables between the previous day and the 7 days before admission. CO = carbon monoxide; C6H6 = benzene; C7H8 = toluene; C8H10 = xylene; NO = nitric oxide; NO2 = nitrogen dioxide; O3 = ozone; SO2 = sulphur dioxide; PM10 = particulate matter with an aerodynamic diameter smaller than 10 μm.

Table 4: Multivariate Predictors of Enzymatic Infarct Size OR

95% CI

p-value

Hypertension

1.85

[1.05–3.27]

0.032

SO2 levels

1.12

[1.031– 1.21]

0.007

NLR

1.08

[1.011–1.17]

0.024

Multivariate predictors of large enzymatic infarct size in 216 patients with acute coronary syndrome and ST-elevation MI. After adjustment for age (p=0.1), sex (p=0.73), diabetes (p=0.27), smoking (p=0.61), dyslipidaemia (p=0.3), time from first medical contact to percutaneous coronary intervention (p=0.33), haemoglobin (p=0.3) and levels and ozone levels (p=0.27). NLR = neutrophil:lymphocyte ratio; SO2 = sulphur dioxide.

and neutrophil counts but lower lymphocyte counts than patients with smaller MIs. The meteorological variables and the levels of particulate and gaseous pollutants are shown in Table 3. No statistically significant differences were observed with regard to the meteorological variables or airborne particles. However, patients with larger MIs had been exposed to higher levels of sulphur dioxide and to lower levels of ozone in the 7 days before to admission. In the multivariate model, arterial hypertension, the sulphur dioxide levels, and the neutrophil:lymphocyte ratio were identified as independent predictors of infarct size in patients with STEACS (Table 4).

Discussion

The main finding of our study is the association found between sulphur dioxide, white cell inflammatory markers and infarct size in patients

Epidemiological Data

Air pollution is the single largest environmental health risk worldwide, with air pollution alone causing a significant number of deaths per year (one in eight of all deaths). In 2016, air pollution was the second most important risk factor for non-communicable diseases worldwide and 91% of the world’s population was exposed to harmful levels of air pollution. This mortality effect of air pollution is mainly due to heart disease and stroke, which are also the leading causes of mortality and morbidity worldwide. Therefore, by reducing air pollution, we could reduce morbidity and mortality from cardiovascular diseases.15

Air Pollution Particles

Air pollutants include gaseous pollutants (such as carbon monoxide, nitrogen oxides, ozone and sulphur dioxide) and PM. PM has been linked to a number of cardiovascular diseases; in particular, it seems that PM2.5 (particles ≤2.5 μm diameter), which comes from traffic and industry, and ultrafine particles (UFPs) are the most closely linked, as both can more easily reach the smaller airways and alveoli, and UFPs can even cross the alveolar-capillary membrane and spread through the systemic circulation to distant organs.

Air Pollution and Cardiovascular Disease

Several pathways have been proposed by which PM cause cardiovascular disease. One of them is the direct pathway, i.e. when PM2.5 and especially UFP move into the bloodstream and reach remote organs. Due to the size, charge and chemical composition of UFP, it is much easier for them to pass through the lung epithelium and the alveolar-capillary barrier than larger particles. This exposure, even at low concentrations, can lead to particulates entering the bloodstream to reach a remote organ and potentially cause cumulative toxicity. This translocation of UFPs to the bloodstream has detrimental effects on the cardiovascular system. After deposition on the vascular endothelium, UFPs can aggravate local oxidative stress and inflammation, resulting in atherosclerotic plaque instability, and may eventually lead to thrombus formation, leading to ACS. Indirect pathways include oxidative stress at the pulmonary level and the inflammatory response, as well as specific pulmonary receptors that would activate the autonomic nervous system.16 Systemic inflammation is a risk factor for the progression of atherosclerosis, and pro-inflammatory mediators are strongly associated with increased blood coagulability and endothelial dysfunction, which may exacerbate myocardial ischaemia. Several studies in the US and Europe have indicated high numbers of hospital admissions due to ischaemic heart disease related to higher PM levels, and a meta-analysis in 11 European cohorts of the ESCAPE project confirmed that long-term exposure to PM is associated with the incidence of coronary events, and this association persists at exposure levels even below the current European limit.17–19 When ambient particles interact with atmospheric gases (ozone, sulphur, nitric oxide and carbon monoxide), they generate secondary particles that are also associated with cardiovascular disease. For example, in a study by Li et al., a 10 μg/m3 increase in 2-day mean concentrations of PM10, SO2 and NO2 was significantly associated with increases in daily coronary heart disease mortality.20

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Air Pollution, Inflammatory Biomarkers and Infarct Size In STEMI Patients Relation of Air Pollution and MI

In the present study, patients with larger MIs had been exposed to higher sulphur dioxide levels and to lower ozone concentrations. Sulphur dioxide emissions are linked to the combustion of coal and other heavy fuels for power generation and in industrial activities. Domínguez-Rodriguez et al. found that patients admitted because of ACS and obstructive lesions had higher sulphur dioxide levels.21 Sulphur dioxide is a gas that at high concentrations can give rise to an inflammatory response at lung level, followed by proinflammatory cytokine release into the systemic circulation, causing endothelial damage and increasing the risk of atherosclerotic plaque rupture and consequent thrombosis.22 Likewise, other studies have reported a direct relationship between environmental sulphur dioxide levels and blood concentrations of proinflammatory and proatherogenic parameters.23 Infarct size is of great prognostic relevance in patients with STEACS. High-sensitivity cardiac troponin T (hs-cTnT) has become the biomarker of choice in assessing myocardial damage in the context of ACS. Its peak concentration has been shown to be a robust indicator of infarct size; as a result, it is widely used in clinical practice. Other biomarkers, such as N-terminal pro-brain natriuretic peptide (NT-pro-BNP) and the NTR (used in our study) are also independent predictors of infarct size in the same way as troponin.24 The NLR relates neutrophils (which reflect the immune response) and lymphocytes (which reflect the adaptive immune response). This parameter has been shown to have greater prognostic relevance than absolute leukocyte count in terms of patient mortality following STEACS.25,26 In our study, the patients with more 1. WHO. The top 10 causes of death. 9 December 2020. https://www.who.int/en/news-room/fact-sheets/detail/thetop-10-causes-of-death (accessed 15 September 2021). 2. Joseph P, Leong D, McKee M, et al. Reducing the global burden of cardiovascular disease, part 1: the epidemiology and risk factors. Circ Res 2017;121:677–94. https://doi. org/10.1161/CIRCRESAHA.117.308903; PMID: 28860318. 3. Instituto Nacional de Estadística. Death Statistic According to Cause of Death. January-May 2019 and 2020. 2020. https:// www.ine.es/dyngs/INEbase/en/operacion.htm?c=Estadistica_ C&cid=1254736176780&menu=ultiDatos&idp=1254735573175 (accessed 15 September 2021). 4. Santos-Gallego CG, Picatoste B, Badimon JJ. Pathophysiology of acute coronary syndrome. Curr Atheroscler Rep 2014;16:401. https://doi.org/10.1007/s11883014-0401-9; PMID: 24504549. 5. Arbab-Zadeh A, Nakano M, Virmani R, Fuster V. Acute coronary events. Circulation 2012;125:1147–56. https://doi. org/10.1161/CIRCULATIONAHA.111.047431; PMID: 22392862. 6. Brook RD, Rajagopalan S, Pope CA, et al. Particulate matter air pollution and cardiovascular disease: an update to the scientific statement from the American Heart Association. Circulation 2010;121:2331–78. https://doi.org/10.1161/ CIR.0b013e3181dbece1; PMID: 20458016. 7. Sunyer J. Atmospheric pollution and mortality. Med Clin (Barc) 2002;119:453–4. https://doi.org/10.1016/S00257753(02)73453-2; PMID: 12385653. 8. Araujo JA. Are ultrafine particles a risk factor for cardiovascular diseases? Rev Esp Cardiol 2011;64:642–5. https://doi.org/10.1016/j.rec.2011.05.006; PMID: 21723025. 9. Miller MR, Newby DE. Air pollution and cardiovascular disease: car sick. Cardiovasc Res 2020;116:279–94. https:// doi.org/10.1093/cvr/cvz228; PMID: 31583404. 10. Miller MR, Shaw CA, Langrish JP. From particles to patients: oxidative stress and the cardiovascular effects of air pollution. Future Cardiol 2012;8:577–602. https://doi. org/10.2217/fca.12.43; PMID: 22871197. 11. Fioletov VE, McLinden CA, Krotkov N, et al. A global catalogue of large SO2 sources and emissions derived from

12.

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16.

17.

18.

19.

extensive infarcts had higher NLRs, in concordance with the aforementioned studies.

Limitations

Our study has several limitations that must be considered. This is a nonrandomised, observational study and our results must be considered hypothesis generating, which can potentially constitute the basis of broader investigations. An inherent problem common in studies that analyse the effects of air pollution is that we cannot exclude the existence of errors in the measurement of exposure due to differences between what is measured by the sampling stations and the actual exposure of each person in a population (interindividual variability). The climate of a region depends on various geographical factors such as latitude, relief and environment; therefore, the results of our study should be verified with those obtained in other geographical areas with different climates from those analysed in this study. Finally, infarct size was not measured by cardiac MRI, which is considered the gold standard for the assessment of myocardial damage and ventricular volumes.

Conclusion

Patients with extensive MIs presented higher levels of white cell inflammatory biomarkers and had previously been exposed to higher sulphur dioxide concentrations than patients with smaller MIs.

the Ozone Monitoring Instrument. Atmos Chem Phys 2016;16:11497–519. https://doi.org/10.5194/acp-16-114972016. Negral L, Suárez-Peña B, Zapico E, et al. Anthropogenic and meteorological influences on PM10 metal/semi-metal concentrations: implications for human health. Chemosphere 2020;243:125347. https://doi.org/10.1016/j. chemosphere.2019.125347; PMID: 31765904. Ibanez B, James S, Agewall S, et al. 2017 ESC guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: the Task Force for the management of acute myocardial infarction in patients presenting with ST-segment elevation of the European Society of Cardiology (ESC). Eur Heart J 2018;39:119–77. https://doi.org/10.1093/eurheartj/ehx393; PMID: 28886621. Austen WG, Edwards JE, Frye RL, et al. A reporting system on patients evaluated for coronary artery disease. Report of the Ad Hoc Committee for Grading of Coronary Artery Disease, Council on Cardiovascular Surgery, American Heart Association. Circulation 1975;51:5–40. https://doi. org/10.1161/01.cir.51.4.5; PMID: 1116248. Tribunal de Cuentas Europeo. Air pollution: our health still does not have enough protection. 2018 [in Spanish]. https:// www.eca.europa.eu/Lists/ECADocuments/SR18_23/SR_AIR_ QUALITY_ES.pdf (accessed 15 September 2021). Du Y, Xu X, Chu M, et al. Air particulate matter and cardiovascular disease: the epidemiological, biomedical and clinical evidence. J Thorac Dis 2016;8:e8–19. https://doi. org/10.3978/j.issn.2072-1439.2015.11.37; PMID: 26904258. Dominici F, Peng RD, Bell ML, et al. Fine particulate air pollution and hospital admission for cardiovascular and respiratory diseases. JAMA 2006;295:1127–34. https://doi. org/10.1001/jama.295.10.1127; PMID: 16522832. von Klot S, Peters A, Aalto P, et al. Ambient air pollution is associated with increased risk of hospital cardiac readmissions of myocardial infarction survivors in five European cities. Circulation 2005;112:3073–9. https://doi. org/10.1161/CIRCULATIONAHA.105.548743; PMID: 16286602. Cesaroni G, Forastiere F, Stafoggia M, et al. Long term

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exposure to ambient air pollution and incidence of acute coronary events: prospective cohort study and metaanalysis in 11 European cohorts from the ESCAPE project. BMJ 2014;348:f7412. https://doi.org/10.1136/bmj.f7412; PMID: 24452269. 20. Li H, Chen R, Meng X, et al. Short-term exposure to ambient air pollution and coronary heart disease mortality in 8 Chinese cities. Int J Cardiol 2015;197:265–70. https://doi. org/10.1016/j.ijcard.2015.06.050; PMID: 26142971. 21. Domínguez-Rodríguez A, Abreu-Afonso J, González Y, et al. Relationship between short-term exposure to atmospheric sulfur dioxide and obstructive lesions in acute coronary syndrome. Med Clin (Barc) 2013;140:537–41. https://doi. org/10.1016/j.medcli.2012.05.040; PMID: 23122610. 22. Araujo JA, Nel AE. Particulate matter and atherosclerosis: role of particle size, composition and oxidative stress. Part Fibre Toxicol 2009;6:24. https://doi.org/10.1186/1743-8977-624; PMID: 19761620. 23. Thompson AMS, Zanobetti A, Silverman F, et al. Baseline repeated measures from controlled human exposure studies: associations between ambient air pollution exposure and the systemic inflammatory biomarkers IL-6 and fibrinogen. Environ Health Perspect 2010;118:120–4. https://doi.org/10.1289/ehp.0900550; PMID: 20056584. 24. Tiller C, Reindl M, Holzknecht M, et al. Biomarker assessment for early infarct size estimation in ST-elevation myocardial infarction. Eur J Intern Med 2019;64:57–62. https://doi.org/10.1016/j.ejim.2019.03.001; PMID: 30878297. 25. Sawant AC, Adhikari P, Narra SR, et al. Neutrophil to lymphocyte ratio predicts short- and long-term mortality following revascularization therapy for ST elevation myocardial infarction. Cardiol J 2014;21:500–8. https://doi. org/10.5603/CJ.a2013.0148; PMID: 24142685. 26. Park JS, Seo KW, Choi BJ, et al. Importance of prognostic value of neutrophil to lymphocyte ratio in patients with ST-elevation myocardial infarction. Medicine (Baltimore) 2018;97:e13471. https://doi.org/10.1097/ MD.0000000000013471; PMID: 30508975.

Coronary Functional Abnormalities

Definitions and Epidemiology of Coronary Functional Abnormalities Andreas Seitz , Johanna McChord , Raffi Bekeredjian , Udo Sechtem

and Peter Ong

Robert-Bosch-Krankenhaus, Department of Cardiology and Angiology, Stuttgart, Germany

Abstract

Coronary functional abnormalities are frequent causes of angina pectoris, particularly in patients with unobstructed coronary arteries. There is a spectrum of endotypes of functional coronary abnormalities with different mechanisms of pathology including enhanced vasoconstriction (i.e. coronary artery spasm) or impaired vasodilatation, such as impaired coronary flow reserve or increased microvascular resistance. These vasomotor abnormalities can affect various compartments of the coronary circulation such as the epicardial conduit arteries and/or the coronary microcirculation. Unequivocal categorisation and nomenclature of the broad spectrum of disease endotypes is crucial both in clinical practice as well as in clinical trials. This article describes the definitions of coronary functional abnormalities with currently accepted cut-off values, as well as diagnostic methods to identify and distinguish endotypes. The authors also provide a summary of contemporary data on the prevalence of the different endotypes of coronary functional abnormalities and their coexistence.

Keywords

Epidemiology; coronary functional abnormalities; angina; vasomotor abnormalities Disclosure: PO is a regional editor on the European Cardiology Review editorial board; this did not influence peer review. All other authors have no conflicts of interest to declare. Received: 28 April 2021 Accepted: 4 September 2021 Citation: European Cardiology Review 2021;16:e51. DOI: https://doi.org/10.15420/ecr.2021.14 Correspondence: Peter Ong, Robert-Bosch-Krankenhaus, Department of Cardiology and Angiology, Auerbachstr. 110, 70376 Stuttgart, Germany. E: Peter.Ong@rbk.de Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Although coronary functional abnormalities have fascinated cardiologists for more than 50 years, their existence has long been neglected.1 Before the advent of percutaneous coronary intervention (PCI), there were a high number of scientific publications regarding coronary functional abnormalities in general and coronary artery spasm in particular. However, after the introduction of PCI, the interest in this topic declined which was accompanied by a reduction in scientific publications on the subject. In recent years interest has grown again and the topic has been receiving more and more attention in the clinical arena. This is why the Coronary Vasomotion Disorders International Study Group (COVADIS) was founded and one of its main aims is to provide unified terminology and definitions for coronary vasomotion disorders.2,3 This may not only facilitate comparison of clinical test results from around the world but would also enhance clinical research and help to provide better care for patients. Knowledge about the definitions and epidemiology of coronary functional abnormalities is essential in this context.

Definitions of Coronary Functional Abnormalities

Although functional coronary abnormalities may occur in the presence or absence of epicardial stenoses they are particularly associated with patients with angina and unobstructed coronary arteries (ANOCA).4 Such patients are often labelled as having ‘non-cardiac chest pain’ and frequently have impaired quality of life.5 However, a significant proportion of these patients suffer from coronary functional abnormalities (for more details, see the below paragraph on epidemiology) and establishing a diagnosis of coronary functional abnormalities followed by stratified medical therapy can significantly improve quality of life.6 Patients with ANOCA may also include patients with angina in whom the haemodynamic

relevance of moderate epicardial stenoses has been ruled out by using a pressure wire, for example. Several invasive investigations in patients with ANOCA are recommended by the European Society of Cardiology Guidelines for the diagnosis and management of chronic coronary syndromes.7 Intracoronary provocation testing in search of coronary spasm holds a Class IIa recommendation and wire-based investigations for measuring coronary flow reserve (CFR) and microvascular resistance in search of abnormalities of microvascular dilating function are equally recommended with a Class IIa recommendation. The comprehensive invasive assessment of coronary function is often referred to as interventional diagnostic procedure (IDP) (Figure 1). In the following section, we will focus on definitions of coronary functional abnormalities in patients with ANOCA. Functional abnormalities of the coronary circulation can be divided into those occurring in the epicardial arteries and those affecting the coronary microcirculation – a constellation also referred to as microvascular angina (Table 1). Usually, the latter is defined by a vessel diameter of <500 µm. It is also possible that vasomotion disorders affect the epicardial and the coronary microvessels in the same patient and a progression from microvascular to epicardial spasm over time has recently been suggested.8 However, data on the frequency of such a constellation are sparse.8–11 The two main mechanisms of functional coronary abnormalities are enhanced vasoconstriction and impaired vasodilatation.12 The former can be diagnosed during intracoronary provocation testing in search of coronary spasm using acetylcholine or ergonovine.4,13 The latter can be

Definitions and Epidemiology of Coronary Functional Abnormalities Figure 1: Comprehensive Assessment of Coronary Function Using an Interventional Diagnostic Procedure

1. Diagnostic angiography 10 min

Acetylcholine

2. Spasm provocation testing 20 min

Nitroglycerin

Adenosine

3. Wire-based assessment of vasodilation 10 min

Monitor: • ECG • Symptoms • Angiogram

CFR and MVR by Doppler or thermodilution

Diagnosis: Coronary spasm (epicardial/microvascular) and/or Impaired vasodilation (CFR/MVR) Total: ~40 min

Following diagnostic angiography, intracoronary acetylcholine spasm provocation testing is performed in search of epicardial and/or microvascular coronary spasm. Next, microvascular dilatory function is measured invasively using either Doppler or thermodilution technique. This comprehensive interventional diagnostic procedure allows the assessment of structural and functional coronary disorders within a total time of about 40 minutes. CFR = coronary flow reserve; MVR = microvascular resistance.

Table 1: Criteria for Microvascular Angina According to the COVADIS Group 1. Symptoms of MI • Effort and/or rest angina • Angina equivalents, such as shortness of breath 2. Absence of obstructive CAD • Coronary CTA • Invasive coronary angiography 3. Objective evidence of MI • Ischaemic ECG changes during an episode of chest pain • Stress-induced chest pain and/or ischaemic ECG changes in the presence or absence of transient/reversible abnormal myocardial perfusion and/or wall motion abnormality 4. Evidence of impaired coronary microvascular function • Coronary microvascular spasm, defined as reproduction of symptoms, ischaemic ECG shifts but no epicardial spasm during acetylcholine testing • Impaired CFR (cut-off values depending on methodology use between ≤2.0 and ≤2.5) • Abnormal coronary microvascular resistance indices (e.g. IMR >25 or HMR >2.5 mmHg/cm/s) • Coronary slow flow phenomenon defined as TIMI frame count >25 Definitive MVA is only diagnosed if all 4 criteria are present. Suspected MVA is diagnosed if criteria 1 and 2 plus either 3 or 4 are present. CAD = coronary artery disease; CFR = coronary flow reserve; CTA computed tomographic angiography; HMR = hyperaemic microvascular resistance; IMR = index of microcirculatory resistance; MVA = microvascular angina TIMI = thrombolysis in MI. Source: Ong et al. 2018.2 Adapted with permission from Elsevier.

diagnosed by non-invasive techniques or invasively when CFR is measured with a dedicated wire (Doppler or thermodilution technique) using adenosine. The CFR is defined as the ratio between maximal coronary blood flow during adenosine-induced hyperaemia and resting

flow at baseline. Usually, a value of ≤2.0–2.5 is considered to be abnormal, i.e. impaired CFR, with strong adverse prognostic data in patients with ANOCA.14,15 It should, however, be noted that an impaired CFR may be due to several constellations of resting and peak flow. On one hand CFR may be impaired because the microcirculation is unable to sufficiently dilate. In such instances resting flow may be normal but peak flow is impaired. On the other hand, a frequent observation is that resting flow is abnormally high, perhaps due to metabolic autoregulation in the presence of cardiovascular risk factors.16 This constellation may also lead to impaired CFR despite normal or near-normal adenosine flow. Whether these two different constellations when measuring CFR carry prognostic information is unknown but is currently under investigation. Another important parameter that can be assessed simultaneously while measuring CFR is the index of microvascular resistance (IMR) when using the thermodilution technique or hyperaemic microvascular resistance (HMR) when using the Doppler technique. Both measurements reflect the coronary microvascular resistance during stimulation with adenosine and it is important to know that its calculation is independent of the resting flow. Impaired vasodilatation of the coronary microcirculation may be associated with structural alterations of the microvasculature, such as arteriolar remodelling and capillary rarefaction.17–19 Thus documentation of elevated hyperaemic resistance could be interpreted as indirect evidence of a structural phenomenon with or without an additional functional coronary abnormality. Theoretically, capillary rarefaction should also be associated with increased resistance at baseline. Nevertheless, microvascular structural alterations are frequently neglected and the term functional coronary abnormalities is often used as a distinction from structural epicardial (stenosing) coronary disease.20 In light of the aforementioned conditions, several disease endotypes can be defined (Figure 2). Here are the definitions of the most frequent endotypes based on the available evidence. Epicardial coronary spasm: • Reproduction of the patient’s symptoms during provocative testing. • Ischaemic ECG shifts on simultaneous 12-lead ECG during provocative testing. • Epicardial coronary constriction ≥90% diameter reduction during provocative testing. Microvascular coronary spasm (Figure 3): • Reproduction of the patient’s symptoms during provocative testing. • Ischaemic ECG shifts on simultaneous 12-lead ECG during provocative testing. • Absence of epicardial coronary constriction ≥90% diameter reduction during provocative testing. • In some centres, further evidence is generated by abnormal lactate concentrations from coronary sinus blood samples during provocative testing. Impaired CFR: • Depending on the Doppler or thermodilution technique, CFR is calculated based on average peak flow velocity (APV) or mean transit time (Tmn), respectively, as follows: CFRDoppler = APVPeak /APVRest and CFRthermo = TmnRest /TmnPeak • Usually, a CFR ≤2.0–2.5 during flow measurements using a dedicated wire (Doppler or thermodilution technique) and adenosine infusions (IV or intracoronary) is considered abnormal.

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Definitions and Epidemiology of Coronary Functional Abnormalities Figure 2: Definition of Functional Coronary Disorder Endotypes as Determined by the Interventional Diagnostic Procedure ADE test

CFR nl MVR nl

ADE nl

CFR nl MVR ↑

ACh test

CFR ↓ MVR nl

CFR ↓ MVR ↑

ACh nl

ADE abnormal

Pathological vasodilation (CFR ↓)

Pathological vasoconstriction epicardial

Pathological vasodilation (MVR ↑)

Pathological vasoconstriction microvascular

Epicardial spasm

Microvascular spasm

ACh abnormal

Definition of endotypes Based on the sequential testing of the coronary vasomotor response to acetylcholine and adenosine during the interventional diagnostic procedure different functional coronary disorder endotypes can be distinguished, which can also be observed in combination. ADE = adenosine; ACh = acetylcholine; CFR = coronary flow reserve; MVR = microvascular resistance; nl = normal.

Enhanced microvascular resistance: • Microvascular resistance is calculated using distal intracoronary pressure and APV or Tmn as follows: HMR = Pd/APVPeak and IMR = Pd* TmnPeak • Different cut-off values for HMR and IMR have been applied depending on the technique and the patient population. • Frequently an IMR of >25 and an HMR of >2.4 are considered abnormal. It is important to remember that in a given patient, several of the abovementioned disease endotypes may be present.21,22 This not only leads to a high number of complex endotypes but also means that there may be patients with more than one coronary functional abnormality, e.g. coronary microvascular spasm and impaired CFR. Consequently, understanding the pathophysiology in an individual patient, as well as creating well-characterised and homogeneous groups of endotypes for clinical trials is challenging.

Epidemiology of Coronary Functional Abnormalities

The true prevalence of patients with coronary functional abnormalities is difficult to determine as there are no reliable non-invasive tests that cover all the endotypes. Novel smart ECG devices may allow detection of ischaemic ECG shifts in patients with chest pain of unknown origin pointing towards a cardiac cause.23,24 It is currently unknown how often these symptoms are caused by stenosing coronary disease or a functional coronary abnormality. While common in patients with coronary artery spasm, the frequency of ischaemic ECG changes in patients with impaired

CFR and/or increased microvascular resistance is unknown. Nevertheless, this represents an interesting area of investigation in contemporary precision medicine and upcoming studies are eagerly awaited. The number of patients with ANOCA will most likely further increase due to the fact that current guidelines recommend performing a coronary CT in patients with stable angina.25 However, despite the advantage of providing information on the presence and morphology of coronary plaque, this CT-based anatomical approach does not allow assessment of functional coronary abnormalities. Although few small studies have recently evaluated the feasibility of static or dynamic adenosine-stress CT perfusion examinations in patients with ANOCA, it is unclear whether these methods will enter clinical routine.26,27 Unfortunately, testing for functional abnormalities of vasoconstriction is not possible using CT.

Chronic Coronary Syndromes with Non-obstructed Coronary Arteries

It is well known that unobstructed coronary arteries are found in more than 50% of cases when looking at patients with chronic coronary syndromes undergoing elective invasive diagnostic coronary angiography for suspected stenosing coronary disease.28 Although this number may be reduced by better patient selection, the number of patients with ANOCA will remain high and they may even generate higher costs over time compared to patients with obstructive coronary disease.29 This underlines the high burden for our healthcare systems and highlights the need for appropriate diagnostic assessments in search of coronary functional abnormalities. The frequency of coronary functional abnormalities in patients with ANOCA has been extensively investigated. Most older studies only looked at certain disease endotypes, such as coronary spasm only or impaired CFR only, and reported a prevalence of 50–60% in selected patients with ANOCA for each

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Definitions and Epidemiology of Coronary Functional Abnormalities Figure 3: Interventional Diagnostic Procedure in a 33-year-old Male Patient with Repeated Episodes of Resting Angina and Unobstructed Coronary Arteries

Figure 4: Frequency of Functional Coronary Disorder Endotypes in Angina and Non-obstructed Coronary Arteries A 100%

90% 80% 70% 60% 50% 40% 30% 20% 10% 0%

A CFR normal/ no spasm Ford et al.22

CFR normal/ spasm Suda et al.21

CFR reduced/ no spasm

CFR reduced/ spasm

Seltz et al.33

Konst et al.10

IMR increased/ no spasm

IMR increased/ spasm

B 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% IMR normal/ no spasm A: Microvascular vasodilatation in response to intracoronary administration of adenosine 200 µg was normal (CFR 4.6, HMR 1.3). B: Acetylcholine spasm provocation testing revealed ischaemic ECG changes (red arrows) but no significant epicardial vasoconstriction (<90%) consistent with microvascular spasm. FFR = fractional flow reserve; CFR = coronary flow reserve; HMR = hyperaemic microvascular resistance.

pathomechanism.30–32 Recent studies focused on the comprehensive assessment of coronary function resulting in a growing body of evidence regarding the frequency of enhanced coronary vasoconstriction, impaired microvascular vasodilatation (i.e. reduced CFR or increased microvascular resistance) or a combination thereof (Figure 4).10,21,22,33 Notably, these trials unanimously suggest that in patients with ANOCA enhanced vasoconstriction (coronary spasm) is much more frequent than impaired vasodilatation. This has important implications not only for future clinical trials but also for daily practice given that – in contrast to impaired CFR which can be assessed non-invasively using positron emission tomography or MRI – coronary vasoconstriction can only be reliably assessed invasively by spasm provocation testing.

Acute Coronary Syndromes with Nonobstructed Coronary Arteries

IMR normal/ spasm

Microvascular function was stratified according to CFR or IMR (CFR normal = ≥2.0; spasm = acetylcholine-induced epicardial and/or microvascular spasm; IMR normal = <25. CFR = coronary flow reserve; IMR = index of microcirculatory resistance.

syndrome, plaque erosion, spontaneous coronary dissection, valvular heart disease, systemic diseases and functional coronary disorders.35 The prevalence of coronary artery spasm is high in this patient population.34,36,37 Although being safe in the acute setting, appropriate testing is rarely performed in clinical practice.34,37,38

Previous Successful Myocardial Revascularisation

Studies have shown that up to 50% of patients with successful PCI complain of ongoing or recurrent angina after the procedure.39,40 Such patients represent another important group of patients in whom investigations of coronary functional abnormalities should be performed. Studies have shown that coronary functional abnormalities can be found in ~60–70% of patients who have had previous successful myocardial revascularisation procedures and have ongoing/recurrent symptoms.41,42

Sex-related Differences

While the frequency of obstructive coronary artery disease is higher in patients with acute coronary syndrome (ACS) compared to those with chronic coronary syndromes, up to 25% of patients presenting with ACS are found to have non-obstructed coronary arteries.34 This group comprises patients with MI with non-obstructed coronary arteries (MINOCA), as well as patients with unstable angina. Various pathomechanisms may be responsible for this emergent clinical scenario, including – but not limited to – pericarditis, myocarditis, takotsubo

Several studies have shown that coronary functional abnormalities are more often found in women compared to men with some trials, such as the WISE study, focusing exclusively on women, however, systematic analyses have found only modest female preponderance.31,43,44 Moreover, prognosis in patients with ANOCA and reduced CFR was found to be equally impaired in men and women.45 Considering the frequent persistence of symptoms following coronary interventions for obstructive coronary artery disease (CAD) one may speculate that many men with obstructive CAD have

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Definitions and Epidemiology of Coronary Functional Abnormalities additional functional coronary abnormalities. Thus, the prevalence of functional abnormalities may be the same in both sexes, but it is under-recognised in men because testing is not performed if coronary stenoses are detected. Coronary functional abnormalities should therefore be considered in all patients with angina in daily clinical practice and future studies should provide more evidence regarding sex differences in this field.32 1. Kaski JC, Crea F, Gersh BJ, Camici PG. Reappraisal of ischemic heart disease. Circulation 2018;138:1463–80. https:// doi.org/10.1161/CIRCULATIONAHA.118.031373; PMID: 30354347. 2. Ong P, Camici PG, Beltrame JF, et al. International standardization of diagnostic criteria for microvascular angina. Int J Cardiol 2018;250:16–20. https://doi.org/10.1016/j. ijcard.2017.08.068; PMID: 29031990. 3. Beltrame JF, Crea F, Kaski JC, et al. International standardization of diagnostic criteria for vasospastic angina. Eur Heart J 2017;38:2565–8. https://doi.org/10.1093/ eurheartj/ehv351; PMID: 26245334. 4. Ford TJ, Ong P, Sechtem U, et al. Assessment of vascular dysfunction in patients without obstructive coronary artery disease: why, how, and when. JACC Cardiovasc Interv 2020;13:1847–64. https://doi.org/10.1016/j.jcin.2020.05.052; PMID: 32819476. 5. Jespersen L, Abildstrom SZ, Hvelplund A, Prescott E. Persistent angina: highly prevalent and associated with long-term anxiety, depression, low physical functioning, and quality of life in stable angina pectoris. Clin Res Cardiol 2013;102:571–81. https://doi.org/10.1007/s00392-013-0568-z; PMID: 23636227. 6. Ford TJ, Stanley B, Good R, et al. Stratified medical therapy using invasive coronary function testing in angina: the CorMicA trial. J Am Coll Cardiol 2018;72:2841–55. https://doi. org/10.1016/j.jacc.2018.09.006; PMID: 30266608. 7. Knuuti J, Wijns W, Saraste A, et al. 2019 ESC guidelines for the diagnosis and management of chronic coronary syndromes. Eur Heart J 2020;41:407–77. https://doi. org/10.1093/eurheartj/ehz425; PMID: 31504439. 8. Nishimiya K, Suda A, Fukui K, et al. Prognostic links between OCT-delineated coronary morphologies and coronary functional abnormalities in patients with INOCA. JACC Cardiovasc Interv 2021;14:606–18. https://doi. org/10.1016/j.jcin.2020.12.025; PMID: 33736768. 9. Martinez Pereyra V, Hubert A, Seitz A, et al. Epicardial and microvascular coronary spasm in the same patient? Acetylcholine testing pointing towards a common pathophysiological background. Coron Artery Dis 2020;31:398–9. https://doi.org/10.1097/ MCA.0000000000000829; PMID: 31658150. 10. Konst RE, Damman P, Pellegrini D, et al. Vasomotor dysfunction in patients with angina and nonobstructive coronary artery disease is dominated by vasospasm. Int J Cardiol 2021;333:14–20. https://doi.org/10.1016/j. ijcard.2021.02.079; PMID: 33711394. 11. Seitz A, Feenstra R, Konst RE, et al. Abstract: Intracoronary nitroglycerine is more effective in preventing epicardial spasm than microvascular spasm during acetylcholine provocation testing. Clinical Research in Cardiology 2021;110:1350. 12. Ong P, Safdar B, Seitz A, et al. Diagnosis of coronary microvascular dysfunction in the clinic. Cardiovasc Res 2020;116:841–55. https://doi.org/10.1093/cvr/cvz339; PMID: 31904824. 13. Seitz A, Beck S, Pereyra VM, et al. Testing acetylcholine followed by adenosine for invasive diagnosis of coronary vasomotor disorders. J Vis Exp 2021;168. https://doi. org/10.3791/62134; PMID: 33616102. 14. Pepine CJ, Anderson RD, Sharaf BL, et al. Coronary microvascular reactivity to adenosine predicts adverse outcome in women evaluated for suspected ischemia results from the National Heart, Lung and Blood Institute WISE (Women’s Ischemia Syndrome Evaluation) study. J Am Coll Cardiol 2010;55:2825–32. https://doi.org/10.1016/j. jacc.2010.01.054; PMID: 20579539. 15. AlBadri A, Bairey Merz CN, Johnson BD, et al. Impact of abnormal coronary reactivity on long-term clinical outcomes in women. J Am Coll Cardiol 2019;73:684–93. https://doi. org/10.1016/j.jacc.2018.11.040; PMID: 30765035. 16. Suppogu N, Wei J, Quesada O, et al. Angina relates to coronary flow in women with ischemia and no obstructive coronary artery disease. Int J Cardiol 2021;333:35–9. https:// doi.org/10.1016/j.ijcard.2021.02.064; PMID: 33662486.

Conclusion

The high number of patients with ANOCA should prompt further assessments in search of functional coronary abnormalities as suggested by the current guidelines. Knowledge about the current definitions and frequencies of coronary functional abnormality endotypes is essential for appropriate classification and selection of the most effective pharmacological treatments.

17. Broyd CJ, Hernandez-Perez F, Segovia J, et al. Identification of capillary rarefaction using intracoronary wave intensity analysis with resultant prognostic implications for cardiac allograft patients. Eur Heart J 2018;39:1807–14. https://doi. org/10.1093/eurheartj/ehx732; PMID: 29253131. 18. Tsagalou EP, Anastasiou-Nana M, Agapitos E, et al. Depressed coronary flow reserve is associated with decreased myocardial capillary density in patients with heart failure due to idiopathic dilated cardiomyopathy. J Am Coll Cardiol 2008;52:1391–8. https://doi.org/10.1016/j. jacc.2008.05.064; PMID: 18940529. 19. Sorop O, van den Heuvel M, van Ditzhuijzen NS, et al. Coronary microvascular dysfunction after long-term diabetes and hypercholesterolemia. Am J Physiol Heart Circ Physiol 2016;311:h1339–51. https://doi.org/10.1152/ ajpheart.00458.2015; PMID: 27591223. 20. Sechtem U, Brown D, Godo S, et al. Coronary microvascular dysfunction in stable ischaemic heart disease (nonobstructive coronary artery disease and obstructive coronary artery disease). Cardiovasc Res 2020;116:771–86. https://doi.org/10.1093/cvr/cvaa005; PMID: 31958128. 21. Suda A, Takahashi J, Hao K, et al. Coronary functional abnormalities in patients with angina and nonobstructive coronary artery disease. J Am Coll Cardiol 2019;74:2350–60. https://doi.org/10.1016/j.jacc.2019.08.1056; PMID: 31699275. 22. Ford TJ, Yii E, Sidik N, et al. Ischemia and no obstructive coronary artery disease: prevalence and correlates of coronary vasomotion disorders. Circ Cardiovasc Interv 2019;12:e008126. https://doi.org/10.1161/ CIRCINTERVENTIONS.119.008126; PMID: 31833416. 23. Spaccarotella CAM, Polimeni A, Migliarino S, et al. Multichannel electrocardiograms obtained by a smartwatch for the diagnosis of ST-segment changes. JAMA Cardiol 2020;5:1176–80. https://doi.org/10.1001/ jamacardio.2020.3994; PMID: 32865545. 24. Drexler M, Elsner C, Gabelmann V, et al. Apple Watch detecting coronary ischaemia during chest pain episodes or an apple a day may keep myocardial infarction away. Eur Heart J 2020;41:2224. https://doi.org/10.1093/eurheartj/ ehaa290; PMID: 32346733. 25. Adamson PD, Williams MC, Dweck MR, et al. Guiding therapy by coronary CT angiography improves outcomes in patients with stable chest pain. J Am Coll Cardiol 2019;74:2058–70. https://doi.org/10.1016/j.jacc.2019.07.085; PMID: 31623764. 26. Sugisawa J, Matsumoto Y, Takeuchi M, et al. Beneficial effects of exercise training on physical performance in patients with vasospastic angina. Int J Cardiol 2020;328:14– 21. https://doi.org/10.1016/j.ijcard.2020.12.003; PMID: 33309635. 27. Bechsgaard DF, Hove JD, Michelsen MM, et al. Myocardial CT perfusion compared with transthoracic Doppler echocardiography in evaluation of the coronary microvascular function: an iPOWER substudy. Clin Physiol Funct Imaging 2021;41:85–94. https://doi.org/10.1111/cpf.12669; PMID: 33030280. 28. Patel MR, Peterson ED, Dai D, et al. Low diagnostic yield of elective coronary angiography. N Engl J Med 2010;362:886– 95. https://doi.org/10.1056/NEJMoa0907272; PMID: 20220183. 29. Shaw LJ, Merz CN, Pepine CJ, et al. The economic burden of angina in women with suspected ischemic heart disease: results from the National Institutes of Health–National Heart, Lung, and Blood Institute-sponsored Women’s Ischemia Syndrome Evaluation. Circulation 2006;114:894– 904. https://doi.org/10.1161/CIRCULATIONAHA.105.609990; PMID: 16923752. 30. Reis SE, Holubkov R, Conrad Smith AJ, et al. Coronary microvascular dysfunction is highly prevalent in women with chest pain in the absence of coronary artery disease: results from the NHLBI WISE study. Am Heart J 2001;141:735–41. https://doi.org/10.1067/mhj.2001.114198; PMID: 11320360. 31. Ong P, Athanasiadis A, Borgulya G, et al. High prevalence of a pathological response to acetylcholine testing in patients with stable angina pectoris and unobstructed coronary

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arteries. The ACOVA Study (Abnormal COronary VAsomotion in patients with stable angina and unobstructed coronary arteries). J Am Coll Cardiol 2012;59:655–62. https://doi. org/10.1016/j.jacc.2011.11.015; PMID: 22322081. Aribas E, van Lennep JER, Elias-Smale SE, et al. Prevalence of microvascular angina among patients with stable symptoms in the absence of obstructive coronary artery disease: a systematic review. Cardiovasc Res 2021. https:// doi.org/10.1093/cvr/cvab061; PMID: 33677526; epub ahead of press. 32. Seitz A, Pirozzolo G, Martínez Pereyra V, et al. Abstract 13340: Microvascular angina is more frequently associated with microvascular spasm than with impaired microvascular vasodilator capacity. Circulation 2019;140(Suppl 1):A13340. 33. Ong P, Athanasiadis A, Hill S, et al. Coronary artery spasm as a frequent cause of acute coronary syndrome: The CASPAR (Coronary Artery Spasm in Patients With Acute Coronary Syndrome) study. J Am Coll Cardiol 2008;52:523–7. https://doi.org/10.1016/j.jacc.2008.04.050; PMID: 18687244. 34. Niccoli G, Camici PG. Myocardial infarction with nonobstructive coronary arteries: what is the prognosis? Eur Heart J Suppl 2020;22(Suppl E):e40–5. https://doi. org/10.1093/eurheartj/suaa057; PMID: 32523437. 35. Pirozzolo G, Seitz A, Athanasiadis A, et al. Microvascular spasm in non-ST-segment elevation myocardial infarction without culprit lesion (MINOCA). Clin Res Cardiol 2020;109:246–54. https://doi.org/10.1007/s00392-01901507-w; PMID: 31236694. 36. Montone RA, Niccoli G, Fracassi F, et al. Patients with acute myocardial infarction and non-obstructive coronary arteries: safety and prognostic relevance of invasive coronary provocative tests. Eur Heart J 2018;39:91–8. https://doi. org/10.1093/eurheartj/ehx667; PMID: 29228159. 37. Probst S, Seitz A, Martinez Pereyra V, et al. Safety assessment and results of coronary spasm provocation testing in patients with myocardial infarction with unobstructed coronary arteries compared to patients with stable angina and unobstructed coronary arteries. Eur Heart J Acute Cardiovasc Care 2021;10:380–7. https://doi. org/10.1177/2048872620932422; PMID: 32508106. 38. Crea F, Bairey Merz CN, Beltrame JF, et al. Mechanisms and diagnostic evaluation of persistent or recurrent angina following percutaneous coronary revascularization. Eur Heart J 2019;40:2455–62. https://doi.org/10.1093/eurheartj/ ehy857; PMID: 30608528. 39. Al-Lamee R, Thompson D, Dehbi HM, et al. Percutaneous coronary intervention in stable angina (ORBITA): a doubleblind, randomised controlled trial. Lancet 2018;391:31–40. https://doi.org/10.1016/S0140-6736(17)32714-9; PMID: 29103656. 40. Pirozzolo G, Seitz A, Martinez Pereyra V, et al. Different vasoreactivity of arterial bypass grafts versus native coronary arteries in response to acetylcholine. Clin Res Cardiol 2021;110:172–82. https://doi.org/10.1007/s00392-02001694-x; PMID: 32613293. 41. Ong P, Athanasiadis A, Perne A, et al. Coronary vasomotor abnormalities in patients with stable angina after successful stent implantation but without in-stent restenosis. Clin Res Cardiol 2014;103:11–9. https://doi.org/10.1007/s00392-0130615-9; PMID: 23995322. 42. Aziz A, Hansen HS, Sechtem U, et al. Sex-related differences in vasomotor function in patients with angina and unobstructed coronary arteries. J Am Coll Cardiol 2017;70:2349–58. https://doi.org/10.1016/j.jacc.2017.09.016; PMID: 29096805. 43. Vermeltfoort IA, Raijmakers PG, Riphagen II, et al. Definitions and incidence of cardiac syndrome X: review and analysis of clinical data. Clin Res Cardiol 2010;99:475–81. https://doi.org/10.1007/s00392-010-0159-1; PMID: 20407906. 44. Murthy VL, Naya M, Taqueti VR, et al. Effects of sex on coronary microvascular dysfunction and cardiac outcomes. Circulation 2014;129:2518–27. https://doi.org/10.1161/ CIRCULATIONAHA.113.008507; PMID: 24787469.

Women and Heart Disease

Why We Need Specialised Centres for Women’s Hearts: Changing the Face of Cardiovascular Care for Women Martha Gulati ,1 Cara Hendry,2 Biljana Parapid

and Sharon L Mulvagh

4,5

1. Division of Cardiology, University of Arizona, Phoenix, AZ, US; 2. Manchester Heart Institute, Manchester University Hospital NHS Trust, Manchester, UK; 3. School of Medicine, University of Belgrade, Belgrade, Serbia; 4. Division of Cardiology, Department of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada; 5. Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN, US

Abstract

Although cardiovascular disease (CVD) is the leading cause of mortality in women globally, cardiovascular care for women remains suboptimal, with poorer outcomes than for men. During the past two decades, there has been an incremental increase in research and publications on CVD in women, addressing sex-specific risk factors, symptoms, pathophysiology, treatment, prevention and identification of inequities in care. Nonetheless, once women have manifested CVD, they continue to have increasingly worse outcomes than men. An approach to addressing these global disparities has been the worldwide establishment of specialised centres providing cardiovascular care for women. These women’s heart centres (WHCs) allow a comprehensive approach to the cardiovascular care of women across the lifespan. The purpose of this article is to define the need for and role of these specialised centres by outlining sex-specific gaps in CVD care, and to provide guidance on components within WHCs that may be considered when establishing such programmes.

Keywords

Sex differences, women, cardiovascular disease, women’s heart centres, prevention, inequities Disclosure: MG is a Guest Editor of the Women and Heart Disease special collection for European Cardiology Review. All other authors have no conflicts of interest to declare. Received: 3 September 2021 Accepted: 19 October 2021 Citation: European Cardiology Review 2021;16:e52. DOI: https://doi.org/10.15420/ecr.2021.49 Correspondence: Sharon L Mulvagh, Division of Cardiology, Department of Medicine, Dalhousie University, 1796 Summer St, Room 2148, Halifax, Nova Scotia B3H 3A7, Canada. E: smulvagh@mayo.edu Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Globally, cardiovascular disease (CVD) accounts for 8.94 million deaths in women, comprising 35% of all deaths in women, making it their leading noncommunicable cause of mortality worldwide, with more women dying from CVD than from all cancers combined.1 In addition, by the last estimation, 275 million women are living with CVD.1

More recently, an international commission from the Lancet emphasised the need for equitable cardiovascular care for women. It identified knowledge gaps that persist in cardiovascular disease that need to be addressed, and that this was central to reducing the global burden of cardiovascular disease in women.7

Despite this, women continue to be inadequately treated when they are diagnosed with CVD, have worse outcomes and have been historically excluded from clinical trials, especially around ischaemic heart disease (IHD).2,3 An approach to the unmet cardiovascular needs of women has been the establishment of Women’s Heart Centres (WHCs), with the ultimate goal of reducing disparities in cardiovascular care for women to improve outcomes.3–5 We aim to briefly review the need for these specialised centres and provide guidance for expanded development of WHCs globally to contribute to the achievement of this ultimate goal.

In response to these identified needs being highlighted, numerous private practices, hospitals and universities responded by establishing of a variety of centres and programmes dedicated to cardiovascular care for women.5

Need for Women’s Heart Programmes

The need for improved cardiovascular care for women was brought to light in the late 1990s, with the recognition that cardiovascular mortality in women had been steadily increasing for almost two decades while, during the same period, a notable decline had been observed in men. The Heart Truth and Go Red For Women public awareness campaigns were established in 2002 and 2004, respectively.6

These centres, which deliver cardiovascular care focused on women, are known by various terms, depending on the institution in which they are located, including women’s heart centres, programs, or clinics. For the purpose of this review, we will refer collectively to these specialised practices as women’s heart centres (WHCs). Although some may have early on discounted WHCs as a marketing tool, the need for improved cardiovascular care of women has only increased, with recent recognition that although, initially declining, CVD mortality has been rising again in both women and men, but disproportionately in younger and midlife women.8,9 Additionally, awareness in women about their risk for CVD as the leading cause of death has unfortunately

Changing the Face of Cardiovascular Care for Women Delays in Care

Figure 1: Traditional and Sex-specific Risk Factors in Women Traditional ASCVD risk factors

Emerging, non-traditional ASCVD risk factors

Diabetes

Preterm delivery

Smoking

Hypertensive disorders of pregnancy

Obesity and overweight

Gestational diabetes

Physical inactivity

Autoimmune disease

Hypertension

Breast cancer treatment

Dyslipidaemia

Depression

Delays in acute cardiovascular care for women are multifactorial and lead to delayed door-to-balloon times.23 There may be patient factors, as reported in studies of STEMI patients, where it has been found that women are less likely to present within 2 hours of onset of symptoms, and have longer intervals than men.24 Additionally, there are healthcare system delays whereby the healthcare team may not recognise when women are presenting with acute coronary syndromes, because of gaps in knowledge and understanding of the differences in symptoms between the sexes; more ominously, there may be delays because of sexism, whether conscious or unconscious.3

ASCVD = atherosclerotic cardiovascular disease. Source: Garcia et al. 2016.34 Reproduced with permission from Wolters Kluwer Health.

decreased in recent years and this, combined with a surprising lack of training and preparedness in internists and specialists to assess and manage CVD risk in women, is alarming.10–11 As emerging research in women’s cardiovascular health is rapidly evolving, WHCs can provide expert consultative services to partner with other healthcare providers, providing contemporary sex-specific, patientcentred preventive and therapeutic care, while also collaborating on professional and public education strategies. The first document to provide guidance towards developing WHCs was published by our group in 2016.5 The intention of this document was not just to provide expertise for CVD prevention and care but also to encourage the establishment of women-focused cardiovascular centres. The need for a team approach, collaboration with other medical specialties and consultative resources, was outlined in this document. Following this document, a white paper from the American Heart Association expanded on the need and components of WHCs.12 It also established the need for WHCs as a new care model, emphasised the lack of and requirement for sex- and gender- specific education to all trainees, in addition to providing a rationale for expanding research in this area.

Gaps in Cardiovascular Care for Women Inadequate Treatment

Women are often undertreated compared with men, as large registries of ST-elevated MI (STEMI) demonstrate. Women with STEMI are less likely to receive guideline-directed medical therapies, less likely to undergo revascularisation or receive thrombolytics, and are less likely to be referred to cardiac rehabilitation.13–16 Those with cardiogenic shock with STEMI obtain less aggressive care, including a lower likelihood of receiving mechanical circulatory support, and have a higher mortality rate.17 These all contribute to worse outcomes for women.

Research and Knowledge Gaps

Women have, historically, been excluded from cardiovascular research.25 Although efforts have been made to increase the inclusion of women, recent estimates of clinical trials continue to show an underrepresentation of female participants in cardiovascular research, particularly in coronary artery disease and heart failure trials.26,27 Even basic science studies often fail to consider sex as a biologic variable by avoidance of female cell lines or a failure to include females in animal studies, or a lack of sex-based reporting of their findings.28 Additionally, many clinical trials that include both men and women fail to report sexdisaggregated findings, limiting our knowledge related to differences between the sexes.29

Why Sex and Gender Matter

The term sex refers to the biological aspects of being male or female, while gender is a social construct influenced by an individual’s environment and includes gender identity.30 Both may impact upon cardiovascular health, including manifestations of traditional CVD risk factors, development of sex-specific risk factors, symptom recognition and diagnosis, and, ultimately, treatment with pharmacologic and/or interventional therapies as indicated (Figure 1).3,31–34 It should not be surprising that many aspects of CVD differ in women and men. Non-obstructive coronary artery disease is a more frequent cause of IHD in women and manifests as INOCA (ischaemia with no obstructive coronary artery disease) or MINOCA (MI with no obstructive coronary artery disease), and has been underappreciated until recently.35,36 Heart failure with preserved ejection fraction is twice as common in women, in contrast with heart failure with reduced ejection fraction, which is more often seen in men. Interestingly, although women have higher left ventricular ejection fractions at baseline, sex-neutral thresholds have been used to define heart failure, with such sex-specific differences in cardiac structure and physiology being disregarded completely.37

Similarly in AF, women are less likely to be offered a rhythm-controlled strategy, less likely to be offered catheter ablation and less likely to receive oral anticoagulation.18,19 Women with heart failure who meet criteria for ICDs, which have the potential to improve survival by preventing sudden death, are less likely to receive such devices than men.20,21

It is beyond the scope of this review to describe all sex differences in CVD; these foregoing examples are but a few that illustrate the need for WHCs that focus on sex differences in the prevention and diagnosis of CVD, in addition to the specialised treatment of CVD conditions unique to women.

Gaps and sex-based inequities exist in the literature relating to primary and secondary cardiovascular disease prevention, with women less likely to be adequately treated.22

Foundational to most WHCs is a team-based approach to the cardiovascular care of women.5,38 This includes cardiologists and advanced practice professionals who may work together as the main

Structure of Women’s Heart Centres

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Changing the Face of Cardiovascular Care for Women Figure 2: Components of a Women’s Heart Centre

Cardioneurologic Heart-brain link: CVD risk factors Dementia Stroke

Menopause/hormones/transgender CVD risk assessment

CVD risk assessment Sex differences in traditional risk factors Sex-specific risk factors Sex-predominant risk factors

Non-obstructive CAD (M)INOCA: CMD SCAD Stress cardiomyopathy Vasospasm

Women’s Heart Centres

Cardio-obstetrics Pre-existing CVD risk factors Pre-existing acquired CVD Adult congenital heart disease Management of adverse pregnancy outcomes

Cardio-oncology History of cancer: radiation, chemotherapy Overlapping CVD risk factors

Advocacy Awareness campaigns for community legislators

Research Enrol in clinical trials and registries

Education Public Professional

CAD = coronary artery disease; CMD = coronary microvascular dysfunction; CVD = cardiovascular disease; INOCA = ischaemia with no obstructive coronary artery disease; MINOCA = MI with no obstructive coronary artery disease; SCAD= spontaneous coronary artery dissection.

providers. Additionally, collaboration with other specialists and services in medicine and surgery are often necessary, including cardiac rehabilitation, nutritional services, physical and occupational therapists, rheumatologists as well as genetics, vascular, neurologic, mental health, obstetricsgynecologic, endocrinologic and integrative specialists. WHCs are not simply confined to outpatient care but are integral to the entire cardiovascular care of women, based on expertise and education that can be delivered in different aspects of care. Although it may not be possible for all WHCs to offer every component outlined in Figure 2, our intent is to present an approach to a comprehensive programme that addresses sex-specific issues in the cardiovascular care of women. A WHC may include the cardiovascular services below.

Cardiovascular Disease Risk Assessment

This may be available to any woman, with or without a prior cardiovascular disease history, using a combination of traditional, sex-specific and sexpredominant risk factors to provide short-term and life-time risk assessments.33 This can also include secondary CVD prevention, ensuring that guideline-directed medical therapies and cardiac rehabilitation are used to improve cardiovascular outcomes in women.

Non-obstructive Coronary Artery Disease

Women with ischaemia or MI, where there are no obstructive coronary arteries, often require further assessment to identify the cause. INOCA and MINOCA are not final diagnoses but classifications that include several potential diagnoses. Further diagnostic testing is frequently required to obtain an aetiologic explanation for the perplexing dilemma of ‘angina and/or MI with normal coronary arteries’. Medical management must be tailored according to the specific diagnosis, which may include coronary microvascular dysfunction (CMD), coronary vasospasm, spontaneous coronary artery dissection (SCAD) or stress (takotsubo)

cardiomyopathy, in addition to other possible causes that can be elicited with a more extensive work-up.35,36

Cardio-obstetrics

There are numerous potential cardio-obstetric reasons for referral to a WHC. Every woman who is referred to a WHC should have a cardioobstetrics history performed to uncover often unrecognised sex-specific cardiovascular risk factors. Women may be referred after an adverse pregnancy outcome (APO) and this may require cardiovascular risk assessment, medical management or, usually, both. Additionally, women with familial hypercholesterolaemia, hypertension or other established cardiac conditions (both acquired or adult congenital heart disease) may be referred before conception or once the pregnancy is established. Partnering with maternal-foetal medicine creates an important link for women during this critical period.

Cardio-oncology

Although cardio-oncology clinics may be separate from a WHC, if there is not a specialised clinic, it is possible that women who have previously received certain cancer therapies (e.g. breast radiation therapy or systemic chemotherapy) may be identified to be at a higher risk for CVD.39 Risk factors for breast cancer, which occurs far more frequently in women, overlap with risk factors for cardiovascular disease. Cardiovascular risk assessment is important in these women and can be addressed in WHCs.

Cardio-rheumatology

In patients with autoimmune disorders, chronic inflammation increases CVD risk.40 Collaboration with rheumatologic specialists may be beneficial in women with these disorders for assessment and guidance on management of increased CVD risk, and/or optimisation of treatment if heart disease has become manifest.41

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Changing the Face of Cardiovascular Care for Women Menopause, Hormones and Cardiovascular Disease

Menopause can often be a time when women are referred as part of seeking care related to menopausal symptoms. Additionally, women may experience unfavourable changes in CVD risk with menopausal-related changes in cholesterol, elevations in blood pressure or increased weight gain and abdominal adiposity that result in referral to a WHC. Understanding the impact of hormones, not just on symptoms but also on potential cardiovascular risk, is an important requirement for providers participating in informed and shared decision-making with women who are in this phase of life.

Cardioneurologic/Geriatric

The awareness of the heart–brain connection is increasing. As risk factors for CVD overlap with those for stroke and vascular cognitive impairment leading to dementia, collaboration with neurology, geriatrics and vascular medicine can be an important aspect of a WHC.

Transgender Cardiovascular Health

This is an emerging area of importance, given the increased cardiovascular risks that have been reported.42 Hormonal changes, and their impact on cardiovascular risk need to be further studied, but risk assessment and management could fall within the domain of a WHC. Other factors that must be considered in the establishment of a WHC include accessibility, cultural and ethnically appropriate care and educational material, both public and professional.12 Additionally, when a WHC is established within an academic medical centre, it is important that the educational component includes the education of medical students, residents and cardiology fellows. Incorporation into the academic curriculum will help broaden the knowledge of appropriate care of women, and further the understanding of the sex differences in cardiovascular disease. WHCs can also incorporate research into their mission. Where possible, establishment of a database registry to follow patients and report on outcomes data could advance the field further. WHCs in academic and clinical research settings may also include opportunities for recruitment into clinical trials to assist in increasing the enrolment of women and expand a knowledge base needed for evidence-based guidelines development.

Growth of Women’s Heart Programmes

There is no regulatory requirement to register WHCs so it is difficult to ascertain how many exist on a global scale. However, there are now WHCs in Australia, Asia, Europe and the Middle East, with the largest numbers are in North America. Each WHC is unique in terms of its funding and clinical programme components; some may deliver exclusively outpatient care. With any WHC, there are opportunities for the entire delivery of cardiovascular care to be transformed; an understanding of 1. GBD 2019 Diseases and Injuries Collaborators. Global burden of 369 diseases and injuries in 204 countries and territories, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet 2020;396:1204–22. https://doi.org/10.1016/S0140-6736(20)30925-9; PMID: 33069326. 2. Gulati M. Yentl’s bikini: sex differences in STEMI. J Am Heart Assoc 2019;8:e012873. https://doi.org/10.1161/ JAHA.119.012873; PMID: 31092095. 3. Gulati M. Improving the cardiovascular health of women in the nation: moving beyond the bikini boundaries. Circulation 2017;135:495–8. https://doi.org/10.1161/ CIRCULATIONAHA.116.025303; PMID: 28153984. 4. Low TT, Chan SP, Wai SH, et al. The women’s heart health programme: a pilot trial of sex-specific

sex differences begins with the recognition of differences between men and women and may begin with education on such differences among other providers. Considering the vast population of women at risk at and living with CVD, the need for specialised care for women could potentially be better served with further global expansion of WHCs. Certainly, the need for WHCs is global, but there are worldwide differences in healthcare that can create barriers to establishing them and affect reimbursement for care.7 As there are knowledge gaps and awareness of the unique aspects of cardiovascular care for women is evolving, expertise in this care has been centred on WHCs, which are usually located within a cardiology division or department. Therefore, patients seen in WHCs should have the same access and coverage as any patient seen by a specialised cardiovascular care team. Additionally, the creation of WHCs can allow women access to clinical research trials within university and hospital systems, and enrolment into registries from any centres. This should be part of development of any WHC (Figure 2). There are a few unaccredited training programmes for women’s cardiovascular health but no established certified training in this specialty, creating a limitation in expertise in the care of women. Additionally, there is no evidence to date demonstrating a direct improvement in the care of women or improvement in cardiovascular outcomes related to the establishment of WHCs. Indeed, because of the complexity of cardiovascular care issues and global population heterogeneity, this may never be able to be demonstrated as a direct effect, and these data may eventually need to be indirectly inferred. Nonetheless, the persistent gaps seen globally require an urgent change in the established, traditional ways of delivering cardiovascular care to women, who comprise the majority of the population. WHCs have been set up to address this urgent need.

Conclusion

Specialised WHCs provide a unique, long-term, sustainable solution to address ongoing deficiencies in cardiovascular health provision for women. The dedicated, multidisciplinary and multispecialty teams in WHCs provide the best opportunity to deliver high-quality research and individualised, accessible care with appropriate female-specific risk stratification and treatment. Large-scale expansion of the female-focused approach to prevention and treatment delivered by WHCs may be the key to delivering what has been lacking to date: a sustained, progressive decline in cardiovascular morbidity and mortality, saving the lives of women for years to come.

cardiovascular management. BMC Womens Health 2018;18:56. https://doi.org/10.1186/s12905-018-0548-6; PMID: 29661196. 5. Garcia M, Miller VM, Gulati M, et al. Focused cardiovascular care for women: the need and role in clinical practice. Mayo Clin Proc 2016;91:226–40. https://doi.org/10.1016/j. mayocp.2015.11.001; PMID: 26848004. 6. Brown N. How the American Heart Association helped change women’s heart health. Circ Cardiovasc Qual Outcomes 2015;8(2 Suppl 1):S60–2. https://doi.org/10.1161/ CIRCOUTCOMES.115.001734; PMID: 25714819. 7. Vogel B, Acevedo M, Appelman Y, et al. The Lancet women and cardiovascular disease Commission: reducing the global burden by 2030. Lancet 2021;397:2385–438. https:// doi.org/10.1016/S0140-6736(21)00684-X; PMID: 34010613.

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women to improve cardiovascular disease prevention. Am J Prev Cardiol 2020;2:100028. https://doi.org/10.1016/j. ajpc.2020.100028; PMID: 34327455. 34. Garcia M, Mulvagh SL, Merz CN, et al. Cardiovascular disease in women: clinical perspectives. Circ Res 2016;118:1273–93. https://doi.org/10.1161/ CIRCRESAHA.116.307547; PMID: 27081110. 35. Tamis-Holland JE, Jneid H, Reynolds HR, et al. Contemporary diagnosis and management of patients with myocardial infarction in the absence of obstructive coronary artery disease: a scientific statement from the American Heart Association. Circulation 2019;139:e891–908. https://doi. org/10.1161/CIR.0000000000000670; PMID: 30913893. 36. Kunadian V, Chieffo A, Camici PG, et al. An EAPCI expert consensus document on ischaemia with non-obstructive coronary arteries in collaboration with European Society of Cardiology Working Group on Coronary Pathophysiology & Microcirculation endorsed by Coronary Vasomotor Disorders International Study Group. Eur Heart J 2020;41:3504–20. https://doi.org/10.1093/eurheartj/ehaa503; PMID: 32626906. 37. Beale AL, Meyer P, Marwick TH, et al. Sex differences in cardiovascular pathophysiology: why women are overrepresented in heart failure with preserved ejection fraction. Circulation 2018;138:198–205. https://doi.org/10.1161/ CIRCULATIONAHA.118.034271; PMID: 29986961. 38. Aggarwal NR, Mulvagh SL. Chapter 29 – women’s heart programs. In: Aggarwal NR, Wood MJ, eds. Sex Differences in Cardiac Disease. Elsevier; 2021: 671–86. https://doi. org/10.1016/B978-0-12-819369-3.00002-2. 39. Gulati M, Mulvagh SL. The connection between the breast and heart in a woman: breast cancer and cardiovascular disease. Clin Cardiol 2018;41:253–7. https://doi.org/10.1002/ clc.22886; PMID: 29446841. 40. Prasad M, Hermann J, Gabriel SE, et al. Cardiorheumatology: cardiac involvement in systemic rheumatic disease. Nat Rev Cardiol 2015;12:168–76. https:// doi.org/10.1038/nrcardio.2014.206; PMID: 25533796. 41. Scanlon EM, Mankad R, Crowson CS, et al. Cardiovascular risk assessment in patients with rheumatoid arthritis: a correlative study of noninvasive arterial health testing. Clin Rheumatol 2017;36:763–71.c10.1007/s10067-016-3515-3; PMID: 27988813. 42. Connelly PJ, Marie Freel E, et al. Gender-affirming hormone therapy, vascular health and cardiovascular disease in transgender adults. Hypertension 2019;74:1266–74. https:// doi.org/10.1161/HYPERTENSIONAHA.119.13080; PMID: 31656099.

Atrial Fibrillation

Neuromodulatory Approaches for Atrial Fibrillation Ablation Moisés Rodríguez-Mañero ,1,2,3 Jose Luis Martínez-Sande,1,2,3 Javier García-Seara,1,2,3 Teba González-Ferrero,1 José Ramón González-Juanatey,1,2,3 Paul Schurmann,4 Liliana Tavares4 and Miguel Valderrábano4 1. Department of Cardiology, University Hospital of Santiago de Compostela, Santiago de Compostela, A Coruña, Galicia, Spain; 2. Institute of Health Research, University of Santiago de Compostela, Santiago de Compostela, A Coruña, Galicia, Spain; 3. Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Spain; 4. Methodist DeBakey Heart and Vascular Center and Methodist Hospital Research Institute, The Methodist Hospital, Houston, TX, US

Abstract

In this review, the authors describe evolving alternative strategies for the management of AF, focusing on non-invasive and percutaneous autonomic modulation. This modulation can be achieved – among other approaches – via tragus stimulation, renal denervation, cardiac afferent denervation, alcohol injection in the vein of Marshall, baroreceptor activation therapy and endocardial ganglionated plexi ablation. Although promising, these therapies are currently under investigation but could play a role in the treatment of AF in combination with conventional pulmonary vein isolation in the near future.

Keywords

AF, ablation, vein of Marshall, neuromodulation Disclosure: The authors have no conflicts of interest to declare. Received: 24 February 2021 Accepted: 23 May 2021 Citation: European Cardiology Review 2021;16:e53. DOI: https://doi.org/10.15420/ecr.2021.05 Correspondence: Moisés Rodríguez-Mañero, Division of Cardiac Electrophysiology, Department of Cardiology, Clinic University Hospital of Santiago de Compostela, Travesía da Choupana SN, PC 15782, Santiago de Compostela, A Coruña, Spain. E: moirmanero@gmail.com Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

AF is the most common sustained cardiac dysrhythmia encountered in clinical practice.1 Treatment strategies involve antiarrhythmic drug therapy and catheter ablation targeting the pulmonary veins (PVs) and other arrhythmogenic sites.2 However, these therapies have limitations and the effect of ablation on hard endpoints remains unclear. For patients with persistent AF in particular, the results of pulmonary vein isolation (PVI) are currently suboptimal. Therefore, there is growing interest in pursuing alternative therapies particularly in the setting of persistent AF able to overcome the modest results of PVI. In this review we seek to describe evolving alternative strategies for the management of AF, including non-invasive and percutaneous autonomic modulation. Approaches to achieve this modulation include tragus stimulation, renal denervation, cardiac afferent denervation, alcohol injection in the vein of Marshall (VOM), baroreceptor activation therapy, endocardial ganglionated plexi (GP) ablation and percutaneous stellate ganglion block (PSGB; Table 1). Although promising, these therapies are currently still under investigation. Nevertheless, they may become part of the treatment of AF in combination with conventional PVI in the near future.

Autonomic Pathways and Ganglionated Plexi

The heart is innervated by the extrinsic (central) and the intrinsic cardiac autonomic nervous system (ANS). The extrinsic ANS consists of the ganglia in the brain or along the spinal cord, where the cell bodies reside, as well as their axons en route to the heart. The intrinsic ANS is comprised of an extensive epicardial neural network of nerve axons, interconnecting neurons and clusters of autonomic ganglia known as GP not only on the

atria, but also on both ventricles.3–4 These GP, most of which are embedded within epicardial fat pads, vary in size from those that contain just a few neurons to those that contain over 400 neurons. Notably, the highest density of autonomic innervation is found at the posterior wall of the left atrium (LA), particularly at the PV–atrial junction. Several studies have demonstrated that the GP are composed of a heterogeneous population of neurons, including efferent, afferent and interconnecting neurons – the latter group comprising the majority of the neural elements within the GP. From a physiological point of view, GP contain both sympathetic and parasympathetic elements. Importantly, the GP serve as the communication centres between the intrinsic and extrinsic central autonomic nervous system, coordinating the response to afferent and efferent neural trafficking to control regional electrophysiological, vascular and contractile function. Anatomically, the four major atrial GP are located in close association with the PVs and each innervate one of the four PVs, as well as the surrounding atrial myocardium. The Oklahoma group renamed the major atrial GP.5 The anterior right GP is located immediately anterior to the right superior PV – often extending inferiorly – to the region anterior to the right inferior PV. The superior left GP is located at the roof of the LA, 1–2 cm medial to the left superior PV. The right and left inferior GP are located at the inferior aspect of the posterior wall of the LA, 2–3 cm below the right and left PVs, respectively (Figure 1). The ligament of Marshall (LOM), located between the left atrial appendage and the left superior PV, also contains autonomic neurons. Several studies have demonstrated that the ANS and the epicardial GP play a central role in the initiation and maintenance of AF, especially in the

Neuromodulatory Approaches for AF Ablation Table 1: Current Status of Developing Neuromodulatory Strategies for Arrhythmias Intervention Target

Applications Representative Studies

Clinical Outcomes

Transcutaneous vagal nerve stimulation

Efferent fibres of the vagus nerve

AF, POTS and VT Stavrakis et al. 2015.20 Randomised study. Patients with paroxysmal AF who presented for AF ablation were randomised to either 1 hour of LLTS or sham control

Pacing-induced AF duration Tingling or pain around VAG-POTS (NCT04632134) decreased significantly the stimulation site tVNS_POAF (NCT04514757) compared with baseline in the LLTS group

RDN

Sympathetic nerves around the renal arteries (afferent)

AF, VT

Significantly greater No procedure-related freedom from AF in the PVI complications + RDN group as compared to PVI only group

Pokushalov et al. 2012.24 Randomised study. Patients with drugrefractory AF and resistant hypertension randomised to PVI alone versus PVI + RDN

Feyz et al. 2019.25 AF burden in min/day Prospective study. decreased Patients with paroxysmal AF and resistant hypertension

Complications

One renal artery dissection

Clinical Trials

H-FIB (NCT01635998) RDPAF (NCT01990911) ASAF (NCT02115100) RDN+AF (NCT01907828) RDN After PVI for Persistent AF (NCT03246568) CPVI Plus Renal Sympathetic Modification Versus CPVI Alone for AF (NCT01686542) Symplicity AF (NCT02064764) RESET-VT (NCT01858194)

Steinberg et al. 2019.26 RCT. Patients with hypertension despite taking at least one antihypertensive medication, paroxysmal AF and plans for ablation

Freedom from AT at 12 No renal artery or months was lower on those femoral artery undergoing PVI alone complications versus PVI + RDN

Cardiac afferent Autonomic AF, POAF denervation ganglionic plexi

Tavares et al. 2019.28 Animal study. Atrial effective refractory period and AF inducibility on single extrastimulation assessed before and during apnoea, and before and after intrapericardial RTX administration

RTX decreased sympathetic and GP nerve activity, abolished apnoea electrophysiological response, and AF inducibility.

ADD-GP (NCT03535818) Atrial Fibrillation Prevention in Post Coronary Artery Bypass Graft Surgery With Cryoablation for Ganglionic Plexi (NCT02035163) AFACT (NCT01091389) Left Atrial Cryoablation Enhanced by GP Ablation in AF (NCT03239262) GANGLIA-AF (NCT02487654)

Alcohol injection VOM in the VOM

Valderrábano et al. 2020.33 Randomised study. Rhythm-control effectiveness of two ablation strategies: catheter ablation alone or combined with VOM ethanol infusion in de novo ablation of AF

At 12 months, the proportion of patients with freedom from AT after a single procedure was better in the catheter ablation combined with VOM ethanol infusion group compared with the catheter ablation alone group

AEs similar between groups. Symptomatic inflammatory pericarditis not requiring drainage occurred in 11 patients in the VOM–catheter ablation and in six in the catheter ablation group

VOM-R01 (NCT01898221) MARSHALINE (NCT04124328) MARSHALL-PLAN (NCT04681872) PLAN-MARSHALL (NCT04206982)

Derval et al. 2021.35 Prospective study. Examination of a novel comprehensive ablation strategy (Marshall bundle elimination, PVI and line completion for anatomical ablation of persistent AF; Marshall-PLAN)

At 12 months, 72% were free from AT after a single procedure in the overall cohort. In the subset of patients with a complete Marshall-PLAN lesion set the single procedure success rate was 79%

AEs were similar between groups

Baroreceptor activation therapy

Carotid and aortic baroreceptors

AF, AHT

BRS and Outcomes in Cardiothoracic Surgery (NCT03243279) Rheos® Diastolic Heart Failure Trial (NCT00718939) UK-BAT (NCT03730519) Nordic BAT (NCT02572024)

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Neuromodulatory Approaches for AF Ablation Table 1: Cont. Intervention Target

Applications Representative Studies

Clinical Outcomes

Complications

Clinical Trials

SGB

POAF

POAF rate in the successful SGB group was 18.2% versus our historical institutional rate of 27% in CABG

No perioperative or postoperative complications related to the SGB procedure

LIVE (NCT04168970) Prospective Randomized Clinical Trial for Effect of Stellate Ganglion Block in Medically Refractory Ventricular Tachycardia (NCT02646501) SGB in Control of Arrhythmia in Laparoscopic Cholecystectomy (NCT04837495)

Percutaneous SGB

Connors et al. 2018.51 Prospective study. Patients scheduled for nonemergent aortic valve replacement and/ or CABG were recruited and enrolled to receive SGB at the time of surgery

AE = adverse event; AHT = arterial hypertension; AT = atrial tachycardia; CABG = coronary artery bypass grafting; GP = ganglionated plexi; LLTS = low-level tragus stimulation; POAF = post-operative AF; POTS = postural orthostatic tachycardia syndrome; PVI = pulmonary vein isolation; QOL = quality of life; SGB = stellate ganglion block; RCT = randomised controlled trial; RDN = renal denervation; RTX = resiniferatoxin; SGB = stellate ganglion block; VA = ventricular arrhythmia; VOM = vein of Marshall; VT = ventricular tachycardia.

early stages.6–9 This makes autonomic modulation an attractive modality for AF therapy. Such modulation can be achieved using a variety of approaches as described in the following sections.

Figure 1: Illustration of the Right and Left Atrium Showing the Anatomical Ganglionic Plexi Locations B

Neuromodulatory Approaches Low-level Tragus Stimulation

Studies in dogs have demonstrated that vagal nerve stimulation (VNS) via direction stimulation of the cervical vagus nerve at voltages significantly below those resulting in sinus rate and atrioventricular conduction slowing is able to suppress AF inducibility and shorten AF duration.10–13 Based on the fact that the auricular branch of the vagus nerve has communication with the skin of the tragus, transcutaneous stimulation of the vagus nerve at this site has been entertained as a possible method of non-invasive vagal stimulation.14 Importantly, it seems that tragus stimulation preferentially activates afferent rather than efferent vagal fibres, which may offer a therapeutic advantage.15 Specifically, tragus stimulation has been shown to activate central vagal projections in the brain in humans, leading to decreased sympathetic output.16 Additionally, tragus stimulation – as opposed to cervical VNS – may avoid concomitant stimulation of sympathetic fibres, which are co-localised with vagal fibres in the vagus nerve and are inadvertently stimulated during cervical VNS in humans.17 Importantly, tragus stimulation may avoid the adverse effects reported with cervical VNS, including cough, nausea, dysphonia and tinnitus.18 Yu et al. performed tragus stimulation in a rapid atrial pacing (RAP) canine model of AF via alligator clips attached directly to the tragus, at 80% of the bradycardia threshold. RAP induced an initial progressive decrease in effective refractory period (ERP), increase in AF inducibility and increase in neural activity from the anterior right GP, all of which were significantly attenuated by subsequent tragus stimulation. Bilateral vagal transection distal to the stimulation site eliminated the ability of tragus stimulation to reverse the effects of RAP on ERP and AF inducibility, confirming the mechanism of tragus stimulation is mediated by the efferent vagus nerve.19 In a human study, Stavrakis et al. randomised 40 patients presenting for ablation of paroxysmal AF to either tragus stimulation or sham stimulation (attachment of the stimulating electrodes with no energy delivery) prior to ablation (frequency 20 Hz; 50% of bradycardia threshold). AF was induced by RAP before and after tragus stimulation (or sham) to assess the effect of stimulation on duration of pacing-induced AF and number of pacing attempts required to induce AF. They reported a significant reduction in pacing-induced AF duration at 1 hour (10.4 ± 5.2 minutes versus 18.5 ± 5.6 minutes; p=0.002) in the active but not in the sham group, number of

E C

A A

F G D D

A: Efferent vagal fibres to the atria travel through aorta–superior vena cava fat pad, located between the medial superior vena cava and the aortic root, superior to the right pulmonary artery; B: Superior left GP; C: VOM; D: Ostium of the coronary sinus; E: Left superior GP seen from the posterior view; F: Left inferior GP; G: Right inferior-posterior GP. GP = ganglionic plexi; VOM = vein of Marshall.

burst pacing attempts required to induce AF, as well as increases in the ERP recorded from the right atrium and LA.20 In the TREAT-AF study, Stavrakis et al. randomised 53 patients to tragus stimulation or sham for 1 hour daily over a 6-month period after individual training on device use. After adjusting for baseline values, AF burden at 6 months was 85% lower in the active group compared to sham, with a concomitant 23% reduction in tumour necrosis factor α levels.21 These results are particularly promising because they show that a selfadministered treatment with essentially no significant risks can have a significant impact on AF burden and levels of systemic inflammation. Lastly, this approach appears to be paradoxical, especially in the context of vagally mediated AF. However, in a canine model, there was no increase in AF inducibility until VNS significantly slowed the heart rate.22 In summary, GP ablation has been evaluated in animal models and human subjects and shown to eliminate vagal response and subsequently abolish AF. Nevertheless, more data will be needed in this particular setting.

Renal Denervation

The peri-renal abdominal aorta and proximal renal arteries are associated with a rich network of sympathetic ganglia and nerve fibres that provide afferent and efferent signalling between the central nervous system (CNS) and the abdominal and pelvic viscera.23 The beneficial effect of renal denervation in AF patients is thought to be related to attenuation of afferent sympathetic input from the aorticorenal ganglion (ARG) to the

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Neuromodulatory Approaches for AF Ablation CNS, as well as attenuation of efferent signalling from the ARG to the renal parenchyma, reducing renin–angiotensin–aldosterone system activation. These effects would be expected to reduce both the electrophysiological and structural remodelling that contributes to the initiation and maintenance of AF.23 Pokushalov et al. randomised 27 patients with drug-refractory AF and resistant hypertension to PVI alone versus PVI with renal denervation. The renal denervation was performed by making discrete lesions (8–10 W for 2 minutes) beginning at the first major renal artery bifurcation tracking longitudinally back to the main artery ostium.24 This technique was repeated rotationally to cover the circumference of the artery. There was a significantly greater freedom from AF in the PVI + renal denervation group compared with the PVI only group (69% versus 29%; p=0.033). In a prospective pilot cohort study, Feyz et al. performed renal denervation in 20 patients with paroxysmal AF and resistant hypertension after placement of an implantable cardiac monitor. The daily AF burden was significantly reduced from median 1.39 minutes (interquartile range: 0–10.9) before renal denervation to median 0.94 minutes (interquartile range: 0–6.0) at 12 months (p=0.03) and there was a positive effect on quality of life.25 With these encouraging results, the ERADICATE-AF study was performed as the first large, multicentre trial to assess the effect of renal denervation on freedom from AF without therapy when added to standard PVI.26 A total of 302 patients with paroxysmal AF and hypertension receiving at least one anti-hypertensive drug were randomised to PVI or PVI + renal denervation. At 12 months, significantly more patients who underwent renal denervation were free from AF off therapy compared with controls (71.4% versus 57.8%; HR 0.61; 95% CI [0.41–0.90]; p=0.011). Of note, seven patients in each group had a complication: 4.7% in the isolation-only group and 4.5% in the renal denervation group for an absolute risk difference of 0.1% (95% CI [−4.0, 4.4%]; p>0.99). There were no renal artery or femoral artery complications. All complications in both groups were attributed to the PVI procedure.

Cardiac Afferent Denervation

It seems well defined that sensory neurons within the GP play a role in the mechanistic origin of AF. Moreover, sensory neurons are very relevant in the relationship between apnoea and AF. Obstructive sleep apnoea syndrome has been strongly associated with AF, affecting its prevalence and the outcomes of PVI.27 However, the ANS response to apnoea and its mechanistic connection to AF are unclear. Our group aimed to shed light on the autonomic response to apnoea and to test the effects of ablation of cardiac sensory neurons using the neurotoxic transient receptor potential vanilloid 1 (TRPV1) agonist resiniferatoxin (RTX) in an animal model.28 Sixteen dogs were anaesthetised and ventilated with apnoea induced by stopping ventilation until oxygen saturations decreased to 80%. Nerve recordings from bilateral vagal nerves, left stellate ganglion and anterior right GP were obtained before and during apnoea. The atrial ERP and AF inducibility on single extrastimulation were assessed before and during apnoea, and before and after intrapericardial RTX administration. Immunohistochemical staining for TRPV1 was performed on GPs. Apnoea increased anterior right GP activity, followed by clustered crescendo vagal bursts synchronised with heart rate and blood pressure oscillations. On further oxygen desaturation, a tonic increase in stellate ganglion activity and blood pressure ensued. Apnoea induced ERP shortening from 110.20 ± 31.3 ms to 90.6 ± 29.1 ms (p<0.001) and AF was

induced in all nine dogs versus none of the nine at baseline. After RTX administration, increases in GP and stellate ganglion activity and blood pressure during apnoea were abolished, ERP increased to 126.7 ± 26.9 ms (p<0.001) and AF was not induced. Vagal bursts remained unchanged. GP cells showed cytoplasmic microvacuolisation and apoptosis. This led us to conclude that apnoea increases GP activity, followed by vagal bursts and tonic stellate ganglion firing. RTX decreases sympathetic and GP nerve activity, abolishes apnoea’s electrophysiological response and AF inducibility. Subsequently, this suggests that sensory neurons mediate the electrophysiological response to apnoea and could be a valid therapeutic target to reduce apnoea-induced AF. Since chronically repeated obstructive sleep apnoea episodes have been shown to cause cardiac remodelling with fibrosis playing a prominent role contributing to AF promotion, this mechanistic study could open the door to future therapies that investigate the chronic effects of chemical ablation of cardiac GP sensory neurons in the setting of AF ablation procedures. Moreover, sensory neurons mediate the electrophysiological response to apnoea and could be a valid therapeutic target to reduce apnoea-induced AF.

Vein of Marshall Ethanol Infusion

The VOM is an embryological remnant of the left superior vena cava. It has been implicated in the pathogenesis of AF, as a source of AF triggers and as a tract for parasympathetic and sympathetic innervations that modulate electrophysiological properties of atrial tissue and contribute to AF maintenance.29–32 The LOM can be conceived as a connecting pathway between intrathoracic cardiac ganglia and intrinsic cardiac ganglia, specifically the inferior left ganglion, which is located below the left inferior PV and would coincide more closely with the VOM as it connects with the coronary sinus. It is also important to recognise that the anatomical location of the LOM–VOM in the LA ridge coincides with the ventrolateral cardiac nerve, destined to provide innervation to the posterolateral left ventricle. We showed that in humans the VOM and its neighbouring atrial myocardium contain intracardiac nerves that can reach the atrioventricular node and induce parasympathetic responses and that this response can be abolished by ethanol infusion in the VOM (Figures 2 and 3).32 Additionally, the VOM is located within the mitral isthmus, critical for perimitral atrial tachycardia (AT).31 Retrograde balloon cannulation and ethanol infusion in the VOM create a local ablation, eliminate AF triggers and VOM innervation, facilitate mitral isthmus ablation, and have shown potential in preliminary studies.32–34 The VENUS trial tested the hypothesis that adding VOM ethanol infusion to de novo catheter ablation of persistent AF could lead to increased chances of maintaining normal rhythm.33 This was a multicentre, randomised clinical trial comparing the rhythm-control effectiveness of two ablation strategies: catheter ablation alone or combined with VOM ethanol infusion in de novo ablation of AF. The primary outcome was freedom from AF or AT lasting longer than 30 seconds after the performance of a single procedure (VOM–catheter ablation or catheter ablation alone), without the use of antiarrhythmic drugs and occurring after the blanking period, including monitoring at 6 and 12 months. Excluding patients in whom VOM ethanol infusion was not performed (astreated analysis), the primary outcome was reached in 80 of the 155 patients in the VOM–catheter ablation group (51.6%; p=0.02), with an absolute difference of 13.6% (95% CI [2.7–24.6%]) and OR 0.57 (95% CI [0.37–0.90]). Differences in the primary outcome were driven by a reduced recurrence of AF or AT in the VOM–catheter ablation group. Kaplan–Meier plots showed significant reduction in AF or AT recurrence in the VOM–catheter

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Neuromodulatory Approaches for AF Ablation ablation group, both in the as-randomised analysis (HR 0.73; 95% CI [0.53–1.00]; p=0.05) and the as-treated analysis (HR 0.67; 95% CI [0.47– 0.93]; p=0.02). At 6 and 12 months, freedom from any AF or AT on 1-month monitoring (zero burden), after repeat procedures, or with the use of antiarrhythmic drugs was achieved in 67.8% of monitoring sessions (184/271) in the catheter ablation group, in 75.8% (232/306) in the VOM– catheter ablation group (absolute difference 8%; 95% CI [0.6–15.2]; p=0.03), and in 78.3% of those undergoing successful VOM ethanol infusion procedures (206/263) (as treated: absolute difference 10.5%; 95% CI [2.9–17.9]; p=0.008). In the subgroup analyses, female sex, longstanding persistent AF and LA volume >75 ml/m2 were associated with a greater effect in the VOM–catheter ablation group. Importantly, in the VENUS trial, ethanol infusion procedure did not increase procedural complications. The most common intraprocedural adverse events were vascular access complications (haematoma or pseudoaneurysm, 11 events) and intraprocedural pericardial effusion (three events). After the procedure, subacute pericardial effusion requiring pericardiocentesis occurred in four patients. There were seven patients with cerebrovascular events and seven with pneumonia after the procedure. Symptomatic inflammatory pericarditis not requiring drainage occurred in 11 patients in the VOM– catheter ablation and in six in the catheter ablation group. Fluid overload requiring diuretic treatment occurred in 10 patients in the VOM–catheter ablation group and in two patients in the catheter ablation group. Derval et al. examined a comprehensive ablation strategy comprising Marshall bundle elimination, PVI and line completion for anatomical ablation of persistent AF (Marshall-PLAN) that was strictly based on anatomical considerations.35 At 12 months, in the overall cohort 54 of 75 patients (72%) were free from AF/AT after a single procedure (no antiarrhythmic drugs). In the subset of patients with a complete MarshallPLAN lesion set (n=68), the single procedure success rate was 79%. After one or two procedures, 67 of 75 patients (89%) remained free from AF/AT (no antiarrhythmic drugs). After one or two procedures, VOM ethanol infusion was complete in 72 of 75 patients (96%). The authors concluded that this approach is feasible, safe and associated with a high rate of freedom from arrhythmia recurrence at 12 months in patients with persistent AF. All in all, these strategies could be superior to linear lesions or ablation of complex potentials, strategies that have failed to improve the outcome of PVI in previous randomized trials.36

Baroreceptor Activation Therapy

Carotid baroreceptor stimulation (BRS) is another strategy to modulate autonomic balance by activation of the baroreflex. While its effects on heart failure and blood pressure are currently under investigation, the effects of BRS on atrial electrophysiology and arrhythmias are unclear. BRS modulates autonomic balance not just by sympathetic withdrawal but also by increased vagal activation, finally resulting in reduced total body sympathetic drive. Reduced sympathetic drive is generally considered to result in an atrial antiarrhythmic effect.37–38 However, increased vagal tone, as also associated with BRS, could potentially shorten atrial refractoriness thereby increasing the vulnerable phase and resulting in the stabilisation of reentry circuits perpetuating AF, comparable to vagal stimulation. Linz et al. observed that BRS, at a stimulation intensity slowing heart rate and reducing blood pressure similar to that described in hypertensive

Figure 2: Ethanol Infusion in the Vein of Marshall

Fluoroscopic image showing a coronary sinus venogram. A: Multipolar mapping catheter and the ablation catheters (left anterior oblique projection); B: Depiction of the VOM; C: The VOM is cannulated using a 1.5-Fr quadripolar catheter (Cardima); D–G: Alcohol injection is performed (right anterior oblique projections), from distal (D) to proximal (G) showing alcohol staining. VOM = vein of Marshall.

patients, resulted in a shortening of atrial refractoriness and in a pronounced increase in AF inducibility in pigs. This was mediated by an increase in vagal tone, as it was attenuated by atropine.37 Dai et al. investigated the effects of low-level BRS (LL-BRS) on AF in three acute dog models: AF induced by 6 hours of rapid atrial pacing, AF induced by acetylcholine injected into the anterior right GP and AF induced by acetylcholine applied to the right atrial appendage.39 LL-BRS could reverse rapid atrial pacing-induced atrial electrical remodelling. This was associated with a reduction in sympathetic activation as indicated by decreased activation of the left stellate ganglion, lower plasma norepinephrine levels and reduced low-frequency/high-frequency ratios describing heart rate variability. In addition, acetylcholine-induced AF could be suppressed. They concluded that the inhibition of the left stellate ganglion activity is likely to contribute to the demonstrated antiarrhythmic effects in different AF models. In addition to these observations, LL-BRS has been previously demonstrated to inhibit GP activation.40 These data suggest that both extrinsic and intrinsic cardiac autonomic systems are modulated by LL-BRS underlying the antiarrhythmic effects of LL-BRS.40 It could indicate that as the effects of vagal activation by BRS may be dependent on the prevailing sympathetic drive, the levels of BRS necessary to reduce blood pressure and heart rate and to shorten atrial refractoriness may be different in normotensive subjects compared with hypertensive subjects. Further studies are necessary to explore the optimal stimulation intensity of BRS to avoid atrial proarrhythmic side effects and to safely display antiarrhythmic effects in patients with AF.

Endocardial Ganglionated Plexi Ablation

PV myocytes have shorter action potential duration and a greater sensitivity to both cholinergic and adrenergic stimulation than adjacent atrial tissue, which may explain why AF usually starts with an extra beat arising from PVs.41–45 Figure 1 depicts the anatomical location of GP. To define the mechanism of how a single PV depolarisation is converted to AF, Scherlag et al. investigated the effects of GP stimulation at voltages ranging from 0.6 to 4.0 V in 14 anaesthetised dogs.41 They demonstrated that stimuli applied to PVs would not induce AF unless there was simultaneous stimulation of the adjacent GP (20 Hz, 0.1 ms pulse width) that excites the atrial myocardium. The same group showed that

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Neuromodulatory Approaches for AF Ablation Figure 3: Vein of Marshall Stimulation, Parasympathetic Atrioventricular Nodal Responses and Ethanol-induced Denervation

Pre-ethanol I

5.7 s

II III RV AF CSp High-frequency stimulation

CSd

Post-ethanol Sinus rhythm

II High-frequency stimulation

III aVR

Top panel: A burst of high-frequency stimulation leads to induction of AF and asystole due to atrioventricular conduction slowing. Bottom panel: after ethanol, AF induction and asystole do not occur. VOM = vein of Marshall.

muscarinic receptor blockade prevented action potential duration shortening and focal firing originating from the adjacent PV.42 Furthermore, Choi et al. demonstrated that activation of intrinsic cardiac ANS is observed prior to the onset of paroxysmal AF in nearly 100% cases, where 20% suffered the attack in the absence of extrinsic cardiac ANS afferent signals, suggesting that intrinsic part or GPs could trigger AF completely independently of extrinsic ones.6 Subsequently, since conventional PVI transects three of the four major atrial GP as well as the LOM, it is possible that in the clinical setting, autonomic denervation caused by PVI might play a central role in the efficacy of PVI. On the other hand, PV based approaches may not be enough for vagal denervation and more selective localisation of GPs during electrophysiological study may improve the results. This approach – neuromodulation through GP ablation in combination with PVI – has been investigated in recent years. In the first human study, Pappone et al. evaluated the potential role of GP ablation by radiofrequency in preventing recurrent AF in patients undergoing circumferential PVI for paroxysmal AF.46 Katritsis et al, performed a randomised study comprising 242 patients with symptomatic paroxysmal AF. They were randomised to treatment as follows: circumferential PVI (n=78), anatomic ablation of the main left atrial GP (n=82), or circumferential PVI followed by anatomic ablation of the main left atrial GP (n=82).47 Freedom from AF or AT was achieved in 44 (56%), 39

(48%), and 61 (74%) patients in the PVI, GP, and PVI + GP groups, respectively (p=0.004 by log-rank test). The PVI GP ablation strategy compared with PVI alone yielded HR 0.53 (95% CI [0.31–0.91]; p=0.022) for recurrence of AF or AT. No serious adverse procedure-related events were encountered. Pokushalov et al. randomised 264 patients with long-lasting persistent (32%) and persistent AF (68%) to PVI GP ablation (n=132) or PVI + linear lesions (LL; n=132).48 By using an implantable monitoring device, they identified that after 3 years, 34% of patients with PVI + LL and 49% of patients with PVI+GP ablation, respectively, maintained sinus rhythm (p=0.035). After a second procedure, long-term success was seen in 52% of the PVI + LL group and in 68% of the PVI + GP group, respectively (p=0.006).49 A main limitation of the study was that techniques were not compared with a PVI-alone strategy. However, due to the feasibility of the technique at the time of PVI and the experience gained for the treatment of patients with neutrally-mediated syncope and severe cardioinhibitory response, this approach might be an alternative not only to increase the success rate but also for those patients with sinus node dysfunction. Of note, some other studies have not shown any statistically significant differences in AF recurrence rates between the study groups with a not insignificant risk of potential complication, such as sinus node dysfunction

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Neuromodulatory Approaches for AF Ablation requiring pacemaker implantation.50 Further studies are urgently needed before the generalisation of the technique. In our experience we have only performed it in exceptional situations.

Percutaneous Stellate Ganglion Block

PSGB provides an alternative and effective non-pharmacological approach to controlling cardiac arrhythmias. The procedure can be performed at the bedside thorough a minimally invasive approach guided by ultrasonography. It has shown a potential benefit in the setting of AF and ventricular arrhythmias. For instance, ablation of bilateral stellate ganglia was shown to eliminate AT episodes in a canine model of pacinginduced heart failure.51 A pilot clinical study of 36 patients undergoing PVI, as well as short duration PSGB (unilateral, left or right) demonstrated lengthened atrial ERP while reducing inducibility and duration of AF.52 With regard to 1. Colilla S, Crow A, Petkun W, et al. Estimates of current and future incidence and prevalence of atrial fibrillation in the U.S. adult population. Am J Cardiol 2013;112:1142–7. https:// doi.org/10.1016/j.amjcard.2013.05.063; PMID: 23831166. 2. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guidelines for the management of patients with atrial fibrillation: a report of the American College of Cardiology/ American Heart Association task force on practice guidelines and the Heart Rhythm Society. Circulation 2014;130:e199–267. https://doi.org/10.1161/ CIR.0000000000000041; PMID: 24682347. 3. Armour JA. Functional anatomy of intrathoracic neurons innervating the atria and ventricles. Heart Rhythm 2010;7:994–6. https://doi.org/10.1016/j.hrthm.2010.02.014; PMID: 20156593. 4. Stavrakis S, Po S. Ganglionated plexi ablation: physiology and clinical applications. Arrhythm Electrophysiol Rev 2017;6:186–90. https://doi.org/10.15420/aer2017.26.1. https:// doi.org/10.15420/aer2017.26.1; PMID: 29326833. 5. Po SS, Nakagawa H, Jackman WM. Localization of left atrial ganglionated plexi in patients with atrial fibrillation. J Cardiovasc Electrophysiol 2009;20:1186–9. https://doi. org/10.1111/j.1540-8167.2009.01515.x; PMID: 19563367. 6. Choi EK, Shen MJ, Han S, et al. Intrinsic cardiac nerve activity and paroxysmal atrial tachyarrhythmia in ambulatory dogs. Circulation 2010;121:2615–23. https://doi.org/10.1161/ CIRCULATIONAHA.109.919829; PMID: 20529998. 7. Patterson E, Jackman WM, Beckman KJ, et al. Spontaneous pulmonary vein firing in man: relationship to tachycardiapause early afterdepolarizations and triggered arrhythmia in canine pulmonary veins in vitro. J Cardiovasc Electrophysiol 2007;18:1067–75. https://doi. org/10.1111/j.1540-8167.2007.00909.x; PMID: 17655663. 8. Patterson E, Lazzara R, Szabo B, et al. Sodium-calcium exchange initiated by the Ca2+ transient: an arrhythmia trigger within pulmonary veins. J Am Coll Cardiol 2006;47:1196–206. https://doi.org/10.1016/j. jacc.2005.12.023; PMID: 16545652. 9. Stavrakis S, Nakagawa H, Po SS, et al. The role of the autonomic ganglia in atrial fibrillation. JACC Clin Electrophysiol 2015;1:1–13. https://doi.org/10.1016/j.jacep.2015.01.005; PMID: 26301262. 10. Sha Y, Scherlag BJ, Yu L, et al. Low-level right vagal stimulation: anticholinergic and antiadrenergic effects. J Cardiovasc Electrophysiol 2011;22:1147–53. https://doi. org/10.1111/j.1540-8167.2011.02070.x; PMID: 21489033. 11. Shen MJ, Shinohara T, Park HW, et al. Continuous low-level vagus nerve stimulation reduces stellate ganglion nerve activity and paroxysmal atrial tachyarrhythmias in ambulatory canines. Circulation 2011;123:2204–12. https:// doi.org/10.1161/CIRCULATIONAHA.111.018028; PMID: 21555706. 12. Sheng X, Scherlag BJ, Yu L, et al. Prevention and reversal of atrial fibrillation inducibility and autonomic remodeling by low-level vagosympathetic nerve stimulation. J Am Coll Cardiol 2011;57:563–71. https://doi.org/10.1016/j. jacc.2010.09.034; PMID: 21272747. 13. Yu L, Scherlag BJ, Sha Y, et al. Interactions between atrial electrical remodeling and autonomic remodeling: how to break the vicious cycle. Heart Rhythm 2012;9:804–9. https:// doi.org/10.1016/j.hrthm.2011.12.023; PMID: 22214613. 14. Fallgatter AJ, Neuhauser B, Herrmann MJ, et al. Far field potentials from the brain stem after transcutaneous vagus

ventricular arrhythmias, Tian et al. evaluated the role of PSGB in 30 consecutive patients with drug-refractory electrical storm. At 24 hours, 60% of patients were free from ventricular arrhythmias.53 Importantly, patients whose ventricular arrhythmias were controlled had a lower hospital mortality rate than patients whose arrhythmias continued (5.6% versus 50.0%; p=0.009).

Conclusion

The understanding of the mechanistic aspects of AF remains incomplete. This may be one of the reasons underlying the suboptimal results of current available therapies. Among potential strategies, autonomic modulation remains a promising strategy, and several approaches for this modulation have been proposed. Larger randomised controlled studies are now needed to better define the subset of AF patients who would benefit most from catheter based autonomic modification, along with the best approach to achieve it and the effect on the success rate.

nerve stimulation. J Neural Transm 2003;110:1437–43. https:// doi.org/10.1007/s00702-003-0087-6; PMID: 14666414. 15. Deuchars SA, Lall VK, Clancy J, et al. Mechanisms underpinning sympathetic nervous activity and its modulation using transcutaneous vagus nerve stimulation. Exp Physiol 2018;103:326–31. https://doi.org/10.1113/ EP086433; PMID: 29205954. 16. Frangos E, Ellrich J, Komisaruk BR. Non-invasive access to the vagus nerve central projections via electrical stimulation of the external ear: fMRI evidence in humans. Brain Stimul 2015;8:624–36. https://doi.org/10.1016/j.brs.2014.11.018; PMID: 25573069. 17. Verlinden TJ, Rijkers K, Hoogland G, et al. Morphology of the human cervical vagus nerve: implications for vagus nerve stimulation treatment. Acta Neurol Scand 2016;133:173– 82. https://doi.org/10.1111/ane.12462; PMID: 26190515. 18. Ben-Menachem E . Vagus nerve stimulation, side effects, and long-term safety. J Clin Neurophysiol 2001;18:415–8. https://doi.org/10.1097/00004691-200109000-00005; PMID: 11709646. 19. Yu L, Scherlag BJ, Li S, et al. Low-level transcutaneous electrical stimulation of the auricular branch of the vagus nerve: a non-invasive approach to treat the initial phase of atrial fibrillation. Heart Rhythm 2013;10:428–35. https://doi. org/10.1016/j.hrthm.2012.11.019; PMID: 23183191. 20. Stavrakis S, Humphrey MB, Scherlag BJ, et al. Low-level transcutaneous electrical vagus nerve stimulation suppresses atrial fibrillation. J Am Coll Cardiol 2015;65:867– 75. c10.1016/j.jacc.2014.12.026; PMID: 25744003. 21. Stavrakis S, Stoner JA, Humphrey MB, et al. REAT AF (Transcutaneous Electrical Vagus Nerve Stimulation to Suppress Atrial Fibrillation): A randomized clinical trial. JACC Clin Electrophysiol 2020;6:282–91. https://doi.org/10.1016/j. jacep.2019.11.008; PMID: 32192678. 22. Zhang Y, Ilsar I, Sabbah HN, et al. Relationship between right cervical vagus nerve stimulation and atrial fibrillation inducibility: therapeutic intensities do not increase arrhythmogenesis. Heart Rhythm 2009;6:244–50. https://doi. org/10.1016/j.hrthm.2008.10.043; PMID: 19187919. 23. Sata Y, Head GA, Denton K, et al. Role of the sympathetic nervous system and its modulation in renal hypertension. Front Med (Lausanne) 2018;5:82. https://doi.org/10.3389/ fmed.2018.00082; PMID: 29651418. 24. Pokushalov E, Romanov A, Corbucci G, et al. A randomized comparison of pulmonary vein isolation with versus without concomitant renal artery denervation in patients with refractory symptomatic atrial fibrillation and resistant hypertension. J Am Coll Cardiol 2012;60:1163–70. https://doi. org/10.1016/j.jacc.2012.05.036; PMID: 22958958. 25. Feyz L, Theuns DA, Bhagwandien R, et al. Atrial fibrillation reduction by renal sympathetic denervation: 12 months’ results of the afford study. Clin Res Cardiol 2019;108:634–42. https://doi.org/10.1007/s00392-018-1391-3; PMID: 30413869. 26. Steinberg JS, Shabanov V, Ivanickiy E, et al. Evaluate renal artery denervation in addition to catheter ablation to eliminate atrial fibrillation (ERADICATE-AF) trial. Heart Rhythm 40th Scientific Sessions 2019, San Francisco, 8–11 May 2019. Abstract: S-LBCT01-03. 27. Huang B, Liu H, Scherlag BJ, et al. Atrial fibrillation in obstructive sleep apnea: neural mechanisms and emerging therapies. Trends Cardiovasc Med 2021;31:127–32. https://doi. org/10.1016/j.tcm.2020.01.006; PMID: 32008837. 28. Tavares L, Rodríguez-Mañero M, Kreidieh B, et al. Cardiac

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afferent denervation abolishes ganglionated plexi and sympathetic responses to apnea: implications for atrial fibrillation. Circ Arrhythm Electrophysiol 2019;12:e006942. https://doi.org/10.1161/CIRCEP.118.006942; PMID: 31164004. 29. Kim DT, Lai AC, Hwang C, et al. The ligament of Marshall: a structural analysis in human hearts with implications for atrial arrhythmias. J Am Coll Cardiol 2000;36:1324–7. https:// doi.org/10.1016/S0735-1097(00)00819-6; PMID: 11028490. 30. Ulphani JS, Arora R, Cain JH, et al. The ligament of Marshall as a parasympathetic conduit. Am J Physiol Heart Circ Physiol 2007;293:1629–35. https://doi.org/10.1152/ ajpheart.00139.2007; PMID: 17545480. 31. Báez-Escudero JL, Morales PF, Dave AS, et al. Ethanol infusion in the vein of Marshall facilitates mitral isthmus ablation. Heart Rhythm 2012;9:1207–15. https://doi. org/10.1016/j.hrthm.2012.03.008; PMID: 22406143. 32. Rodríguez-Mañero M, Schurmann P, Valderrábano M. Ligament and vein of Marshall: a therapeutic opportunity in atrial fibrillation. Heart Rhythm 2016;13:593–601. https://doi. org/10.1016/j.hrthm.2015.10.018; PMID: 26576705. 33. Valderrábano M, Peterson LE, Swarup V, et al. Effect of catheter ablation with vein of Marshall ethanol infusion vs catheter ablation alone on persistent atrial fibrillation: the VENUS randomized clinical trial. JAMA 2020;324:1620–8. https://doi.org/10.1001/jama.2020.16195; PMID: 33107945. 34. Báez-Escudero JL, Keida T, Dave AS, et al. Ethanol infusion in the vein of Marshall leads to parasympathetic denervation of the human left atrium: implications for atrial fibrillation. J Am Coll Cardiol 2014;63:1892–901. https://doi.org/10.1016/j. jacc.2014.01.032; PMID: 24561151. 35. Derval N, Duchateau J, Denis A, et al. Marshall bundle elimination, Pulmonary vein isolation, and Line completion for ANatomical ablation of persistent atrial fibrillation (Marshall-PLAN): prospective, single-center study. Heart Rhythm 2021;18:529–37. https://doi.org/10.1016/j. hrthm.2020.12.023; PMID: 33383226. 36. Fink T, Schlüter M, Heeger CH, et al. Stand-alone pulmonary vein isolation versus pulmonary vein isolation with additional substrate modification as index ablation procedures in patients with persistent and long-standing persistent atrial fibrillation: the randomized Alster-LOST-AF trial (Ablation at St Georg Hospital for Long-standing Persistent Atrial Fibrillation). Circ Arrhythm Electrophysiol 2017;10:e005114. https://doi.org/10.1161/CIRCEP.117.005114; PMID: 28687670. 37. Linz D, Ukena C, Mahfoud F, et al. Atrial autonomic innervation: a target for interventional antiarrhythmic therapy? J Am Coll Cardiol 2014;63:215–24. https://doi. org/10.1016/j.jacc.2013.09.020; PMID: 24140663. 38. Linz D, van Hunnik A, Ukena C, et al. Renal denervation: effects on atrial electrophysiology and arrhythmias. Clin Res Cardiol 2014;103:765–74. https://doi.org/10.1007/s00392-0140695-1; PMID: 24682223. 39. Dai M, Bao M, Zhang Y, et al. Low-level carotid baroreflex stimulation suppresses atrial fibrillation by inhibiting left stellate ganglion activity in an acute canine model. Heart Rhythm 2016;13:2203–12. https://doi.org/10.1016/j. hrthm.2016.08.021; PMID: 27520541. 40. Liao K, Yu L, Zhou X, et al. Low level baroreceptor stimulation suppresses atrial fibrillation by inhibiting ganglionated plexus activity. Can J Cardiol 2015;31:767–74. https://doi.org/10.1016/j.cjca.2015.01.007; PMID: 26022989. 41. Scherlag BJ, Yamanashi W, Patel U, et al. Autonomically

Neuromodulatory Approaches for AF Ablation induced conversion of pulmonary vein focal firing into atrial fibrillation. J Am Coll Cardiol 2005;45:1878–86. https://doi. org/10.1016/j.jacc.2005.01.057; PMID: 15936622. 42. Po SS, Scherlag BJ, Yamanashi WS, et al. Experimental model for paroxysmal atrial fibrillation arising at the pulmonary vein-atrial junctions. Heart Rhythm 2006;3:201–8. https://doi.org/10.1016/j.hrthm.2005.11.008; PMID: 16443537. 43. Patterson E, Lazzara R, Szabo B, et al. Sodium-calcium exchange initiated by the Ca2+ transient: an arrhythmia trigger within pulmonary veins. J Am Coll Cardiol 2006;47:1196–206. https://doi.org/10.1016/j. jacc.2005.12.023; PMID: 16545652. 44. Chen YJ, Chen SA, Tai CT, et al. Role of atrial electrophysiology and autonomic nervous system in patients with supraventricular tachycardia and paroxysmal atrial fibrillation. J Am Coll Cardiol 1998; 32:732–8. https://doi. org/10.1016/S0735-1097(98)00305-2; PMID: 9741520. 45. Tan AY, Zhou S, Ogawa M, et al. Neural mechanisms of paroxysmal atrial fibrillation and paroxysmal atrial tachycardia in ambulatory canines. Circulation 2008;118:916– 25. https://doi.org/10.1161/CIRCULATIONAHA.108.776203;

PMID: 18697820. 46. Pappone C, Santinelli V, Manguso F, et al. Pulmonary vein denervation enhances long-term benefit after circumferential ablation for paroxysmal atrial fibrillation. Circulation 2004;109:327–34. https://doi.org/10.1161/01. CIR.0000112641.16340.C7; PMID: 14707026. 47. Katritsis DG, Pokushalov E, Romanov A, et al. Autonomic denervation added to pulmonary vein isolation for paroxysmal atrial fibrillation: a randomized clinical trial. J Am Coll Cardiol 2013;62:2318–25. https://doi.org/10.1016/j. jacc.2013.06.053; PMID: 23973694. 48. Pokushalov E, Romanov A, Katritsis DG, et al. Ganglionated plexus ablation vs linear ablation in patients undergoing pulmonary vein isolation for persistent/long-standing persistent atrial fibrillation: a randomized comparison. Heart Rhythm 2013;10:1280–6. https://doi.org/10.1016/j. hrthm.2013.04.016; PMID: 23608592. 49. Romanov A, Pokushalov E, Ponomarev D, et al. Long-term suppression of atrial fibrillation by botulinum toxin injection into epicardial fat pads in patients undergoing cardiac surgery: Three-year follow-up of a randomized study. Heart

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Rhythm. 2019;16:172–7. https://doi.org/10.1016/j. hrthm.2018.08.019. PMID: 30414841. 50. Driessen AHG, Berger WR, Krul SPJ, et al. Ganglion plexus ablation in advanced atrial fibrillation: the AFACT study. J Am Coll Cardiol 2016;68:1155–65. https://doi.org/cc10.1016/j. jacc.2016.06.036; PMID: 27609676. 51. Ogawa M, Tan AY, Song J, et al. Cryoablation of stellate ganglia and atrial arrhythmia in ambulatory dogs with pacing-induced heart failure. Heart Rhythm 2009;6:1772–9. https://doi.org/10.1016/j.hrthm.2009.08.011; PMID: 19959128. 52. Connors CW, Craig WY, Buchanan SA, et al. Efficacy and efficiency of perioperative stellate ganglion blocks in cardiac surgery: a pilot study. J Cardiothorac Vasc Anesth 2018;32:e28–30. https://doi.org/c10.1053/j.jvca.2017.10.025; PMID: 29162313. 53. Tian Y, Wittwer ED, Kapa S, et al. Effective use of percutaneous stellate ganglion bcc. Circ Arrhythm Electrophysiol 2019;12:e007118. https://doi.org/10.1161/ CIRCEP.118.007118; PMID: 31514529.

APSC Consensus Statements

Asian Pacific Society of Cardiology Consensus Recommendations on Dyslipidaemia Natalie Koh ,1 Brian A Ference,2 Stephen J Nicholls,3 Ann Marie Navar ,4 Derek P Chew ,5 Karam Kostner,6 Ben He,7 Hung Fat Tse ,8 Jamshed Dalal,9 Anwar Santoso ,10 Junya Ako ,11 Hayato Tada ,12 Jin Joo Park ,13 Mei Lin Ong ,14 Eric Lim,1 Tavin Subramaniam ,15 Yi-Heng Li ,16 Arintaya Phrommintikul ,17 SS Iyengar ,18 Saumitra Ray ,19 Kyung Woo Park ,20 Hong Chang Tan ,21 Narathip Chunhamaneewat ,22 Khung Keong Yeo and Jack Wei Chieh Tan 1,23

1. National Heart Centre Singapore, Singapore; 2. University of Cambridge, UK; 3. Victorian Heart Institute, Melbourne, Australia; 4. UT Southwestern Medical Center, Texas, US; 5. Flinders University of South Australia, Australia; 6. Mater Hospital and University of Queensland, Australia; 7. Shanghai Chest Hospital, China; 8. University of Hong Kong, Hong Kong; 9. Centre for Cardiac Sciences, Kokilaben Dhirubhai Ambani Hospital, Mumbai, India; 10. National Cardiovascular Centre, Harapan Kita Hospital, Department of Cardiology-Vascular Medicine, Universitas Indonesia, Indonesia; 11. Department of Cardiovascular Medicine, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan; 12. Kanazawa University Hospital, Japan; 13. Seoul National University Bundang Hospital, South Korea; 14. Gleneagles Hospital Penang, Malaysia; 15. Khoo Teck Puat Hospital, Singapore; 16. National Cheng Kung University Hospital, Taiwan; 17. Chiang Mai University, Thailand; 18. Manipal Hospital, Bangalore, India; 19. Vivekananda Institute of Medical Sciences, Kolkata, India; 20. Seoul National University Hospital, Seoul, Korea; 21. Singapore General Hospital, Singapore; 22. Siriraj Hospital, Mahidol University, Bangkok, Thailand; 23. Sengkang General Hospital, Singapore.

Abstract

The prevalence of dyslipidaemia has been increasing in the Asia-Pacific region and this is attributed to dietary changes and decreasing physical activity. While there has been substantial progress in dyslipidaemia therapy, its management in the region is hindered by limitations in awareness, adherence and healthcare costs. The Asian Pacific Society of Cardiology (APSC) developed these consensus recommendations to address the need for a unified approach to managing dyslipidaemia. These recommendations are intended to guide general cardiologists and internists in the assessment and treatment of dyslipidaemia and are hoped to pave the way for improving screening, early diagnosis and treatment. The APSC expert panel reviewed and appraised the evidence using the Grading of Recommendations Assessment, Development, and Evaluation system. Consensus recommendations were developed, which were then put to an online vote. The resulting consensus recommendations tackle contemporary issues in the management of dyslipidaemia, familial hypercholesterolaemia and lipoprotein(a) in the Asia-Pacific region.

Keywords

Asia-Pacific, consensus, dyslipidaemia, familial hypercholesterolaemia, lipoprotein(a). Disclosure: This work was funded through Asian Pacific Society of Cardiology by unrestricted educational grants from Abbott Vascular, Amgen, AstraZeneca, Bayer and Roche Diagnostics. JWCT has received honoraria from AstraZeneca, Bayer, Amgen, Medtronic, Abbott Vascular, Biosensors, Alvimedica, Boehringer Ingelheim and Pfizer; research and educational grants from Medtronic, Biosensors, Biotronik, Philips, Amgen, AstraZeneca, Roche, Ostuka, Terumo and Abbott Vascular; and consulting fees from Elixir and CSL Behring. JWCT is on the European Cardiology Review editorial board; this did not influence peer review. AMN has received research funding from BMS, Esperion, Amgen and Janssen; and honoraria and consulting fees from Amarin, Amgen, AstraZeneca, Boehringer Ingelheim , Esperion, Janssen, Lilly, Sanofi, Regeneron, NovoNordisk, Novartis, The Medicines Company, New Amsterdam, 89Bio and Pfizer. MLO has received consulting fees, lecture fees and travel grants from Abbott, Asian Pacific Society of Cardiology, Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Menarini, MSD, Novartis, Novo Nordisk, Pfizer and Sanofi. HFT has received grants, research support, speakers bureau, honoraria or consulting fees from Abbott, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Daiichi Sankyo, Medtronic, Novartis, Pfizer and Sanofi. SSI has received investigator fees from Amgen and lecture honoraria from Reddy’s Lab, Sanofi, and Novartis. TS has received advisory board honoraria from Amgen, AstraZeneca, MSD, Novo Nordisk, Pfizer, Novartis and Sanofi. SJN has received research support from AstraZeneca, Amgen, Anthera, Eli Lilly, Esperion, Novartis, Cerenis, The Medicines Company, Resverlogix, InfraReDx, Roche, Sanofi-Regeneron and LipoScience; and is a consultant for AstraZeneca, Akcea, Eli Lilly, Anthera, Omthera, Merck, Takeda, Resverlogix, Sanofi-Regeneron, CSL Behring, Esperion and Boehringer Ingelheim. KKY has received institutional research funding from Medtronic, Boston Scientific, Amgen, AstraZeneca and Shockwave Medical; consulting or honoraria fees from Medtronic, Boston Scientific, Abbott Vascular, Amgen, Bayer and Novartis; and speaker or proctor fees from Abbott Vascular, Boston Scientific, Medtronic, Philips, Shockwave Medical, Alvimedica, Menarini, AstraZeneca, Amgen and Bayer. All other authors have no conflicts of interest to declare. Acknowledgements: Medical writing support was provided by Agnes Agustin and Ivan Olegario of MIMS Pte Ltd. Received: 15 July 2021 Accepted: 4 October 2021 Citation: European Cardiology Review 2021;16:e54. DOI: https://doi.org/10.15420/ecr.2021.36 Correspondence: Jack Wei Chieh Tan, National Heart Centre, Singapore, 5 Hospital Dr, Singapore 169609. E: jack.tan.w.c@singhealth.com.sg Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

APSC Consensus Recommendations on Dyslipidaemia Table 1: High Thrombotic Risk ‘Coronary– Vascular–Disease’ Algorithm

2. Moderate (authors believe that the true effect is probably close to the estimated effect). 3. Low (true effect might be markedly different from the estimated effect). 4. Very low (true effect is probably markedly different from the estimated effect).3

Assessment of High-risk Chronic Coronary Syndrome C = CORONARY

V = VASCULAR

• Prior coronary event • High-risk coronary

• Established peripheral • Diabetes on treatment artery disease‡ • eGFR <60 mg/min/1.73 m2 • Cerebrovascular • Micro- and macro-

anatomy* • Documented multi-vessel coronary disease†

disease§

D = DISEASE

The authors adjusted the level of evidence if the estimated effect when applied in the Asia-Pacific region might differ from the published evidence because of various factors such as ethnicity, cultural differences and/or healthcare systems and resources.

albuminuria

• Heart failure due to

coronary artery disease

The available evidence was then discussed during two consensus meetings (May 2020 and December 2020). Consensus recommendations were developed during the meetings, which were then put to an online vote. Each recommendation was voted on by each panel member using a threepoint scale (agree, neutral, or disagree). Consensus was reached when 80% of votes for a recommendation were agree or neutral. In the case of nonconsensus, the recommendations were further discussed using email, then revised accordingly until the criteria for consensus were fulfilled.

Dyslipidaemia, one of the major risk factors of atherosclerotic cardiovascular disease (ASCVD), is a condition marked by the imbalance of atherogenic and protective lipids, such as triglycerides, LDL cholesterol (LDL-C) and HDL cholesterol (HDL-C). As ASCVD is one of the leading causes of mortality worldwide, effective management of dyslipidaemia is more important than ever. The increasing prevalence of dyslipidaemia in the Asia Pacific is associated with dietary changes and decreasing physical activity.1 While there has been substantial progress in dyslipidaemia therapy, its management in the region is hindered by limitations in awareness, adherence and healthcare costs.

Consensus Recommendations Dyslipidaemia Recommendation 1. Patients with chronic coronary syndrome (CCS) should be assessed according to the Coronary–Vascular–Disease (‘CVD’) system (APSC CCS consensus recommendations2) and categorised as having high-risk CCS (one risk factor) or very-high-risk CCS (more than one risk factor). Level of evidence: Low. Consensus: 96.3% agree, 3.7% neutral, 0% disagree.

The Asian Pacific Society of Cardiology (APSC) developed these consensus recommendations to address the need for a unified approach to managing dyslipidaemia. These recommendations are intended to guide general cardiologists and internists in the assessment and treatment of dyslipidaemia. Although there is limited published clinical evidence and a lack of country-specific guidelines on dyslipidaemia management in the region, these recommendations hope to pave the way for improving screening, early diagnosis, and treatment throughout the region.

In these consensus statements, CCS is defined as the clinically stable phase between the index cardiovascular event and recurrent events in patients with coronary artery disease (CAD).2 To ensure that these consensus recommendations are aligned with other recommendations by the APSC, these recommendations adopted the ‘CVD’ classification of high-risk and very-high-risk CCS developed by the APSC.2 The ‘CVD’ system was developed to serve as the backbone of risk classification for the patient with dyslipidaemia. The presence of any single factor listed would indicate high clinical risk in a CCS patient. The presence of factors from multiple (more than one) categories (but not two factors from the same category only) would indicate even higher risk of clinical events in the patient. The assessment table was created through a separate APSC consensus and followed the pattern of levels of total cardiovascular risk presented in the 2019 European Society of Cardiology and European Atherosclerosis Society guidelines for the management of dyslipidaemia.4

Methods

The APSC convened an expert consensus panel to review the literature on the assessment of dyslipidaemia, discuss gaps in current management, determine areas where further guidance is needed to and develop consensus recommendations on the use of LDL-C lowering therapies. The 26 experts of the panel are members of the APSC who were nominated by national societies and endorsed by the APSC consensus board or invited international experts. The expert consensus panel comprised cardiologists from Australia, China, Hong Kong, India, Indonesia, Japan, South Korea, Malaysia, Philippines, Singapore, Taiwan, Thailand, UK and US. For the development of these consensus recommendations, the panel agreed to use the APSC ‘CVD’ system for defining high-risk and very-high-risk patients (Table 1).2

Some countries in the Asia Pacific have created their own guidelines for the prevention, assessment and management of dyslipidaemia. These guidelines were also taken into consideration during the creation of the consensus recommendations to create a unified approach in the region.

After a comprehensive literature search using the broad search terms “dyslipidemia” and [“Asia” OR “Asia Pacific”], selected applicable articles were reviewed and appraised using the Grading of Recommendations Assessment, Development, and Evaluation system, as follows:

It should be noted that total cardiovascular risk estimation is a part of a continuum. The cut-off points that were used to define high-risk levels are partly based on clinical trial evidence and – by necessity – partly based on clinical judgement. As the categories are based on an ideal setting with unlimited resources and best available evidence, appropriate measures within the local healthcare system should still be considered in clinical practice.4

1. High (authors have high confidence that the true effect is similar to the estimated effect.

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APSC Consensus Recommendations on Dyslipidaemia each 1 mmol/l reduction in LDL cholesterol produced an absolute reduction in major vascular events of about 11 per 1,000 over 5 years in individuals with a 5-year risk of major vascular events of less than 10%.10

Recommendation 2. High-intensity statins are recommended for all patients with clinically manifest CCS, regardless of risk. Level of evidence: Moderate. Level of consensus: 88.9% agree, 11.1% neutral, 0% disagree.

There is limited evidence on the effectiveness of statins for primary prevention among Asian people, especially in developing countries. However, subgroup analyses with the CTT Collaboration meta-analysis of statin trials suggests that the proportional reduction in risk per mmol/l reduction in LDL-C among Asian participants enrolled in the statin trials was similar to the reduction in risk observed among participants from other countries. A few Asian guidelines recommend the use of statins for primary prevention, but these guidelines come from developed nations and were based on western studies.11–14 In primary prevention, physicians should consider individual baseline risk, a person’s potential absolute risk reduction, patient preferences, and potential harm, including adverse effects and the need to take a medication daily for an extended period.15

Recommendation 3. LDL-C treatment targets for high-risk CCS are both a reduction from baseline LDL-C of at least 50% and achieving an on-treatment level at least <1.8 mmol/l. Level of evidence: Low. Level of consensus: 96.3% agree, 3.7% neutral, 0% disagree. Recommendation 4. LDL-C treatment targets for very high-risk CCS are a reduction from baseline LDL-C of at least 50% and achieving an on-treatment level at least <1.4 mmol/l. Level of evidence: Low. Level of consensus: 96.3% agree, 3.7% neutral, 0% disagree.

The expert panel agreed that there is a need to aggressively treat the high-risk group as lipid treatment targets are often not reached in the region. Non-statin pharmacological options, such as ezetimibe and PCSK9 inhibitors, can also be effective in lowering cardiovascular event rates in high-risk and very-high-risk patients, when used in combination with statins.16,17 Upfront initiation of combination therapy may be considered early in very-high-risk patients to shorten the time to achieve LDL-Clowering targets.

Recommendation 5. For high-risk CCS patients already treated with maximally tolerated statins, ezetimibe and/or a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor may be added for those who do not achieve target. Level of evidence: Moderate. Level of consensus: 100% agree; 0% neutral; 0% disagree. Recommendation 6. For very-high-risk CCS, upfront initiation of combination therapy with high-intensity statins and ezetimibe may be considered. A PCSK9 inhibitor may be added for those who do not achieve target within 4 weeks of initial therapy. Level of evidence: Moderate. Level of consensus: 96.3% agree; 3.7% neutral; 0% disagree.

Reassessment of lipid levels after 4 weeks of therapy to assess treatment response and the need for uptitration of therapy was agreed on for patients with very-high-risk CCS to avoid treatment inertia and ensure that targets are reached in the shortest time possible. The recommendations for dyslipidaemia are summarised in Figure 1.

Familial Hypercholesterolaemia

Statins reduce the risk of cardiovascular events and ischaemic strokes, in both primary and secondary prevention populations.5,6 It is recommended that a high-intensity statin is prescribed up to the highest tolerated dose to reach the goals set for the specific level of risk.7–9 High-intensity statin therapy is defined as a statin dose that, on average, reduces LDL-C by ≥50%.4 Of note, the 40 mg dose of rosuvastatin is not approved or recommended in China, South Korea and Japan and the 80 mg dose of atorvastatin is not approved or not recommended in some of these countries.

Recommendation 7. Familial hypercholesterolaemia (FH) should be considered in people with: • Severely elevated LDL-C (in adults, >4.9 mmol/l; in children up to age 19 years, >3.9 mmol/l); • LDL-C of >2.6 mmol/l while adherent to a high-intensity statin; • Premature ASCVD (age <55 years for men and <60 years for women); • Elevated LDL-C (in adults >4.1 mmol/l) AND a first-degree relative with premature cardiovascular disease; and • A first-degree relative with FH, tendon xanthoma or arcus cornealis. Level of evidence: Low. Level of consensus: 100% agree, 0% neutral, 0% disagree.

Several meta-analyses of randomised trials have been performed to evaluate the clinical benefit of statin therapy. The Cholesterol Treatment Trialists’ (CTT) collaboration meta-analysis of individual participant data from randomised trials involving at least 1,000 participants with at least 2 years of follow-up comparing either more versus less intensive statin regimens (five trials; n=39,612; median follow-up 5.1 years) or statin versus placebo or usual care control (21 trials; n=129,526; median follow-up 4.8 years) showed that lowering LDL cholesterol safely reduced the incidence of heart attack, revascularisation and ischaemic stroke, with each 1.0 mmol/l reduction in LDL-C reducing the incidence of major vascular events by over a fifth.8

Recommendation 8. Clinical criteria can be used to identify and diagnose suspected FH. The choice of criteria used may vary across and within countries. Level of evidence: Low. Level of consensus: 96.3% agree, 3.7% neutral, 0% disagree.

Another meta-analysis by the CTT Collaboration that included individual participant data from 22 trials of statin versus control (n=134,537; mean LDL cholesterol difference at 1 year of 1.08 mmol/l; median follow-up 4.8 years) and five trials of more versus less intensive statin (n=39,612; difference 0.51 mmol/l; median follow-up 5.1 years) reported that with statin therapy,

Recommendation 9. Confirmation of FH via genetic testing is not necessary for treatment initiation but may be discussed for the purposes of diagnostic confirmation and cascade screening to identify family members with FH.

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APSC Consensus Recommendations on Dyslipidaemia Figure 1: Treatment Algorithm for Dyslipidaemia in Patients with High-risk CCS Assess ‘CVD’ risk factors

Very high-risk CCS

High-risk CCS

Treatment goal: 50% reduction and LDL cholesterol <1.4 mmol/l

Treatment goal: 50% reduction and LDL cholesterol <1.8 mmol/l

High-intensity statin +/− ezetimibe

High-intensity statin

4 weeks Add ezetimibe if treatment goal not reached

Reached treatment goal?

Yes

Continue high intensity statin +/− ezetimibe

Consider and discuss PCSK9 inhibitor use

Consider and discuss PCSK9 inhibitor if treatment goal not reached

The presence of any single ‘CVD’ factor listed in Table 1 would indicate high thrombotic risk in a patient with CCS. Presence of factors from multiple categories (but not two factors from the same category only) would indicate very high risk. 92.6% agree, 7.4% neutral, 0% disagree. CCS = chronic coronary syndrome; ‘CVD’ = Coronary–Vascular–Disease; PCSK9 = proprotein convertase subtilisin/ kexin type 9.

availability of genetic testing.20 Therefore, data on the prevalence of FH are very limited in Asian countries. The genetic epidemiology of FH in Asian countries may be different from that in European cohorts.21 The panel acknowledged the various clinical criteria used in the region to diagnose FH. Internationally, the three most widely used diagnostic criteria were developed by the US MEDPED program, the UK Simon Broome Registry Group (SBRG) and the Dutch Lipid Clinic Network (DLCN). Across 16 Asian countries, six used DLCN, five used SBRG, three used MEDPED and 14 used their own criteria.22 Japan, South Korea and China, in particular, have developed their own diagnostic criteria that are localised for their population. Of note, the cut-off is >4.7 mmol/l in guidelines from Japan and China and might vary between countries according to the distribution of LDL-C levels in the countries.23,24

Level of evidence: Low. Level of consensus: 100% agree, 0% neutral, 0% disagree. Recommendation 10. Once an index case is diagnosed, family cascade screening (lipid profile) is recommended. Level of evidence: Low. Level of consensus: 96.3% agree, 3.7% neutral, 0% disagree. Recommendation 11. Patients with FH and ASCVD or another major cardiovascular risk factor are considered to be very high risk. All other patients with FH are considered to be high risk. These patients should be treated with lipid-lowering therapies in accordance with their risk profile. Level of evidence: Low. Level of consensus: 96.3% agree, 0% neutral, 3.7% disagree.

The availability of genetic testing is also variable within and between Asian countries. Hence, the panel has voted to allow individual countries to adopt the clinical criteria most appropriate for their population.

FH screening is important as FH is the most common monogenic lipid disorder and the most strongly related to ASCVD. The pooled prevalence of FH from a meta-analysis of 19 studies was 0.40% (95% CI [0.29%– 0.52%]), which corresponds to a frequency of 1 in 250 individuals.18 However, only a small fraction of people with FH are identified and properly treated. If left untreated, FH patients typically develop premature CAD due to lifelong elevation of plasma LDL-C, with the risk of coronary heart disease (CHD) estimated to be increased at least 10-fold (>50% lifetime risk of fatal CAD). The Copenhagen General Population Study showed that the prevalence of CHD among people with definite/probable FH was 33% and only 48% received statins.19

The panel recommended opportunistic and cascade screening of FH. Index cases can be detected by opportunistic or targeted systematic screening in primary care, guided by severely elevated LDL-C levels, persistently elevated LDL-C despite statin therapy; or a family history of ASCVD, FH, tendon xanthoma or arcus cornealis. FH testing was found to be cost-effective in a genetic screening programme that showed 3.3 years of life gained for each new diagnosed case.25 A more recent study determined that cascade testing from index patients with both clinically defined definite and possible FH using DNA testing for the family mutation when it can be identified, or LDL-cholesterol levels when it cannot, was the most cost-effective strategy with an incremental cost-effectiveness ratio of £3,666 per quality-adjusted lifeyear gained.26 Nonetheless, because of wide disparity in healthcare resources across the Asia-Pacific region, genetic testing may be

While there is a growing awareness of FH worldwide, there are still limited studies about FH in the Asia-Pacific region. These gaps are because of low disease awareness, lack of national screening programs and limited

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APSC Consensus Recommendations on Dyslipidaemia unavailable or cost-prohibitive in some areas. In these circumstances, clinical evaluation and lipid testing should be emphasised.

The panel agreed on the contemporary need to include lipoprotein(a) in the consensus recommendations. It is also acknowledged that there is a lack of evidence regarding lipoprotein(a) in the region and that it will be more useful as a risk modifier rather than a treatment target.

The Copenhagen General Population Study found that CHD was increased 13-fold among patients with definite/probable FH not receiving statins, while the risk remained 10-fold higher among persons treated with a statin.19 This suggests that high-intensity statin therapy is needed in many FH patients. A study of 70 patients with heterozygous FH treated with high-dose statins and ezetimibe found that the regimen improved total cholesterol (p<0.05), LDL-C (p<0.05), triglycerides (p<0.05) and apolipoprotein-B (p<0.05) in comparison to statin monotherapy over a 12-month follow-up period.27 Furthermore, a study of 50 patients with homozygous FH found that patients receiving ezetimibe plus atorvastatin or simvastatin (40 mg or 80 mg for either drug) significantly reduced LDL-C levels compared with those receiving 80 mg of either statin as monotherapy (−20.7% versus −6.7%, p=0.007).28 The study also found that the addition of ezetimibe was safe and well tolerated.

Lipoprotein(a) kits are widely available in the West and in developed AsiaPacific regions, such as Australia, New Zealand, Singapore, Japan and South Korea. However, the availability and the cost of testing are prohibitive elsewhere in the Asia-Pacific region, and lipoprotein(a) testing is often not reimbursed by national insurers. The 2018 Cholesterol Clinical Practice Guideline has recognised elevated lipoprotein(a) as an ASCVD risk enhancer.31 Among patients with enhanced risk because of elevated lipoprotein(a) levels, the initiation or intensification of statin therapy may be considered. The current management strategies for persons with elevated lipoprotein(a) include cascade screening as well as aggressive prevention and control of all modifiable risk factors.32 In particular, this should emphasise more intensive lowering of LDL-C as the initial therapeutic action. Currently available treatments have not been shown to lower ASCVD risk via lipoprotein(a) lowering per se. While PCSK9 inhibitors lower lipoprotein(a) by 30%, and this may explain some of their benefit, most of their benefit is because of their effect on LDL-C.33

Lipoprotein(a) Recommendation 12. Resources permitting, lipoprotein(a) measurement should be performed at least once in each adult person’s lifetime, especially those with family history of premature ASCVD. Those with very high inherited lipoprotein(a) levels >430 nmol/l (>180 mg/dl) may have a lifetime risk of ASCVD equivalent to the risk associated with heterozygous FH. Level of evidence: Low. Level of consensus: 92.6% agree, 7.4% neutral, 0% disagree.

New therapies are under development that potently and specifically lower lipoprotein(a) levels. Lp(a)HORIZON (NCT04023552) is a large phase 3 cardiovascular outcome trial underway that is evaluatating whether lowering lipoprotein(a) with one of these newer agents will reduce the risk of major cardiovascular events. Increasing screening for elevated lipoprotein(a) to identify individuals who may benefit from these therapies will allow more rapid integration of these therapies into clinical practice in the future. Mendelian randomisation implies that lipoprotein(a) plays a causal role in both ASCVD and aortic stenosis. If so, lowering lipoprotein(a) may be favourable.34

Recommendation 13. Lipoprotein(a) measurement should be considered in selected patients with a family history of premature cardiovascular disease. Level of evidence: Low. Level of consensus: 92.6% agree, 7.4% neutral, 0% disagree.

Conclusion

Recommendation 14. As lipoprotein(a) is a risk enhancer, measurement may be considered for people who are borderline between high- and very-high risk. Level of evidence: Low. Consensus: 92.6% agree, 7.4% neutral, 0% disagree.

These consensus recommendations aim to provide a comprehensive guide on the management of dyslipidaemia, in patients in the Asia-Pacific region. The 14 recommendations presented in this paper aim to guide clinicians based on the most updated evidence. However, given the varied clinical situations and healthcare resources present in the region, these recommendations should not replace clinical judgement. The management of dyslipidaemia should be managed on an individual basis, accounting for an individual’s baseline risk, clinical characteristics and comorbidities, as well as patient concerns and preferences. Clinicians should also be aware of the challenges that may limit the applicability of these consensus recommendations, such as the availability and affordability of specific drugs, interventions and other technologies, differences in each country’s healthcare resources and currently accepted standards of care along with cultural factors.

The INTERHEART study demonstrated how lipoprotein(a) can be used for the risk assessment of acute MI in ethnically diverse populations. South Asian people with elevated lipoprotein(a) concentrations had the highest odds for acute MI (OR 2.14; 95% CI [1.59–2.89]; p<0.001) and the highest population-attributable risk (10%) of ASCVD (adjusted for age, sex, apolipoprotein-A, and apolipoprotein-B).29,30 This was followed by Southeast Asian people, with an OR of 1.83 (95% CI [1.17–2.88]; p=0.009). 1. Lin C-F, Chang Y-H, Chien S-C, et al. Epidemiology of dyslipidemia in the Asia Pacific region. Int J Gerontol 2018;12:2-6. https://doi.org/10.1016/j.ijge.2018.02.010. 2. Tan JWC, Chew DP, Brieger D, et al. 2020 Asian Pacific Society of Cardiology consensus recommendations on antithrombotic management for high-risk chronic coronary syndrome. Eur Cardiol 2021;16:e26. https://doi.org/10.15420/ ecr.2020.45; PMID: 34249148. 3. Balshem H, Helfand M, Schünemann HJ, et al. GRADE guidelines: 3. Rating the quality of evidence. J Clin Epidemiol 2011;64:401–6. https://doi.org/10.1016/j.jclinepi.2010.07.015; PMID: 21208779. 4. Mach F, Baigent C, Catapano AL, et al. 2019 ESC/EAS guidelines for the management of dyslipidaemias: lipid

modification to reduce cardiovascular risk. Eur Heart J 2020;41:111–88. https://doi.org/10.1093/eurheartj/ehz455; PMID: 31504418. 5. Cholesterol Treatment Trialists’ (CTT) Collaborators. The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials. Lancet 2012;380:581–90. https://doi.org/10.1016/S01406736(12)60367-5; PMID: 22607822. 6. Tramacere I, Boncoraglio GB, Banzi R, et al. Comparison of statins for secondary prevention in patients with ischemic stroke or transient ischemic attack: a systematic review and network meta-analysis. BMC Med 2019;17:67. https://doi. org/10.1186/s12916-019-1298-5; PMID: 30914063.

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7. Brugts JJ, Yetgin T, Hoeks SE, et al. The benefits of statins in people without established cardiovascular disease but with cardiovascular risk factors: meta-analysis of randomised controlled trials. BMJ 2009;338:b2376. https://doi. org/10.1136/bmj.b2376; PMID: 19567909. 8. Baigent C, Blackwell L, Emberson J, et al. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet 2010;376:1670–81. https://doi. org/10.1016/S0140-6736(10)61350-5; PMID: 21067804. 9. Mills EJ, Rachlis B, Wu P, et al. Primary prevention of cardiovascular mortality and events with statin treatments. J Am Coll Cardiol 2008;52:1769–81. https://doi.org/10.1016/j. jacc.2008.08.039; PMID: 19022156.

APSC Consensus Recommendations on Dyslipidaemia 10. Cholesterol Treatment Trialists’ (CTT) Collaboratio. Efficacy and safety of LDL-lowering therapy among men and women: meta-analysis of individual data from 174,000 participants in 27 randomised trials. Lancet 2015;385:1397– 405. https://doi.org/10.1016/S0140-6736(14)61368-4; PMID: 25579834. 11. Cheung BMY, Cheng CH, Lau CP, et al. 2016 consensus statement on prevention of atherosclerotic cardiovascular disease in the Hong Kong population. Hong Kong Med J 2017;23191–201. https://doi.org/10.12809/hkmj165045; PMID: 28387202. 12. Kinoshita M, Yokote K, Arai H, et al. Japan Atherosclerosis Society (JAS) guidelines for prevention of atherosclerotic cardiovascular diseases 2017. J Atheroscler Thromb 2018;25:846–984. https://doi.org/10.5551/jat.GL2017; PMID: 30135334. 13. Rhee E-J, Kim HC, Kim JH, et al. 2018 Guidelines for the management of dyslipidemia in Korea. Korean J Intern Med 2019;34:1171. https://doi.org/10.3904/kjim.2019.188.e1; PMID: 31466435. 14. Minisytry of Health Singapore. Lipids: MOH Clinical Practice Guidelines 2/2016. Singapore: Ministry of Health, 2016. 15. Byrne P, Cullinan J, Smith A, Smith SM. Statins for the primary prevention of cardiovascular disease: an overview of systematic reviews. BMJ Open 2019;9:e023085. https:// doi.org/10.1136/bmjopen-2018-023085; PMID: 31015265. 16. Papademetriou V, Stavropoulos K, Papadopoulos C, et al. Role of PCSK9 inhibitors in high risk patients with dyslipidemia: focus on familial hypercholesterolemia. Curr Pharm Des 2018;24:3647–53. https://doi.org/10.2174/13816128 24666181010124657; PMID: 30317985. 17. Choi JY, Na JO. Pharmacological strategies beyond statins: Ezetimibe and PCSK9 inhibitors. J Lipid Atheroscler 2019;8:183–91. https://doi.org/10.12997/jla.2019.8.2.183; PMID: 32821708. 18. Akioyamen LE, Genest J, Shan SD, et al. Estimating the prevalence of heterozygous familial hypercholesterolaemia: a systematic review and meta-analysis. BMJ Open 2017;7:e016461. https://doi.org/10.1136/bmjopen-2017-016461;

PMID: 28864697. 19. Benn M, Watts GF, Tybjaerg-Hansen A, Nordestgaard BG. Familial hypercholesterolemia in the Danish general population: prevalence, coronary artery disease, and cholesterol-lowering medication. J Clin Endocrinol Metab. 2012;97:3956–64. https://doi.org/10.1210/jc.2012-1563; PMID: 22893714. 20. Jackson CL, Zordok M, Kullo IJ. Familial hypercholesterolemia in Southeast and East Asia. Am J Prev Cardiol 2021;6:100157. https://doi.org/10.1016/j. ajpc.2021.100157; PMID: 34327494. 21. Livy A, Lye S. Familial hypercholesterolemia in Asia: a review. Journal OMICS Research 2011;1:22–31. 22. Zhou M, Zhao D. Familial hypercholesterolemia in Asian populations. J Atheroscler Thromb 2016;23:539–49. https:// doi.org/10.5551/jat.34405; PMID: 27075771. 23. Harada-Shiba M, Arai H, Ishigaki Y, et al. Guidelines for diagnosis and treatment of familial hypercholesterolemia 2017. J Atheroscler Thromb 2018;25:751–70. https://doi. org/10.5551/jat.CR003; PMID: 29877295. 24. Atherosclerosis and Coronary Heart Disease Group of the Chinese Society of Cardiology of Chinese Medical Association; Editorial Board of Chinese Journal of Cardiology. Chinese expert consensus on screening, diagnosis and treatment of familial hypercholesterolemia. Zhonghua Xin Xue Guan Bing Za Zhi 2018;46:99–103 [in Chinese]. https://doi.org/10.3760/ cma.j.issn.0253-3758.2018.02.006; PMID: 29495231. 25. Wonderling D, Umans-Eckenhausen M, Marks D, et al. Costeffectiveness analysis of the genetic screening program for familial hypercholesterolemia in the Netherlands. Semin Vasc Med 2004;4:97–104. https://doi.org/10.1055/s-2004-822992; PMID: 15199439. 26. Nherera L, Marks D, Minhas R, et al. Probabilistic costeffectiveness analysis of cascade screening for familial hypercholesterolaemia using alternative diagnostic and identification strategies. Heart 2011;97:1175–81. https://doi. org/10.1136/hrt.2010.213975; PMID: 21685482. 27. Pitsavos C, Skoumas I, Tousoulis D, et al. The impact of

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ezetimibe and high-dose of statin treatment on LDL levels in patients with heterozygous familial hypercholesterolemia. Int J Cardiol 2009;134:280–1. https://doi.org/10.1016/j. ijcard.2007.12.065; PMID: 18353459. 28. Gagné C, Gaudet D, Bruckert E, Group ES. Efficacy and safety of ezetimibe coadministered with atorvastatin or simvastatin in patients with homozygous familial hypercholesterolemia. Circulation 2002;105:2469–75. https:// doi.org/10.1161/01.cir.0000018744.58460.62; PMID: 12034651. 29. Paré G, Çaku A, McQueen M, et al. Lipoprotein(a) levels and the risk of myocardial infarction among 7 ethnic groups. Circulation 2019;139:1472–82. https://doi.org/10.1161/ CIRCULATIONAHA.118.034311; PMID: 30667276. 30. Enas EA, Varkey B, Dharmarajan TS, et al. Lipoprotein(a): An independent, genetic, and causal factor for cardiovascular disease and acute myocardial infarction. Indian Heart J 2019;71:99–112. https://doi.org/10.1016/j.ihj.2019.03.004; PMID: 31280836. 31. Grundy SM, Stone NJ, Bailey AL, et al. AHA/ACC/AACVPR/ AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation 2019;139:e1082–143. https://doi.org/10.1161/ CIR.0000000000000625; PMID: 30586774. 32. Afshar M, Thanassoulis G. Lipoprotein(a): new insights from modern genomics. Curr Opin Lipidol 2017;28:170–6. https://doi.org/10.1097/MOL.0000000000000392; PMID: 28059953. 33. Bittner VA, Szarek M, Aylward PE, et al. Effect of alirocumab on lipoprotein(a) and cardiovascular risk after acute coronary syndrome. J Am Coll Cardiol 2020;75:133–44. https://doi.org/10.1016/j.jacc.2019.10.057; PMID: 31948641. 34. Schnitzler JG, Ali L, Groenen AG, et al. Lipoprotein(a) as orchestrator of calcific aortic valve stenosis. Biomolecules 2019;9:760. https://doi.org/10.3390/biom9120760; PMID: 31766423.

ESC Highlights

2021 ESC Guidelines on Cardiac Pacing and Cardiac Resynchronisation Therapy Gheorghe-Andrei Dan Carol Davila University of Medicine, Bucharest, Romania

Keywords

Guidelines, cardiac pacing, cardiac resynchronisation therapy, devices Disclosure: GAD is on the European Cardiology Review editorial board. Received: 2 November 2021 Accepted: 2 November 2021 Citation: European Cardiology Review 2021;16:e55. DOI: https://doi.org/10.15420/ecr.2021.51 Correspondence: Gheorghe-Andrei Dan, Carol Davila University of Medicine, Colentina University Hospital, Bucharest, Romania. E: andrei.dan@gadan.ro Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Eight years have passed since the last European guidelines on cardiac pacing and resynchronisation therapy (CRT), an interval in which concepts have been refined and new concepts developed based on new data. These have been included in the recently published 2021 guidelines.1 Among the novel approaches included in the updated guidelines is a comprehensive algorithm to evaluate patients with bradycardia or conduction disease. The algorithm includes: polysomnography; genetic testing in patients with early onset of progressive cardiac conduction disease (<50 years old); specific laboratory tests when a determined cause is suspected (such as thyroid function tests, Lyme titer, electrolytes); cardiac imaging when structural myocardial disease is suspected; carotid sinus massage (after excluding carotid stenosis) and tilt tests for patients who have suspected recurrent reflex syncope. There is also exercise testing for patients who experience symptoms during or after exercise or there is a raised suspicion of chronotropic incompetence and infranodal site of block. Electrophysiological testing is reserved for patients with bifascicular block when the cause of syncope is still unexplained, when the cause of bradycardia is not excluded by non-invasive testing or when urgent empirical pacemaker (PMK) implantation is preferred based on clinical judgement. Ambulatory ECG monitoring (with longer periods of recording as the frequency of symptoms decreases) is recommended to correlate the rhythm disturbance with symptoms and an implanted loop recorder (ILR) is recommended for patients with infrequent episodes of bradycardia (less than once per month) in whom the non-invasive testing was irrelevant. Several new recommendations for pacing include patients with the bradycardia-tachycardia form of sinus node disease (SND) both for symptomatic relief and to enable pharmacological treatment if ablation of tachyarrhythmia is not possible. Minimisation of the unnecessary ventricular pacing is a class IA indication in patients with SND and a DDD type of PMK. Dual-chamber pacing should be considered in patients with adenosinesensitive syncope and paroxysmal atrioventricular block (AVB) lasting for more than 10 seconds and in patients aged over 40 years with severe,

recurrent, unpredictable syncope and asystolic pauses (>3 seconds if symptomatic or >6 seconds if asymptomatic) documented spontaneously or accompanied by symptoms during carotid sinus massage or tilt test.2 Several refined indications offer advice on device management in special conditions. PMK implantation is recommended if AVB does not resolve in less than 5 days in patients with acute MI (AMI). Also, a new recommendation refers to early device implantation (defibrillator CRT – CRT-D/or pacemaker CRT – CRT-P) in selected patients with anterior AMI and acute heart failure. Permanent PMK implantation is a class I indication for patients with persistent AVB or new onset alternating bundle branch block after transcatheter aortic valve implantation (TAVI); also, this indication should be applied in patients with pre-existing right bundle branch block with new conduction disturbance peri-procedure for TAVI. CRT is recommended for patients with heart failure in sinus rhythm with left ventricular ejection fraction (LVEF) <35%, QRS duration >150 ms, and left bundle branch block (LBBB) QRS morphology despite optimised medical therapy. With a narrower QRS of 130–149 ms and non-LBBB morphology, the recommendation is less sustained. A CRT-D device should be implanted in patients suitable for CRT who are also indicated for an ICD. CRT rather than right ventricular (RV) pacing is recommended in patients with LVEF <40% and AF and anticipated RV pacing >20% or LVEF <50% who are undergoing AV junctional ablation. His bundle pacing should be considered in patients with an indication for CRT in whom the coronary sinus lead implantation was unsuccessful. Leadless pacing could be considered in patients with difficult or impossible upper venous access or who are at high risk for pocket infection. Temporary transvenous pacing is recommended in cases of haemodynamic compromising bradyarrhythmia refractory to intravenous chronotropic drugs. MRI could be performed safely following manufacturer’s instructions in patients implanted with MRI-conditional PMK and leads. Despite the many gaps still limiting our knowledge, the 2021 guidelines on cardiac pacing and CRT represent a major step forward and should be rapidly implemented in clinical practice.

1. Glikson M, Nielsen JC, Kronborg MB, et al. 2021 ESC guidelines on cardiac pacing and cardiac resynchronization therapy. Eur Heart J 2021;42:3427–520. https://doi.org/10.1093/eurheartj/ehab364; PMID: 34455430. 2. Michowitz Y, Kronborg MB, Glikson M, Nielsen JC. The ‘10 commandments’ for the 2021 ESC guidelines on cardiac pacing and cardiac resynchronization therapy. Eur Heart J 2021;42:4295. https://doi.org/10.1093/eurheartj/ehab699; PMID: 34586378.

ISCP Posters

25th Annual Scientific Meeting of the International Society of Cardiovascular Pharmacotherapy Jack Wei Chieh Tan President, International Society of Cardiovascular Pharmacotherapy

Citation: European Cardiology Review 2021;16:e56. DOI: https://doi.org/10.15420/ecr.2021.16.POGE Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

The ISCP and team Singapore were extremely happy and proud to be able to curate key opinion leaders and multidisciplinary stakeholders to take part in our 25th Annual Scientific Meeting which was organised virtually on 24–25 July 2021. We were joined by 1,770 delegates from 42 different counties and topics covered were of broad interest. The congress was spearheaded by cardiovascular specialists across multiple disciplines, including pharmacologists, cardiac physicians and surgeons, pharmacists, scientists, nurses and medical practitioners. The scientific programme focused on cardiovascular pharmacotherapy in disease management which is the core aim of the ISCP. The abstracts reflect the quality of offerings and our prize winners fully

deserved their recognition. I congratulate all the submitters and winners. Well done. We would express our gratitude and thanks to our host the Singapore Cardiac Society and the many sponsor partners who made this event possible. Our 26th Annual Scientific Meeting will be held in Bucharest on 27–29 October 2022. We hope to welcome you back to join us again next year. Stay safe, stay engaged with ISCP. Jack Tan President, ISCP

ISCP Posters

Young Investigator Award

Compound A, a Ginger Extract, Significantly Reduces Pressure Overload-induced Systolic Heart Failure in Mice Yuto Kawase,1 Kana Shimizu,1,2 Masafumi Funamoto,1,2 Yoichi Sunagawa,1,2,3 Yasufumi Katanasaka,1,2,3 Yusuke Miyazaki,1,2,3 Satoshi Shimizu,1,2 Koji Hasegawa1,2 and Tatuya Morimoto1,2,3 1. University of Shizuoka, Shizuoka, Japan; 2. Clinical Research Institute, Kyoto Medical Center, National Hospital Organization, Kyoto, Japan; 3. Shizuoka General Hospital, Shizuoka, Japan

Citation: European Cardiology Review 2021;16:e57. DOI: https://doi.org/10.15420/ecr.2021.16.PO1 Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Objectives: Cardiac remodelling is a compensatory mechanism associated with cardiomyocyte hypertrophy and cardiac fibrosis. This process eventually results in chronic heart failure. In this study, we screened a natural compound library for compounds that suppress both hypertrophic and fibrotic responses, and found compound A, a ginger extract. The purpose of this study is to investigate the effect of compound A on cardiomyocyte hypertrophy, cardiac fibrosis and the development of heart failure. Materials and methods: First, primary cultured cardiomyocytes and cardiac fibroblasts were treated with 1 µM compound A, then stimulated with phenylephrine or transforming growth factor-β (TGF-β), respectively. Immunofluorestaining and qPCR were performed on cardiomyocytes. Measurement of L-proline incorporation, qPCR and western blotting were carried out on cardiac fibroblasts. C57BL/6J mice were subjected to transverse aortic constriction (TAC) surgery, then given a daily oral

administration of 1 mg/kg compound A for 8 weeks. Echocardiographic analysis and measurement of heart weight to body weight (HW/BW) ratio were performed. Results: In cultured cardiomyocytes, 1 µM of compound A suppressed phenylephrine-induced increases in the surface area of cardiomyocytes and in the mRNA levels of ANF and BNP. In cultured cardiac fibroblasts, the compound also suppressed TGF-β-induced L-proline incorporation, and mRNA and protein levels of α-smooth muscle actin. In heart failure model mice, echocardiographic analysis showed that 1 mg/kg of compound A prevented a TAC-induced increase in posterior wall thickness and a decrease in systolic dysfunction. The compound also suppressed a TAC-induced increases in HW/BW ratio. Conclusion: Compound A may be an effective agent for heart failure therapy.

ISCP Posters

Oral Presentation Award Winner

β3 Adrenergic Receptors in the Sinoatrial Node for Heart Rate Regulation Shu Nakao,1,2 Kazuki Yanagisawa,1 Tomoe Ueyama,1 Koji Hasegawa2 and Teruhisa Kawamura1,2 1. Ritsumeikan University, Kusatsu, Japan; 2. Kyoto Medical Center, Kyoto, Fushimi-ku, Japan

Citation: European Cardiology Review 2021;16:e58. DOI: https://doi.org/10.15420/ecr.2021.16.PO2 Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Objectives: β1-adrenergic receptor (AR) signalling has a positive chronotropic effect in the heart. However, the role of β3-AR, a minor cardiac β-AR isoform, in heart rate regulation remains unknown. β3-ARs are highly expressed in adipose tissue, and promote energy expenditure. We here investigated whether β3-ARs are expressed in the sinoatrial node (SAN), the primary pacemaking site, and regulate heart rate in mice. Materials and methods: Adult C57BL/6 male mice were used for electrocardiogram recording under mild anaesthesia with isoflurane inhalation with or without β-AR inhibitors. The right atrial wall including the SAN region was dissected and subjected to electrophysiological recording, immunolabelling and gene expression analysis. Results: mRNA expression analysis revealed that β3-AR transcripts were

detected at a modest level in the SAN region. Immunolabelling revealed that β3-ARs were expressed at low levels in SAN myocytes and at high levels in adipocytes and nerve fibres. In electrocardiogram recordings in vivo, the heart rate was decreased by a β1-AR inhibitor. A subsequent injection of a specific β3-AR inhibitor further reduced the heart rate and prolonged PR intervals. In electrophysiological experiment in vitro, SANdriving intrinsic heart rate was significantly increased by a specific β3-AR agonist. Conclusion: There may be direct and indirect mechanisms linking β3-ARs to impulse generation and propagation. This mechanism possibly presents in SAN myocytes as well as the adjacent adipose tissue, which may provide energy for action potential firing.

ISCP Posters

Oral Presentation Award Winner

Polysaccharide Peptide of Ganoderma lucidum Reduces Endothelial Injury in Stable Angina and High-risk Patients Eliana Susilowati,1 Djanggan Sargowo2 and Nadia Ovianti1 1. Biomedical Department, Medical Faculty, Brawijaya University, Malang, Indonesia; 2. Cardiology Department, Medical Faculty, Brawijaya University, Malang, Indonesia

Citation: European Cardiology Review 2021;16:e59. DOI: https://doi.org/10.15420/ecr.2021.16.PO3 Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Objective: This study aims to prove the effect of the polysaccharide peptide (PsP) of Ganoderma lucidum to reduce endothelial injury and improve endothelial function.

Results: During follow-up, nine patients were considered to drop-out because of non-adherence. No significant adverse effects were documented.

Material and methods: This is a clinical trial with pre-post-test design, conducted in 40 high-risk and 40 stable angina patients, determined based on the 2016 European Society of Cardiology guideline for stable coronary artery disease.

CEC significantly reduced both in high-risk and stable angina patients, with the average count of CEC reduced from 7.91 to 1.76 cells/ml in stable angina patients, and from 7.38 to 2.23 cells/ml in high-risk patients (p=0.001). EPC count significantly reduced in high-risk and stable angina with p=0,000, with average count of 15.11 cells/ml reduced to 6.14 cells/ml in stable angina and 12.94 to 6.10 cells/ml in the high-risk group.

Stable angina and high risk patients were given PsP 750 mg/day in three divided doses for 90 days in addition to their regular medications, given by their cardiologist. Informed consent was obtained and ethical clearance was published. Endothelial injury was measured with circulating endothelial cells (CEC) count using flow cytometry, and endothelial regeneration, measured with the endothelial progenitor cells (EPC) count using flow cytometry. Non-adherence of >80% was considered to be drop-out case.

Conclusion: PsP of G lucidum could reduce endothelial injury significantly, but the following reduction of EPC needs further research whether because of the minimal endothelial injury that was not enough to induce EPC mobilisation.

ISCP Posters

Oral Presentation Award Winner

Clinical Efficacy of Intracoronary Papaverine After Nicorandil Administration for Safe and Optimal Fractional Flow Reserve Measurement Shinjo Sonoda Saga University Medical Center, 5-1-1, Nabeshima, Japan

Citation: European Cardiology Review 2021;16:e60. DOI: https://doi.org/10.15420/ecr.2021.16.PO4 Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Background: Fractional flow reserve (FFR) is considered the standard for the assessment of the physiological significance of coronary artery stenosis. Intracoronary papaverine (PAP) is the most potent vasodilator used for the achievement of maximal hyperaemia. However, its use can provoke ventricular tachycardia (VT) due to excessive QT prolongation. We evaluated the clinical efficacy and safety of the administration of PAP after nicorandil (NIC), a potassium channel opener that prevents VT, for optimal FFR measurement. Methods: A total of 127 patients with 178 stenoses were enrolled. The FFR values were measured using NIC (NIC-FFR) and PAP (PAP-FFR). We administered PAP following NIC (NIC-PAP). Changes in the FFR and electrogram parameters (baseline versus NIC versus PAP) were assessed and the incidence of arrhythmias after PAP was evaluated. In addition, we

analysed another 41 patients with 51 stenoses, which were assessed the FFR using PAP before NIC (PAP-NIC). After propensity score matching, the electrogram parameters between 2 groups were compared. Results: The mean PAP-FFR was significantly lower than the mean NICFFR (0.82 ± 0.11 versus 0.81 ± 0.11, p<0.05). The mean baseline-QTc, NICQTc, and PAP-QTc values were 425 ± 37 ms1/2, 424 ± 41 ms1/2, and 483 ± 54 ms1/2, respectively. VT occurred in only one patient (0.6%). Although PAP induced QTc prolongation (p<0.05), the PAP-QTc duration was significantly shorter in NIC-PAP compared to PAP-NIC (p<0.05). Conclusion: The administration of PAP with NIC may induce sufficient hyperaemia and prevent fatal arrhythmia through reductions in the PAPinduced QTc prolongation during FFR measurement.

ISCP Posters

Prevalence of CYP2C19 Gene Polymorphism in Patients with Coronary Artery Disease Undergoing Percutaneous Coronary Intervention Maya Rosana Amalia1 and Susi Herminingsih2 1. West Nusa Province Hospital, Mataram, Indonesia; 2. Dr Kariadi General Hospital, Semarang, Indonesia

Citation: European Cardiology Review 2021;16:e61. DOI: https://doi.org/10.15420/ecr.2021.16.PO5 Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Objective: CYP2C19 is the hepatic enzyme involved in biotransformation of clopidogrel to its active metabolite. Polymorphism of CYP2C19 genes would jeopardise clopidogrel’s efficacy as an antiplatelet agent. We aim to gain genetic polymorphism data of the CYP2C19 gene from patients with coronary artery disease undergoing PCI. Materials and methods: This is a descriptive cross-sectional populationbased study on patients with coronary artery disease (CAD) undergoing PCI at Dr Kariadi General Hospital Semarang from March 2019 to March 2020. Results: From 79 subjects, there were 53 (67.1%) with chronic CAD and 26

(32.91%) with acute coronary syndromes. The frequency of CYP2C19*1 wild type allele was 77.8% (123), CYP2C19*2 681G>A gene was 20.9% (33), and CYP2C19*3 was 1.3% (2). We found CYP2C19*1/*2 genotype 25.31% (20 subjects) was higher than CYP2C19*1/*3 genotype of 1.26% (1). CYP2C19*2/*2 genotype frequency was 5.06% (4) and CYP2C19*3/*3 was 1.26% (1). Conclusion: Prevalence of CYP2C19 gene polymorphisms in patients with CAD undergoing percutaneous coronary intervention at Dr Kariadi General Hospital Semarang consisted of 20.9% (33) with CYP2C19*2 681G>A genes and 1.3% (2) with CYP2C19*3 636G>A genes.

ISCP Posters

Simvastatin is Independently Improving Uremic Cardiomyopathy Through Intercommunication Between Macrophage and Cardiomyocyte in Renal Failure Model Barinda Agian Jeffilano,1,2 Wawaimuli Arozal,1 Ulfa Tri Wahyuni,3 Vivian Soetikno1 and Nafrialdi Nafrialdi1 1. Department of Pharmacology and Therapeutics, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia; 2. Metabolic Disorder, Cardiovascular, and Aging Cluster, Indonesia Medical Education and Research Institute (IMERI), Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia; 3. Masters Programme in Biomedical Sciences, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia

Citation: European Cardiology Review 2021;16:e62. DOI: https://doi.org/10.15420/ecr.2021.16.PO6 Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Objective: Uremic cardiomyopathy (UC) is thought to be a significant cause of mortality in renal failure (RF). Several pharmacological interventions have been established for improving RF-induced cardiomyopathy. However, those drugs have not successfully treated the disease yet. Under uremic toxin conditions, the macrophage is able to polarise into M1 type pro-inflammatory and secreting pro-inflammatory factors into cardiomyocyte in RF. Materials and methods: We analysed the effect of simvastatin on cardiac remodelling in the 5/6 nephrectomy (5/6 NX) uremic rat model in conjunction with the interaction of RAW 265.7 Macrophage and H9C2 cardiomyocyte cells in the cell culture system. Results: Simvastatin failed to improve the RF phenotype. However, interestingly simvastatin prevented cardiac remodelling. Mechanistically,

we found that simvastatin prevented uremic toxin-mediated M1 polarisation in macrophage cells, thus preventing the production of FGF23 from macrophage, suggesting that simvastatin improved UC phenotype through ameliorating inflammation phenotype in macrophage. To identify the direct effect of pro-inflammatory macrophage secretome into cardiomyocytes, we incubated the H9C2 cardiomyocyte cell with the conditioned medium derived from RAW macrophage previously treated with indoxyl sulfate-induced uremic toxin/M1 stimulation and simvastatin. We showed that simvastatin prevented the enhancement of hypertrophy and fibrosis markers at mRNA levels in those H9C2 cells. Conclusion: Our data highlight direct evidence of uremic toxin-mediated M1 macrophage and cardiomyocyte interaction to induce cardiac remodelling in RF through FGF-23 secretion and thus provides statin as a bonafide treatment for RF-induced cardiomyopathy.

ISCP Posters

Retrospective Study to Assess the Effect of Telmisartan on Urine Albumin to Creatinine Ratio in Indian Hypertensive Patients Balram Sharma,1 Hanmant Barkate,2 Sachin Suryawanshi,2 Mayur Jadhav,2 Obaidullah Khan2 and Gauri Dhanaki2 1. Sawai Mansingh Hospital, Jaipur, India; 2. Glenmark Pharmaceuticals Ltd, Mumbai, India

Citation: European Cardiology Review 2021;16:e63. DOI: https://doi.org/10.15420/ecr.2021.16.PO7 Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Objectives: To assess the impact of telmisartan on urine albumin to creatinine ratio (UACR) and blood pressure (BP) among Indian hypertensive patients on telmisartan monotherapy. Material and methods: This was a retrospective cohort study. Hypertensive patients prescribed with Telmisartan monotherapy with UACR records of at least two analysable visits were enrolled in the study. The study was approved by an independent ethics committee. The data of enrolled patients was analysed retrospectively to assess the change in UACR and BP from visit one to visit two.

(p=0.0012) with telmisartan monotherapy in overall population (mean duration 278 days). Overall 48% patients reverted to normoalbuminuria (UACR<30 mg/g). Reductions in systolic BP and diastolic BP were −8.5 mmHg and −3.8 mmHg, respectively (both p<0.001, mean duration of 99.6 days between visits one and two). The UACR reduced from 83.3 ± 312.4 mg/g at visit one to 58.27 ± 231.47 mg/g at visit two in hypertensive patients with diabetes (n=945, mean duration 292 days). Significant reductions in systolic BP (−8.7 mmHg) and diastolic BP (−3.8 mmHg) were also found in diabetic hypertensive patients (mean duration 101.5 days).

Results: Data of 1,095 patients was available for analysis. The average age was 54.0 ± 11.7 years. There was a significant reduction in UACR from 113.58 ± 443.74 mg/g at visit one to 77.29 ± 326.76 mg/g at visit two

Conclusion: The present study demonstrated that telmisartan monotherapy prevents the progression of microalbuminuria along with causing significant reductions in BP.

ISCP Posters

The Role of Isocitrate Dehydrogenases in Direct Reprogramming to Cardiomyocytes Tomoaki Ishida,1 Tomoe Ueyama,1 Ai Baba,1 Koji Hasegawa2 and Teruhisa Kawamura1 1. Department of Biomedical Sciences, College of Life Sciences, Ritsumeikan University, Kusatsu, Japan; 2. Division of Translational Research, Kyoto Medical Center, National Hospital Organization, Kyoto, Japan

Citation: European Cardiology Review 2021;16:e64. DOI: https://doi.org/10.15420/ecr.2021.16.PO8 Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Objectives: Direct reprogramming with introduction of Gata4, Mef2c and Tbx5 (GMT) genes involved in cardiogenesis can convert fibroblasts to induced cardiomyocyte-like cells (iCMs), whereas only a low percentage of iCMs are obtained due to the low proliferative capacity. Recent studies suggest that oestrogen-related receptors (ERRs) are involved in cardiomyocyte maturation during the differentiation from pluripotent stem cells. In addition, ERRγ regulates the density and morphology of mitochondria in matured cardiomyocytes accounting for prominent aerobic metabolism. ERRγ is also known to induce the transcription of isocitrate dehydrogenases (IDHs), one of the tricarboxylic acid cycle regulators. In the present study, we investigate whether ERRγ-IDHmediated mitochondria regulation is involved in cellular metabolism during direct reprogramming to iCMs. Materials and methods: We used retroviral vectors encoding GMT to reprogram mouse embryonic fibroblasts into iCMs with or without pharmacological inhibition of mitochondrial respiration or gene silencing

with shRNAs against ERRγ and IDHs. We analysed iCM reprogramming efficiency with quantitative PCR and immunofluorescence labelling with cardiomyocyte marker molecules. Results: In the course of direct reprogramming, a mitochondrial respiration inhibitor, rotenone, decreased the iCM reprogramming efficiency. In experiments of IDHs knockdown, IDH3α significantly repressed iCM formation. In contrast, overexpression of IDH3α resulted in improvement of iCM programming efficiency, evaluated by QPCR analysis and the incidence of cardiac marker-positive cells. These results suggest the involvement of ERR-IDH-mediated energy metabolism in GMTmediated iCM production. Conclusion: We emphasise the significance of aerobic metabolism during direct reprogramming into iCMs that may provide clues to improve the efficiency.

ISCP Posters

Chrysanthemum morifolium Extract Prevents the Development of Doxorubicin-induced Heart Failure Masaya Ono,1 Yoichi Sunagawa,1,2,3 Yasufumi Katanasaka,1,2,3 Koji Hasegawa1,2 and Tatsuya Morimoto1,2,3 1. Division of Molecular Medicine, School of Pharmaceutical Sciences, University of Shizuoka, Japan; 2. Division of Translational Research, Clinical Research Institute, Kyoto Medical Center, National Hospital Organization, Japan; 3. Shizuoka General Hospital, Japan

Citation: European Cardiology Review 2021;16:e65. DOI: https://doi.org/10.15420/ecr.2021.16.PO9 Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Objectives: Doxorubicin, an anthracycline anticancer drug, induces a cumulative and dose-dependent cardiotoxicity. Recently, Chrysanthemum morifolium extract (CME), produced from the purple chrysanthemum flower, has been reported to possess various physiological activities, such as antioxidant and anti-inflammatory effects. However, it is unknown whether CME prevents doxorubicin-induced cardiotoxicity. The aim of this study is to investigate the effectiveness of CME against doxorubicininduced cardiotoxicity. Materials and methods: H9C2 cardiomyocytes were treated with CME for 2 hours, and then stimulated with 1 µM doxorubicin. After 24 hours incubation, surviving cells were evaluated by MTT assay. Cellular apoptosis markers were assessed by western blotting. Next, to investigate the effect of CME on doxorubicin-induced cardiomyopathy in vivo, C57BL6 mice were orally administered with CME (400 mg/kg/day) or vehicle daily for 2 days before being treated with doxorubicin (20 mg/kg)

intraperitoneally once. At 7 days after doxorubicin injection, an echocardiographic analysis and a TUNEL assay were performed. Results: Administering 1 mg/ml CME significantly reduced doxorubicininduced cytotoxicity in H9C2 cells. Western blotting showed that CME suppressed doxorubicin-induced increases in four markers of apoptosis: p53, phosphorylated p53, and cleaved caspase-9 and -3. The survival ratio of the CME-treated group was significantly higher than that of the vehicle-treated group in vivo. CME significantly improved doxorubicininduced left ventricular systolic dysfunction and suppressed doxorubicininduced apoptosis in mice. Conclusion: This study indicates that CME treatment reduces doxorubicininduced cardiotoxicity by suppressing apoptosis. Further studies are expected to apply CME in clinical settings for the prevention of doxorubicininduced heart failure.

ISCP Posters

Discovery of Novel Small Molecules for Heart Failure Therapy Using Cultured Cardiomyocyte by High Throughput Screening Assay Satoshi Shimizu,1,2 Miho Yamada,1 Takahiro Katagiri,1 Yoichi Sunagawa,1,2,3 Yasufumi Katanasaka,1,2,3 Yusuke Miyazaki,1,2,3 Masafumi Funamoto,1,2 Sari Nurmila,1 Kana Shimizu,1,2 Naohisa Ogo,4 Akira Asai,4 Koji Hasegawa1,2 and Tatsuya Morimoto1,2,3 1. Division of Molecular Medicine, Graduate School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan; 2. Division of Translational Research, Clinical Research Institute, Kyoto Medical Center, National Hospital Organization, Kyoto, Japan; 3. Shizuoka General Hospital, Shizuoka, Japan; 4. Centre for Drug Discovery, Graduate School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan;

Citation: European Cardiology Review 2021;16:e66. DOI: https://doi.org/10.15420/ecr.2021.16.PO10 Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Introduction: Heart failure (HF) is one of the leading causes of death in the world. Although pharmacological therapies for HF, such as angiotensin 2 receptor blockers, angiotensin-converting enzyme inhibitors and β-blockers, are established, the mortality of patients with severe HF remains still high. The developing of the agent for HF therapy is strongly required. To identify a pharmacological therapy for HF, we developed a high throughput screening system using primary neonatal rat cardiomyocytes. Methods: Primary culture of neonatal rat cardiomyocytes were isolated and cultured on 48 well plates for 36 hours. These cells were treated with a library of 268 small molecules for 2 hours and stimulated with 30 μM PE for 48 hours. Cardiomyocytes were stained with an anti-α-actinin antibody, and nuclei were stained with Hoechst 33258. Immuno-fluorescence was detected and cardiomyocyte surface area was measured using

ArrayScan® system. Inhibition rate was calculated using the following formula: Inhibition rate: (PE(+) − compound) / (PE(+) − PE(−)). Compounds of 50%-150% inhibition were classified as first hits. The already reported ones were excluded. In the second screening, the mRNA levels of hypertrophic response genes, such as ANF and BNP, were quantified by RT-PCR. Results: ArrayScan® system could automatically selected and evaluated the area of α-actinin-positive cardiomyocytes. 35 compounds were hits as inhibitor as cardiomyocyte hypertrophy. Eight compounds suppressed PEinduced hypertrophic response gene activations. Conclusion: We discovered eight small molecule inhibitors of cardiomyocyte hypertrophy by high throughput screening. Further animal examinations are needed to clarify the effects of these compounds on HF.

ISCP Posters

Citation: European Cardiology Review 2021;16:e67. DOI: https://doi.org/10.15420/ecr.2021.16.PO11 Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Several elderly heart failure (HF) patients were observed to have decreased activities of daily living (ADL) during hospitalisation. Shortening of hospital stays is especially important in the elderly, as decreasing ADL is associated with prognosis. The effect of the length of hospital stay for the elderly compared with younger population was investigated, focusing on the early initiation of tolvaptan (TLV) after hospitalisation. A total of 146 patients under 80 years old and 101 patients over 80 years old who were hospitalised with HF from February 2011 to June 2016 and had initiated TLV were analysed. The relationship between the time until commencement of TLV and the length of hospital stay was evaluated. Additionally, a comparison was made between the TLV early start group (within the median) and the

delayed start group (after the median) for both groups. A significant correlation was observed between TLV initiation duration and the length of hospital stay (under 80: r=0.382, p<0.001; over 80: r=0.395, p<0.001). The length of hospital stay in the early group was significantly longer than that in the delayed group between both groups (under 80: early 21.0 ± 13.0 days and 33.0 ± 22.7 days, p<0.001; over 80: early 21.3 ± 12.5 days and 32.9 ± 17.9 days, p<0.001). Conversely, no statistically significant difference was found in the length of hospital stay after initiation of TLV. Moreover, no increase in adverse events in the elderly was observed. The early initiation of TLV after hospitalisation is useful for HF patients, regardless of age.

ISCP Posters

The Polyunsaturated Fatty Acids EPA and DHA Prevent Myocardial Infarction-induced Heart Failure by Inhibiting p300-HAT Activity in Rats Yoichi Sunagawa,1,2,3 Ayumi Katayama,1 Masafumi Funamoto,1,2 Kana Shimizu,1,2 Satoshi Shimizu,1,2 Yasufumi Katanasaka,1,2,3 Yusuke Miyazaki,1,2,3 Koji Hasegawa1,2 and Tatsuya Morimoto1,2,3 1. University of Shizuoka, Shizuoka, Japan; 2. National Hospital Organization, Kyoto Medical Center, Kyoto, Japan; 3. Shizuoka General Hospital, Shizuoka, Japan

Citation: European Cardiology Review 2021;16:e68. DOI: https://doi.org/10.15420/ecr.2021.16.PO12 Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Introduction: While the cardioprotective functions of eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and omega-3 unsaturated fatty acids have been previously demonstrated, little is known about their effects on cardiomyocyte hypertrophy. In this study, we compared the effects of EPA and DHA on hypertrophic responses in cardiomyocytes and development of heart failure in rats with MI. Methods and results: Both EPA and DHA significantly suppressed phenylephrine- and p300-induced cardiomyocyte hypertrophy, transcription of hypertrophy response genes, and acetylation of histone H3K9 in cardiomyocytes. EPA and DHA directly inhibited p300-histone acetyltransferase activity (IC50: 37.8 and 30.6 μM, respectively). Further, EPA and DHA induced allosteric inhibition of histones and competitive inhibition of acetyl-CoA, and significantly prevented p300-induced hypertrophic responses. Rats with moderate MI (left ventricular fractional

shortening [FS] <40%) were randomly assigned to three groups, namely, vehicle (saline), EPA (1 g/kg), and DHA (1 g/kg). One week after the operation, rats were orally administrated with test agents for 6 weeks. Echocardiographic analysis demonstrated that both EPA and DHA treatments preserved FS and prevented MI-induced left ventricular remodelling. Furthermore, EPA and DHA significantly suppressed the MIinduced increase in myocardial cell diameter, perivascular fibrosis, mRNA levels of hypertrophic markers, fibrosis, and acetylation of histone H3K9. The effects on hypertrophic responses and the development of heart failure were not different between EPA and DHA groups. Conclusion: Both EPA and DHA suppressed hypertrophic responses and the development of heart failure to the same extent through the inhibition of p300-HAT activity.

ISCP Posters

A Novel Curcumin Formulation, ASD-Cur, Suppressed the Development of Systolic Dysfunction After Myocardial Infarction in Rats Hidemichi Takai,1 Yoichi Sunagawa,1,2,3 Masafumi Funamoto,1,2 Kana Shimizu,1,2 Satoshi Shimizu,1,2 Yasufumi Katanasaka,1,2,3 Yusuke Miyazaki,1,2,3 Atsusi Imaizumi,4 Tadashi Hashimoto,4 Hiromichi Wada,2 Koji Hasegawa1,2 and Tatsuya Morimoto1,2,3 1. University of Shizuoka, Shizuoka, Japan; 2. Kyoto Medical Center, Kyoto, Japan; 3. Shizuoka General Hosipital, Shizuoka, Japan; 4. Therabiopharma Inc, Japan

Citation: European Cardiology Review 2021;16:e69. DOI: https://doi.org/10.15420/ecr.2021.16.PO13 Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Objective: It has previously been reported that curcumin prevents the development of heart failure in animal models, demonstrating that the compound is a potential treatment for the disease in humans. Although curcumin is known to be safe, its therapeutic efficiency is limited due to its low bioavailability. To overcome this problem, we developed ASD-Cur, an amorphous formulation of curcumin. In this study, we investigated the effect of ASD-Cur and compared it with Theracurmin®, a colloidal submicron dispersion of curcumin. Material and methods: Male SD rats were subjected to MI or sham surgery. One week after surgery, the MI rats were randomly assigned to four groups: vehicle, ASD-Cur (0.2 mg/kg curcumin), or Theracurmin (0.2 or 0.5 mg/kg curcumin). Daily oral administration of these compounds was repeated for 6 weeks. After echocardiographic examination, myocardial

cell diameter, perivascular fibrosis, mRNA levels, and the acetylation of histone H3K9 were measured. Results: Echocardiographic analysis of the rat hearts showed that 0.2 mg/kg ASD-Cur and 0.5 mg/kg Theracurmin significantly improved both MI-induced reduction in fractional shortening (FS) and left ventricular hypertrophy to the same extent. Both treatments significantly suppressed MI-induced increases in myocardial cell diameter, perivascular fibrosis, mRNA levels of hypertrophic markers and cardiac fibrosis, and acetylation of histone H3K9 to the same extent. Conclusion: These findings indicated that ASD-Cur has greater therapeutic potency towards MI-induced heart failure at a lower dose than Theracurmin.

ISCP Posters

The Natural Product Zerumbone Suppresses Pressure Overload-Induced Cardiac Dysfunction by Inhibiting Cardiac Hypertrophy and Fibrosis Mikuto Tojima,1 Yasufumi Katanasaka,1,2,3 Yoichi Sunagawa,1,2,3 Koji Hasegawa1,2 and Tatsuya Morimoto1,2,3 1. Division of Molecular Medicine, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan; 2. Division of Translational Research, Kyoto Medical Center, Kyoto, Japan; 3. Shizuoka General Hospital, Shizuoka, Japan

Citation: European Cardiology Review 2021;16:e70. DOI: https://doi.org/10.15420/ecr.2021.16.PO14 Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Objectives: We assessed the hypothesis that zerumbone (ZER) , a major active terpene found in endemic wild ginger species, suppresses cardiac hypertrophy and fibrosis in vitro and in vivo. Materials and methods: The effects of ZER on phenylephrine (PE)-induced hypertrophic and on transforming growth factor beta (TGF-β)-induced fibrotic responses were examined in primary cultured cardiomyocytes and fibroblasts from neonatal rats. Transverse aortic constriction model mice (n=6–10) were randomly divided into two groups and orally administered with ZER 20 mg/kg or vehicle for 8 weeks. Cardiac function was evaluated by echocardiography. Changes in cardiomyocyte surface area and degree of fibrosis were observed by histological analysis (HE and WGA staining). The total mRNA levels of the genes associated with hypertrophy and fibrosis were measured by qRT-PCR. Akt phosphorylation and protein expression of α-SMA were assessed by western blotting.

Results: ZER significantly suppressed PE-induced increases in cell size, ANF and BNP gene expression, and Akt phosphorylation in cardiomyocytes. TGF-β-induced increases in collagen synthesis, mRNA levels of POSTN and α-SMA, and protein expression of α-SMA were lower in the ZERtreated cultured cardiac fibroblasts. Echocardiography results showed that left ventricular fractional shortening was increased and wall thickness was reduced in the ZER group compared with the vehicle group. Histological analysis showed that pressure overload-induced cardiac hypertrophy and cardiac fibrosis were inhibited in the ZER group compared with the vehicle group. Conclusion: These results suggest that zerumbone ameliorates pressure overload-induced cardiac dysfunction, at least in part by suppressing both cardiac hypertrophy and fibrosis.

ISCP Posters

Evaluation of β-blocker Dose Optimisation Among Patients Attending Heart Failure Clinic at Sarawak Heart Centre, Malaysia Yii Ching Wong, Tiong Kiam Ong and Yee Ling Cham Sarawak Heart Centre, Kuching, Malaysia

Citation: European Cardiology Review 2021;16:e71. DOI: https://doi.org/10.15420/ecr.2021.16.PO15 Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Objective: The aim of the study was to evaluate the rate of optimisation of β-blockers to target dose among patients attending the heart failure clinic at Sarawak Heart Centre, Kuching, Malaysia. Materials and methods: Data were collected retrospectively all the patients who registered from January 2016 to June 2018 and had at least 6 months follow-up period with the heart failure clinic. Results: A total of 106 patients were recruited and 85.8% of them were men. Of the 106 patients, 9.4% were initiated with β-blockers in heart failure clinic and 90.6% of the patients had uptitration of their β-blocker therapy in the clinic. By the tenth clinic visits, 83.1% patients achieved ≥50% of target dose of β-blockers and 56.9% of them achieved 100%

target dose. After 6 months of follow-up, 87.7% patients tolerated ≥ 50% of target dose of β-blocker and 45.3% of them tolerated 100% target dose. The baseline median heart rate was 73.5 BPM and the median heart rate was reduced to 64 BPM after 10 clinic visits. The number of patients with suboptimal heart rate (≥ 70 BPM) was 32.3% after 10 clinic visits and within this group, 80.9% of them were on ≥50% of β-blocker target dose while 61.9% were on 100% target dose. Conclusion: In conclusion, β-blocker optimisation in the heart failure clinic at Sarawak Heart Centre is achieved in more than 75% of the patients who tolerated ≥50% target dose and in approximately half of the patients who tolerated 100% target dose after 6 months’ follow-up.

ISCP Posters

Prevalence of Aspirin and Clopidogrel Resistance in Patients with Recurrent Ischaemic Cerebrovascular Disease Niyata Hananta Karunawan1 and Rizaldy Taslim Pinzon2 1. Tugurejo General Hospital, Semarang, Indonesia, 2. Duta Wacana Christian University, Yogyakarta, Indonesia

Citation: European Cardiology Review 2021;16:e72. DOI: https://doi.org/10.15420/ecr.2021.16.PO16 Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Objective: This study aimed to identify the prevalence of antiplatelet and clopidogrel resistance in ischaemic cerebrovascular disease patients at Bethesda Hospital, Yogyakarta, Indonesia. Material and methods: This study was performed using a descriptive method with a cross-sectional study of 260 patients. The inclusion criteria were male or female, age >18 years, have a recurrent ischaemic cerebrovascular disease, and have antiplatelet medication. The data were obtained from the electronic stroke register at Bethesda Hospital. A point-of-care analyser, Verify Now (Accumetrics), was used to measure the responsiveness of antiplatelet therapy. Aspirin resistance was defined

as an aspirin reaction unit (ARU) ≥550. Clopidogrel resistance was defined as P2Y12 PRU ≥230. Results: Of 260 patients with recurrent ischaemic cerebrovascular disease on antiplatelet therapies, 205 patients were on aspirin therapy, 72 on clopidogrel therapy and on both antiplatelet drugs. Subjects were mainly men and >60 years old. Forty-one of 205 aspirin users (20%) were resistant to aspirin, 24 of 72 (33%) clopidogrel users were resistant to clopidogrel, and 2 of 17 resistant to both antiplatelets. Conclusion: The prevalence of clopidogrel resistance was higher than aspirin resistance in recurrent ischaemic cerebrovascular disease patients at Bethesda Hospital, Yogyakarta.

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