ICR 14.2 by Radcliffe Cardiology

Interventional Cardiology Review Volume 14 • Issue 2 • Summer 2019

Volume 14 • Issue 2 • Summer 2019

www.ICRjournal.com

Outcomes After Percutaneous Coronary Intervention in Women: Are There Differences When Compared with Men? Usha Rao, G Louise Buchanan and Angela Hoye

Update on the Current Landscape of Transcatheter Options for Tricuspid Regurgitation Treatment Jonathan Curio, Ozan M Demir, Matteo Pagnesi, Antonio Mangieri, Francesco Giannini, Giora Weisz and Azeem Latib

Lessons Learned from RADIOSOUND-HTN: Different Technologies and Techniques for Catheter-based Renal Denervation and Their Effect on Blood Pressure Philipp Lurz and Karl Fengler

How to Diagnose and Manage Angina Without Obstructive Coronary Artery Disease: Lessons from the British Heart Foundation CorMicA Trial Thomas J Ford and Colin Berry

ISSN: 1756-1477

LIMA-LAD bypass grafting to treat the subtotal LAD occlusion

INOCA: a stable coronary syndrome

Invasive coronary angiography showing a subtotal occlusion of the proximal LAD

Cardiology

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JULY 26- 27, 2019 I N T E R C O N T I N E N TA L C H I CAG O CHICAGO

13th Annual

Complex Interventional Cardiovascular Therapy A Case-Based Workshop CONFERENCE AIMS

PROGRAM HIGHLIGHTS

The goal of the CICT Conferences is to provide a novel educational platform based on integration of patient-centered decision-making and the evidence-base in the field of Interventional cardiovascular Medicine. The conference content is focused on case presentations and open debate format with input from the faculty and attendees. The conference will address complex cardiovascular interventional topics that still present a challenge to the clinician with respect to choosing the appropriate therapy (surgery vs. catheter-based therapy) and with respect to using optimal technique to ensure the safety and efficacy of the procedure.

Coronary Track

TARGET AUDIENCE The CICT Conferences are designed to meet the educational needs of Interventional Cardiologists, Non-Invasive Cardiologists and Cardiology Fellows along with Cath Lab Nurses and Technicians and other medical professionals who care for patients undergoing catheter-based cardiovascular interventions.

•

Left main coronary stenting vs. bypass surgery: Where are we in 2019? How we decide?

•

Recanalization of CTOs: Practice evolution. Reconciling theory and evidence

Structural Heart Disease Track •

Aortic valve replacement in low risk patients: Experts debate the paradigm shift!

•

TAVR in complex patient subsets: Case-Based Learning

Peripheral Arterial Disease Track •

Paclitaxel-Based Interventional Devices for PAD: To Be or Not to BE!

•

Trans Catheter Management of Sub Massive Pulmonary Embolism: Time to get involved!

Only for Radcliffe Readers: Save 20% of the full ticket price when using code CICT19 - Radcliffe Readers Register at

www.cictsymposium.com

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DIRECTORS

CO-DIRECTORS

Issam D. Moussa, MD, MBA Joseph De Gregorio, MD Horst Sievert, MD

Antonio Colombo, MD Charles Davidson, MD Verghese Mathew, MD Jonathan M. Tobis, MD

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Volume 14 • Issue 2 • Summer 2019

www.ICRjournal.com

Editor-in-Chief Simon Kennon Interventional Cardiologist and TAVI Operator, Barts Heart Centre, St Bartholomew’s Hospital, London

Section Editor – Structural

Section Editor – Coronary

Darren Mylotte

Angela Hoye

Galway University Hospitals, Galway

Castle Hill Hospital, Hull

Editorial Board Fernando Alfonso

Hospital Universitario de La Princesa, Madrid

Andrew Archbold

Thoraxcenter, Erasmus University Medical Center, Rotterdam

Divaka Perera Guy’s & St Thomas’ Hospital and King’s College London, London

Demosthenes Katritsis

Jeffrey Popma

Athens Euroclinic, Athens

Beth Israel Deaconess Medical Center, Boston

Tim Kinnaird

Gennaro Sardella

University Hospital of Wales, Cardiff

Sapienza University of Rome, Rome

Ajay Kirtane

Andrew SP Sharp

Columbia University Medical Center and New York-Presbyterian Hospital, New York

Royal Devon and Exeter Hospital and University of Exeter, Exeter

Quebec Heart-Lung Institute, Laval University, Quebec

Azeem Latib

Elliot Smith

Lutz Buellesfeld

Didier Locca

London Chest Hospital, Barts Health NHS Trust, London

Sergio Baptista

Hospital CUF Cascais and Hospital Fernando Fonseca, Cascais

Marco Barbanti

Ferrarotto Hospital, Catania

Olivier Bertrand

University Hospital, Bern

Jonathan Byrne

King’s College Hospital, London

Antonio Colombo

San Raffaele Hospital, Milan

Justin Davies

Imperial College NHS Trust, London

Carlo Di Mario

Royal Brompton & Harefield NHS Foundation Trust, London

London Chest Hospital, Barts Health NHS Trust, London

San Raffaele Hospital, Milan

Lausanne University Hospital, Lausanne

Lars Søndergaard

Roxana Mehran

Rigshospitalet - Copenhagen University Hospital, Copenhagen

Mount Sinai Hospital, New York

Thomas Modine

Gregg Stone

CHRU de Lille, Lille

Columbia University Medical Center and New York-Presbyterian Hospital, New York

Jeffrey Moses

Corrado Tamburino

Columbia University Medical Center and New York-Presbyterian Hospital, New York

Ferrarotto & Policlinico Hospital and University of Catania, Catania

Marko Noc

Nicolas Van Mieghem

Center for Intensive Internal Medicine, University Medical Center, Ljubljana

Erasmus University Medical Center, Rotterdam

Sameer Gafoor

Keith Oldroyd

CVPath Institute, Maryland

CardioVascular Center, Frankfurt

Golden Jubilee National Hospital, Glasgow

Juan Granada

Crochan J O’Sullivan

CRF Skirball Research Center, New York

Triemli Hospital, Zurich

London Chest Hospital, Barts Health NHS Trust, London

Thomas Johnson

Nicolo Piazza

Nina C Wunderlich

Eric Eeckhout

Centre Hospitalier Universitaire Vaudois, Lausanne

University Hospitals Bristol, Bristol

Cover image © Shutterstock

A Pieter Kappetein

McGill University Health Center, Montreal

Renu Virmani Mark Westwood

Cardiovascular Center Darmstadt, Darmstadt

Editorial

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Managing Editor Ashlynne Merrifield | Production Editor Aashni Shah Publishing Director Leiah Norcott | Senior Designer Tatiana Losinska Contact ashlynne.merrifield@radcliffe-group.com

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Marketing Manager Anne-Marie Benoy Contact anne-marie.benoy@radcliffe-group.com

Chief Executive Officer David Ramsey Chief Operations Officer Liam O’Neill

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 © 2019 All rights reserved ISSN: 1756–1477 • eISSN: 1756–1485

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Established: June 2006 | Frequency: Tri-annual | Current issue: Summer 2019

Aims and Scope

Submissions and Instructions to Authors

• Interventional Cardiology Review aims to assist time-pressured physicians to stay abreast of key advances and opinion in interventional cardiology practice. • Interventional Cardiology Review comprises balanced and comprehensive articles written by leading authorities, addressing the most pertinent developments in the field. • Interventional Cardiology Review provides comprehensive updates on a range of salient issues to support physicians in continuously developing their knowledge and effectiveness in day-to-day clinical practice.

• Contributors are identified by the Editor-in-Chief with the support of the Section Editors and Managing Editor, and guidance from the Editorial Board. • Following acceptance of an invitation, the author(s) and Managing Editor, in conjunction with the Editor-in-Chief and Section Editors, formalise the working title and scope of the article. • The ‘Instructions to Authors’ document and additional submission details are available at www.ICRjournal.com • Leading authorities wishing to discuss potential submissions should contact the Managing Editor, Ashlynne Merrifield ashlynne.merrifield@radcliffe-group.com

Structure and Format • Interventional Cardiology Review is a tri-annual journal comprising review articles, expert opinion articles and guest editorials. • 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. • Articles are fully referenced, providing a comprehensive review of existing knowledge and opinion. • Each edition of Interventional Cardiology Review is available in full online at www.ICRjournal.com

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

Interventional Cardiology Review is abstracted, indexed and listed in PubMed, Embase, Scopus and Google Scholar. All articles are published in full on PubMed Central one month after publication.

Peer Review • On submission, all articles are assessed by the Editor-in-Chief to determine their suitability for inclusion. • The Managing Editor, following consultation with the Editor-in-Chief, Section Editors and/or a member of the Editorial Board, sends the manuscript to reviewers who are selected on the basis of their specialist knowledge in the relevant area. All peer review is conducted double-blind. • Following review, manuscripts are accepted without modification, accepted pending modification (in which case the manuscripts are returned to the author(s) to incorporate required changes), or rejected outright. The Editor-in-Chief reserves the right to accept or reject any proposed amendments. • Once the authors have amended a manuscript in accordance with the reviewers’ comments, the manuscript is assessed to ensure the revised version meets quality expectations. The manuscript is sent to the Editor-in-Chief for final approval prior to publication.

All articles included in Interventional Cardiology Review are available as reprints. Please contact the Publishing Director, Leiah Norcott leiah.norcott@radcliffecardiology.com

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Open Access, Copyright and Permissions Articles published within this journal are open access, which allows users to copy, redistribute and make derivative works for non-commercial 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 Cardiology retain 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 Cardiology charge 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.

Online All manuscripts published in Interventional Cardiology Review are available free-to-view at www.ICRjournal.com. Also available at www.radcliffecardiology.com are manuscripts from other journals within Radcliffe Cardiology’s cardiovascular portfolio – including, Arrhythmia and Electrophysiology Review, Cardiac Failure Review, European Cardiology Review and US Cardiology Review. n

Cardiology

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Contents

Foreword Simon Kennon

DOI: https://doi.org/10.15420/icr.2019.14.2.FO1

Structural Update on the Current Landscape of Transcatheter Options for Tricuspid Regurgitation Treatment

Jonathan Curio, Ozan M Demir, Matteo Pagnesi, Antonio Mangieri, Francesco Giannini, Giora Weisz and Azeem Latib DOI: https://doi.org/10.15420/icr.2019.5.1

Long-term Transcatheter Aortic Valve Durability

Giuliano Costa, Enrico Criscione, Denise Todaro, Corrado Tamburino and Marco Barbanti DOI: https://doi.org/10.15420/icr.2019.4.2

Coronary Outcomes After Percutaneous Coronary Intervention in Women: Are There Differences When Compared with Men?

Usha Rao, G Louise Buchanan and Angela Hoye DOI: https://doi.org/10.15420/icr.2019.09

How to Diagnose and Manage Angina Without Obstructive Coronary Artery Disease: Lessons from the British Heart Foundation CorMicA Trial

Thomas J Ford and Colin Berry DOI: https://doi.org/10.15420/icr.2019.04.R1

Diagnosis and Management of Anomalous Coronary Arteries with a Malignant Course

Christoph Gräni, Philipp A Kaufmann, Stephan Windecker and Ronny R Buechel DOI: https://doi.org/10.15420/icr.2019.1.1

Coronary Artery Vasospasm Induced by 5-fluorouracil: Proposed Mechanisms, Existing Management Options and Future Directions

Jun Hua Chon and Arjun K Ghosh DOI: https://doi.org/10.15420/icr.2019.12

Thrombus Embolisation: Prevention is Better than Cure

Fizzah A Choudry, Roshan P Weerackody, Daniel A Jones and Anthony Mathur DOI: https://doi.org/10.15420/icr.2019.11

Renal Denervation Lessons Learned from RADIOSOUND-HTN: Different Technologies and Techniques for Catheter-based Renal Denervation and Their Effect on Blood Pressure

102

Philipp Lurz and Karl Fengler DOI: https://doi.org/10.15420/icr.2019.03.R1

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Foreword

Simon Kennon is an interventional cardiologist and TAVI operator at Barts Heart Centre, St Bartholomew’s Hospital, London. He trained at Manchester University, St Bartholomew’s Hospital, the London Chest Hospital and St Vincent’s Hospital, Melbourne. His research interests relate to aortic valve and coronary interventions.

This year has seen a fundamental shift in the balance between transcatheter aortic valve implantation (TAVI) and aortic valve replacement surgery for the treatment of aortic stenosis. This has come about as a result of the publication of the Placement of Aortic Transcatheter Valves (PARTNER) 3 trial in 2019, followed shortly afterwards by Mick Jagger undergoing what looks to have been a successful and uncomplicated TAVI. The 2017 European Society of Cardiology guidelines for the management of valvular heart disease suggested that TAVI should be considered for anyone over the age of 75 years. These new developments have effectively pushed this cut off to 70 years, and I think this will be translated quickly into important shifts in patient flows with knock-on effects on cardiac surgical departments. The one major concern about TAVI is prosthesis durability and this has been analysed in detail in this issue of the journal by Marco Barbanti et al. The other structural paper is provided by Azeem Latib et al., who have concisely summarised the current available options for transcatheter treatment of tricuspid regurgitation. An excellent review of the Randomized Comparison of Ultrasound Versus Radiofrequency Denervation in Patients With Therapy Resistant Hypertension (RADIOSOUND-HTN) trial of renal denervation by Phillip Lurz et al. completes the non-coronary papers. Angela Hoye et al. have provided an excellent review and analysis of the differences in outcomes following percutaneous coronary intervention for men and women. Fizzah Choudhury et al. review the available data on thrombus embolisation during primary angioplasty – an event inevitably associated with a poor prognosis. The remaining three papers are reviews of conditions routinely encountered by interventional cardiologists and as such will, I hope, be of direct use. The management of angina with unobstructed coronary arteries is reviewed by Tom Ford et al.; Christoph Gräni et al. review the assessment and management of anomalous coronary arteries; and Arjun Ghosh et al. provide a comprehensive review of 5-fluorouracil cardiotoxicity.

DOI: https://doi.org/10.15420/icr.2019.14.2.FO1

Foreword_Kennon_14.2_v2.indd 53

Access at: www.ICRjournal.com

14/05/2019 21:45

Structural

Update on the Current Landscape of Transcatheter Options for Tricuspid Regurgitation Treatment Jonathan Curio, 1,2 Ozan M Demir, 3 Matteo Pagnesi, 1 Antonio Mangieri, 4 Francesco Giannini, 4 Giora Weisz 5 and Azeem Latib 5 1. Unit of Cardiovascular Interventions, IRCCS San Raffaele Scientific Institute, Milan, Italy; 2. Charité University Medical Care, Berlin, Germany; 3. Department of Cardiology, Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, UK; 4. Interventional Cardiology Unit, GVM Care & Research Maria Cecilia Hospital, Cotignola, Italy; 5. Department of Cardiology, Montefiore Medical Center, New York, NY, US

Abstract Most patients with severe tricuspid regurgitation lack treatment options because of prohibitive surgical risk. New transcatheter treatments under development and investigation might be able to address this unmet clinical need. This article gives an update on the landscape of devices for transcatheter tricuspid regurgitation treatment including different approaches (i.e. repair with leaflet approximation or annuloplasty and replacement using orthotopic or heterotopic valves) at different stages of development, from experimental to clinical trial. Repair devices such as the Cardioband or the MitraClip are leading the field with promising preliminary data and further trials are ongoing. However, with implantations of the Gate bioprosthesis, replacement devices are catching up. Potential advantages of different approaches and most recent data are discussed.

Keywords Tricuspid regurgitation, tricuspid valve, transcatheter, treatment options, devices, repair, annuloplasty, replacement Disclosure: AL is a consultant for Medtronic, Abbott Vascular, Mitralign and Millipede. All other authors have no conflicts of interest to declare. Received: 21 January 2019 Accepted: 21 March 2019 Citation: Interventional Cardiology Review 2019;14(2):54–61. DOI: https://doi.org/10.15420/icr.2019.5.1 Correspondence: Azeem Latib, Department of Cardiology, Montefiore Medical Center, New York, NY, US. E: alatib@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.

Tricuspid regurgitation (TR) is common, affecting 5% of the elderly population and, when its severity reaches moderate to severe, is an independent predictor of increased mortality.1–3 The pathophysiology of TR is mainly functional as it occurs in the context of pulmonary hypertension, left-sided heart disease and AF.4 These lead to deformation of the right ventricle (RV) and the right atrium (RA), which consequently causes dilation of the tricuspid valve (TV) apparatus.5–7

Evolving Transcatheter Options for Tricuspid Regurgitation Treatment There are two main approaches with different subgroups that exist for percutaneous TR treatment – repair (i.e. leaflet approximation or annuloplasty) and replacement (in the orthotopic or heterotopic position; Figure 1).

Repair Currently, surgery is the only treatment option for patients who remain symptomatic on medical therapy. However, TV surgery is associated with an unacceptably high risk of operative mortality and poor outcomes.8,9 Therefore, TR remains noticeably undertreated and surgery in most cases is only performed as an additional procedure in concomitant left-sided interventions.10–12 Consequently, there is an unmet clinical need in patients with severe TR.13,14 A potential remedy in these patients may be new transcatheter options, which offer a less invasive alternative that could be used in high-surgical risk patients. At present, a wide range of devices are under development or under evaluation in first-in-human studies; of note, only one has been approved in Europe for the treatment of TR (Figure 1 and Table 1).15,16 Several concepts are targeting the tricuspid leaflets or the tricuspid annulus (TA) to repair the valve or replace it in an orthotopic or heterotopic position. The aim of this article is to provide an overview of all devices and approaches for transcatheter TR treatment that are available or under development.

Access at: www.ICRjournal.com

ICR_Latib_FINAL.indd 54

Leaflet Approximation/Coaptation Devices MitraClip in the Tricuspid Position The MitraClip system (Abbott Vascular) is well established for the percutaneous treatment of degenerative and functional mitral regurgitation (MR) in patients at a high surgical risk.17–20 Extensive operator experiences as well as widespread availability have led to its use in the tricuspid position in more than 1,000 cases of severe TR. In the TriValve registry, which merged data on transcatheter tricuspid repair from 18 centres, the MitraClip was used in 66% of patients.21 Using one or more clips resulting in bicuspidisation of the valve by approximation of anterior and septal leaflets, or mimicking the clover technique by connecting the septal with the anterior and posterior leaflets, resulting in a triple orifice, are possible.22,23 The best results appear to occur by approximating the anterior and/ or posterior leaflet to the septal leaflet, which also potentially reduces annular dimensions. Clipping the antero-posterior leaflets is generally avoided in functional TR because it may distort the valve and worsen TR.

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Update on Transcatheter Options for TR Treatment A multicentre European registry showed reduction of TR by at least one grade in 91% of patients, accompanied by a significant reduction in effective regurgitation orifice area, vena contracta (VC) width and regurgitant volume, as well as an improvement in New York Heart Association (NYHA) class and 6-minute walk distance.24 Of note, predominantly central and anteroseptal jets have been identified as predictors of procedural success.25 In many cases, procedures were successfully performed in combination with mitral valve repair.24,25 A modified version of the MitraClip device and its delivery system to address the specifics of TV anatomy is under investigation in the multicentre Evaluation of Treatment With Abbott Transcatheter Clip Repair System in Patients With Moderate or Greater Tricuspid Regurgitation (TRILUMINATE) study (NCT03227757) which has completed enrolment in Europe.26

Pascal The repositionable and recapturable Pascal system (Edwards Lifesciences), initially designed for the treatment of MR, incorporates design features of the MitraClip. It has two paddle-shaped, independently closable, grasping arms (called clasps) as well as a central spacer that is intended to fill the regurgitant jet area.27 The first case of the Pascal system in the tricuspid position was reported in early 2018 and, recently, a case series of 12 patients was presented.28–30 In seven patients, two devices were implanted; four patients received one device and one procedure was unsuccessful because of imaging problems. TR reduction of ≥1 grade was achieved in 92% in the six patients, which persisted at 30-day follow-up. Twothirds of the devices were placed between septal and anterior leaflets, while one-third were placed between septal and posterior leaflets. One device detached while the patient was in hospital.30 Despite promising initial results, more data on the device’s durability and safety as well as an evaluation in a clinical trial are needed.

TriCinch The TriCinch Coil System (4Tech Cardio), which is delivered through the femoral vein, is a second-generation update of the initial TriCinch device.31–33 While the first-generation device was anchored in the TA using a corkscrew-shaped anchor, this updated version is secured with an epicardial coil with two haemostasis seals. After the coil is implanted in the mid-anterior part of the TA, a nitinol stent, connected to the coil through a Dacron band, is placed in the inferior vena cava (IVC), to maintain tension applied to the TA. To enable safe deployment of the coil and ensure visibility in the epicardial space, a controlled pneumopericardium can be created using CO2.34 However, this device has limitations, including dehiscence and pericardial bleeding. In the Percutaneous Treatment of Tricuspid Valve Regurgitation With the TriCinch System™ (PREVENT) trial (NCT02098200), 24 patients were treated with the first-generation device.35 Successful implantation was achieved in 18 cases with a significant (≥1 grade) reduction of TR in 94% of them. Two patients experienced haemopericardium after the procedure and, in four patients, late detachment of the TA anchor was observed. Follow-up at 6 months showed significantly improved 6-minute walk distance and quality of life (QoL), with 75% of the patients being in NYHA class I or II. Firstin-human cases of the second-generation device at 30-day follow-up have shown maintained significant TR reduction from severe to mild as well as improvements in NYHA class (from III to I) and QoL.34,36

INTERVENTIONAL CARDIOLOGY REVIEW

ICR_Latib_FINAL.indd 55

Figure 1: Transcatheter Tricuspid Landscape Surgical predicates

Kay Direct suture annuloplasty

Trialign

PASTA

MIA

Hetzer

De Vega

Cardioband

Millipede

DaVingi

TRAIPTA

Direct ring annuloplasty

Edge-to-edge TriCinch

Forma

Croi

Mitralix Cerclage-TR

Coaptation enhancement Clip

Pascal

Navigate

Trisol

Lux

TRiCares TricValve

TriCento

Valve replacement

MIA = minimally invasive annuloplasty; PASTA = pledget-assisted suture tricuspid annuloplasty; TRAIPTA = transatrial intrapericardial tricuspid annuloplasty.

Two trials are enrolling patients to generate further safety and performance data (NCT03294200 and NCT03632967).

Forma Spacer The Forma Repair System (Edwards Lifesciences), which is placed in the regurgitant orifice and creates a new surface for leaflet coaptation, consists of a foam-filled spacer that is inserted via the subclavian or the axillary vein and, after successful deployment, is anchored in the RV apex.37 The first-in-human experience dates back to 2015.38 Procedural success was achieved in 16 (89%) of 18 treated patients.39 In one of the two unsuccessful procedures, right ventricular perforation required conversion to open heart surgery. Sustained reduction to moderate-to-severe TR was present in only six (46%) of 13 assessed patients after 1 year. However, in 79% of patients, significant reduction in NYHA class, increase in 6-minute walk distance and improvement in heart failure symptoms were observed at 1 year.39 Similar results were obtained after 1 year in the US Forma early feasibility study (NCT02471807), which enrolled 29 patients.40 Long-term outcomes at 24–36 months of the first-in-human cohort showed significant improvement of functional status and significant reduction of VC width from ‘massive’ to ‘severe’ values.41,42 Additional data is expected from the Repair of Tricuspid Valve Regurgitation Using the Edwards TricuSPid TrAnsCatheter REpaiR System (SPACER) trial (NCT02787408). The initial findings have led to several modifications to the secondgeneration device: larger spacers are available to address ‘torrential’ forms of TR; and anchoring is improved by a new sheath as well as by a radiopaque apposition indicator.40,43 This new iteration of the Forma device will have to prove its safety and efficacy in a future study.

Cerclage TR-block The Cerclage-TR block (Tau-PNU Medical) is an experimental device being evaluated in porcine models.44 It is based on the platform of the Mitral Loop Cerclage Annuloplasty device (Tau-PNU Medical), which has been shown to be able to significantly reduce MR in four of five patients studied in a first-in-human study.45,46 This device is anchored in the subclavian vein and creates a loop structure surrounding 360° of the mitral annulus. One arm of the device enters the coronary sinus, then the great cardiac vein and, finally, a septal vein. This vein is perforated, the septum is traversed and the device is snared in the RV

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Structural Table 1: Ongoing Studies on Transcatheter Tricuspid Regurgitation Treatment Device

Study

Patients

Primary endpoints

MitraClip

TRILUMINATE (NCT03227757)

Echocardiographic TR reduction ≥1 grade (30 days), composite of MAE (6 months)

MitraClip for Severe TR (NCT02863549)

100

Echocardiographic TR grade and MACCE (1–12 months)

Forma

SPACER (NCT02787408)

Cardiac mortality at 30 days, compared to literature-derived performance goal based on surgical outcomes

Early Feasibility Study of the Edwards FORMA Tricuspid Transcatheter Repair System (NCT02471807)

Device success and freedom from device or procedure related SAEs at 30 days

Cardioband

TRI-REPAIR (NCT02981953)

Successful access, deployment, positioning and septolateral diameter reduction (intra-procedural), major SAEs and SADE (30 days)

Edwards Cardioband Tricuspid Valve Reconstruction System Early Feasibility Study (NCT03382457)

Freedom from device or procedure-related adverse events (30 days)

TriBAND (NCT03779490)

150

TR at discharge (approximately 2-8 days post-procedure)

DaVingi

FiH Study of the DaVingi™ TR System in the Treatment of Patients With Functional Tricuspid Regurgitation (NCT03700918)

Implant technical success as successful adjustment of the ring at the annulus (post-procedure), Incidence and severity of SADE (30 days)

Trialign

SCOUT II (NCT03225612)

All-cause mortality at 30 days

TriCinch

Clinical Trial Evaluation of the Percutaneous 4Tech TriCinch Coil Tricuspid Valve Repair System (NCT03294200)

All-cause mortality at 30 days

Early Feasibility Study of the Percutaneous 4Tech TriCinch Coil Tricuspid Valve Repair System (NCT03632967) (USA study)

All-cause mortality at 30 days

MIA

STTAR (not registered)

Rate of MAEs at 30 days, technical success rate and reduction in valve area

CAVI with Sapien

HOVER (NCT02339974)

Procedural success including device success and no device/procedure related SAEs (30 days), Individual patient success defined by device success and clinical outcomes/improvements

CAVI with TricValve

TRICUS (NCT03723239)

MAEs at 30 days, Change of NYHA functional class at 6 months

CAVI = caval valve implantation; MACCE = major adverse cardiac and cerebrovascular events; MAE = major adverse events; SADE = serious adverse device effects; SAE = severe adverse event; TR = tricuspid regurgitation.

outflow tract. Here, the first device arm is connected with the second device arm that originates from the RA, crosses the TV plane and is positioned underneath the septal tricuspid leaflet. This cerclage then can be cinched to reduce MR. The Cerclage-TR block adds a crescentshaped ‘T-leaflet’ to the device arm crossing the TV plane. This T-leaflet serves as an extension of the septal leaflet and improves coaptation of the native tricuspid leaflets. In preclinical (n=5) and isolated heart (n=5) models of functional and degenerative regurgitation, TR reduction by at least 1 grade was observed.44 The elegance of this procedure is the combined treatment of TR and MR with a single device. However, clinical first-in-human data is needed to further explore the potential and shortcomings of this approach.

Mistral The spiral-shaped Mistral device (Mitralix) targets the sub-valvular chordae tendinae of diverged tricuspid leaflets and is delivered via an 8.5 Fr delivery system. Its spiral is rotated in the RV to grasp the chordae of two adjacent leaflets that are pulled together to improve coaptation.

Further clinical evaluation to establish the safety and efficacy of the Mistral device are required as well as an evaluation of whether multiple devices may be necessary.

CroíValve The preclinical CroíValve system (CroíValve) aims to assist coaptation of dilated tricuspid leaflets.50 It is anchored in the superior vena cava (SVC) and placed between the native leaflets to reduce the size of the regurgitation orifice and provide a surface for coaptation. In addition to being a pure spacer, CroíValve has an inner part that consists of a tri-leaflet valve apparatus to support diastolic forward flow through the TV and thus potentially reduce the risk of device thrombosis. In-vivo and ex-vivo preclinical testing in a porcine model showed significant TR reduction and 30-day follow-up showed long-term stability of the anchors as well as atraumatic coaptation with the native leaflets. In advance of first-in-human cases, longer-term animal studies are planned.50

Annuloplasty Using Rings While it was originally intended for the mitral position, two first-inhuman cases addressing TR have now been presented.47–49 In both cases, the device was implanted at the antero-septal commissure, resulting in a TR reduction from ‘severe-to-massive’ to ‘mild-tomoderate’ in the first case and from ‘severe-to-massive’ to ‘moderateto-severe’ in the second case.49

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Cardioband The Cardioband Tricuspid Repair System (Edwards Lifesciences) is the first transcatheter device that received CE mark approval for TR treatment, following promising results in the mitral position for the treatment of MR.51,52 It consists of a Dacron, surgical-like band that is implanted at the atrial side of the tricuspid valve by advancing up to

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Update on Transcatheter Options for TR Treatment 17 screws through the band into the tissue of the TA. After implantation at the anterior and posterior parts of the TA using fluoroscopy and transoesophageal echocardiography guidance, the device is cinched to reduce anteroposterior and septolateral diameters. Six-month results of the TRI-REPAIR trial were recently reported.53 Technical success (including access, deployment and positioning) was achieved in 100% of the 30 enrolled patients. At 30-day follow-up, one device-related death was observed. Significant reductions of TA diameter, effective regurgitation orifice area and VC were sustained at 6-month follow-up. Furthermore, there were significant increases in 6-minute walk distance and Kansas City Cardiomyopathy Questionnaire scores, and a reduction in NYHA class at 6-month follow-up.53 Similar to the mitral position, staged procedures combining a Cardioband implantation with subsequent MitraClip implantation in the tricuspid position have been shown to be possible, resulting in significant reduction of TR severity.54–56 Besides the European TrIcuspid Regurgitation RePAIr With CaRdioband Transcatheter System (TRI-REPAIR) trial (NCT02981953) and the Transcatheter Repair of Tricuspid Regurgitation With Edwards Cardioband TR System Post Market Study (TriBAND) post-market study (NCT03779490), a US-based study evaluating early feasibility is under way (NCT03382457).

Iris The Iris Transcatheter Annuloplasty Ring (Millipede) consists of a semirigid complete ring. Anchors are screwed into the TA and a zigzagshaped ring attached to the screws. Collars attached to each angle of the zigzag ring can be adjusted to reduce the diameter of the frame and to approximate neighboring screws, thereby cinching the TA. To date, the Iris ring has been implanted surgically in two patients in a combined procedure to treat TR and MR. Significant reduction in TR to trace degrees was noted, with an average TA diameter reduction of 36% that was stable at 6-month and 12-month follow-up.57,58 A dedicated catheter for the tricuspid space is under development. These promising initial results will have to be proven in larger patient cohorts.

Transatrial Intrapericardial Tricuspid Annuloplasty Transatrial intrapericardial tricuspid annuloplasty (TRAIPTA; National Institutes of Health and Cook Medical) is a fully retrievable transcatheter system for indirect tricuspid annuloplasty in the pericardial space. Access to the pericardium is gained through a puncture of the right atrial appendage. Then, the actual implant, consisting of a hollow tube of braided nitinol wire, which allows for a longitudinal shortening of more than 50%, is placed in the atrioventricular groove. After the device has been tightened, the delivery system is retrieved, and the atrial appendage puncture is closed using nitinol or bioresorbable occluders. In nine naive pigs, significant reductions of anteroposterior and septolateral diameters, TA area and perimeter were achieved, while leaflet coaptation length was significantly increased. In an additional four pigs with functional TR, the severity of regurgitation was reduced.59 There are plans for a first-in-human evaluation.60

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DaVingi The DaVingi neo-annulus (Cardiac Implants) is a two-stage concept that was initially presented in 2015 for use in the tricuspid space.61 In the first stage, a flexible ring with an internal adjustment chord is delivered to the atrial side of the TA using a 22 Fr catheter featuring a distal balloon to support stabilisation of the device; this is attached to the annulus by simultaneously firing all the anchors. The resulting chronic healing response creates a tissue bond to secure the implant. The adjustment chord is fixed at the jugular venous access site. In the second stage, the final cinching of the neo-annulus is performed using a dedicated 16 Fr adjustment device. A first-in-human study is ongoing; the first five patients are being enrolled (NCT03700918) and an early feasibility study has been filed with the Food and Drug Administration (FDA).62

Annuloplasty Using Other Approaches Trialign The Trialign device (Mitralign) uses transcatheter suture annuloplasty to mimic surgical Kay bicuspidisation. Through jugular vein access, an insulated radiofrequency wire is advanced into the RV to then retrogradely cross the TA tissue. In this way, two pledgets are placed at the posteroseptal as well as the anteroposterior commissures, which are then cinched to obliterate the posterior tricuspid leaflet, creating a bicuspid valve and thus reducing TR.63,64 In the Early Feasibility of the Mitralign Percutaneous Tricuspid Valve Annuloplasty System (PTVAS) Also Known as TriAlign™ (SCOUT) trial (NCT02574650), implantation success was achieved in all 15 patients. However, one patient required right coronary artery stenting because of extrinsic compression. At 30-day follow-up, the technical success rate was 80%; three patients developed single-pledget TA detachment, but they did not require reintervention.65 In the remaining patients, significant reductions of TA areas and effective regurgitation orifice area were observed while left ventricular stroke volume improved. In addition, NYHA class, 6-minute walk distance and QoL were significantly improved. After 12 months, one nondevice or procedure-related death was recorded and one patient received elective reintervention. Improvements in NYHA class and QoL were sustained at follow-up.66 It has been postulated that the problem of pledget dehiscence may be resolved by optimising pledget distance during implantation.67 The small footprint of the device, which leaves a significant amount of native anatomy undisturbed for subsequent procedures, is a notable advantage. The Safety and Performance of the Trialign Percutaneous Tricuspid Valve Annuloplasty System (PTVAS) (SCOUT-II) trial (NCT03225612), which will include 60 patients from up to 15 sites to further assess safety and performance of the Trialign device, has started enrolment.

Minimally Invasive Annuloplasty with PolyCor Anchors Minimally invasive annuloplasty (MIA™) technology (Micro Interventional Devices) consists of low-mass, polymeric, self-tensioning PolyCor anchors and the thermoplastic MyoLast polymer for tensioning of the anchors. In the completed first arm of the Study of Transcatheter Tricuspid Annular Repair (STTAR) trial assessing surgical deployment of the twobarbed PolyCor anchors in three patients, feasibility was proven, as implantation was successful in this small cohort without any adverse

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Structural events or anchor detachment. An average 43% reduction in TA area was achieved with a reduction of TR from severe and moderate to mild/trace at 6-month follow-up.68

the ventricular septum. Therefore, nominal sizing may be used, which, considering the danger of paravalvular regurgitation, is probably better tolerated in the low-pressure system of the right heart.

The percutaneous version of the device, deployed using a dedicated 12 Fr delivery catheter, is aimed at creating a bicuspidisation of the TV by implanting multiple PolyChor anchors in the region between the posteroseptal and anteroposterior commissures that are tensioned after deployment, resulting in an obliteration of the posterior leaflet.

Device iteration and a smaller dedicated delivery system with a greater degree of flexion for transjugular or transfemoral approach may improve outcomes. Further data including long-term follow-up are needed to identify the optimal patient population for this device.

TriSol Enrolment of 40 patients in the percutaneous arm of the STARR trial has started and the first four procedures were recently performed.69 In these four patients, no adverse events have been recorded so far and significant TR reductions to mild/moderate with TA area reductions of 48% were reported. Further results from this study will show if the unique PolyChor anchoring design has any advantage over other anchoring approaches.

Pledget-Assisted Suture Tricuspid Annuloplasty (PASTA) The transcatheter pledget-assisted suture tricuspid annuloplasty (PASTA) technique mimics the surgical Hetzer double-orifice suture using marketed devices. Sutures and pledgets are placed at midanterior and posterior-septal parts of the TA in a ‘double-bite’ manner to enhance pull-through force. The suture limbs are then tightened and secured using a Cor-Knot device (LSI Solutions).70 In 22 pigs, the concept was proven and distinct reductions in TA dimension and TR were achieved.71 Recently, first-in-human compassionate use cases were performed but suture dehiscence remains an important limitation.72 This challenging technique might present a future possibility in selected patients who lack other options.

The TriSol valve (TriSol Medical) is mounted on a self-expanding nitinol stent featuring a ventricular skirt of porcine pericardium and an atrial polyester skirt. The conical stent shape conforms to native anatomy, and anchoring through axial instead of radial forces protects the conduction system. The retrievable and repositionable valve is delivered through the jugular vein using a 30 Fr delivery system. The unique valve concept consists of a single bovine pericardial structure with a single dome-shaped leaflet that is attached in two opposite central commissures to create a bileaflet valve. During diastole, the two leaflets move to the centre of the valve and open two lateral orifices for RV inflow. During systole, the leaflets coapt with the circumference of the cone-shaped stent forming a dome shaped structure that enables a larger RV closing volume.77 This is expected to offer RV pressure relief and preserve RV function, which are needed as the sudden increase in afterload after TV replacement may lead to RV failure resulting in poor long-term outcomes.78 In 12 acute swine models, the valve was successfully deployed and, in four chronic swine models, up to 5 months’ follow-up showed stable outcomes in healthy animals without signs of heart failure.79 A first-inhuman implantation after further preclinical testing is planned for 2020.

Orthotopic Transcatheter Tricuspid Valve Replacement NaviGate

LUX-Valve

The Gate self-expanding bioprosthesis (NaviGate Cardiac Structures) for orthotopic tricuspid valve replacement consists of a tapered nitinol stent with atrial winglets and ventricular graspers for anchoring the TA and leaflets and carries three xenogeneic pericardial leaflets. The device currently is the only TV replacement system with firstin-human experience and is available in four sizes intended for TA diameters ranging from 36 mm to 52 mm, with oversizing of around 2–5% performed. A 42 Fr introducer sheath is used to deliver the valve through a transjugular or surgical transatrial approach (minimally invasive right thoracotomy). The delivery system features two degrees of motion at the tip and allows for a 90° angulation.73 An extensive description of relevant imaging and procedural steps was recently published.74

The LUX-Valve (Jenscare Biotechnology) is a self-expanding bovine pericardial tissue valve on a nitinol stent covered by a layer of polyethylene terephthalate. After transatrial insertion via a minimally invasive right thoracotomy, it is secured in the upper part of the RV using a D-shaped special anchoring mechanism that attaches it to the interventricular septum. A self-adaptive skirt to avoid paravalvular regurgitation encircles the valve.

First-in-human cases were performed in 2016 and 2017 and, cumulatively to date, 32 patients have received a Gate valve on compassionate grounds.75,76 After baseline severe or torrential TR in all patients, postoperative TR was mild or less in 96% and moderate in the remaining 4%. Postoperative NYHA class improved to I or II in 91% of the patients and 30-day mortality was 12.5%. A single-site experience in five patients recently reported RV remodelling, increased cardiac output and sustained NYHA class improvement in four patients who survived until 30-day follow-up; it also found that poor baseline RV function was associated with worse outcomes.74 While the right coronary artery is not compromised by the implantation, oversizing of the Gate valve may cause damage to the conduction system or

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In an experimental animal study, 10 goats showed promising results, with nine goats surviving for more than 6 months.80 Long-term effects and possible first-in-human use need further evaluation.

TRiCares The TRiCares valve (TRiCares SAS, Paris, France) is a self-expanding bovine pericardial valve mounted on a nitinol stent frame with atrial and ventricular widening to enable secure anchoring in the TA. Firstin-human use of the TRiCares valve is being planned.

Heterotopic Tricuspid Valve Replacement Heterotopic caval valve implantation (CAVI) does not directly address TR but is intended to lower caval backflow of TR by implanting a valve in the IVC and SVC, thus reducing overload of the venous system. However, as this does not treat the underlying pathology of TR and results in a chronic overload of the RA as well as consequently increased RV afterload, CAVI is reserved for advanced stages of TR (Figure 2).

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Update on Transcatheter Options for TR Treatment Figure 2: Different Stages of Tricuspid Regurgitation and Suitable Transcatheter Treatments Heterogeneity of TR Population Proposed classification of TR stages and potential treatment options Stage 1

Percutaneous treatment

Stage 2

Potential future target for percutaneous options as minimally invasive option could change natural history with minimal risk

Stage 3

Potential candidates for isolated TR surgery who could be enrolled in upcoming IDE RCTs

Stage 4

Stage 5

Current group of patients being treated in EFS if high-risk for surgery. May reguire combination of annuloplasty and leaflet device or TVR

Prohibitive risk and potentially futile. (Palliative procedures can be considered in highly selected patients)

Early

Progressive

Late

RV: Initial dilatation TA: Subsequent initial dilatation

RV: Progressive dilatation TA: Progressive dilatation lack of leaflet coaptation

RV/TA: Progressive distortion and subsequent further leaflet tethering

Annuloplasty Leaflet Approximation Replacement (orthotopic)

± Annuloplasty Leaflet Approximation Replacement (orthotopic)

± Leaflet Approximation Replacement (heterotopic) Replacement (orthotopic; depending on RV function)

RV = right ventricle; TA = tricuspid annulus; TR = tricuspid regurgitation. Adapted from: Hahn 201888 and Latib et al. 2018.13 Used with permission from Europa Digital & Publishing.

Sapien Off-label Use In heterotopic off-label use, 29 mm Sapien valves (Edwards Lifesciensces; approved for transcatheter aortic valve replacement) were implanted in the IVC in two first-in-human cases, and in the IVC and SVC in a third first-in-human case.81 Results of the randomised Treatment of Severe Secondary TRIcuspid Regurgitation in Patients With Advance Heart Failure With CAval Vein Implantation of the Edwards Sapien XT VALve (TRICAVAL) trial (NCT02387697), which compared Sapien valve implantation in the IVC to optimal medical treatment, have been recently reported.82 The trial was prematurely ended after 28 patients had been enrolled, as no differences were found in eight patients with CAVI at 3-month follow-up in oxygen uptake, NYHA class or QoL compared to medical treatment. Results of the Heterotopic Implantation Of the Edwards-Sapien Transcatheter Aortic Valve in the Inferior VEna Cava for the Treatment of Severe Tricuspid Regurgitation (HOVER) trial (NCT02339974), which is assessing the short-term safety (<30 days) and efficacy (6 months) of IVC CAVI with Sapien valves in 15 patients, are awaited.

TricValve Limitations of off-label use of other valves and the complexity of caval anatomy reiterate the need for dedicated CAVI valves. The TricValve (P&F Products & Features) device consists of two pericardial tissue self-expandable valves on a nitinol stent frame, one specifically for the IVC and one specifically for the SVC.83 The valves have little radial force and do not require pre-stenting of the vena cava. First-in-human experience showed immediate abolition of caval backflow and clinical improvement at 12-month follow-up in a patient with SVC and IVC valves in areas such as NYHA class, hepatic synthetic function and 6-minute walk distance.84,85 The Safety and Efficacy of the

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TricValve® Device (TRICUS) study (NCT03723239), assessing safety and efficacy of the TricValve, recently started to enrol around 10 patients.

Tricento The Tricento (NVT) CAVI device consists of a bicavally anchored nitinol stent deployed top down from the SVC to the IVC. A lateral bicuspid porcine pericardium valve permits inflow into the RA. The device is inserted transfemorally through a 24 Fr delivery system. It needs to be custom made for each patient so has a high cost. After successful evaluation in seven bovine models, a first-in-human case was recently reported.86,87 A 74-year-old woman received a Tricento valve without procedural complications. The caval vein regurgitant volume was reduced from 50 ml to 24 ml and renal function as well as functional capacity improved. At 3-month follow-up, the prosthesis was in place without transvalvular regurgitation; however, after 4 months, the patient died from terminal kidney failure.

Outlook Several devices that adopt multiple approaches to treat TR are under development or investigation and it is too early to predict which device or approach will succeed. Several repair devices are leading the field as the first clinical data including mid-term follow-up are available, but replacement devices are catching up. While repair devices, especially in experienced hands, have specific advantages (e.g. the ability to target individual anatomy, preservation of native valve structure and greater operator experience), replacement devices theoretically promise significant advantages (e.g. a combined platform for primary and secondary TR, reproducibility, a standardised procedure, an easier learning curve and complete elimination of TR) and different approaches might be applicable for different TR stages

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Structural (Figure 2). However, the risk of afterload mismatch, valve thrombosis and the long-term impact on RV function are potential limitations of replacement.

benefits.42 Principally, to enable sufficient reimbursement and widespread use, devices will have to prove themselves in comparison to optimal medical treatment or maybe even surgical intervention.

As first-generation devices are assessed in clinical trials, identification of correct and clinically relevant endpoints is crucial. A new TR grading addressing the different stages of severe TR might be necessary to measure TR improvement after the procedure and, furthermore, a detailed QoL assessment is fundamental to elucidating procedural

In summary, as the vast unmet clinical need is obvious, development and investigation of devices to treat TR will continue. No device or approach is clearly leading the field, with some repair devices as first among equals because of the availability of promising initial clinical data.

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for the treatment of severe tricuspid regurgitation: 1-year clinical and echocardiographic results. JACC Cardiovasc Interv. 2017;10:1994–2003. https://doi.org/10.1016/j.jcin.2017.06.036; PMID:28780036. Perlman G. The FORMA Spacer – technology and clinical updates. Presented at: Transcatheter Cardiovascular Therapeutics, San Diego, 23 September 2018. Asmarats L. Long-term outcomes following transcatheter tricuspid valve repair with the FORMA system. Presented at Transcatheter Cardiovascular Therapeutics, San Diego, 21 September 2018. Hahn RT, Zamorano JL. The need for a new tricuspid regurgitation grading scheme. Eur Heart J Cardiovasc Imaging 2017;18:1342–3. https://doi.org/10.1093/ehjci/jex139; PMID:28977455. Asmarats L, Philippon F, Bédard E, Rodés-Cabau J. FORMA tricuspid repair system: device enhancements and initial experience. EuroIntervention 2018;pii: EIJ-D-18-00956. https:// doi.org/10.4244/EIJ-D-18-00956; PMID: 30585783; epub ahead of press. Chon MK. Novel concept of catheter-based treatment for tricuspid regurgitation (Cerclage-TR block). Presented at Transcatheter Cardiovascular Therapeutics, San Diego, 21 September 2018. Park YH, Chon MK, Lederman RJ, et al. Mitral loop cerclage annuloplasty for secondary mitral regurgitation: first human results. JACC Cardiovasc Interv. 2017;10:597–610. https://doi. org/10.1016/j.jcin.2016.12.282; PMID:28335897. Kim JH, Sung SC, Chon MK, et al. Mitral loop cerclage as a variant form of mitral cerclage annuloplasty that adds a device (CSTV) for preventing potential complications: a preclinical proof of concept and feasibility study. EuroIntervention 2016;11:e1669–79. https://doi.org/10.4244/ EIJV11I14A319; PMID:27056114. Maisano F, Alfieri O, Banai S, et al. The future of transcatheter mitral valve interventions: competitive or complementary role of repair vs. replacement? Eur Heart J 2015;36:1651–9. https:// doi.org/10.1093/eurheartj/ehv123; PMID:25870204. Testa L, Latib A, Montone RA, Bedogni F. Transcatheter mitral valve regurgitation treatment: State of the art and a glimpse to the future. J Thorac Cardiovasc Surg 2016;152:319–27. https:// doi.org/10.1016/j.jtcvs.2016.04.055; PMID:27239007. Planer D, Beeri R, Danenberg H. MATTERS study: First-in-man transcatheter tricuspid valve repair by the Mistral device. Presented at Transcatheter Cardiovascular Therapeutics, San Diego, 21 September 2018. Quinn M. CroíValve tricuspid valve repair: pre-clinical results. Presented at PCR London Valves Innovators Day, London, 9 September 2018. Maisano F, Taramasso M, Nickenig G, et al. Cardioband, a transcatheter surgical-like direct mitral valve annuloplasty system: early results of the feasibility trial. Eur Heart J 2016;37:817–25. https://doi.org/10.1093/eurheartj/ehv603; PMID:26586779. Kuwata S, Taramasso M, Nietlispach F, Maisano F. Transcatheter tricuspid valve repair toward a surgical standard: first-in-man report of direct annuloplasty with a cardioband device to treat severe functional tricuspid regurgitation. Eur Heart J 2017;38:1261. https://doi.org/10.1093/ eurheartj/ehw660. Nickenig G. Transcatheter tricuspid valve repair: results from the multicentre CE mark trial – six-month outcomes. Presented at PCR London Valves, London, 9 September 2018. Mangieri A, Colombo A, Demir OM, et al. Percutaneous direct annuloplasty with edge-to-edge technique for mitral regurgitation: replicating a complete surgical mitral repair in a one-step procedure. Can J Cardiol 2018;34:1088.e1–1088.e2. https://doi.org/10.1016/j.cjca.2018.04.003; PMID: 30056846. von Bardeleben RS, Ruf T, Schulz E, Muenzel T, Kreidel F. First percutaneous COMBO therapy of tricuspid regurgitation using direct annuloplasty and staged edge-to-edge repair in a surgical-like Clover technique. Eur Heart J 2018;39: 3621–2. https://doi.org/10.1093/eurheartj/ehy536; PMID: 30184056. Sugiura A, Weber M, Sinning JM, Werner N, Nickenig G. Staged transcatheter valve repair via MitraClip XTR after Cardioband for tricuspid regurgitation. Eur Heart J Cardiovasc Imaging 2019;20:118. https://doi.org/10.1093/ehjci/jey153; PMID: 30358806. Rogers J. Transcatheter Tricuspid Valve Therapies 5: Millipede. Presented at Transcatheter Cardiovascular Therapeutics, Washington DC, 1 November 2016.

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Update on Transcatheter Options for TR Treatment 58. R ogers J. Millipede Ring for the Tricuspid Valve. Presented at Transcatheter Cardiovascular Therapeutics, Denver, 1 November 2017. 59. Rogers T, Ratnayaka K, Sonmez M, et al. Transatrial intrapericardial tricuspid annuloplasty. JACC Cardiovasc Interv 2015;8:483–91. https://doi.org/10.1016/j.jcin.2014.10.013; PMID:25703872. 60. Rogers T. TRAIPTA – an update for 2017. Presented at Transcatheter Cardiovascular Therapeutics, Denver, 1 November 2017. 61. Kuck KH. Cardiac implants’ complete ring delivery system for mitral and tricuspid valve annuloplasty. Presented at Transcatheter Cardiovascular Therapeutics, San Francisco, 12 October 2015. 62. Kerner A. DaVingi™ Tricuspid repair system: technology and clinical updates. Presented at Transcatheter Cardiovascular Therapeutics, San Diego, 23 September 2018. 63. Schofer J, Bijuklic K, Tiburtius C, et al. First-in-human transcatheter tricuspid valve repair in a patient with severely regurgitant tricuspid valve. J Am Coll Cardiol 2015;65:1190–5. https://doi.org/10.1016/j.jacc.2015.01.025; PMID:25748096. 64. Besler C, Meduri CU, Lurz P. Transcatheter treatment of functional tricuspid regurgitation using the trialign device. Interv Cardiol. 2018;13:8-13. https://doi.org/10.15420/ icr.2017:21:1; PMID:29593830. 65. Hahn RT, Meduri CU, Davidson CJ, et al. Early feasibility study of a transcatheter tricuspid valve annuloplasty: SCOUT Trial 30-day results. J Am Coll Cardiol 2017;69:1795–806. https://doi. org/10.1016/j.jacc.2017.01.054; PMID:28385308. 66. Hahn RT. SCOUT I 12-month data. Presented at Transcatheter Cardiovascular Therapeutics, Denver, 1 November 2017. 67. Lurz P, Besler C, Kiefer P, Ender J, Seeburger J. Early experience of the trialign system for catheter-based treatment of severe tricuspid regurgitation. Eur Heart J 2016;37:3543. https://doi.org/10.1093/eurheartj/ehw253; PMID:27354054. 68. Williams M. Minimally Invasive Tricuspid Valve Annuloplasty Repair Technology (MIATM, MicroInterventional Devices): Early Clinical Experience. Presented at Transcatheter Cardiovascular Therapeutics, San Diego, 21 September 2018. 69. Micro Interventional Devices, Inc.™ announces continued successful enrollment in STTAR trial. Press release. Available

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at: https://www.prnewswire.com/news-releases/microinterventional-devices-inc-announces-continued-successfulenrollment-in-sttar-trial-300757860.html (accessed 9 April 2019) Khan J, Rogers T, Greenbaum A, et al. Transcatheter PledgetAssisted Suture Tricuspid Annuloplasty (PASTA). Presented at Transcatheter Cardiovascular Therapeutics, Denver, 30 October 2017. Khan JM, Rogers T, Schenke WH, et al. Transcatheter pledgetassisted suture tricuspid annuloplasty (PASTA) to create a double-orifice valve. Catheter Cardiovasc Interv 2018;92:E175–84. https://doi.org/10.1002/ccd.27531; PMID:29405564. Greenbaum AB. Transcatheter tricuspid valve repair: available techniques and patient candidates criteria. Presented at Cardiovascular Research Technologies, Washington DC, 4 March 2018. Fam N. NaviGate – early clinical experience of NaviGate transcatheter tricuspid valve replacement in patients with severe tricuspid valve regurgitation. Presented at PCR London Valves Innovators Day, London, 9 September 2018. Hahn RT, George I, Kodali SK, et al. Early single-site experience with transcatheter tricuspid valve replacement. JACC Cardiovasc Imaging 2019;12:416–29. https://doi.org/10.1016/j.jcmg.2018. 08.034; PMID: 30553658. Navia JL, Kapadia S, Elgharably H, et al. First-in-human implantations of the NaviGate Bioprosthesis in a severely dilated tricuspid annulus and in a failed tricuspid annuloplasty ring. Circ Cardiovasc Interv 2017;10:pii: e005840. https://doi.org/10.1161/CIRCINTERVENTIONS.117.005840; PMID: 29246915. Hahn RT. NAVIGATE transcatheter tricuspid valve replacement early findings – technology and clinical updates. Presented at Transcatheter Cardiovascular Therapeutics. San Diego, 23 September 2018. Weisz G. TRISOL Tricuspid valve replacement: a comprehensive solution for tricuspid regurgitation and RV dysfunction. Presented at The Structural Heart Disease Summit, Chicago, 22 June 2018. Chin KM, Kim NH, Rubin LJ. The right ventricle in pulmonary hypertension. Coron Artery Dis 2005;16:13–8. https://doi. org/10.1097/00019501-200502000-00003; PMID:15654194. Weisz G. Comprehensive solution for tricuspid regurgitation

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and RV dysfunction: Trisol Medical. Presented at Transcatheter Cardiovascular Therapeutics, San Diego, 22 September 2018. Lu F, Xu Z, Song Z, et al. TCT 88: catheter-based tricuspid valve replacement via right atrium: an animal experimental study. Presented at Transcatheter Cardiovascular Therapeutics, Denver, 31 October 2017. Laule M, Stangl V, Sanad W, Lembcke A, Baumann G, Stangl K. Percutaneous transfemoral management of severe secondary tricuspid regurgitation with Edwards Sapien XT bioprosthesis: first-in-man experience. J Am Coll Cardiol 2013;61:1929–31. https://doi.org/10.1016/j.jacc.2013.01.070; PMID:23500268. Dreger H. Treatment of Severe TRIcuspid Regurgitation in Patients with CAval Vein Implantation of the Edwards Sapien XT VALve (TRICAVAL): a controlled propective randomized trial. Presented at Transcatheter Cardiovascular Therapeutics, San Diego, 21 September 2018. Figulla HR, Kiss K, Lauten A. Transcatheter interventions for tricuspid regurgitation – heterotopic technology: TricValve. EuroIntervention 2016;12:Y116–8. https://doi.org/10.4244/ EIJV12SYA32; PMID:27640022. Lauten A, Ferrari M, Hekmat K, et al. Heterotopic transcatheter tricuspid valve implantation: first-in-man application of a novel approach to tricuspid regurgitation. Eur Heart J 2011;32:1207–13. https://doi.org/10.1093/eurheartj/ ehr028; PMID:21300731. Lauten A, Doenst T, Hamadanchi A, et al. Percutaneous bicaval valve implantation for transcatheter treatment of tricuspid regurgitation: clinical observations and 12-month follow-up. Circ Cardiovasc Interv 2014;7:268–72. https://doi. org/10.1161/CIRCINTERVENTIONS.113.001033; PMID: 24737337. Kuetting M. New valve technology – TriCento: Novel device for the treatment of tricuspid insufficiency. Presented at PCR London Valves Innovators Day, London, 9 September 2018. Toggweiler S, De Boeck B, Brinkert M, et al. First-in-man implantation of the Tricento transcatheter heart valve for the treatment of severe tricuspid regurgitation. EuroIntervention 2018;14:758–61. https://doi.org/10.4244/EIJ-D-18-00440; PMID:29969434. Hahn RT. Performance of tricuspid valve interventions guided by peri-procedural echocardiography. Presented at PCR London Valves, London, 9 September 2018.

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Structural

Long-term Transcatheter Aortic Valve Durability Giuliano Costa, Enrico Criscione, Denise Todaro, Corrado Tamburino and Marco Barbanti Vittorio Emanuele Hospital, University of Catania, Catania, Italy

Abstract Transcatheter aortic valve implantation (TAVI) has become the standard of care for high-risk and inoperable surgical patients and a valid alternative to surgery for low- and intermediate-risk patients with severe, symptomatic aortic stenosis. It is increasingly being used for younger, lower-risk patients, so it is important to ensure the durability for long-term transcatheter aortic valves. The lack of standard definitions of structural valve degeneration (SVD) had made comparison among studies on prosthetic valve durability problematic. The 2017 standardised definitions of SVD by the European Association of Percutaneous Cardiovascular Intervention), the European Society of Cardiology and the European Association for Cardio-Thoracic Surgery, and the 2018 definitions by the Valve In Valve International Data group, has generated an increased uniformity in evaluations. This article examines the potential mechanisms and rates of SVD of transcatheter bioprostheses and the role of redo TAVI as a treatment option.

Keywords Bioprosthesis, degeneration, durability, structural valve dysfunction, transcatheter aortic valve implantation Disclosure: MB is a consultant for Edwards Lifesciences. CT received speaker honoraria from Medtronic, Abbott Vascular, Edwards Lifesciences and Boston Scientific. All other authors have no conflicts of interest to declare. Received: 27 January 2019 Accepted: 29 April 2019 Citation: Interventional Cardiology Review 2019;14(2):62–9. DOI: https://doi.org/10.15420/icr.2019.4.2 Correspondence: Marco Barbanti, Division of Cardiology, Policlinico – Vittorio Emanuele Hospital, University of Catania, Via Santa Sofia 78, 95123, Catania, Italy. E: mbarbanti83@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 developed countries and its prevalence is projected to increase over the next decade as the population ages.1,2 Transcatheter aortic valve implantation (TAVI) is an established alternative to surgery for treatment of patients with symptomatic, severe AS.3

Causes and Mechanisms of Bioprosthesis Degeneration

As the latest multicentre trials have established the role of TAVI alongside surgery for treatment of lower-risk patients, it will be offered to younger people in the upcoming years.4,5 In this particular subset, life expectancy is expected to exceed that of the initial highrisk candidates for TAVI, which were older and had multiple, severe comorbidities. This makes it crucial to gather data on the durability of long-term transcatheter valve prosthesis.

Leaflet Degeneration

The lack of standard definitions of structural valve degeneration (SVD) had made it difficult to compare studies on the durability of surgical or transcatheter bioprostheses due to the high heterogeneity of adopted criteria. 6 –11 Since the release of standardised SVD definitions by the European Association of Percutaneous Cardiovascular Intervention (EAPCI), the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS), an increasing number of studies have reported encouraging outcomes after TAVI with either balloonand self-expanding transcatheter aortic valves (TAV) up to 7 and 8 years. In cases of bioprosthesis failure due to SVD, redo TAVI has been shown to be a reliable alternative to redo surgery. This article will examine the emerging issue of TAV degeneration and its management.

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Bioprosthesis degeneration can be related to different aetiologies, including leaflet degeneration, endocarditis, thrombosis and paravalvular leak (Table 1 and Figure 1).

The main mechanism behind bioprosthesis degeneration is leaflet degeneration. This happens in a similar way as for the native aortic valve and consists in a step-wise process leading to tissue calcification and consequent valve stenosis or regurgitation.12 Although TAVs demonstrated to degenerate in a manner comparable to surgical bioprostheses, three key differences between TAV and surgical aortic valve (SAV) degeneration mechanisms have been identified:13 • The presence of turbulence in the aortic root due to the combined presence of bulky calcium nodules in the sinuses of Valsalva and the prosthetic aortic valve. This may affect blood flow, resulting in chronic mechanical stresses on the prosthetic valve leaflets, leading to early degeneration. • The trauma that may occur to prosthetic valve leaflets when loading into a delivery catheter before being established in its anatomical position. • After deployment, TAVs, particularly the self-expanding ones, often have an oval shape which could affect the normal valvular functioning. Native aortic cusps calcifications, the conformation of the left ventricular outflow tract (usually non-circular) and prosthetic valve oversizing (for reducing paravalvular leakage)

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Transcatheter Aortic Valve Durability lead TAVs to become non-circular, which could affect long-term durability, although the real impact is not known.14

Endocarditis Infective endocarditis has been reported to occur in 0.5–3.4% of cases after TAVI and 1–6% after surgical aortic valve replacement (SAVR).13,15 The predominant agents reported to have caused prosthetic valve endocarditis were Staphylococci (31.5%), Enterococci (20%) and Streptococci (14%), based on 29 certain cases of endocarditis from about 4000 TAVI patients of a multicenter registry.15 Diagnosis of TAV endocarditis can be difficult as older patients may present with subtle and atypical symptoms.16 Endocarditis is shown with echocardiography as mobile vegetations, aortic root abscess formation, or progressive stenosis/regurgitation (due to prosthetic valve dehiscence). Intraprosthetic regurgitation occurring late after TAVI is suggestive of infective endocarditis, particularly when it is not associated with valve stenosis.13

Table 1: Potential Factors in Bioprosthesis Degeneration TAVI procedurespecific factors

• Leaflet injury (crimping/loading/dilatation) • Abnormal trans- and/or paravalvular flow patterns • Non-circular/irregular/incomplete stent deployment

Patient-related factors

• Dyslipidaemia, diabetes, metabolic syndrome • Dysregulation of phosphocalcic metabolism • Immune rejection • Hypertension

Bioprosthesisrelated factors

• Absence of anti-mineralisation treatment • Flaws in bioprosthesis design • Severe prosthesis-patient mismatch • Small prosthesis size

Figure 1: Risk Factors, Mechanisms and Clinical Consequences of Transcatheter Aortic Valve Deterioration

Bioprosthesis Thrombosis

stent as well as its metallic nature seem to be two of the main factors increasing the risk of subclinical thrombosis.13

Paravalvular Leak Paravalvular leak is mainly caused by the incomplete sealing of the prosthesis to the aortic annulus. Although this is more frequently an early finding, the importance of paravalvular regurgitation may become clinically evident later as it contributes to leaflet degeneration. Treatment mainly consists in re-intervention or percutaneous paravalvular leakage closure. Next-generation TAVs have incorporated additional features with the aim to prevent paravalvular regurgitation, such as the possibility to recapture and reposition the device and the implementation of an external sealing skirt in the inflow portion of the valve.

Definitions and Diagnosis of Structural Valve Degeneration SVD in bioprosthesis has been poorly defined for a long time. Traditionally, it is considered an acquired intrinsic bioprosthetic valve abnormality characterised by the deterioration of the leaflets or supporting structures. One of the causes of SVD is the mechanical stress and the abnormal flow at the surface of the leaflet, which leads to tissue disruption or thickening, collagen fibre disruption and tissue calcification, but the precise mechanism is not known. Risk factors often associated with bioprosthetic SVD are younger age, mitral valve position, end-stage renal disease, higher calcium-phosphorus product, hyperparathyroidism, hypertension and pregnancy.19–22 Other clinical valve abnormalities that do not cause deterioration of valve tissue, are not included in the definition of SVD. These include patient-prosthesis mismatch, device malposition, paravalvular regurgitation and abnormal frame expansion in the case of self-

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Normal bioprosthetic valve Valve stent or struts Annular calcification and calcified native leaflets

Valve leaflets

Non-structural valve deterioration Leaflet thrombosis

Aortic sinuses

Paravalvular leakage

TAVI-specific factors

Endocarditis

Patient-related factors Prosthesis-related factors Increased leaflet mechanical stress Abnormal transvalvular flow patterns Inflammation

Pharmacotherapy

Bioprosthesis thrombosis has been reported in two different forms. First, as a symptomatic obstructive valve thrombosis, resulting in an increase in the transvalvular gradient and reduction in the effective orifice area measured by echocardiography, which is a rare event and reported in about 0.5% of TAVI patients.13,17 Second, as asymptomatic subclinical valve thrombosis causing thickening and reduced leaflet motion of bioprosthetic aortic valves detected by CT scan with normal transvalvular gradients at transthoracic ECG. This form is reported to be more frequent in patients treated percutaneously, ranging from 5% to 40% of TAVI patients.18 The incomplete expansion of a TAV’s

Structural valve deterioration Valve seam disruption

Stent fracture

Leaflet calcification

Leaflet tear

Haemodynamic valve deterioration

Normal bioprosthetic valve Pharmacotherapy

Bioprosthesis failure Vavle re-intervention

Follow-up

This figure shows the interaction between patient-related, prosthesis-related and TAVIspecific factors in the pathogenesis of structural and non-structural valve deterioration. Red arrows indicate the potentially reversible pathway. Schematic representations of the transcatheter valves with structural or non-structural structural valve degeneration are adapted from Bagur et al.55 TAVI = transcatheter aortic valve implantation.

expanding transcatheter bioprostheses. 10,13,22 Prosthetic valve thrombosis and infective endocarditis are not included in the definition of SVD, but these complications may subsequently lead to SVD, even if treated successfully.17,23,24 The lack of standard definitions for bioprosthesis dysfunction have affected the possibility of a proper comparison of durability studies. Most studies regarding surgical prosthesis have associated SVD with the need for reoperation, but did not provide any specific criteria to define SVD and/or the indication for reoperation. Furthermore, reoperation does not necessary imply presence of SVD as well as SVD does not always lead to reoperation, and older patients are often refused redo surgery because of their high or prohibitive surgical risk profile and their frailty.25 With the worldwide increase in TAVI

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Structural Table 2: Current Standardised Definition of Structural Valve Degeneration Capodanno et al. 201726

Dvir et al. 201827

Not defined

SVD Stage 0: no significant No significant new haemodynamic change from immediate post- abnormality (all the following): implantation • mean gradient <20 mmHg • intravalvular regurgitation less than moderate (<2+/4+) • no morphological leaflet abnormality, such as leaflet thickening)

Structural valve degeneration

Morphological SVD (any of the following): • Leaflet integrity abnormality (i.e. torn or flail causing intra-frame regurgitation) • Leaflet structure abnormality – pathological thickening and/or calcification causing valvular stenosis or central regurgitation • Leaflet function abnormality (i.e. impaired mobility resulting in stenosis and/or central regurgitation) • Strut/frame abnormality (i.e. fracture) Moderate haemodynamic SVD (any of the following):

SVD Stage 1: morphological leaflet abnormality without significant hemodynamic changes

Leaflet calcification, sclerosis, thickening or new leaflet motion disorder. The SVD definition excludes infective endocarditis, valve thrombosis, isolated patient-prosthesis mismatch without deterioration in valve function, isolated paravalvular regurgitation and frame distortion without abnormal leaflet function. Nevertheless, these conditions may account for Stage 1 SVD because these bioprostheses could be prone for early SVD.

SVD Stage 2S: moderate stenosis

• Mean transprosthetic gradient ≥20 mmHg and <40 mmHg • Mean transprosthetic gradient ≥10 and <20 mmHg change from baseline concomitant with decrease in EOA and DVI.

• Mean transprosthetic gradient ≥20 mmHg and <40 mmHg • Mean transprosthetic gradient ≥10 mmHg and <20 mmHg change from baseline • Moderate intra-prosthetic aortic regurgitation, new or worsening (>1+/4+) from baseline

Need to clinically exclude thrombotic leaflet thickening. If reversible with anticoagulation should be considered as valve thrombosis. SVD Stage 2R: moderate regurgitation

• AR≥ 2+/4+ If the main component is paravalvular, then it should not be considered as SVD.

SVD Stage 2RS: moderate stenosis AND moderate reurgitation Severe haemodynamic SVD (any of the following):

SVD Stage 3: severe stenosis • Mean transprosthetic gradient and/or severe regurgitation ≥40 mmHg • Mean transprosthetic gradient ≥ 40 mmHg • Mean transprosthetic gradient • Mean transprosthetic gradient ≥20 mmHg change ≥20 mmHg change from baseline from baseline • Severe intra-prosthetic aortic • Severe intra-prosthetic aortic regurgitation, new regurgitation, new or worsening (>2+/4+) or worsening (>2+/4+) from baseline from baseline concomitant with decrease in EOA and DVI. Bioprosthetic valve failure

• Autopsy findings of bioprosthetic valve dysfunction, likely related to the cause of death, or valve-related death (i.e. any death caused by bioprosthetic valve dysfunction or sudden unexplained death following diagnosis of bioprosthetic valve dysfunction) • Repeat intervention (i.e. valve-in-valve TAVI, paravalvular leak closure or SAVR) following confirmed diagnosis of bioprosthetic valve dysfunction • Severe haemodynamic SVD

Not defined

AR = aortic regurgitation; DVI = Doppler velocity index; EOA = effective orifice area; SAVR = surgical aortic valve replacement; SVD = structural valve degeneration; TAVI = transcatheter aortic valve implantation.

procedures and the expansion of its indication to include younger, lower-risk patients, a clear definition of TAV durability and comparison with its surgical counterpart is needed. In 2017, a taskforce of the EAPCI, ESC and EACTS released new standardised definitions of SVD and a new patient-oriented clinical endpoint named bioprosthetic valve failure (BVF), with the aim of

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making possible future comparisons between studies on bioprostheses’ long-term durability.26 The taskforce characterised structural valve dysfunction as ‘haemodynamic SVD’ and/or ‘morphological SVD’. Haemodynamic SVD is defined as the presence of permanent changes in valve function assessed by echocardiography, even without evidence of morphological SVD. There are two different degrees of haemodynamic SVD. Moderate is defined by the presence of a mean gradient

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Transcatheter Aortic Valve Durability Table 3: Long-term Durability After Surgical Aortic Valve Replacement Author

Prosthesis Type

Mean

SVD Requiring Reintervention,

Freedom from

Follow-up

n (%)

SVD, Years (%)

(years) Repossini et al. 201632

565

Freedom SOLO (Sorin Group)

7 ±4

23 (4)

10 (90.8)

Johnston et al. 201548

12,569

Carpentier-Edwards PERIMOUNT (Edwards Lifesciences)

155 reoperated 268 SVD without reoperation (3.3)

Bourguignon et al. 201549

2,758

Carpentier-Edwards PERIMOUNT

6.7 ±4.8

123 reoperated 34 SVD without reoperation

15 (78.6 ± 2.2) 20 (48.5 ± 4.6)

Guenzinger et al. 201550

455

Biocor (St Jude Medical)

8 ±6

37 (8.1) 13 were inoperable or refused surgery

5 (97.9 ± 0.8) 10 (92.1 ± 1.7) 15 (84.8 ± 3.0) 20 (67.0 ± 7.3)

Bourguignon et al. 201535

373

Carpentier-Edwards PERIMOUNT

9 ±6

78 (20)

10 (86.8 ± 2.5) 15 (66.8 ± 4.2) 20 (37.2 ± 5.4)

Christ et al. 201529

Toronto (St Jude Medical)

14 ±6

24 (48)

5 (97.7 ± 2.2) 10 (76.0 ± 6.7) 15 (44.1 ± 8.9)

Bach and Kon 201431

725

Freestyle (Medtronic)

34 (4.6)

10 (96.4 ±1.4) 15 (85.1 ± 4.9)

Sénage et al. 201425

617

Mitroflow (Sorin)

3.8 ±2.0

4 (10.3); 35 SVD without reoperation

5 (91.6)

Forcillo et al. 201334

2,405

Carpentier-Edwards

6 ±9

91 (3.7) 2 refused redo surgery

5 (98.0 ± 0.2) 10 (96 ± 1) 20 (67 ± 4)

Mohammadi et al. 201251

430

Freestyle

9.1 ±4.4

<60 years 10 (94) 15 (62.6) ≥60 years 10 (96.3) 15 (88.4)

David et al. 201033

1,134

Hancock II (Medtronic)

87 (7.6) 13 were inoperable

5 (99.7 ± 0.2) 10 (97.6 ± 0.6) 15 (86.6 ± 1.8) 20 (63.4 ± 4.2)

Mykén and Bech-Hansen 200952 1,518

Biocor

6 ±5

77 (5)

20 (61.1 ± 8.5)

Yankah et al. 200853

1513

Mitroflow

4 ±0.12

64 (4.2)

20 (62.3 ± 5.0)

David et al. 200730

357

Toronto

8 ±3

49 (13.7) 4 were inoperable

10 (86 ± 3) 12 (69 ± 4)

Jamieson et al. 200554

1823

Carpentier-Edwards SAV

8 ±5

132 (7.2)

15 (74.9 ±2.3) 18 (64.0 ±3.6)

SAV = surgical aortic valve; SVD = structural valve degeneration.

≥20 mmHg and <40 mmHg and/or ≥10 mmHg and <20 mmHg change from gradient at baseline (valuated before discharge or within 30 days of valve implantation) and/or the onset of moderate, new or worsening (>1+/4+) of intra-prosthetic valve regurgitation; severe, with mean gradient ≥40 mmHg and/or ≥20 mmHg change from baseline and/or severe, new or worsening (>2+/4+) intra-prosthetic aortic regurgitation. Morphological SVD includes abnormalities in leaflet integrity, structure, function and strut/frame. The diagnosis is based on imaging or autopsy findings. BVF definition integrates severe haemodynamic SVD and its clinical consequences. It is important to stress that BVF could be a consequence of pathophysiological processes unrelated to SVD, such as thrombosis, endocarditis or non-structural valve dysfunction. BVF includes any of the following (Table 2): • Bioprosthetic valve dysfunction at autopsy, very likely related to the cause of death, or ‘valve-related death’, defined as any death

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caused by bioprosthetic valve dysfunction in the absence of confirmatory autopsy. • Aortic valve reintervention (i.e. valve-in-valve TAVI, paravalvular leak closure or SAVR). • Severe hemodynamic SVD. In 2018, the Valve In Valve International Data (VIVID) group proposed a definition of SVD which emphasises the progressive character of bioprosthetic valve degeneration, similar to that of the native valve, and provided recommendations for timing of clinical and imaging assessment at follow-up.27 The first stage (Stage 1) is defined as early morphological leaflet changes without haemodynamic sequelae, such as leaflet fluttering and leaflet thickening, and limited, delayed or asymmetrical leaflet opening or closure. Valves with definite morphological abnormalities are classified as Stage 1 SVD even if the abnormality is corrected, such as leaflet thickening relieved

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Structural Table 4: Long-term Durability After Transcatheter Aortic Valve Implantation Using EAPCI/ESC/EACTS Definitions

Author

Prosthesis Type

Mean Follow-up

Freedom from SVD (%)

(Years) Deutsch et al. 2018

n (%)

300

CoreValve (Medtronic) and SAPIEN (Edwards)

Eltchaninoff et al. 201839

378

Percutaneous Valve Technologies, 3.1 Cribier-Edwards, SAPIEN and SAPIEN XT

8 years: 87.2

2 (0.58 8 years, all reoperated)

Barbanti et al. 201840

288

Medtronic CoreValve and SAPIEN XT

6.7

8 years: 97.5 (severe SVD)

11 (8 years estimated: 4.51) Two reoperated

Holy et al. 201842

152

CoreValve

6.3 ± 1.0

8 years estimated: 4.5% Five reoperated

Antonazzo et al. 201841

278

CoreValve

6.8

5 (3.1) + 2 probable bioprosthetic valve failure 3 reoperated

Didier et al. 201843

4,201

CoreValve and SAPIEN and SAPIEN XT

• Moderate SVD: 12.4% between 4 and 5 years • Severe SVD: 2.9% between 4 and 5 years

7.14

Bioprosthetic Valve Failure,

1 3 5 7

year: 90.1 years: 83.9 years: 82.0 years: 77.3

11 4 reoperation

SVD = structural valve degeneration.

with anticoagulation, because these leaflets might still be prone to recurrent leaflet thickening or accelerated SVD, requiring more frequent follow-up. Stage 2 SVD refers to morphological abnormalities of valve leaflets associated with haemodynamic dysfunction. This stage is divided into Stage 2S and Stage 2R, depending on the kind of dysfunction, stenosis or regurgitation respectively, because the clinical implications and pace of deterioration are likely to differ between these two failure modes. Stage 2S can be determined by the mandatory presence of an increase of transvalvular gradient (≥10 mmHg) and a concomitant decrease in valvular area. In this way, the presence of abnormal leaflet morphology and deterioration in valve haemodynamic must coexist to define SVD. Furthermore, bioprosthetic valves with a combination of moderate stenosis and moderate regurgitation may be considered differently than those with isolated stenosis or regurgitation.28 VIVID definition categorises these mixed moderate stenosis/regurgitation valves at Stage 2RS. Patients in stage 2 could be considered for reintervention in case of symptoms’ onset. The most severe stage of SVD is the development of severe stenosis or regurgitation (stage 3). Reintervention is recommended when patients with stage 3 bioprosthesis SVD start to develop symptoms (Table 2).

Bioprostheses Durability Data Long-term durability is one of the main limitations of surgical bioprostheses, compared with their mechanical counterparts. Several studies have reported encouraging data on valve performance during the first decade after valve implantation, with rates of freedom from SVD >85% at 10 years.29–33 Data on surgical bioprostheses durability at 20 years are limited. Two studies reported results about durability of the Carpentier-Edwards Perimount pericardial bioprostheses (Edwards Lifesciences) at 20 years. Forcillo et al. reported 67% rate of freedom from reoperation at 20 years, whereas Bourguignon et al. reported a rate of freedom from SVD of 48.5%.34,35 Unfortunately, the lack of standard definitions for valve dysfunction affects any comparison between different studies (Table 3). It is well known that transcatheter aortic valves can degenerate in a manner similar to surgical bioprostheses, but durability of TAVs could be shorter than their surgical counterpart because of the possible

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trauma that can occur during initial valve preparation and compression, balloon dilatation or as a suboptimal leaflet coaptation, leaflet folding or leaflet-frame contact due to asymmetrical frame expansion.14 Several limitations prevent robust evaluation of TAV’s durability. Firstly, TAVI is a relatively young technology as its wider adoption started when it gained its CE mark in 2007 and US Food and Drug Administration approval in 2011. This means there can be little data on valve durability analysis beyond 10 years. Secondly, current data on long-term outcomes over 5 years refers to the first-generation TAVs, which were implanted by relatively inexperienced operators and and suffered from higher valve malpositioning rates and sizing problems. Finally, the major limitation of long-term durability evaluation is the older age of TAVI population, which is affected by multiple comorbidities and usually have high-risk profiles conditioning a limited life expectancy and therefore a paucity of patients (usually <50% of the initial population) available at long-term follow-up. In the past few years the results of several TAVI studies with more than 5 years of follow-up data have been published. The Placement of AoRTic TraNscathetER Valve Trial (PARTNER-1) trial showed no evidence of SVD at 5-year follow-up.8,36 Moreover, the PARTNER-1A substudy demonstrated similar echocardiographic valve performance of TAVs and SAVs, with a mean transvalvular gradient of 10.7 and 10.6 mmHg, and an aortic valve area of 1.6 and 1.5cm2, respectively.8,37 This evaluation confirmed the satisfactory haemodynamic profile of transcatheter aortic valves up to 5 years post-implantation, even if moderate or severe aortic regurgitation caused by paravalvular regurgitation – which is not included in the SVD definition – was shown to be more common in the TAVI group. Toggweiler et al. showed a 3.4% incidence of SVD at a 5-year followup in a cohort of 88 patients who had received a balloon-expandable SAPIEN TAV (Edwards Lifesciences).6 Moderate aortic regurgitation, stenosis, or a combination of the two occurred in one patient each, and no patients required reintervention. Our group reported a 5-year experience with the CoreValve system (Medtronic) and found five cases (1.4%) of SVD, with two patients requiring reintervention (valve-in-valve) because symptoms developed 4 and 4.6 years after TAVI.7 Furthermore, 10 patients (2.8%) showed late mild stenosis, with a mean transaortic gradient ranging from 20 to 40 mmHg.7

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Transcatheter Aortic Valve Durability Figure 2: Late Transcatheter Aortic Valve Failure Management Late TAV failure Determine mode of failure Paravalvular leak Paravalvular leak closure

Redo TAVI No Antibiotic therapy Effective

Yes

Not effective

Surgical THV removal and AVR

Intraprosthetic regurgitation

Stenosis

Exclude THV endocarditis

Exclude THV thrombosis

Positive blood culture

Oral anticoagulation Not effective

Effective

Possible THV degeneration

THV thrombosis confirmed

Redo TAVI

Follow-up

AVR = aortic valve replacement; PVL = paravalvular leak; TAVI = transcatheter aortic valve; TAVI = transcatheter aortic valve implantation; THV = transcatheter heart valve.

After the introduction of EAPCI/ESC/EACTS standardised criteria of SVD in 2017, an increasing number of studies have been reporting outcomes after TAVI with either the SAPIEN (Edwards Lifesciences) or CoreValve TAVs up to 7 and 8 years (Table 4).38–41 Three single-centre studies demonstrated stable trans-prosthetic gradients over time and a rate of severe TAV dysfunction of 2.4%, 3.2% and 3.6%.39–41 Holy et al. analysed long-term outcomes of 152 consecutive patients who had undergone TAVI with the self-expanding CoreValve between 2007 and 2011.42 Echocardiographic follow-up was achieved at 6.3 ± 1.0 years (5.0–8.9 years) and was 88% complete (60 of the 68 participants who survived beyond 5 years). No case of SVD was reported and five patients (3.3%) had undergone redo TAVI or surgery due to paravalvular leakage. An analysis by Deutsch et al. showed an overall crude cumulative incidence of SVD of 14.9% at 7 years after TAVI (CoreValve 11.8% versus SAPIEN 22.6%; p=0.01).38 Reports from national registries confirm low rates of TAV dysfunction at long-term follow-up. Data from the French Aortic National CoreValve and Edwards (FRANCE-2) registry showed an incidence of severe and moderate/severe SVD of 2.5% and 13.3%, respectively, in surviving patients at 5 years from the procedure, while Blackman et al. reported an incidence of severe and moderate SVD of 0.4% and 8.7% respectively up to 10 years in the UK TAVI Registry.43,44 Finally, a recent analysis from the Nordic Aortic Valve Intervention (NOTION) trial reported lower rates of moderate-to-severe SVD after TAVI compared with surgery (24% versus 4.8% for TAVI and SAVR respectively), whereas there was no difference in terms of BVF (6.7% versus 7.5% for TAVI and SAVR respectively).45

aortic regurgitation, transcatheter heart valve retrieval and SAVR should be considered. Redo TAVI is an alternative in those patients in which infection has been controlled and blood cultures are negative.14 In patients with suspected bioprosthesis thrombosis, oral anticoagulation is the treatment of choice both in patients with clear evidence of thrombosis and in those with high transvalvular gradient with evidence of reduced leaflet motion. This therapeutic approach is often sufficient to restore transvalvular gradient and leaflet mobility.17 Vitamin K antagonists are the most used anticoagulants but novel oral anticoagulation therapy has also been shown to be effective.46 In obstructive TAV thrombosis, anticoagulation has been shown to normalise transvalvular gradients in 2–3 months and patients should have lifelong follow up with interval imaging.17 SAVR should be considered for patients with worsening valve function despite oral anticoagulation therapy. The observation of valve thrombosis has raised the question of treatment necessity with oral anticoagulation for a certain period after TAVI to prevent leaflet thrombosis, but the debate is still ongoing. Redo TAVI is another option in the management of TAV failure. This strategy has been demonstrated to be safe and it is associated with favourable clinical and echocardiographic outcomes.47 When a balloonexpandable TAV fails, implantation of a second same-sized balloonexpandable TAV is the most commonly used approach.47 On the other hand, a supra-annular TAV may be preferable in cases of small native annulus due to the possibility of a high residual transvalvular gradient. Redo TAVI strategy has several advantages:

Structural TAV Dysfunction Management Management of older people with TAV failure is similar to that of surgical bioprosthesis dysfunction. Any decision about the appropriate approach should be guided by a careful clinical assessment and surgical risk evaluation by a heart team. Management options include medical therapy and reintervention with TAVI or SAVR. Understanding the causal mechanism of TAV degeneration is essential as treatment varies (Figure 2).

• It is safe, with lower risk of periprocedural complications compared with redo SAVR, which is technically challenging and carries a higher risk of mortality and morbidity than the first valve procedure.12 • The presence of the first device represents a fluoroscopic marker for the landing zone, indicating second TAV sizing and facilitating deployment.

Intraprosthetic regurgitation occurring late after TAVI suggests infective endocarditis, particularly when not associated with stenosis.13 In this case, targeted antibiotic therapy represents the first line of treatment. In patients presenting with severe

Despite its advantages, there are two main concerns associated with redo TAVI: the lack of data on the long-term performance of valve-invalve implantation; and the access to coronary arteries, especially in the case of a second self-expanding CoreValve device implantation

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Structural when a double layer of close cell metallic frame would face the coronary ostia. When the mechanism of TAV failure is paravalvular regurgitation, there are two possible scenarios: the paravalvular regurgitation is mainly caused by valve implantation that is too high or too low; or it is secondary to incomplete frame expansion or suboptimal sealing because of severe annular calcification. In this latter case, balloon post-dilatation could represent an alternative, although it may cause annular injury when large-diameter balloons are used. However, for either scenario, potential treatments could be represented by a redo TAVI procedure using any TAV type in the proper position (in the case of high or low implant), or a second TAV with higher radial force – SAPIEN or Lotus (Boston Scientific) – if greater expansion and

10.

11.

12.

13.

14.

15.

16.

17.

Nkomo VT, Gardin JM, Skelton TN, et al. Burden of valvular heart diseases: a population-based study. Lancet 2006;368:1005–11. https://doi.org/10.1016/S01406736(06)69208-8; PMID: 16980116. Otto CM, Prendergast B. Aortic-valve stenosis – from patients at risk to severe valve obstruction. N Engl J Med 2014;371:744–56. https://doi.org/10.1056/NEJMra1313875; PMID: 25140960. Baumgartner H, Falk V, Bax JJ, et al. 2017 ESC/EACTS guidelines for the management of valvular heart disease. Eur Heart J 2017;38:2739–86. https://doi.org/10.1093/eurheartj/ ehx391; PMID: 28886619. 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:[Epub ahead of print]. https://doi. org/10.1056/NEJMoa1816885; PMID: 30883053. Mack MJ, Leon MB, Thourani VH, et al. Transcatheter aorticvalve replacement with a balloon-expandable valve in low-risk patients. N Engl J Med 2019. https://doi.org/10.1056/ NEJMoa1814052; PMID: 30883058; epub ahead of press. Toggweiler S, Humphries KH, Lee M, et al. 5-year outcome after transcatheter aortic valve implantation. J Am Coll Cardiol 2013;61:413–9. https://doi.org/10.1016/j.jacc.2012.11.010; PMID: 23265333. Barbanti M, Petronio AS, Ettori F, et al. 5-Year outcomes after transcatheter aortic valve implantation with corevalve prosthesis. JACC Cardiovasc Interv 2015;8:1084–91. https://doi. org/10.1016/j.jcin.2015.03.024; PMID: 26117458. Mack MJ, Leon MB, Smith CR, et al. 5-year outcomes of transcatheter aortic valve replacement or surgical aortic valve replacement for high surgical risk patients with aortic stenosis (PARTNER 1): a randomised controlled trial. Lancet 2015;385:2477–84. https://doi.org/10.1016/S01406736(15)60308-7; PMID: 25788234. Muratori M, Fusini L, Tamborini G, et al. Five-year echocardiographic follow-up after TAVI: structural and functional changes of a balloon-expandable prosthetic aortic valve. Eur Hear J Cardiovasc Imaging 2018;19:389–97. https://doi. org/10.1093/ehjci/jex046; PMID: 28379513. Arsalan M, Walther T. Durability of prostheses for transcatheter aortic valve implantation. Nat Rev Cardiol 2016;13:360–7. https://doi.org/10.1038/nrcardio.2016.43; PMID: 27053461. Del Trigo M, Mu-oz-Garcia AJ, Wijeysundera HC, et al. Incidence, timing, and predictors of valve hemodynamic deterioration after transcatheter aortic valve replacement. J Am Coll Cardiol 2016;67:644–55. https://doi.org/10.1016/j. jacc.2015.10.097; PMID: 26868689. Dvir D, Barbanti M, Tan J, Webb JG. Transcatheter aortic valvein-valve implantation for patients with degenerative surgical bioprosthetic valves. Curr Probl Cardiol 2014;39:7–27. https://doi. org/10.1016/j.cpcardiol.2013.10.001; PMID: 24331437. Mylotte D, Andalib A, Theriault-Lauzier P, et al. Transcatheter heart valve failure: a systematic review. Eur Heart J 2015;36:1306–27. https://doi.org/10.1093/eurheartj/ehu388; PMID: 25265974. Barbanti M, Tamburino C. Late degeneration of transcatheter aortic valves: pathogenesis and management. EuroIntervention 2016;12:Y33–6. https://doi.org/10.4244/EIJV12SYA8; PMID: 27640028. Latib A, Naim C, De Bonis M, et al. TAVR-associated prosthetic valve infective endocarditis. J Am Coll Cardiol 2014;64:2176–8. https://doi.org/10.1016/j.jacc.2014.09.021; PMID: 25457406. Habib G, Hoen B, Tornos P, et al. Guidelines on the prevention, diagnosis, and treatment of infective endocarditis (new version 2009): The task force on the prevention, diagnosis, and treatment of infective endocarditis of the european society of cardiology (ESC). Eur Heart J 2009;30:2369–413. https://doi.org/10.1093/eurheartj/ehp285; PMID: 19713420. Latib A, Naganuma T, Abdel-Wahab M, et al. Treatment and clinical outcomes of transcatheter heart valve thrombosis. Circ Cardiovasc Interv 2015;8:pii:e001779. https://doi.org/10.1161/

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sealing are required. In addition, paravalvular regurgitation closure with dedicated devices (plugs) has been demonstrated to be a feasible and safe alternative.

Conclusion With the expansion of TAVI indication to younger, lower-risk patients, data on long-term TAV durability are essential. The first studies reporting on SVD up to eight years after TAVI showed very low rates of TAV degeneration, comparing favourably with its surgical counterpart. The release of standardised definitions of SVD represents a fundamental step in allowing data comparison from different centres, with the aim of obtaining a better insight into its real incidence. Evidence suggests that redo TAVI seems to be a feasible and safer alternative to surgery for treatment of bioprostheses failure.

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34. Forcillo J, Pellerin M, Perrault LP, et al. Carpentier-Edwards pericardial valve in the aortic position: 25-years experience. Ann Thorac Surg 2013;96:486–93. https://doi.org/10.1016/j. athoracsur.2013.03.032; PMID: 23684486. 35. Bourguignon T, El Khoury R, Candolfi P, et al. Very long-term outcomes of the Carpentier-Edwards perimount aortic valve in patients aged 60 or younger. Ann Thorac Surg 2015;100:853–9. https://doi.org/10.1016/j.athoracsur.2015.03.105; PMID: 26187006. 36. Kapadia SR, Leon MB, Makkar RR, et al. 5-year outcomes of transcatheter aortic valve replacement compared with standard treatment for patients with inoperable aortic stenosis (PARTNER 1): a randomised controlled trial. Lancet 2015;385:2485–91. https://doi.org/10.1016/S01406736(15)60290-2; PMID: 25788231. 37. Daubert MA, Weissman NJ, Hahn RT, et al. Long-term valve performance of TAVR and SAVR. JACC Cardiovasc Imaging 2017;10:15–25. https://doi.org/10.1016/j.jcmg.2016.11.004; PMID: 28017714. 38. Deutsch M-A, Erlebach M, Burri M, et al. Beyond the fiveyear horizon: long-term outcome of high-risk and inoperable patients undergoing TAVR with first-generation devices. EuroIntervention 2018;14:41–9. https://doi.org/10.4244/EIJ-D-1700603; PMID: 29581084. 39. Eltchaninoff H, Durand E, Avinée G, et al. Assessment of structural valve deterioration of transcatheter aortic bioprosthetic balloon-expandable valves using the new European consensus definition. EuroIntervention 2018;14:e264– 71. https://doi.org/10.4244/EIJ-D-18-00015; PMID: 29599103. 40. Barbanti M, Costa G, Zappulla P, et al. Incidence of long-term structural valve dysfunction and bioprosthetic valve failure after transcatheter aortic valve replacement. J Am Heart Assoc 2018;7:e008440. https://doi.org/10.1161/JAHA.117.008440; PMID: 30371244. 41. Panico AR, Giannini C, De Carlo M, et al. Long-term results and durability of the CoreValve transcatheter aortic bioprosthesis: outcomes beyond five years. EuroIntervention 2019;14:1639–47. https://doi.org/10.4244/EIJ-D-18-00779; PMID: 30561369. 42. Holy EW, Kebernik J, Abdelghani M, et al. Long-term durability and haemodynamic performance of a selfexpanding transcatheter heart valve beyond five years after implantation: a prospective observational study applying the standardised definitions of structural deterioration and valve failure. EuroIntervention 2018;14:e390–6. https://doi. org/10.4244/EIJ-D-18-00041; PMID: 29741488. 43. Didier R, Eltchaninoff H, Donzeau-Gouge P, et al. Five-year clinical outcome and valve durability after transcatheter aortic valve replacement in high-risk patients. Circulation 2018;138:2597–607. https://doi.org/10.1161/ CIRCULATIONAHA.118.036866; PMID: 30571260. 44. Blackman DJ, Saraf S, MacCarthy PA, et al. Long-term durability of transcatheter aortic valve prostheses. J Am Coll Cardiol 2019;73:537–45. https://doi.org/10.1016/j. jacc.2018.10.078; PMID: 30732706. 45. Søndergaard L, Ihlemann N, Capodanno D, et al. Durability of transcatheter and surgical bioprosthetic aortic valves in patients at lower surgical risk. J Am Coll Cardiol 2019;73:546–53. https://doi.org/10.1016/j.jacc.2018.10.083; PMID: 30732707. 46. Ruparelia N, Panoulas VF, Frame A, et al. Successful treatment of very early thrombosis of SAPIEN 3 valve with direct oral anticoagulant therapy. J Heart Valve Dis 2016;25:211–3. PMID: 27989069. 47. Barbanti M, Webb JG, Tamburino C, et al. Outcomes of redo transcatheter aortic valve replacement for the treatment of postprocedural and late occurrence of paravalvular regurgitation and transcatheter valve failure. Circ Cardiovasc Interv 2016;9:e003930. https://doi.org/10.1161/ CIRCINTERVENTIONS.116.003930; PMID: 27578840. 48. Johnston DR, Soltesz EG, Vakil N, et al. Long-term durability of bioprosthetic aortic valves: Implications from 12,569 implants. Ann Thorac Surg 2015;99:1239–47. https://doi.org/10.1016/j.

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Transcatheter Aortic Valve Durability

athoracsur.2014.10.070; PMID: 25662439. 49. Bourguignon T, Bouquiaux-Stablo A-L, Candolfi P, et al. Very long-term outcomes of the CarpentierEdwards Perimount valve in aortic position. Ann Thorac Surg 2015;99:831–7. https://doi.org/10.1016/j. athoracsur.2014.09.030; PMID: 25583467. 50. Guenzinger R, Fiegl K, Wottke M, Lange RS. Twentyseven-year experience with the St Jude Medical biocor bioprosthesis in the aortic position. Ann Thorac Surg 2015;100:2220–6. https://doi.org/10.1016/j. athoracsur.2015.06.027; PMID: 26421496.

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51. Mohammadi S, Tchana-Sato V, Kalavrouziotis D, et al. Long-term clinical and echocardiographic followup of the freestyle stentless aortic bioprosthesis. Circulation 2012;126:S198–204. https://doi.org/10.1161/ CIRCULATIONAHA.111.084806; PMID: 22965983. 52. Mykén PSU, Bech-Hansen O. A 20-year experience of 1712 patients with the Biocor porcine bioprosthesis. J Thorac Cardiovasc Surg 2009;137:76–81. https://doi.org/10.1016/j. jtcvs.2008.05.068; PMID: 19154907. 53. Yankah CA, Pasic M, Musci M, et al. Aortic valve replacement with the Mitroflow pericardial bioprosthesis: Durability results

up to 21 years. J Thorac Cardiovasc Surg 2008;136:688–96. https:// doi.org/10.1016/j.jtcvs.2008.05.022; PMID: 18805273. 54. Jamieson WRE, Burr LH, Miyagishima RT, et al. CarpentierEdwards supra-annular aortic porcine bioprosthesis: Clinical performance over 20 years. J Thorac Cardiovasc Surg 2005;130:994–1000. https://doi.org/10.1016/j. jtcvs.2005.03.040; PMID: 16214510. 55. Bagur R, Pibarot P, Otto CM. Importance of the valve durability- life expectancy ratio in selection of a prosthetic aortic valve. 2017;103:1756–9. https://doi.org/10.1136/ heartjnl-2017-312348; PMID: 28903992.

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Coronary

Outcomes After Percutaneous Coronary Intervention in Women: Are There Differences When Compared with Men? Usha Rao, 1 G Louise Buchanan 2 and Angela Hoye 1 1. Department of Cardiology, Castle Hill Hospital, Kingston upon Hull, UK; 2. Department of Cardiology, Cumberland Infirmary, Newtown Road, Carlisle, UK

Abstract Despite advances in the diagnosis and treatment of coronary artery disease, there remains evidence of a disparity in the outcomes for women when compared with men. This article provides a review of the evidence for this discrepancy and discusses some of the potential contributing factors.

Keywords Outcomes, women, percutaneous coronary intervention, men, gender inequality, cardiovascular disease, guidelines-based interventions Disclosure: The authors have no conflicts of interest to declare. Received: 10 March 2019 Accepted: 10 April 2019 Citation: Interventional Cardiology Review 2019;14(2):70–5. DOI: https://doi.org/10.15420/icr.2019.09 Correspondence: Angela Hoye, Department of Academic Cardiology, Castle Hill Hospital, Kingston upon Hull HU16 5JQ, UK. E: angela.hoye@hull.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.

Cardiovascular disease is a major cause of morbidity and is the leading cause of death in women and men in Western societies.1 Despite the major advances seen in the field of interventional cardiology and pharmacotherapy, which have translated into better outcomes, a disparity is evident in the clinical outcomes between men and women. This was clearly evident in a recent systematic review and metaanalysis published in 2018.2 The authors evaluated the outcome of 1,032,828 patients (258,713 women) included in 49 studies of percutaneous coronary intervention (PCI) with respect to sex. Mortality was significantly lower in male patients at all follow-up time points – in-hospital mortality (OR 0.58; 95% CI [0.52–0.63]; p<0.001); 30-day mortality (OR 0.64; 95% CI [0.61–0.66]; p=0.04); 1-year mortality (OR 0.67; 95% CI [0.60–0.75]; p<0.001); and at least 2-year mortality (OR 0.71; 95% CI [0.63–0.79]; p=0.005). The majority of studies included in the analysis had been published in the last 10 years, indicating that this issue remains relevant to contemporary practice. The postulated causes for this disparity in PCI outcomes are multifactorial and include atypical presentation in women, delays in diagnosis and treatment in women, as well as the underuse of evidence-based medical therapies in female patients. The issue is compounded by the fact that women are under-represented in major trials, so extrapolating outcome data to the entire population may not necessarily be correct.

treatment offered to patients. This is different to ACS caused by spontaneous coronary artery dissection (SCAD) which is significantly more likely to occur in women who account for 90% of patients and may be best managed medically.4 Despite advancements in the management of ACS, various studies have shown a clear disparity in the clinical outcomes between men and women, with women having worse outcomes.5–10 Women are more likely to present with atypical symptoms, have delays in the administration of treatment and therefore have longer ischaemic times.11 There is also evidence to suggest that women with ACS are less likely to receive evidence-based treatments and less likely to undergo cardiac catheterisation and revascularisation.5–7,9,12–19 Table 1 demonstrates the in-hospital mortality according to sex in several ACS studies. The proportion of female patients in the studies ranged from 27–41%. The unadjusted mortality is significantly higher in women, although appears less so once adjusted for confounders.12,16

Acute Coronary Syndrome

A large UK study evaluating the treatment of patients with ACS with respect to sex has been published this year.20 Women (n=238,489) comprised 34.5% of the study and were older (76.7 years versus 67.1 years) and less likely to present with ST-elevation MI (STEMI) (33.9% versus 42.5%). Women were less likely to receive guidelineindicated care when compared with men including timely reperfusion therapy for STEMI (76.8% versus 78.9%; p<0.001), and timely coronary angiography for non-STEMI (24.2% versus 36.7%; p<0.001).

There are pathophysiological differences in the causes of acute coronary syndrome (ACS) with respect to sex. In men, there is typically rupture of a thin-capped atheromatous plaque which triggers thrombosis. Women are more likely to develop thrombosis caused by endothelial erosion.3 However, there is no evidence to suggest that this difference in pathophysiology should affect the

Women also received sub-optimal medical therapy with less dual antiplatelet therapy (75.4% versus 78.7%) and less secondary prevention therapies (87.2% versus 89.6% for statins, 82.5% versus 85.6% for angiotensin-converting enzyme (ACE) inhibitor/angiotensin receptor blockers and 62.6% versus 67.6% for beta-blockers; all p<0.001). This

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Outcomes After PCI in Women Table 1: In-Hospital Mortality According to Sex in Acute Coronary Syndrome Trials Study

Patients (n)

Women (%)

Women Mortality (%)

Men Mortality (%)

Significance

35,875

41.0

5.6

4.3

OR 1.27 (adjusted)

Elkoustaf et al. 200623

1,197

31.8

0.3

1.1

p=0.137

Heer et al. 2006

Blomkalns et al. 2005

16,817

34.1

6.8

4.1

p<0.001

Alfredsson et al. 200714

53,781

37.0

7.0

5.0

p=NS

Radovanovic et al. 200715

20,290

28.0

10.7

6.3

p<0.001

Jneid et al. 2008

78,254

39.0

8.2

5.7

p<0.0001

199,690

34.1

2.2

1.4

p=0.52 (adjusted)

Akhter et al. 200916 Al-Fiadh et al. 2011

2,952

27.2

3.9

2.0

p<0.001

Bugiardini et al. 201118

6,558

31.8

3.4

2.2

p=0.0078

Poon et al. 2012

14,196

34.3

2.7

1.6

p<0.001

study demonstrated that the 30-day adjusted mortality was higher for women than men – median 5.2% (interquartile ratio [IQR] 1.8%–13.1%) versus 2.3% (IQR 0.8%–7.1%; p<0.001) and the authors estimated that 8,243 deaths among women could have been prevented over the study period if they had been treated equally to the male patients. Previous studies have demonstrated that when men and women receive similar treatment (including high use of an early invasive strategy in NSTEMI), there is no significant difference in 1-year mortality for women when compared with men, supporting the need for equality of care.21–23 Evidence supports the use of stent implantation for patients with coronary artery disease and ACS. However, a large French registry of 74,389 consecutive patients (30% women) demonstrated a lower rate of PCI with stenting in women having an acute MI (14.2% versus 24.4%; p<0.001).24 In the same study, the in-hospital mortality was significantly higher in women (14.8% versus 6.1%; p<0.0001). The Women in Innovation Initiative and Drug-Eluting Stents (WIN-DES) collaboration is an initiative set up to specifically evaluate outcomes of drug-eluting stent (DES) implantation in women. Recently published data demonstrates the safety and efficacy of the use of contemporary DES in 2,176 women after acute MI.25 At 3 years, the use of newgeneration DES was associated with lower risk of death, MI or target lesion revascularisation (14.9% versus 18.4%; adjusted HR 0.78; 95% CI [0.61–0.99]) compared with first generation DES, as well as definite or probable stent thrombosis (1.4% versus 4.0%; adjusted HR 0.36; 95% CI [0.19–0.69]).

Invasive Strategy in Non-ST-elevation MI The benefit of an early invasive strategy for non-ST-elevation MI (NSTEMI) is less clear in women compared with men, with some studies suggesting they might even have worse outcomes. This has been attributed to older age at time of presentation, presence of multiple co-morbidities and smaller body habitus.26,27 Both the Fragmin and Fast Revascularisation during InStability in Coronary artery disease (FRISC) II and the three Randomised Intervention Trial of unstable Angina (RITA) trials demonstrated a clear benefit for a routine early invasive strategy in men; however women in the invasive strategy groups had worse outcomes.28,29 Further analysis of the FRISC II trial demonstrated that the higher event rate in women treated with an early invasive strategy seemed largely due to an increased rate of death and MI in the women who

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underwent coronary artery bypass grafting (CABG) as the means of revascularisation. Conversely, the Treat Angina with Aggrastat and Determine Cost of Therapy with an Invasive or Conservative StrategyThrombolysis in Myocardial Infarction-18 (TACTICS-TIMI 18) trial did show benefit of an early invasive strategy in both sexes.30 In patients with elevated biomarkers, there was a reduction in the primary endpoint of death, MI or rehospitalisation for ACS at 6 months. A subsequent meta-analysis did lend support to the use of an early invasive strategy in women in the presence of elevated biomarkers.31 Furthermore, the large Swedish Web-System for Enhancement and Development of Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapies (SWEDEHEART) registry of 46,455 patients also demonstrated that an early invasive strategy for NSTEMI was associated with a marked and similar reduction in mortality in women (RR 0.46; 95% CI [0.38–0.55]) and men (RR 0.45; 95% CI [0.40–0.52]).22 These data indicate that in women with elevated biomarkers, an early invasive strategy is warranted and women should therefore be undergoing angiography at a comparable rate to that of their male counterparts.

ST-elevation MI The literature demonstrates that the benefit of early reperfusion therapy in STEMI in both sexes is unquestionable and this is reflected in current practice guidelines.32 Nevertheless, women presenting with STEMI are less likely than men to be admitted to a hospital which has the ability to perform PCI.33 The mortality rate of women after STEMI is higher than that of men. In one meta-analysis of 68,536 patients (27% female, n=18,555), mortality was higher in women both in hospital (RR 1.93; 95% CI [1.75–2.14]; p<0.001) and at 1 year (RR 1.58; 95% CI [1.36–1.84]; p<0.001).34 However, women tend to be older and have more co-morbidities with a higher rate of diabetes, hypertension and high cholesterol. When these factors were taken into account, the higher 1-year mortality rate in women was no longer evident in this meta-analysis (RR 0.90; 95% CI [0.69–1.17]; p=0.42). Contrary to this, a recent study analysed patient-level data from 10 randomised trials and evaluated the rate of death or heart failure hospitalisation within 1 year.35 The study evaluated 2,632 patients (22% female, n=587) and found that, despite there being no difference in the size of infarct, the adverse event rate was higher in women at 1 year: the mortality was 3.5% versus 1.8%, p=0.01; and death or heart failure

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Coronary Table 2: Ischaemia Time in Women Versus Men Presenting With ST-elevation MI Study

Number of Women/ Total Number of

Time from Symptom Onset to Help (Minutes)

Door to Balloon Time (Minutes)

Women

Men

Women

Men

Participants (%) Zimmermann et al. 200936

161/566 (28%)

262 (±235)

236 (±263)

<0.02

57 (±45)

63 ±58

0.4

Ferrante et al. 201137

138/481 (29%)

270 (165–485)

205 (140–395)

0.009

94 (57–148)

76 (52–117)

0.02

202/907 (22%)

204 (±135)

176 (±119)

0.005

16 (±6)

16 (±7)

0.97

Otten et al. 201340

708/3,714 (19%) (age<65 years)

165 (110–285)

150 (100–240)

<0.001

45 (30–64)

44 (30–66)

0.32

Otten et al. 201340

1,047/3,032 (35%) (age≥65 years)

180 (120–291)

165 (110–254)

<0.001

48 (33–73)

46 (33–73)

0.12

Velders et al. 201341

868/3,483 (25%)

192 (141–286)*

175 (128–279)*

0.002

46 (33–68)

46 (33–67)

0.4

Wijnbergen et al. 2013

*Symptom onset to balloon time.

hospitalisation rate was 7.9% versus 3.4%, p<0.001. When adjusted for age, risk factors and infarct size, the risk of death or heart failure hospitalisation was still significantly higher in women (adjusted HR 2.13; 95% CI [1.34–3.38]; p=0.001).

14%, p<0.05).46 In this study, female sex was an independent predictor of PCI failure (OR 1.54; 95% CI [1.01–2.38]) and the authors concluded that special care should be taken when PCI is performed in women who are at higher risk for failure when presenting with STEMI.

Several studies consistently demonstrate longer ischaemia times for women presenting with STEMI, driven mainly by a delay in seeking help (Table 2).36-41 A large national study from Poland of 26,035 patients (34.5% women), showed that significantly fewer women with STEMI underwent primary PCI within 12 hours from symptom onset (35.8% versus 44.0%; p<0.0001).38 Both the time between the onset

Stable Angina

of symptoms to balloon time – 255 minutes (IQR 175–375) versus 241 minutes (IQR 165–360), p<0.0001 – as well as the door to balloon time – 45 minutes (IQR 30–70) versus 44 minutes (IQR 30–68), p=0.032 – were longer. The multicentre Examining Heart Attacks in Young Women (VIRGO) study evaluated 1,465 patients aged 18 to 55 years admitted with STEMI.42 This US study was specifically designed to evaluate outcomes in young patients admitted with STEMI with respect to sex and it enrolled more women than men. In accordance with other studies, women were more likely to have atypical symptoms and presented later. Of those patients deemed suitable for reperfusion therapy (women=761; men=477), the study found that women were more likely to be untreated (9% versus 4%; p=0.002) and women who did receive reperfusion experienced a longer delay to receiving therapy. 42 Mortality in STEMI is strongly associated with ischaemic time – every 30-minute delay of revascularisation increases annual mortality by 7.5%. 43 One contributor to delay is that women do not perceive heart disease as a risk to their own health.44,45 The delay in women seeking help appears to be irrespective of age. 40,42 It is therefore important that public health campaigns highlight the need for all women to seek medical help promptly. Awareness should be raised among medical professionals to ensure that therapeutic pathways are optimised for women, particularly in those with an atypical presentation. There is some evidence to suggest that PCI for women presenting with STEMI may be more challenging. Patients who have an unsuccessful PCI procedure for STEMI that fails to restore perfusion have an increased mortality. In a registry of 2,900 consecutive STEMI patients, failed PCI occurred in 4% and was associated with a significantly increased risk of both in-hospital (18% versus 4%) and long-term death (48% versus

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Women are also less likely to receive optimal medical therapy for stable angina compared with men. One observational study evaluated 3,779 patients (42% female) from the Euro Heart Survey.47 Women were less likely to undergo diagnostic coronary angiography (49% versus 31%; p<0.001), and even in those with proven coronary artery disease (CAD), revascularisation was performed in significantly fewer women than men (adjusted OR 0.70; 95% CI [0.52–0.94]; p=0.019). Women were also less likely than men to receive aspirin (73% versus 81%; p<0.001) and statin therapy (45% versus 51%; p<0.001). Importantly, in patients with confirmed CAD, women were more likely to die (2.9% versus 1.5%) or have MI (5.8% versus 2.7%) during follow-up. There is some evidence to suggest that women may have poorer outcomes after PCI, both in terms of adverse clinical events as well as target vessel failure.48–50 One of the possible contributing factors to this could be that women have smaller coronary vessels compared with men. PCI in small vessels is associated with a higher rate of restenosis and target vessel failure. The benefits of using DES rather than a bare metal stent are greater when treating smaller vessels. Contrary to this, the German Arbeitsgemeinschaft Leitende Kardiologische Krankenhausärzte registry of patients stented between 2005 and 2009 (100,704 stent implantations) found that despite having smaller vessel size, women were significantly less likely to receive a DES compared with men – 28.2 versus 31.3%, adjusted OR 0.93; 95% CI [0.89–0.97].51 Numerous studies of DES have demonstrated efficacy irrespective of sex.52–54 The multicentre Clinical Evaluation of the XIENCE Everolimus Eluting Coronary Stent System in the Treatment of Women With de Novo Coronary Artery Lesions (XIENCE V SPIRIT Women) study specifically evaluated the outcomes of 1,573 women treated with everolimus-eluting stents.55 The adverse event rate (death, MI or target vessel revascularisation) was 12% at 1 year and 15% at 2 years. These data were compared with male patients enrolled into the SPIRIT V study and once again female patients had a longer delay to therapy. The total referral time for coronary intervention in women was 4 days longer than that for men (p=0.0003). This may be attributed to the fact that women were more likely to have atypical angina (9% versus 6%) or indeed no chest pain (17% versus 13%) compared with men.

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Outcomes After PCI in Women Complex Percutaneous Coronary Intervention The WIN-DES collaboration has published data demonstrating the safety and efficacy of the use of contemporary DES in 4,629 women treated for complex CAD (defined as total stent length >30 mm, two or more stents implanted, two or more lesions treated or bifurcation lesion).56 Compared with non-complex PCI, women who had complex PCI had a higher 3-year risk of major adverse cardiac events (MACE) (adjusted HR 1.63; 95% CI [1.45 to 1.83]; p<0.0001). The use of newgeneration DES for complex PCI, compared with first-generation stents, was associated with significantly lower 3-year risk of MACE (adjusted HR 0.81; 95% CI [0.68–0.96]), target lesion revascularisation (adjusted HR 0.74; 95% CI [0.57–0.95]), and definite or probable stent thrombosis (adjusted HR 0.50; 95% CI [0.30–0.83]).

Left Main Stem Percutaneous Coronary Intervention Disease of the left main stem (LMS) merits specific attention as revascularisation confers prognostic benefits over and above medical therapy alone. Although CABG is the gold standard, recent trials have supported the concept of PCI as a revascularisation modality for patients without a heavy burden of concomitant disease indicated by a low or intermediate SYNTAX score.57 The outcome of PCI for LMS disease is dependent on the complexity of disease. Lesions that involve the bifurcation are subject to a higher rate of adverse events, driven mainly by the need for repeat revascularisation.58 Women may be more likely than men to have disease at the ostium of the LMS.59 Studies have shown that PCI for ostial LMS disease has a low rate of MACE not significantly different to the results after CABG.60 As with other revascularisation trials, women have been relatively under-represented in the studies of LMS disease comparing PCI with CABG. However, a study by Buchanan et al. specifically evaluated the outcomes of 817 women after PCI versus CABG for unprotected LMS disease.61 Propensity matching was used to identify 175 pairs and demonstrated no difference in death, MI or stroke. There was an increased need for repeat revascularisation in the group treated with PCI compared with the CABG group. This risk of restenosis may be compounded in women because of their smaller vessel size; in one angiographic study, the mean LMS diameter was 3.9 ± 0.4 mm in women versus 4.5 ± 0.5 mm in men.62 The Evaluation of XIENCE Versus Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization (EXCEL) trial was a randomised study designed to specifically evaluate the outcomes of 1,905 patients with LMS disease randomised to either PCI with everolimus-eluting stents versus CABG.63 At 3 years, PCI was found to be non-inferior to CABG for the primary composite endpoint of death, stroke or MI. However, the study found that women undergoing PCI had worse outcomes (19.7% versus 14.1% for the primary composite endpoint) and might be better treated with CABG. A recent analysis was undertaken to explore this further.64 Investigators showed that compared with men, women in the EXCEL trial were older, had a higher rate of hypertension, hyperlipidaemia and diabetes and there were fewer smokers. However, they also had lower coronary anatomic burden and complexity of disease (mean SYNTAX score 24.2 versus 27.2; p<0.001). On multivariate analysis, sex was not an independent predictor of the primary endpoint at 3 years (HR 1.10; 95% CI [0.82–1.48]; p=0.53). However, women treated with PCI had a higher rate of peri-procedural MI compared with men and the authors

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concluded that sex is an important factor to be considered and that further studies are required to determine the optimal revascularisation modality for women with this type of complex coronary artery disease.

Peri-procedural Complications A major concern has been that women undergoing PCI have been shown to have higher rates of peri-procedural bleeding and vascular complications compared with men.26,65–67 Registry data demonstrate that women are more likely to have vascular complications, contrastinduced nephropathy, gastrointestinal bleeding, stroke, infection and death. Women are more likely to suffer femoral complications requiring vascular intervention and retroperitoneal haemorrhage. Major bleeding and receiving a blood transfusion for any reason is strongly associated with MACE and mortality.68 The issue of vascular complications and bleeding has been mitigated by the switch to using radial access for PCI. Although women have an increased rate of radial access failure due to the relatively small size and problems of radial artery spasm, this route is still feasible in the vast majority. The Study of Access Site for Enhancement of Percutaneous Coronary Intervention (SAFE-PCI) involved 1,787 women undergoing either catheterisation or PCI randomised to either radial or femoral access.69 There was no significant difference in the primary efficacy endpoint, however there were significantly fewer bleeding and vascular complications in the radial group (0.6% versus 1.7%; OR 0.32; 95% CI [0.12–0.90]). Additional large randomised studies have also supported the use of a radial approach in reducing vascular complications and bleeding.70,71 One of these, the MATRIX trial, enrolled 8,404 patients (26.7% women) and specifically evaluated the impact of sex.72 After adjustment, the overall adverse event rate was not significantly different for men versus women, however women still had an overall higher risk of access-site bleeding (RR 0.64; p=0.0016), severe bleeding (RR 0.17; p=0.0012) and need for transfusion (RR 0.56; p=0.0089). The benefit of trans-radial access in reducing MACE was more evident in women than in men and was statistically significantly (RR 0.73; 95% CI [0.56–0.95]; p=0.019) compared with the use of a femoral approach. Notably, although the radial approach was successful in the majority, the crossover rate for those randomised to a radial approach was higher in women than in men (7.6% versus 5.2%).

Conclusion In contemporary PCI practice, there remains a disparity between the outcomes of women versus men, with women having significantly worse outcomes and a higher mortality. The causes are multifactorial and relate to differences in health-seeking behaviour as well as suboptimal medical therapy. Women are less likely to undergo cardiac catheterisation and revascularisation; are not treated as quickly as men; and are less likely to receive optimal pharmacotherapy. There is no data to suggest that women benefit any less than men from guideline-recommended primary and secondary prevention cardiovascular medication and revascularisation. Medical professionals need to ensure that the management of women is not biased by a perception of increased risk, such as bleeding, which might potentially deny women from receiving evidence-based therapies. Future studies should focus on evaluating health behaviours, patterns of disease and clinical outcomes, in a sex-specific way.

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Coronary 1. 2.

10.

11.

12.

13.

14.

15.

16.

17.

18.

19.

20.

21.

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PMID: 11779263. 22. A lfredsson J, Lindback J, Wallentin L, Swahn E. Similar outcome with an invasive strategy in men and women with non-ST-elevation acute coronary syndromes: from the Swedish Web-System for Enhancement and Development of Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapies (SWEDEHEART). Eur Heart J 2011;32:3128–36. https://doi.org/10.1093/eurheartj/ehr349; PMID: 21911338. 23. Elkoustaf RA, Mamkin I, Mather JF, et al. Comparison of results of percutaneous coronary intervention for non-STelevation acute myocardial infarction or unstable angina pectoris in men versus women. Am J Cardiol 2006;98:182–6. https://doi.org/10.1016/j.amjcard.2006.01.071; PMID: 16828589. 24. Milcent C, Dormont B, Durand-Zaleski I, Steg PG. Gender differences in hospital mortality and use of percutaneous coronary intervention in acute myocardial infarction: microsimulation analysis of the 1999 nationwide French hospitals database. Circulation 2007;115:833–9. https://doi.org/10.1161/CIRCULATIONAHA.106.664979; PMID: 17309933. 25. Giustino G, Harari R, Baber U, et al. Long-term safety and efficacy of new-generation drug-eluting stents in women with acute myocardial infarction: From the Women in Innovation and Drug-Eluting Stents (WIN-DES) Collaboration. JAMA Cardiol 2017;2:855–62. https://doi.org/10.1001/jamacardio.2017.1978; PMID: 28658478. 26. Duvernoy CS, Smith DE, Manohar P, et al. Gender differences in adverse outcomes after contemporary percutaneous coronary intervention: an analysis from the Blue Cross Blue Shield of Michigan Cardiovascular Consortium (BMC2) percutaneous coronary intervention registry. Am Heart J 2010;159:677–83 e1. https://doi.org/10.1016/j.ahj.2009.12.040; PMID: 20362729. 27. Peterson ED, Lansky AJ, Kramer J, et al. National Cardiovascular Network Clinical I. Effect of gender on the outcomes of contemporary percutaneous coronary intervention. Am J Cardiol 2001;88:359–64. https://doi. org/10.1016/S0002-9149(01)01679-4; PMID: 11545754. 28. Lagerqvist B, Safstrom K, Stahle E, et al. Is early invasive treatment of unstable coronary artery disease equally effective for both women and men? FRISC II Study Group Investigators. J Am Coll Cardiol 2001;38:41–8. https://doi. org/10.1016/S0735-1097(01)01308-0; PMID: 11451294. 29. Clayton TC, Pocock SJ, Henderson RA, et al. Do men benefit more than women from an interventional strategy in patients with unstable angina or non-ST-elevation myocardial infarction? The impact of gender in the RITA 3 trial. Eur Heart J 2004;25:1641–50. https://doi.org/10.1016/j.ehj.2004.07.032; PMID: 15351164. 30. Glaser R, Herrmann HC, Murphy SA, et al. Benefit of an early invasive management strategy in women with acute coronary syndromes. JAMA 2002;288:3124–9. https://doi.org/10.1001/ jama.288.24.3124; PMID: 12495392. 31. O’Donoghue M, Boden WE, Braunwald E, et al. Early invasive vs conservative treatment strategies in women and men with unstable angina and non-ST-segment elevation myocardial infarction: a meta-analysis. JAMA 2008;300:71–80. https://doi. org/10.1001/jama.300.1.71; PMID: 18594042. 32. 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. 33. Fang J, Alderman MH. Gender differences of revascularization in patients with acute myocardial infarction. Am J Cardiol 2006;97:1722–6. https://doi.org/10.1016/j. amjcard.2006.01.032; PMID: 16765121. 34. Pancholy SB, Shantha GP, Patel T, Cheskin LJ. Sex differences in short-term and long-term all-cause mortality among patients with ST-segment elevation myocardial infarction treated by primary percutaneous intervention: a metaanalysis. JAMA Intern Med 2014;174:1822–30. https://doi. org/10.1001/jamainternmed.2014.4762; PMID: 25265319. 35. Kosmidou I, Redfors B, Selker HP, et al. Infarct size, left ventricular function, and prognosis in women compared to men after primary percutaneous coronary intervention in ST-segment elevation myocardial infarction: results from an individual patient-level pooled analysis of 10 randomized trials. Eur Heart J 2017;38:1656–63. https://doi.org/10.1093/ eurheartj/ehx159; PMID: 28407050. 36. Zimmermann S, Ruthrof S, Nowak K, et al. Short-term prognosis of contemporary interventional therapy of ST-elevation myocardial infarction: does gender matter? Clin Res Cardiol 2009;98:709–15. https://doi.org/10.1007/s00392009-0055-8; PMID: 19690904. 37. Ferrante G, Corrada E, Belli G, et al. Impact of female sex on long-term outcomes in patients with ST-elevation myocardial infarction treated by primary percutaneous coronary intervention. Can J Cardiol 2011;27:749–55. https://doi. org/10.1016/j.cjca.2011.07.002; PMID: 21924580. 38. Sadowski M, Gasior M, Gierlotka M, et al. Gender-related differences in mortality after ST-segment elevation myocardial infarction: a large multicentre national registry. EuroIntervention 2011;6:1068–72. https://doi.org/10.4244/EIJV6I9A186; PMID: 21518678.

39. W ijnbergen I, Tijssen J, van’t Veer M, et al. Gender differences in long-term outcome after primary percutaneous intervention for ST-segment elevation myocardial infarction. Catheter Cardiovasc Interv 2013;82:379–84. https://doi. org/10.1002/ccd.24800; PMID: 23553888. 40. Otten AM, Maas AH, Ottervanger JP, et al. Is the difference in outcome between men and women treated by primary percutaneous coronary intervention age dependent? Gender difference in STEMI stratified on age. Eur Heart J Acute Cardiovasc Care 2013;2:334–41. https://doi. org/10.1177/2048872612475270; PMID: 24338292. 41. Velders MA, Boden H, van Boven AJ, et al. Influence of gender on ischemic times and outcomes after ST-elevation myocardial infarction. Am J Cardiol 2013;111:312–8. https://doi. org/10.1016/j.amjcard.2012.10.007; PMID: 23159214. 42. D’Onofrio G, Safdar B, Lichtman JH, et al. Sex differences in reperfusion in young patients with ST-segment-elevation myocardial infarction: results from the VIRGO study. Circulation 2015;131:1324–32. https://doi.org/10.1161/ CIRCULATIONAHA.114.012293; PMID: 25792558. 43. De Luca G, Suryapranata H, Ottervanger JP, Antman EM. Time delay to treatment and mortality in primary angioplasty for acute myocardial infarction: every minute of delay counts. Circulation 2004;109:1223–5. https://doi.org/10.1161/01. CIR.0000121424.76486.20; PMID: 15007008. 44. Mosca L, Mochari H, Christian A, et al. National study of women’s awareness, preventive action, and barriers to cardiovascular health. Circulation 2006;113:525–34. https://doi. org/10.1161/CIRCULATIONAHA.105.588103; PMID: 16449732. 45. Mosca L, Jones WK, King KB, et al. Awareness, perception, and knowledge of heart disease risk and prevention among women in the United States. American Heart Association Women’s Heart Disease and Stroke Campaign Task Force. Arch Fam Med 2000;9:506–15. https://doi.org/10.1001/ archfami.9.6.506; PMID: 10862212. 46. Barbash IM, Ben-Dor I, Torguson R, et al. Clinical predictors for failure of percutaneous coronary intervention in ST-elevation myocardial infarction. J Interv Cardiol 2012; 25:111–7. https://doi.org/10.1111/j.1540-8183.2011.00707.x; PMID: 22372924. 47. Daly C, Clemens F, Lopez Sendon JL, et al. Gender differences in the management and clinical outcome of stable angina. Circulation 2006;113:490–8. https://doi.org/10.1161/ CIRCULATIONAHA.105.561647; PMID: 16449728. 48. Ellis SG, Roubin GS, King SB 3rd, et al. Angiographic and clinical predictors of acute closure after native vessel coronary angioplasty. Circulation 1988;77:372–9. https://doi. org/10.1161/01.CIR.77.2.372; PMID: 2962787. 49. Argulian E, Patel AD, Abramson JL, et al. Gender differences in short-term cardiovascular outcomes after percutaneous coronary interventions. Am J Cardiol 2006;98:48–53. https://doi. org/10.1016/j.amjcard.2006.01.048; PMID: 16784919. 50. Lansky AJ, Ng VG, Mutlu H, et al. Gender-based evaluation of the XIENCE V everolimus-eluting coronary stent system: clinical and angiographic results from the SPIRIT III randomized trial. Catheter Cardiovasc Interv 2009;74:719–27. https://doi.org/10.1002/ccd.22067; PMID: 19530147. 51. Russ MA, Wackerl C, Zeymer U, et al. Gender based differences in drug eluting stent implantation – data from the German ALKK registry suggest underuse of DES in elderly women. BMC Cardiovasc Disord 2017;17:68. https://doi. org/10.1186/s12872-017-0500-y; PMID: 28241861. 52. Lansky AJ, Costa RA, Mooney M, et al. Gender-based outcomes after paclitaxel-eluting stent implantation in patients with coronary artery disease. J Am Coll Cardiol 2005;45:1180–5. https://doi.org/10.1016/j.jacc.2004.10.076; PMID: 15837246. 53. Solinas E, Nikolsky E, Lansky AJ, et al. Gender-specific outcomes after sirolimus-eluting stent implantation. J Am Coll Cardiol 2007;50:2111–6. https://doi.org/10.1016/j. jacc.2007.06.056; PMID: 18036446. 54. Mikhail GW, Gerber RT, Cox DA, et al. Influence of sex on longterm outcomes after percutaneous coronary intervention with the paclitaxel-eluting coronary stent: results of the ‘TAXUS Woman’ analysis. JACC Cardiovasc Interv 2010;3:1250–9. https://doi.org/10.1016/j.jcin.2010.08.020; PMID: 21232718. 55. Morice MC, Mikhail GW, Mauri I, et al. SPIRIT Women, evaluation of the safety and efficacy of the XIENCE V everolimus-eluting stent system in female patients: referral time for coronary intervention and 2-year clinical outcomes. EuroIntervention 2012;8:325–35. https://doi.org/10.4244/ EIJV8I3A51; PMID: 22829508. 56. Giustino G, Baber U, Aquino M, et al. Safety and efficacy of new-generation drug-eluting stents in women undergoing complex percutaneous coronary artery revascularization: from the WIN-DES collaborative patient-level pooled analysis. JACC Cardiovasc Interv 2016;9:674–84. https://doi.org/10.1016/j. jcin.2015.12.013; PMID: 27056305. 57. 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. 58. 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://

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Outcomes After PCI in Women doi.org/10.1016/j.jcin.2013.08.005; PMID: 24355114. 59. Y ildirimturk O, Cansel M, Erdim R, et al. Coexistence of left main and right coronary artery ostial stenosis: demographic and angiographic features. Int J Angiol 2011;20:33–8. https:// doi.org/10.1055/s-0031-1272550; PMID: 22532768. 60. Guo CL, Yu XP, Yang BG, et al. Long-term outcomes of PCI vs. CABG for ostial/midshaft lesions in unprotected left main coronary artery. J Geriatr Cardiol 2017;14:254–60. https://doi.org.10.11909/j.issn.1671-5411.2017.04.004; PMID: 28663763. 61. Buchanan GL, Chieffo A, Meliga E, et al. Comparison of percutaneous coronary intervention (with drug-eluting stents) versus coronary artery bypass grafting in women with severe narrowing of the left main coronary artery (from the Women-Drug-Eluting stent for LefT main coronary Artery disease Registry). Am J Cardiol 2014;113:1348–55. https://doi.org/10.1016/j.amjcard.2014.01.409; PMID: 24581924. 62. Dodge JT Jr, Brown BG, Bolson EL, Dodge HT. Lumen diameter of normal human coronary arteries. Influence of age, sex, anatomic variation, and left ventricular hypertrophy or dilation. Circulation 1992;86:232–46. https://doi.org/10.1161/01. CIR.86.1.232; PMID: 1535570. 63. Stone GW, Sabik JF, Serruys PW, et al. Everolimus-eluting stents or bypass surgery for left main coronary artery

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disease. N Engl J Med 2016;375:2223–35. https://doi. org/10.1056/NEJMoa1610227; PMID: 27797291. Serruys PW, Cavalcante R, Collet C, et al. Outcomes after coronary stenting or bypass surgery for men and women with unprotected left main disease: The EXCEL Trial. JACC Cardiovasc Interv 2018;11:1234–43. https://doi.org/10.1016/j. jcin.2018.03.051; PMID: 29976359. Scott P Farouque O, Clark D. Percutaneous coronary intervention in women: should management be different? Interventional Cardiology 2014;6:527–36. https://doi.org/10.2217/ ica.14.51. Perdoncin E, Duvernoy C. Treatment of coronary artery disease in women. Methodist Debakey Cardiovasc J 2017;13:201–8. doi: 10.14797/mdcj-13-4-201. PMID: 29744012 Jibran R, Khan JA, Hoye A. Gender disparity in patients undergoing percutaneous coronary intervention for acute coronary syndromes – does it still exist in contemporary practice? Ann Acad Med Singapore 2010;39:173–8. PMID: 20372751. Romaguera R, Wakabayashi K, Laynez-Carnicero A, et al. Association between bleeding severity and long-term mortality in patients experiencing vascular complications after percutaneous coronary intervention. Am J Cardiol 2012;109:75–81. https://doi.org/10.1016/j. amjcard.2011.08.007; PMID: 21962994.

69. R ao SV, Hess CN, Barham B, et al. A registry-based randomized trial comparing radial and femoral approaches in women undergoing percutaneous coronary intervention: the SAFE-PCI for Women (Study of Access Site for Enhancement of PCI for Women) trial. JACC Cardiovasc Interv 2014;7:857–67. https://doi.org/10.1016/j.jcin.2014.04.007; PMD: 25147030. 70. Jolly SS, Yusuf S, Cairns J, et al. Radial versus femoral access for coronary angiography and intervention in patients with acute coronary syndromes (RIVAL): a randomised, parallel group, multicentre trial. Lancet 2011;377:1409–20. https://doi. org/10.1016/S0140-6736(11)60404-2; PMID: 22090240. 71. Valgimigli M, Frigoli E, Leonardi S, et al. Radial versus femoral access and bivalirudin versus unfractionated heparin in invasively managed patients with acute coronary syndrome (MATRIX): final 1-year results of a multicentre, randomised controlled trial. Lancet 2018; 392:835–48. https://doi.org/10.1016/S0140-6736(18)31714-8; PMID: 30153988. 72. Gargiulo G, Ariotti S, Vranckx P, et al. Impact of sex on comparative outcomes of radial versus femoral access in patients with acute coronary syndromes undergoing invasive management: data from the randomized MATRIX-Access trial. JACC Cardiovasc Interv 2018;11:36–50. https://doi.org/10.1016/j. jcin.2017.09.014; PMID: 29301646.

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Coronary

How to Diagnose and Manage Angina Without Obstructive Coronary Artery Disease: Lessons from the British Heart Foundation CorMicA Trial Thomas J Ford 1,2 and Colin Berry 1,2 1. West of Scotland Heart and Lung Centre, Golden Jubilee National Hospital, UK; 2. British Heart Foundation Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, University of Glasgow, UK

Abstract Patients with symptoms and/or signs of ischaemia but no obstructive coronary artery disease (INOCA) present a diagnostic and therapeutic challenge. Microvascular and/or vasospastic angina are the two most common causes of INOCA; however, invasive coronary angiography lacks the sensitivity to diagnose these functional coronary disorders. In this article, the authors summarise the rationale for invasive testing in the absence of obstructive coronary disease, namely that correct treatment for angina patients starts with the correct diagnosis. They provide insights from the CORonary MICrovascular Angina (CorMicA) study, where an interventional diagnostic procedure was performed with linked medical therapy to improve patient health. Identification of these distinct disorders (microvascular angina, vasospastic angina or non-cardiac chest pain) is key for stratifying INOCA patients, allowing prognostic insights and better patient care with linked therapy based on contemporary guidelines. Finally, they propose a framework to diagnose and manage patients in this common clinical scenario.

Keywords Stable angina pectoris, elective coronary angiography, microvascular angina, vasospastic angina, coronary vasoreactivity testing, coronary physiology, ischaemia Disclosure: TJF has no conflicts of interest. CB is employed by the University of Glasgow, which holds consultancy and research agreements with companies that have commercial interests in the diagnosis and treatment of angina. These companies include Abbott Vascular, AstraZeneca, Boehringer Ingelheim, GSK, Menarini Pharmaceuticals, Opsens, Philips and Siemens Healthcare. CorMicA study is an investigator-initiated clinical trial that was funded by the British Heart Foundation (PG/17/2532884; RE/13/5/30177; RE/18/634217). Clinicaltrials.gov: NCT03193294. Received: 10 February 2019 Accepted: 17 April 2019 Citation: Interventional Cardiology Review 2019;14(2):76–82. DOI: https://doi.org/10.15420/icr.2019.04.R1 Correspondence: Tom J Ford, British Heart Foundation Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, University of Glasgow, 126 University Place, Glasgow, G12 8TA, UK. E: tom.ford@glasgow.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.

Ischaemic heart disease persists as the leading global cause of death and lost life years in adults.1 Angina is a common clinical presentation of ischaemic heart disease related to a supply:demand mismatch of myocardial blood flow, typically provoked by exertion or stress. Invasive coronary angiography is the reference test for angina and identifies obstructive coronary artery disease (CAD) as a cause for symptoms. In Europe and the US, approximately 4 million elective coronary angiograms are performed each year.2,3 However, up to half of all angina patients undergoing elective coronary angiography with symptoms and/or signs of ischaemia have no obstructive epicardial coronary artery disease (INOCA).3 This large, heterogeneous group includes patients with microvascular angina (MVA), vasospastic angina (VSA) or both conditions together. The burden of these conditions on physical and mental wellbeing can be profound; they are associated with morbidity4 and a reduction in quality of life.5 Patients with these conditions commonly attend primary and secondary care, driving up health resource utilisation.6 We propose that optimal clinical management starts with the correct diagnosis; hence we begin by summarising the rationale and protocol for invasive tests of coronary function in INOCA patients. We discuss

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drivers of myocardial ischaemia and reappraise existing consensus guideline-based management in light of the CORonary MICrovascular Angina (CorMicA) study, the first randomised controlled trial of invasive coronary function testing linked to stratified medical therapy in angina. This review aims to educate and empower the invasive cardiologist to perform vasoreactivity testing and to provide them with an understanding of the positive impact of personalised medicine for individual angina patients. We conclude pointing to future directions in care and the benefits of improved diagnosis linked to translational clinical research to develop targeted disease-modifying therapy.

Background and Aetiology of Angina Without Obstructive Coronary Disease INOCA is a recently proposed ‘umbrella’ term conveying the importance of stable coronary syndromes beyond obstructive CAD (Figure 1). INOCA aligns with the sibling term MINOCA, which stands for myocardial infarction with no obstructive CAD. MINOCA is a similarly diverse syndrome with distinct underlying causes.7 Depending on the patient population studied and the techniques used, between one-third and two-thirds of angina patients with a

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How to Diagnose and Manage Angina Without Obstructive Coronary Artery Disease negative angiogram have an underlying disorder of coronary vascular function.8,9 Importantly, the two most common causes of INOCA (MVA and VSA) are not excluded by a negative non-invasive CT coronary angiogram or invasive coronary angiogram.6 For affected patients, symptom burden, morbidity and health resource utilisation can be considerable.5,10,11 As cardiologists, we often adopt a ‘stenosis-centric’ approach. However, as clinicians we must appreciate the complexity and individual contributors to ischaemia in patients without obstructive epicardial disease (Figure 1). Systemic factors, including heart rate, blood pressure (and their product) and myocardial supply:demand ratio (Buckberg index), are important.12,13 Coronary factors are well recognised, but certain nuances are overlooked. For example, Gould and Johnson recently used their quantitative myocardial perfusion database of over 5,900 patients to show that occult coronary diffuse obstructive coronary disease or flush ostial stenosis may be overlooked on angiography and mislabelled as microvascular angina with suboptimal treatment.14 Other coronary factors that can cause ischaemia and propensity to acute coronary syndromes include structural microvascular dysfunction, endothelial impairment, myocardial bridging and/or epicardial vasospasm.15,16 The final group of factors that can drive INOCA is cardiac, including left ventricular hypertrophy or restrictive cardiomyopathy where subendocardial ischaemia results from challenges with arteriolar vessels penetrating deeper into the myocardial tissue with shorter diastole and enhanced systolic myocardial vessel constriction.17 Heart failure (with reduced or preserved ejection fraction) can lead to elevated left-ventricular end diastolic pressures that reduce the physiological myocardial perfusion gradient. Valvular heart disease, e.g. aortic stenosis or left ventricular outflow tract obstruction, is a well-recognised cause of INOCA, although controversy exists over whether symptoms in mechanical outflow tract obstruction (aortic stenosis) relate to microvascular dysfunction, supply:demand factors or both.18 Most experts support haemodynamic factors as the main cause of ischaemia here, especially since symptoms and coronary flow reserve improve immediately after valve replacement.19

Non-invasive Functional Testing Non-invasive tests provide indirect assessments of myocardial resistance by assessing perfusion during exercise or pharmacological stress, typically using systemic adenosine. Nevertheless, perfusion assessment lacks the sensitivity to diagnose the relative contributions of epicardial and microvascular disease to myocardial blood flow reduction. In addition, some patients with a propensity to vasospastic chest pain syndromes may have normal findings from pharmacological and exercise stress testing. This review focuses on the invasive diagnosis and related management of angina subjects without obstructive disease; the non-invasive workup is covered elsewhere.20,21

Diagnosis and Rationale for Invasive Testing In the cardiac catheterisation laboratory, coronary vascular function may be assessed ad hoc during the patient’s index coronary angiogram. This often involves an interventional diagnostic procedure (IDP) where a guidewire-based assessment of coronary blood flow is performed at rest and during interrogation with pharmacological probes, typically adenosine and acetylcholine.

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Figure 1: Ischaemia with No Obstructive Coronary Artery Disease: A Coronary Syndrome Systemic factors 1

Coronary factors

INOCA

• Myocardial supply: demand ratio (SEVR or Buckberg index) • Pulse rate • Blood pressure • Heightened sympathetic activation

• Microvascular dysfunction • Endothelial impairment • Occult diffuse epicardial CAD • Coronary artery spasm • Myocardial bridging

Cardiac factors

2 3

• Impaired diastolic relaxation • Left ventricular hypertrophy • Diastolic dysfunction • Valvular heart disease • Left ventricular outflow tract obstruction

The traditional paradigm where angina is ubiquitously associated with obstructive epicardial disease overlooks the importance other determinants of myocardial ischaemia. These three groups of factors combine to determine the physiological myocardial perfusion gradient. CAD = coronary artery disease; INOCA = ischaemia but no obstructive coronary artery disease; SEVR = subendocardial viability ratio.

The rationale for an IDP is three-fold. First, these patients often present with typical angina for invasive coronary angiography, which offers an opportunity for the cardiologist to provide patients with an accurate diagnosis and explanation for their symptoms. Second, discrimination of MVA, VSA and non-cardiac chest pain permits distinct treatment outlined in consensus practice guidelines. Third, evidence of coronary vascular dysfunction carries prognostic insights for patients and their clinicians. However, in contemporary standard practice, additional invasive tests on patients with unobstructed coronary arteries are very rarely performed. The IDP consists of two steps: assessment of coronary circulation vasorelaxation using invasive coronary physiology at rest and with hyperaemia; and second, assessment of the propensity of the coronary circulation to excessive vasoconstriction using intra-arterial acetylcholine (microvascular and/or epicardial vasospasm) (Table 1). We typically prefer the left anterior descending coronary artery as the target vessel because it subtends the largest myocardial mass. While regional microvascular dysfunction is well recognised, interrogation of multiple vessels increases the procedural duration such that the benefits of testing may be outweighed by the risks.

Assessment of Coronary Vasorelaxation and Resistance Using Diagnostic Guidewire The purpose of step one is to assess the coronary flow reserve (CFR) and microvascular resistance, typically using the index of microcirculatory resistance (IMR; Figure 2). Flow-limiting epicardial coronary disease may be assessed using fractional flow reserve (FFR), which is the ratio of mean distal coronary pressure to mean aortic pressure at maximal hyperaemia. Abnormal FFR is defined as ≤0.80 or alternatively a non-hyperaemic pressure ratio with different cut-off may be used, e.g. diastolic-only pressure ratio.22,23 The CFR is determined by dividing the hyperaemic coronary blood flow by the resting flow. This is also termed the vasodilator capacity and reflects the ability of the coronary circulation to augment blood flow from rest. CFR is calculated using thermodilution as the resting mean transit time divided by hyperaemic mean transit time; an abnormal CFR is defined as ≤2.24,25 Microcirculatory resistance can be assessed using

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Coronary Table 1: Definition and Invasive Diagnostic Criteria for Disorders of Coronary Artery Function Disorder

Symptoms

Clinical measurement

Microvascular angina

Abnormal microvascular resistance

• IMR ≥2527 • Hyperaemic microvascular resistance ≥2.5 mmHg/cm/s28

Impaired coronary vasorelaxation

• CFR by thermodilution <2.025

Microvascular spasm

Angina symptoms with ACh infusion AND: • ST-segment deviation on ECG • No significant epicardial coronary spasm (<90% diameter reduction)

Epicardial spasm

Angina symptoms during ACh bolus (e.g. 100 μg acetylcholine over 20 seconds) AND: • ST-segment deviation on ECG • >90% epicardial coronary constriction during ACh reduction34

Vasospastic angina

Non-cardiac

• E xclusion of significant epicardial coronary disease (fractional flow reserve >0.8) without any of the following abnormalities of coronary function: CFR <2.0, IMR ≥25 or positive ACh response.

ACh = acetylcholine; CFR = coronary flow reserve; IMR = index of microvascular resistance.

Figure 2: Interventional Diagnostic Procedure in Ischaemia with No Obstructive Coronary Artery Disease for Diagnosis and Stratified Management

Invasive coronary angiography No obstructive CAD

No obstructive CAD

Diagnostic guidewire (adenosine) No substrate for angina: (FFR 0.84, CFR 5.3, IMR 9)

ACh

GTN

Microvascular dysfunction (FFR 0.95, CFR 1.3, IMR 33)

Vasoreactivity (acetylcholine)

Vasospasm with ACh (resolves with nitrate)

ACh

GTN

Vasospastic Angina

Microvascular Angina

• Calcium channel blocker • Long-acting nitrate • Avoid betablockers • Smoking cessation • Lifestyle factors and cardiac rehabilitation

• Beta-blocker • Consider an ACEI or statin • Smoking cessation • Weight loss, cardiac rehabilitation • Avoid long-acting nitrates

ACEI = angiotensin-converting enzyme inhibitor; ACh = acetylcholine; CAD = coronary artery disease; FFR = fractional flow reserve; GTN = glyceryl trinitrate; IMR = index of microcirculatory resistance.

thermodilution or Doppler. The IMR is calculated as the distal coronary pressure at maximal hyperaemia multiplied by the hyperaemia mean transit time.26 Increased IMR (≥25) is representative of microvascular dysfunction.27 If Doppler wires are used, the hyperaemic microvascular resistance may be calculated as the ratio between hyperaemia distal coronary pressure and hyperaemia average peak velocity, with measurements >2.5 mmHg/cm/s being abnormal.28 In brief, 50–70 U/kg intravenous heparin should be administered and a guiding catheter used to engage the coronary artery. We induce hyperaemia pharmacologically with intravenous adenosine 140 μg/ kg/minute, although other pharmacological agents or exercise may be used. A pressure–temperature sensor guidewire (PressureWire X™, Abbott Vascular) or a Doppler wire (ComboWire XT® or FloWire®, Philips Volcano Corporation) may be used. In this technique, the guidewire wirelessly transmits data to a workstation or computer using dedicated analysis software (e.g. CoroFlow™, Coroventis). Typically, intra-arterial

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After equalisation and passing the diagnostic guidewire into the distal third of the vessel, the blood flow at rest is assessed either by thermodilution (akin to right heart catheterisation with Swan–Ganz/ bolus of normal saline) or by Doppler wire.

Assessment for Propensity to Coronary Vasoconstriction: Acetylcholine Provocation Endothelial dysfunction without vasospasm to ACh

Diagnosis and management

glyceryl trinitrate is given as for standard FFR assessment, although we suggest using ≤200 μg. The half-life of glyceryl trinitrate is around 2 minutes; thus after 10 minutes only 3% of the medication is active and it is unlikely to suppress a false-positive test for vasospasm in step two. Conversely if acetylcholine (ACh) testing is performed first, then resting flow and CFR assessment may be inaccurate, particularly after a positive vasospasm test.

In healthy endothelium, ACh stimulates abluminal release of nitric oxide, mediating vascular smooth muscle relaxation and increased blood flow. At high doses or in patients with endothelial dysfunction, ACh directly stimulates vascular smooth muscle, causing vasoconstriction that can precipitate epicardial vasospasm and/or microvascular vasospasminduced ischaemia. Typically, infusions of ACh at concentrations approximating 0.182, 1.82, and 18.2 µg/ml (10−6, 10−5 and 10−4 mol/l, respectively) at 1 ml/min for 2–3 minutes are given via a mechanical pump. These doses were historically derived using experiments adopting subselective infusion through an infusion catheter into the left anterior descending artery, assuming a resting flow of 80 ml/min. The effective concentration at tissue level was estimated at 10−8 to 10−6 M. The assessment of Doppler response to ACh involves intracoronary infusion catheters in combination with Doppler wire and requires larger guiding catheter sizes (7 Fr) and a 3 Fr infusion catheter into the coronary artery. Centres in Japan with over four decades of experience with ACh testing adopt a pragmatic and streamlined approach using sequential bolus doses of ACh via the guiding catheter. Doses start from 20 µg, increasing to 50 and 100 up to 200 µg in the left system (or 20, 50 and 80 µg into the right coronary) over 20 seconds followed by up to 3 minutes between doses.29 Coronary angiography is performed when either ST segment changes or chest pain (or both) occur, or after 1 minute following the completion of each injection. We routinely use a well-engaged guiding catheter to deliver ACh via a 2-minute infusion using an external mechanical pump without an additional infusion catheter. This approach facilitates smaller guiding catheters and reduces risk, time and procedural cost.

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How to Diagnose and Manage Angina Without Obstructive Coronary Artery Disease Epicardial coronary artery spasm is defined according to the Coronary Vasomotion Disorders International Study Group criteria whereby chest pain is reproduced with ST segment deviation and ≥90% vasoconstriction to 100 µg of ACh (5.5 ml of 10−4 M over 20 seconds). Microvascular spasm is defined chest pain and ST segment deviation without significant luminal constriction (<90%) and represents a functional subtype of microvascular angina. Severe epicardial endothelial dysfunction is defined by ≥20% luminal constriction during ACh infusion (up to 10−4 M); this finding implies a significant reduction in coronary artery blood flow with prognostic implications when compared with patients whose arteries are <20% constricted.30 Bradycardia with ACh is common and usually self-limiting, although a reduced dose during interrogation of the right coronary artery (maximum 50–80 μg ACh) may reduce occurrence.

CorMicA and Clinical Evidence Despite a wealth of clinical evidence from observational studies, until recently there has not been a single randomised controlled trial of coronary function testing. In the absence of randomised trials demonstrating patient benefits, observational evidence has rarely been applied in practice. CorMicA now provides proof-of-concept clinical evidence to support the case for patient benefits when management is guided by invasive tests of coronary artery function (IDP). Ad hoc adoption of coronary function testing for patients with INOCA is currently restricted to a few interested academic centres. In part this relates to lack of evidence that an IDP has clinical utility or improves patient well-being. Supported by the British Heart Foundation and the patients who kindly agreed to take part, we delivered the CorMicA trial to specifically address this gap in evidence.31,32 We hypothesised that stratified medicine, including an IDP with linked medical therapy, would be routinely feasible and lead to improvements in angina and quality of life in patients with no obstructive CAD. A total of 391 patients with definite or probable angina, as determined on the Rose angina questionnaire,were enrolled over a 12-month period from November 2016 at two large tertiary referral centres serving around half the population of Scotland (approximately 2.5 million people).33 Coronary angiography revealed no obstructive CAD in 185 (47%) of the patients who completed the Rose questionnaire and 151 individuals were immediately randomised to one of two arms: the intervention group (stratified medical therapy, IDP disclosed) or the control group (standard care, IDP sham procedure, results not disclosed). The mean age of subjects was 62 years and 74% were female. The diagnostic intervention included a guidewire-based assessment of a major coronary artery, usually the left anterior descending coronary artery, followed by pharmacological coronary reactivity testing (Figure 2). This diagnostic assessment aligned with contemporary guidelines.34,35 The IDP involved measurement of CFR (abnormal <2.0), microcirculatory resistance (IMR; abnormal ≥25) and FFR (abnormal ≤0.80). Vasoreactivity testing was then performed by infusing incremental concentrations of ACh followed by a bolus of ACh of up to 100 μg to assess for epicardial or microvascular vasospasm. The diagnosis of a clinical endotype (MVA, VSA, both or none) was linked to distinct guideline-based management stratified by diagnosis.36 The primary endpoint was the mean difference in angina severity at 6 months as assessed by the Seattle Angina Questionnaire summary score.37

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Figure 3: Prevalence and Treatment of Ischaemia with No Obstructive Coronary Artery Disease A

B MVA VSA Mixed (both) Non-cardiac

52% 17% 20% 11%

Consider statin and ACEI Vasospastic angina

Microvascular angina

1st

Ca2+ antagonist

Beta-blocker

2nd

Nitrate

Ca2+ antagonist

3rd Nicorandil

Ranolazine

Nicorandil

A:The overall prevalence of coronary artery vasomotion disorders in the CorMicA study. B: Authors’ interpretation of the evidence for recommended therapy for angina patients without obstructive CAD stratified by diagnosis. This formed the basis of pharmacological treatment for patients in the British Heart Foundation CorMicA study. ACEI = angiotensinconverting enzyme inhibitor; MVA = microvascular angina; VSA = vasospastic angina.

In an all-comers study design, the IDP revealed isolated MVA in 78 subjects (52%), isolated VSA in 25 subjects (17%), mixed angina (both) in 31 subjects (20%) and non-cardiac chest pain in 17 subjects (11%) (Figure 3). The intervention was associated with a mean improvement of 11.7 units in Seattle Angina Questionnaire summary score at 6 months (95% CI [5.0–18.4], p=0.001). In addition, the intervention led to improvements in the mean quality of life score (EQ-5D index 0.10 units; 95% CI [0.01–0.18]; p=0.024) and visual analogue score (14.5 units; 95% CI [7.8–21.3]; p<0.001).31 Notably, after the disclosure of coronary function testing, over half of the treating clinicians changed their diagnosis. There were no differences in major adverse cardiac events after 6 months of follow-up (2.6% controls versus 2.6% intervention; p=1.00). Thus, we showed that in patients undergoing invasive coronary angiography, obstructive coronary disease is excluded in half of all patients; and within this large group of patients, the majority have a readily identifiable disorder of coronary vasomotion. Specifically, the IDP with linked medical therapy was routinely feasible and safe, resulting in improvements in angina and quality of life at 6 months in this group of patients. CorMicA was undertaken in a real-world setting and the results appear to be transferable to clinical practice. Future trials are anticipated to determine the wider external validity of this approach.

Stratified Medicine in Angina We start by considering the patient in the context of non-coronary contributors to INOCA (Figure 1). Non-pharmacological therapies encompassing lifestyle modification, risk factor control, evidencebased pharmacological therapy and patient education are also essential for stratifying treatment. Lifestyle recommendations are covered in detail in the recent European Society of Cardiology guidelines.38 We will focus on the two most common diagnostic groups to guide distinct medical treatments.

Microvascular Angina The diagnosis of MVA may be suspected in angina patients without obstructive CAD who have evidence of microvascular dysfunction. In the IDP above, microvascular dysfunction consists of abnormal CFR (<2.0), abnormal IMR (≥25) and/or microvascular spasm during ACh provocation. Clearly, this is a heterogenous entity akin to the syndrome of heart failure with preserved ejection fraction (HFpEF) with diverse aetiology.39

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Coronary Table 2: Pharmacological and Non-pharmacological Treatment Options for Angina Diagnosis

Investigation

Pathophysiology

Treatment

Effects

Microvascular angina ↓ vasorelaxation

↓ CFR and/or ↑ microvascular resistance

Anatomical remodelling, vascular rarefaction, disturbed coronary regulation

Beta-blockers (e.g. nebivolol 2.5–10mg)

↓ myocardial oxygen consumption

ACE inhibitors (e.g. ramipril 2.5 mg)

Improve CFR, ↓ workload, may improve small vessel remodelling

Ranolazine (e.g. 375 mg twice daily)

Improves microvascular perfusion reserve index in patients with MVA and reduced CFR

Calcium antagonists (e.g. amlodipine 10 mg)

Vascular smooth muscle relaxation, ↓ myocardial oxygen consumption

ACE inhibitors (e.g. ramipril 2.5 mg)

Improves endothelial vasomotor dysfunction

Nicorandil (e.g. 5–10mg twice daily)

Potassium-channel activator with coronary microvascular dilatory effect

Statins (e.g. rosuvastatin 10–20 mg)

Improve coronary endothelial function, pleiotropic effects including reduced vascular inflammation

Hormone replacement therapy

Oestrogen therapy improves symptoms but not proven to improve ischaemia or endothelial function

Tricyclic antidepressants (e.g. imipramine up to 25 mg)

Improved symptom burden potentially through ↓ visceral pain

Xanthine derivatives (e.g. aminophylline 225 mg twice daily)

Anti-algogenic effect (due to the direct involvement of adenosine in cardiac pain generation)

Calcium channel blockers (e.g. amlodipine 10 mg or verapamil 240 mg SR)

↓ spontaneous and inducible coronary spasm via vascular smooth muscle relaxation and ↓ oxygen demand

Nitrates (e.g. isosorbide mononitrate XL 30 mg)

↓ spontaneous and inducible coronary spasm via large epicardial vasodilation, ↓ oxygen demand, lack of efficacy in microvascular angina with potential deleterious effect

Microvascular angina ↑ vasoconstriction

Hyper-reactivity to stimuli (e.g. acetylcholine, exercise, stress)

Microvascular angina Abnormal pain processing

↑ nociception

Vasospastic angina

Propensity to coronary vasospasm

Adjunctive nonpharmacological interventions

May be useful in all endotypes

Endothelial dysfunction, inappropriate pre-arteriolar vasoconstriction

Dysfunctional cortical pain processing

Vascular smooth muscle hyper-reactivity

Metabolic syndrome, endothelial dysfunction, cardiovascular risk factors, anxiety/depression

Smoking cessation, exercise, cardiac rehabilitation, Mediterranean diet, cognitive behavioural therapy93

ACE = angiotensin converting enzyme; CFR = coronary flow reserve; MVA = microvascular angina; SR = sustained-release preparation.

Baseline “disease-modifying” therapies that have demonstrated benefit in clinical trials of microvascular angina include angiotensin-converting enzyme inhibitors40 and statins.41 We particularly support these baseline therapies in patients with diffuse CAD without epicardial obstruction. European Society of Cardiology guidelines for patients with MVA recommend beta-blockers as first-line and calcium antagonists if the former are not tolerated or efficacious (Table 2).36 Dihydropyridine calcium blockers, e.g. amlodipine 5–10 mg, may be added to betablockers if blood pressure permits. There is accumulating evidence that long-acting nitrates are ineffective or even detrimental in MVA.42 Lack of efficacy may relate to poor tolerability, steal syndromes through regions of adequately perfused myocardium and/or related to the reduced responsiveness of nitrates within the coronary microcirculation.43 There is significant clinical overlap between MVA and HFpEF,44 so inferences about nitrate response may be drawn from the Nitrate’s Effect on Activity, Tolerance in HFpEF (NEAT-HFpEF) study. In this randomised controlled trial, HFpEF patients on isosorbide mononitrate actually did worse with reduced activity levels assessed using an accelerometer.45 Ranolazine is a relatively new and well-researched antianginal therapy that may improve myocardial perfusion by decreasing sodium

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and calcium overload, thereby improving myocyte relaxation and ventricular compliance.46 In a randomised placebo-controlled clinical trial of ranolazine led by the Women’s Ischemic Syndrome Evaluation investigators, although there were no overall improvements in angina and myocardial perfusion with ranolazine, patients with a reduced CFR (<2.5) benefitted from ranolazine, with significant improvements in myocardial perfusion (p=0.014) and angina frequency (p=0.027).47 Multiple other drugs that reduce angina may be added, including nicorandil and ivabradine.21

Vasospastic Angina VSA is often characterised by rest angina, often with preserved effort tolerance. The poor nitrate response or tolerance seen in MVA contrasts with patients with vasospastic angina, in whom nitrates are a cornerstone therapy and beta-blockers are relatively contraindicated.36 Dual pathology (VSA with underlying microvascular disease) is not uncommon.48,49 A positive diagnosis of VSA facilitates treatment using nondihydropyridine calcium antagonists, e.g. controlled-release diltiazem at up to 500 mg daily, which are usually very effective. High doses of

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How to Diagnose and Manage Angina Without Obstructive Coronary Artery Disease calcium channel blockers (non-dihydropyridine and dihydropyridine) may be required either alone or in combination. Overall, calcium channel blockers are effective in treating >90% of patients.50 Unfortunately, ankle swelling, constipation and other side-effects may render some patients intolerant. Long-term nitrates may be used with good efficacy in this group.51 In about 10% of cases, coronary artery spasm may be refractory to optimal vasodilator therapy and require large doses of calciumchannel blockers or nitrates. Alpha-blockers, e.g. clonidine, may be helpful in selected patients with persistent vasospasm. In patients with poor nitrate tolerance, the potassium-channel-opener nicorandil can be tried. In refractory cases of VSA in patients with acute coronary syndrome, coronary angioplasty may be a useful bailout option.52 In such recalcitrant disease, it is worth reappraising the underlying diagnosis and considering coronary vasculitis as a presentation of multisystem disease.53

Beyond Pharmacotherapy The importance of addressing lifestyle factors cannot be overemphasised, particularly given that half of the patients in the CorMicA study were clinically obese. Strategies to help address this, including exercise programmes and cardiac rehabilitation, may help facilitate important long-term lifestyle changes.51 Additionally, a new diagnosis of angina may increase the use of non-pharmacological therapies, including cardiac rehabilitation which may benefit patients with ischaemic heart disease.54,55 After clarifying the diagnosis, patients may be more motivated to pursue important lifestyle changes, including diet, exercise and smoking cessation. We are assessing these and longer-term events according to randomised group at 12 months. In the CorMicA study, we noted significantly lower illness perception scores at 6 months among the intervention arm, representing a less threatening view of illness. Angina reduction and improved quality of life scores could be in part related to better patient understanding and

ang H, Naghavi M, Allen C, et al. Global, regional, and W national life expectancy, all-cause mortality, and causespecific mortality for 249 causes of death, 1980–2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet 2016;388:1459–544. https://doi.org/10.1016/ s0140-6736(14)61682-2; PMID: 27733281. Cook S, Walker A, Hugli O, et al. Percutaneous coronary interventions in Europe: prevalence, numerical estimates, and projections based on data up to 2004. Clin Res Cardiol 2007;96:375–82. https://doi.org/10.1007/s00392-007-0513-0; PMID: 17453137. 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.NEJMoa0907272; PMID: 20220183. Jespersen L, Hvelplund A, Abildstrom SZ, et al. Stable angina pectoris with no obstructive coronary artery disease is associated with increased risks of major adverse cardiovascular events. Eur Heart J 2012;33:734–44. https://doi. org/10.1093/eurheartj/ehr331; PMID: 21911339. Maddox TM, Stanislawski MA, Grunwald GK, et al. Nonobstructive coronary artery disease and risk of myocardial infarction. JAMA 2014;312:1754–63. https://doi. org/10.1001/jama.2014.14681. PMID: 25369489. Tavella R, Cutri N, Tucker G, et al. Natural history of patients with insignificant coronary artery disease. Eur Heart J Qual Care Clin Outcomes 2016;2:117–24. https://doi.org/10.1093/ehjqcco/ qcv034; PMID: 29474626. Ford TJ, Corcoran D, Sidik N, et al. MINOCA: requirement for definitive diagnostic work-up. Heart Lung Circ 2019;28:e4–e6. https://doi.org/10.1016/j.hlc.2018.04.001; PMID: 30654950. Sara JD, Widmer RJ, Matsuzawa Y, et al. Prevalence of coronary microvascular dysfunction among patients with chest pain and nonobstructive coronary artery disease. JACC Cardiovasc Interv 2015;8:1445–53. https://doi.org/10.1016/j. jcin.2015.06.017; PMID: 26404197. Mygind ND, Michelsen MM, Pena A, et al. Coronary microvascular function and cardiovascular risk factors

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a less threatening perception of the illness. Longitudinal studies of other cardiovascular diseases have shown that illness perception is an important predictor of longer-term outcomes, including disability and returning to work.56 The Objective Randomised Blinded Investigation with optimal medical Therapy of Angioplasty in stable angina (ORBITA) trial highlights a placebo effect and we support that the positive diagnosis may be therapeutic in itself.57 Angina symptoms are often subjective and multifactorial in origin, so patient education and validation of symptoms may facilitate further improvement.

Future Directions Our hope is for a personalised medicine approach whereby patients with different angina subtypes, defined by the results of coronary function tests, may benefit from targeted therapy. Further research is needed to determine whether this approach may lead to patient benefits. More widespread invasive testing allows identification of diagnostic subgroups for the development of targeted therapies guided by mechanistic studies. We recently identified systemic vascular abnormalities in patients with MVA and VSA, highlighting a potential therapeutic role for endothelin-receptor antagonists targeting the ETa receptor.58 In addition, Rho-kinase inhibitors represent a potential future therapeutic option with anti-effects in patients with excessive vascular smooth muscle constriction. More research is needed in welldefined patients endotypes (subgroups).

Conclusion Patients with INOCA present a diagnostic and therapeutic challenge to physicians. MVA and/or VSA are the two most common causes of INOCA and may be overlooked using anatomical coronary tests alone. Invasive diagnostic testing permits a positive diagnosis to be made, or excluded, during the patients’ index presentation. Correct diagnosis of the underlying cause of angina permits stratified treatment of the distinct disorders (MVA, VSA or non-cardiac chest pain). CorMicA has shown this approach to be safe, feasible with demonstrable benefit for patients.

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Eur Heart J 2016;37:1504–13. https://doi.org/10.1093/eurheartj/ ehv647; PMID: 26614823. Corcoran D, Ford TJ, Hsu L-Y, et al. Rationale and design of the Coronary Microvascular Angina Cardiac Magnetic Resonance Imaging (CorCMR) diagnostic study: the CorMicA CMR substudy. Open Heart 2018;5:e000924. https://doi.org/10.1136/ openhrt-2018-000924; PMID: 30687508. Akasaka T, Yoshida K, Hozumi T, et al. Comparison of coronary flow reserve between focal and diffuse vasoconstriction induced by ergonovine in patients with vasospastic angina. Am J Cardiol 1997;80:705–10. https://doi.org/10.1016/s00029149(97)00499-2; PMID: 9315573. Nishigaki K, Inoue Y, Yamanouchi Y, et al. Prognostic effects of calcium channel blockers in patients with vasospastic angina – a meta-analysis. Circ J 2010;74:1943–50. https://doi. org/10.1253/circj.cj-10-0292; PMID: 20668353. Lombardi M, Morales MA, Michelassi C, et al. Efficacy of isosorbide-5-mononitrate versus nifedipine in preventing spontaneous and ergonovine-induced myocardial ischaemia. A double-blind, placebo-controlled study. Eur Heart J 1993;14:845–51. https://doi.org/10.1093/eurheartj/14.6.845; PMID: 1681355. Marti V, Ligero C, Garcia J, et al. Stent implantation in variant angina refractory to medical treatment. Clin Cardiol 2006;29:530–3. https://doi.org/10.1002/clc.1; PMID: 17190178. Kajihara H, Tachiyama Y, Hirose T, et al. Eosinophilic coronary periarteritis (vasospastic angina and sudden death), a new type of coronary arteritis: report of seven autopsy cases and a review of the literature. Virchows Arch 2013;462:239–48. https://doi.org/10.1007/s00428-012-1351-7; PMID: 23232800. Szot W, Zajac J, Kubinyi A, Kostkiewicz M. The effects of cardiac rehabilitation on overall physical capacity and myocardial perfusion in women with microvascular angina. Kardiol Pol 2016;74:431–8. https://doi.org/10.5603/ KP.a2015.0198; PMID: 26412475. Anderson L, Thompson DR, Oldridge N, et al. Exercisebased cardiac rehabilitation for coronary heart disease. Cochrane Database Syst Rev 2016:CD001800. https://doi. org/10.1002/14651858.cd001800.pub3; PMID: 26730878. Petrie KJ, Weinman J, Sharpe N, Buckley J. Role of patients’ view of their illness in predicting return to work and functioning after myocardial infarction: longitudinal study. BMJ 1996;312:1191–4. https://doi.org/10.1136/bmj.312.7040.1191; PMID: 8634561. Kirtane AJ. ORBITA2. Circulation 2018;138:1793-6. https://doi. org/10.1161/CIRCULATIONAHA.118.035331; PMID: 29789301. Ford TJ, Rocchiccioli P, Good R, et al. Systemic microvascular dysfunction in microvascular and vasospastic angina. Eur Heart J 2018;39:4086–97. https://doi.org/10.1093/eurheartj/ehy529; PMID: 30155438.

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Coronary

Diagnosis and Management of Anomalous Coronary Arteries with a Malignant Course Christoph Gräni, 1,2 Philipp A Kaufmann, 2 Stephan Windecker 1 and Ronny R Buechel 2 1. Department of Cardiology, Bern University Hospital, Bern, Switzerland; 2. Department of Nuclear Medicine, University Hospital Zurich, Zurich, Switzerland

Abstract Although the prevalence of anomalous coronary artery from the opposite sinus (ACAOS) in the general population is low, more frequent use of invasive and non-invasive imaging to rule out coronary artery disease has seen an increase in absolute numbers of ACAOS. ACAOS are traditionally classified as malignant (with an interarterial course) and benign variants. Malignant variants have been recognised in autopsy studies to be an underlying cause of sudden cardiac death in young athletes. Conversely, it seems that older people with ACAOS are less predisposed to adverse cardiac events. Non-invasive anatomic imaging is complementary to invasive imaging and helps to further identify high-risk anatomic features. Using functional non-invasive perfusion imaging can assess potential ischaemia induced by dynamic compression of malignant ACAOS. Information gained from clinical imaging guides the management of these patients.

Keywords Anomalous coronary artery from the opposite sinus of Valsalva; coronary artery anomaly; sudden cardiac death; non-invasive imaging Disclosure: The authors have no conflicts of interest to declare. Received: 18 January 2019 Accepted: 11 March 2019 Citation: Interventional Cardiology Review 2019;14(2):83–8. DOI: https://doi.org/10.15420/icr.2019.1.1 Correspondence: Christoph Gräni, Non-invasive Cardiac Imaging, Department of Cardiology, Bern University Hospital, Freiburgstrasse 10, 3010 Bern, Switzerland. E: christoph.graeni@insel.ch 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.

Anomalous origin of the coronary artery from the opposite sinus of Valsalva (ACAOS) is a rare inborn disease that is characterised by an anomalous course and/or termination of a native coronary vessel.1,2 The traditional definition of ACAOS differentiates between benign and malignant variants. Malignant ACAOS has an interarterial course (IAC) of the anomalous vessel between the pulmonary artery and the aorta. Benign variants represent all other courses, such as in front of the pulmonary artery (prepulmonic) or a retroaortic course.2 The term malignant originates from autopsy studies in young athletes, where ACAOS with IAC was found to be a potential underlying cause of sudden cardiac death (SCD).3 It is suggested that people with ACAOS and IAC may be at risk for myocardial ischaemia and consecutive arrhythmia, even in the absence of atherosclerotic lesions, as the anomalous vessel is prone to dynamic compression during physical exercise. Beside the classical malignant variant of ACAOS with IAC, other anatomic high-risk features are known, such as a slit-like ostium, acute take-off angle, or an intramural course where the proximal part of the anomalous vessel passes in the tunica media of the aortic wall, with proximal narrowing and an elliptic vessel shape.1,4 The prevalence of ACAOS in the general population is about 1%.5 A recent study from 2018 screened 5,169 children aged between 11 and 18 years old with cardiac MRI (CMR) and showed a prevalence of ACAOS with intramural course of 0.44%.6 In a study from our centre evaluating mainly middle-aged and older patients with suspected coronary artery disease (CAD) undergoing coronary CT angiography (CCTA), 66 of the 5,634 evaluated patients showed an ACAOS. Of these, 36 patients had an ACAOS with IAC – a prevalence of 0.64%.2 Shi et al.

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demonstrated that CCTA outperforms invasive angiography to identify the origin and course of ACAOS due to its high spatial and temporal resolution.7 The 3D visualisation enabled by CCTA makes this imaging modality superior to other techniques such as echocardiography and it has become the primary investigative tool in patients with ACAOS.4 Doctors are seeing more patients with ACAOS because it is detected incidentally with the increasing use of CCTA, echocardiography and CMR to evaluate symptomatic patients. Accurate assessment is crucial to guide the management of affected patients and determine their sports activity, invasive treatment versus surgical correction and medical treatment.

Risk of Adverse Cardiovascular Events in ACAOS It has been reported that strenuous physical exercise is associated with an increased risk of SCD in people with ACAOS. Autopsy studies from the US and Europe have shown an association of sports-related SCD with ACAOS in young athletes.3,8–10 In most of the sports-related SCD cases, ACAOS showed an IAC of the anomalous vessel.11 In a study analysing autopsy findings among young athletes with sports-related SCD in Switzerland, 7% of the cases had ACAOS.12 In large study of young military recruits in the US, left-ACAOS (L-ACAOS) describing take-off of the left coronary artery from the right coronary sinus of Valsalva with IAC of the anomalous vessel, was a frequent underlying cause of SCD.13 Although L-ACAOS is primarily associated with cardiac events, they also occur in people with right-ACAOS (R-ACAOS) with the right coronary artery originating from the left coronary sinus of Valsalva.14 Although there is a risk for SCD among young athletes with

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Coronary Figure 1: A Case of Atypical Chest Pain

This is a case of a middle-aged patient with atypical chest pain. A coronary CT angiography was performed to rule out coronary artery disease. It showed a RCA originating from the left coronary sinus with an interarterial course of the anomalous vessel between the aorta and the pulmonary artery (A, B). A physical stress test using single-photon emission CT was performed to rule out ischaemia due to possible dynamic compression of the anomalous coronary vessel during exercise. There was no perfusion defect detected under maximal stress conditions (heart rate was 112% of maximal predicted heart rate; C) and under rest conditions (D). The anomalous coronary artery was interpreted as a coincidental finding and the patient was conservatively managed. No symptoms were reported at 1-year follow-up. LAD = left anterior descending artery; LCX = left circumflex artery; PA = pulmonary artery; RCA = right coronary artery.

ACAOS, the absolute calculated risk is low. Using data from Maron et al. and Brothers et al., the calculated cumulative risk of SCD over a 20-year period in children and young adults with ACAOS (aged 15–35 years) participating in competitive sports was 6.3% for L-ACAOS and 0.2% for R-ACAOS.10,15,16 Even though these analyses are prone to ascertainment bias as well as underreporting, it does seem that the risk of SCD attributed to ACAOS is far lower than that reported in autopsy series.3,8–10

Pathophysiology of ACAOS The underlying mechanisms of ACAOS leading to adverse cardiac events are not clearly understood. It has been suggested that high-risk anatomic features may contribute to repetitive coronary insufficiency under strenuous physical activity with consecutive ischaemia, scarring and ventricular arrhythmia. The pathomechanism of high-risk anatomic features during physical exercise (when tachycardia and hemodynamic overload induce increased myocardial demand while decreasing coronary flow) include kinking of the acute take-off angled anomalous vessel, lateral compression of the aorta on the intramural segment, intermittent closure of the slit-like orifice and compression of the interarterial segment by the aorta and pulmonary artery. Probably the most threatening feature is the intramural course and its length.3,8,9,13 Therefore, using the differentiation between intramural versus nonintramural might be more accurate than using interarterial versus noninterarterial for the classification of malignant versus benign variants. For some patients with L‐ACAOS who have angina at rest and no relevant coronary artery stenosis, one commonly invoked hypothesis is that coronary spasm causes intermittent narrowing of the artery.17 In clinical practice, spasm is not observed in L‐ACAOS with intramural course unless cannulation during a procedure inadvertently results in trauma.17 In ACAOS with intramural course, the artery is embedded in the aortic tunica media, which cannot cause coronary spasm because it has elastic tissue but no functional smooth muscle cells. Recently, Angelini et al. used acetylcholine to test for endothelial dysfunction in L‐ACAOS patients with suggestive symptoms, especially in prepulmonic and retroaortic cases, which do not exhibit any identifiable mechanism of intrinsic ischaemia. When spasms occurred in such cases, they were usually diffuse, reproduced by intracoronary acetylcholine infusion and

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resolved quickly after administration of nitroglycerine.17 Implementing the recent evidence, a coronary artery anomaly can therefore only be considered benign if beside the non-interarterial course other highrisk features are absent, namely there is no slit-like ostium, a normal take-off angle, no intramural course, no proximal elliptic vessel shape/ proximal narrowing and no evidence of anomalous vessel-induced ischaemia, spasm or scar. Whether the associated risk of ACAOS in young athletes is also applicable to symptomatic middle-aged or older people with newly diagnosed ACAOS among patients undergoing non-invasive imaging to rule out CAD, is unknown. Our group published data from 66 patients with a mean age of 56 (±11) years with unknown coronary anatomy and newly detected ACAOS found by CCTA and compared with their outcome to a cohort score-matched for age, gender, history of coronary revascularisation and segment stenosis. At a median follow-up of 4 years, the occurrence of major adverse cardiac events (MI, revascularisation and cardiac death) were not significantly different between the groups. The annual event rate of ACAOS versus controls was not significantly different and was 4.9% versus 4.8% with a hazard ratio of 0.94 (95%; CI: 0.39–2.28; p=0.89). Similarly, in a subgroup analysis, the annual event rate of ACAOS with IAC (n=40) was not significantly different compared with matched controls (5.2% versus 4.3%). The hazard ratio was 1.01 (95% CI [0.39–2.58]; p=0.99) of ACAOS with IAC.18 Only three patients underwent surgery and the other patients were treated conservatively. It is unclear whether older patients with ACAOS are less susceptible to adverse cardiac events or whether a selection bias towards low-risk patients who survived beyond early adulthood may have influenced our results. Although our analysis represents the largest study of outcomes, the patient number is still small. Nevertheless, it may be hypothesised that with ageing for cardiovascular adverse events due to ACAOS becomes less relevant against the background of the increasing risk of CAD related cardiac events.19 Therefore surgical treatment of ACAOS in this age group might not be mandatory in all cases.20 When analysing a subgroup of this middle-aged population with ACAOS who underwent hybrid imaging with CCTA and single photon emission CT (SPECT), MI or myocardial scar due to ACAOS was rare and was more likely attributable to concomitant CAD.19 When analysing sports behaviour in this age group, we found that in those with newly detected ACAOS, sporting activity at the time of diagnosis and after a median follow-up of 4.2 years did not differ significantly. This was not the case in patients engaged in competitive sports (17.5% versus 12.7%, p=0.62) nor those engaged in recreational sports (58.7% versus 61.9%, p=0.86).21 The IAC of the anomalous vessel did not have an impact either on sport-related symptoms, and outcomes were favorable in all athletes irrespective of surgical correction.21 This emphasises that middle-aged or older people with newly detected ACAOS do not automatically need to restrict sports activity and should be assessed differently compared with younger people.

Diagnosis of ACAOS There is not a typical clinical presentation for ACAOS and in some cases, SCD or aborted SCD is the first presentation. While some patients present with chest pain, syncope or arrhythmia, most are asymptomatic and ACAOS will be detected incidentally during invasive or non-invasive cardiac imaging performed for other reasons, for example because of electrocardiogram changes or heart murmurs. Screening people for ACAOS is not recommended. However, CCTA

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Anomalous Coronary Arteries with a Malignant Course Table 1: Different Anatomic Features and Imaging Modalities for Evaluation of ACAOS Anatomic feature

Rating of imaging methods Possible mechanism used to detect different

of ischaemia

How to diagnose physiological

Correction options

consequence

high-risk features Interarterial course

CCTA/CMR>ICA (IVUS)>TTE

Dynamic compression

Re-implantation, pulmonary artery dislocation, unroofing (if intramural segment is present)

Slit-like ostium

CCTA>ICA (IVUS)>CMR

Valve-like occlusion

Unroofing (if intramural segment is present), re-implantation, potentially PCI

Acute take-off angle

CCTA>CMR>TTE>ICA

Kinking

Intramural course

ICA (IVUS)/CCTA>CMR>TTE

Dynamic compression

Intramural length

ICA (IVUS)/CCTA>CMR>TTE

Dynamic compression

Diastolic proximal narrowing/ elliptic vessel shape

CCTA/ICA (IVUS)>CMR

Dynamic compression under stress

Systolic proximal narrowing/ elliptic vessel shape

ICA (IVUS)>CCTA>CMR

‘Milking’ and dynamic compression in rest and stress

ICA (IVUS) using dobutamine

Arrhythmogenic substrate

Recurrent intermittent ischaemia leading to myocardial scarring

Fibrosis possibly assessable using CMR

SPECT/PET/CMR (using physical stress or dobutamine), alternatively ICA (FFR) using dobutamine or adenosine

Unroofing (if intramural segment is present), re-implantation, potentially PCI

Unroofing, re-implantation, potentially PCI

Unclear, potentially medication (beta-blocker)

CCTA = coronary CT angiography; CMR = cardiac MRI; FFR = fractional flow reserve; ICA = invasive coronary angiography; IVUS = intravascular ultrasound; PCI = percutaneous coronary intervention; SPECT = single photon emission CT; TTE = transthoracic echocardiography.

is the primary imaging tool to evaluate high-risk anatomic features in patients with either a suspected or incidental finding of ACAOS followed by non-invasive ischaemic testing (Figure 1).4 The different anatomic high-risk features, possible pathophysiology and preferred imaging modalities to evaluate ACAOS can be found in Table 1. For non-invasive testing for ischaemia, physical exercise with maximal heart rate is preferred to mimic real-life conditions. Alternatively, an inotropic and chronotropic agent, such as dobutamine stress testing, with SPECT, PET, CMR or echocardiography, can be performed to imitate physical exercise. CMR can be used as an alternative to CCTA to describe high-risk anatomic features. It has a slightly lower spatial resolution than CCTA and it can assess valvular function, ventricular function, regional contractility, and myocardial viability.22 Cardiac catheterisation can be performed in people with ACAOS if the anatomy cannot be defined with non-invasive imaging and in adults with high probability for coexistent CAD. As the standard distribution models of myocardial perfusion territories subtended by coronary arteries do not correspond well with individual anatomy in patients with ACAOS, hybrid imaging, using CCTA/SPECT or CCTA/ PET may help to non-invasively discriminate the impact of ACAOS on myocardial ischaemia from concomitant CAD (Figure 2).19,23 Linsen et al. performed dobutamine stress perfusion CT in a patient with L-ACAOS, but whether this functional imaging modality is a valid alternative for ACAOS needs to be investigated in a larger series with an established standard of reference.24 As an invasive option, the cross-sectional area of stenosis can be most accurately assessed by using intravascular ultrasound (IVUS) or optical coherence tomography (OTC) to depict the exact proximal anatomy of the anomalous vessel.25–27 IVUS is highly sensitive and reveals fundamental information on delicate changes of stenosis severity that phasically change during the cardiac cycle and with

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exercise. Furthermore, fractional flow reserve (FFR) measurement, with the ratio of mean distal (non‐ectopic coronary) pressure to mean aortic pressure using adenosine and/or dobutamine and adrenaline, can help to invasively assess the functional severity of stenosis and ischaemia in patients with ACAOS.25,27,28 However, it must be emphasised that a normal stress test is unable to definitively rule out ACAOS; these tests have a low negative predictive value and are only helpful if they are positive.16 More studies are needed that compare invasive findings made with IVUS with non-invasive findings as this will help us better understand the pathophysiological consequences of ACAOS, which in turn will affect management options.

Management of Patients with ACAOS Overview Treatment options for patients with ACAOS include surgical correction, percutaneous coronary intervention, and medical and conservative treatment with or without sports restriction. The risk calculation and decision for treatment are difficult as there is no uniform way to stratify these patients. In patients with ACAOS and IAC who have symptoms such as chest pain, syncope, ventricular arrhythmia, SCD, or aborted SCD, and/or the presence of ischaemia on stress testing should be restricted from competitive sports and should undergo surgical or percutaneous correction. Resumption of competitive sports should usually be allowed 3 months after the intervention if they have no inducible ischaemia and no symptoms.29 The treatment dilemma occurs when asymptomatic patients are newly diagnosed with ACAOS, especially when the patient presents with R-ACAOS and IAC and negative stress testing. The dilemma is even more aggravated if the patient presents with a small R-ACAOS and IAC and left coronary artery dominance with only a small amount of left ventricular myocardium at risk.30 In these cases, stress testing would

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Coronary Figure 2: A Case of Anomalous Origin of Left Circumflex and Left Anterior Descending Arteries

Figure 3: A Case of Restrosternal Pressure and Burning

This is a case of an anomalous origin of the LCX and LAD from the RCA with a retroaortic benign vessel course. Hybrid coronary CT angiography with stress single-photon emission CT showed no perfusion defect in the anomalous vessel distribution territory. LAD = left anterior descending artery; LCS = left coronary sinus; LCX = left circumflex artery; NCS = non-coronary sinus; RCA = right coronary artery; RCS = right coronary sinus.

most probably not detect any left ventricular ischaemia, and as right ventricular ischaemia is difficult to assess, clinical presentation and occurrence of stress-induced arrhythmias should be included in the decision-making. In these cases, IVUS and FFR measurement can help to evaluate stenosis and ischaemia.30 The American Heart Association and American College of Cardiology Scientific Statement differentiates between the much higher-risk L-ACAOS with IAC and the lower-risk R-ACAOS with IAC and states that those with R-ACAOS who are asymptomatic can return to competitive sports after exclusion of ischaemia.31 L-ACAOS without IAC and R-ACAOS with intraseptal, prepulmonic or retroaortic courses are generally considered benign with scarce reports of cases with ischaemia.32 These patients are usually not referred for surgery and are not restricted from competitive sports, but stress testing should be negative before allowing them to participate in sports. An extensive discussion regarding sports and the risk and benefits of surgical treatment versus conservative management should take place between the patient, their carers and parents if they are children, and the treating physicians.

Surgical Therapy The most frequently used and established surgical correction-technique is ‘unroofing’, where the intramural segment in the aorta is opened and a neo-ostium is created (Figure 3). This technique is only appropriate for patients with an intramural segment and unroofing corrects the mechanism of dynamic lateral phasic systolic compression of the arterial wall to the anomalous coronary vessel. The goal of unroofing is not to release the possible compression between the great vessels, but to resect the inner wall of the intramural segment. Alternatively, re-implantation of the aberrant coronary artery can be performed, especially when there is little or no intramural component of the anomalous vessel and when two separate ostiae exist.16 Pulmonary artery translocation is another technique used in patients with ACAOS without an intramural course and single coronary artery. The goal of this operation is to decompress the interarterial course of the anomalous vessel by repositioning the pulmonary artery confluence away from the anomalous artery either laterally or anteriorly.16 Bypass surgery is usually not recommended as the rate of bypass graft patency is disappointingly low due to competing flow in the native vessel (Figure 3).4 Although the risk of surgery for patients with ACAOS is very low with excellent outcome at follow-up, the long-term impact of surgery on the coronary arteries is unknown.33,34

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In this case, a 66-year-old man had retrosternal pressure and burning when playing volleyball, hiking or working in his garden. During the treadmill test, he had similar symptoms and the ECG showed non-significant ST depressions. Invasive coronary angiography (A) showed a subtotal occlusion of the proximal LAD and an anomalous origin of the RCA (B). Coronary CT angiography confirmed the subtotal occlusion of the LAD and an RCA originating from the left coronary sinus (C–E) with an interarterial course between the aorta and the pulmonary artery. There was an acute take-off angle (red circle), intramural course with proximal narrowing and elliptic proximal vessel shape. LIMA-LAD bypass grafting was performed (F–G) to treat the subtotal LAD occlusion. Further unroofing of the anomalous RCA vessel was also performed. The intramural segment (H) of the anomalous coronary was unroofed and the common wall debulked and the neo-orifice in the left sinus was created. Bypass grafting of the anomalous vessel was not performed as competitive flow of the native RCA could results in an unfavourable long-term patency of the bypass graft. The patient was symptom-free at followup after 2 years. LA = left atrium; LAD = left anterior descending artery; LIMA = left internal mammary artery; PA = pulmonary artery; RA = right atrium; RCA = right coronary artery.

Percutaneous Coronary Intervention There are no trials available that compare surgery and percutaneous coronary intervention in patients with ACAOS. However, it appears that percutaneous coronary intervention is a safe and successful alternative in patients with R-ACAOS.35 In a study including 42 patients with R-ACAOS, percutaneous coronary intervention was successfully

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Anomalous Coronary Arteries with a Malignant Course performed in all cases and correlated with improved symptoms at more than one-year follow-up in the majority of patients. No ACAOSrelated deaths occurred. The in-stent restenosis rate was four out of 30 (13%) at a mean follow-up time of 5 years.35 Long-term follow-up data for this procedure in adults are limited. A percutaneous intervention of ACAOS is not advisable for children because they are still growing, which presents safety issues.

Medical Therapy It is unclear whether beta-blockers can be used as an alternative therapy compared to surgical or interventional procedure. In case reports and in a series of 56 middle-aged/older people with ACAOS who were treated conservatively with beta-blockers, no SCD was observed at 5-year follow-up.20,36 However, these were only R-ACAOS variants and no evidence is available for young people. It is unknown whether patients with an arrhythmogenic substrate due to an ACAOS may benefit from a beta-blocker therapy. The treatment plan for people with ACAOS should be based on an interdisciplinary decision made between the treating physician, patient, cardiovascular imaging experts, cardiologists and heart surgeons depending on symptoms, age, sports behaviour, anatomic features of ACAOS and ischaemia testing. Follow-up for patients with ACAOS is recommended as short- and mid-term complications may occur, depending on the procedure that was performed. After surgical intervention, aortic valve regurgitation, aortic stenosis, re-stenosis of the anomalous vessel, and ischaemic changes on postoperative provocative testing may occur.37,38

ngelini P. Coronary artery anomalies: an entity in search A of an identity. Circulation 2007;115:1296–305. https://doi. org/10.1161/CIRCULATIONAHA.106.618082; PMID: 17353457. 2. Grani C, Benz DC, Schmied C, et al. Prevalence and characteristics of coronary artery anomalies detected by coronary computed tomography angiography in 5,634 consecutive patients in a single centre in Switzerland. Swiss Med Wkly 2016;146:w14294. https://doi.org/10.4414/ smw.2016.14294; PMID: 27124568. 3. Maron BJ, Haas TS, Ahluwalia A, et al. Demographics and epidemiology of sudden deaths in young competitive athletes: from the United States National Registry. Am J Med 2016;129:1170–7. https://doi.org/10.1016/ j.amjmed.2016.02.031; PMID: 27039955. 4. Grani C, Buechel RR, Kaufmann PA, Kwong RY. Multimodality imaging in individuals with anomalous coronary arteries. JACC Cardiovasc Imaging 2017;10:471–81. https://doi.org/10.1016/ j.jcmg.2017.02.004; PMID: 28385257. 5. Yamanaka O, Hobbs RE. Coronary artery anomalies in 126,595 patients undergoing coronary arteriography. Cathet Cardiovasc Diagn 1990;21:28–40. https://doi.org/10.1002/ccd.1810210110; PMID: 2208265. 6. Angelini P, Cheong BY, Lenge De Rosen VV, et al. High-risk cardiovascular conditions in sports-related sudden death: prevalence in 5,169 schoolchildren screened via cardiac magnetic resonance. Tex Heart Inst J 2018;45:205–13. https:// doi.org/10.14503/THIJ-18-6645; PMID: 30374227. 7. Shi H, Aschoff AJ, Brambs HJ, Hoffmann MH. Multislice CT imaging of anomalous coronary arteries. Eur Radiol 2004;14:2172–81. https://doi.org/10.1007/s00330-004-2490-2; PMID: 15490179. 8. Lorenz EC, Mookadam F, Mookadam M, et al. A systematic overview of anomalous coronary anatomy and an examination of the association with sudden cardiac death. Rev Cardiovasc Med 2006;7:205–13. PMID: 17224864. 9. Basso C, Maron BJ, Corrado D, Thiene G. Clinical profile of congenital coronary artery anomalies with origin from the wrong aortic sinus leading to sudden death in young competitive athletes. J Am Coll Cardiol 2000;35:1493–501. https://doi.org/10.1016/S0735-1097(00)00566-0; PMID: 10807452. 10. Maron BJ, Doerer JJ, Haas TS, et al. Sudden deaths in young competitive athletes: analysis of 1866 deaths in the United States, 1980–2006. Circulation 2009;119:1085–92. https://doi. org/10.1161/CIRCULATIONAHA.108.804617; PMID: 19221222. 11. Maron BJ, Shirani J, Poliac LC, et al. Sudden death in young competitive athletes. Clinical, demographic, and pathological profiles. JAMA 1996;276:199–204. https://doi.org/10.1001/ jama.1996.03540030033028; PMID: 8667563. 12. Grani C, Chappex N, Fracasso T, et al. Sports-related

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13.

14.

15.

16.

17.

18.

19.

20.

21.

22.

The current evidence on therapeutic and follow-up recommendations in patients with ACAOS is scarce and is mainly based on case reports and expert opinions. Prospective randomised trials are lacking but remain difficult to perform due to ethical considerations. In addition, registries or observational trials comparing the different therapeutic techniques, including percutaneous coronary intervention versus surgical treatment are not available. The different therapeutic options should be evaluated in a prospective manner in multicentre studies so that current recommendations can be adapted.

Conclusion ACAOS with IAC of the anomalous vessel is a potential underlying cause of SCD in young athletes. However, middle-aged and older people with newly detected ACAOS seem to be at lower risk for adverse cardiac events and in most cases may be treated conservatively. A precise anatomic description made using invasive and non-invasive imaging modalities and further functional perfusion assessment can help to stratify a patient’s risk. A recommendation to restrict participation in sports and the anatomical correction of the anomaly should only be made after incorporating all available information such as age, type of symptoms, sports behavior and imaging information, and should be individually balanced against the risk of an interventional procedure. If a decision is made towards anatomical correction, unroofing is a safe, established and preferred surgical procedure in patients with ACAOS and intramural course, whereas percutaneous coronary intervention represents an alternative method in selected cases. More evidence is needed to improve risk stratification in this patient group.

sudden cardiac death in Switzerland classified by static and dynamic components of exercise. Eur J Prev Cardiol 2016;23:1228–36. https://doi.org/10.1177/2047487316632967; PMID: 26915579. Eckart RE, Scoville SL, Campbell CL, et al. Sudden death in young adults: a 25-year review of autopsies in military recruits. Ann Intern Med 2004;141:829–34. https://doi. org/10.7326/0003-4819-141-11-200412070-00005; PMID: 15583223. Jo Y, Uranaka Y, Iwaki H, et al. Sudden cardiac arrest: associated with anomalous origin of the right coronary artery from the left main coronary artery. Tex Heart Inst J 2011;38:539–43. PMID: 22163129. Brothers J, Carter C, McBride M, et al. Anomalous left coronary artery origin from the opposite sinus of Valsalva: evidence of intermittent ischemia. J Thorac Cardiovasc Surg 2010;140:e27-9. https://doi.org/10.1016/j.jtcvs.2009.06.029; PMID: 19717171. Brothers JA, Frommelt MA, Jaquiss RDB, et al. Expert consensus guidelines: anomalous aortic origin of a coronary artery. J Thorac Cardiovasc Surg 2017;153:1440–57. https://doi. org/10.1016/j.jtcvs.2016.06.066; PMID: 28274557. Angelini P, Uribe C. Anatomic spectrum of left coronary artery anomalies and associated mechanisms of coronary insufficiency. Catheter Cardiovasc Interv 2018;92:313–21. https:// doi.org/10.1002/ccd.27656; PMID: 30051621. Grani C, Benz DC, Steffen DA, et al. Outcome in middle-aged individuals with anomalous origin of the coronary artery from the opposite sinus: a matched cohort study. Eur Heart J 2017;38:2009–16. https://doi.org/10.1093/eurheartj/ehx046; PMID: 28329166. Grani C, Benz DC, Schmied C, et al. Hybrid CCTA/SPECT myocardial perfusion imaging findings in patients with anomalous origin of coronary arteries from the opposite sinus and suspected concomitant coronary artery disease. J Nucl Cardiol 2017;24:226–34. https://doi.org/10.1007/s12350015-0342-x; PMID: 26711099. Kaku B, Shimizu M, Yoshio H, et al. Clinical features of prognosis of Japanese patients with anomalous origin of the coronary artery. Jpn Circ J 1996;60:731–41. https://doi. org/10.1253/jcj.60.731; PMID: 8933235. Grani C, Benz DC, Steffen DA, et al. Sports behavior in middleaged individuals with anomalous coronary artery from the opposite sinus of Valsalva. Cardiology 2018;139:222–30. https:// doi.org/10.1159/000486707; PMID: 29486483. Ripley DP, Saha A, Teis A, et al. The distribution and prognosis of anomalous coronary arteries identified by cardiovascular magnetic resonance: 15-year experience from two tertiary centres. J Cardiovasc Magn Reson 2014;16:34. https://doi. org/10.1186/1532-429X-16-34; PMID: 24886614.

23. G rani C, Benz DC, Possner M, et al. Fused cardiac hybrid imaging with coronary computed tomography angiography and positron emission tomography in patients with complex coronary artery anomalies. Congenit Heart Dis 2017;12:49–57. https://doi.org/10.1111/chd.12402; PMID: 27539240. 24. Linsen PVM, Kofflard MJM, Lam SW, Kock M. First in humans: dobutamine stress cardiac computed tomography to evaluate dynamic compression of an anomalous left coronary artery. Coron Artery Dis 2018;29:607–8. https://doi.org/10.1097/ MCA.0000000000000641; PMID: 29923848. 25. Agrawal H, Molossi S, Alam M, et al. Anomalous coronary arteries and myocardial bridges: risk stratification in children using novel cardiac catheterization techniques. Pediatr Cardiol 2017;38:624–30. https://doi.org/10.1007/s00246-016-1559-4; PMID: 28214966. 26. Unzue L, Garcia E, Lopez-Melgar B, Agudo-Quilez P. Percutaneous treatment of an anomalous left main arising from the opposite sinus with subpulmonic course. Cardiovasc Revasc Med 2018;19(5 Pt B):632–7. https://doi.org/10.1016/ j.carrev.2018.01.008; PMID: 29506965. 27. Driesen BW, Warmerdam EG, Sieswerda GT, et al. Anomalous coronary artery originating from the opposite sinus of Valsalva (ACAOS), fractional flow reserve- and intravascular ultrasound-guided management in adult patients. Catheter Cardiovasc Interv 2018 [Epub ahead of print] https://doi. org/10.1002/ccd.27578; PMID: 29521471. 28. Agrawal H, Qureshi AM, Alam M, et al. Anomalous aortic origin of a coronary artery with an intraseptal course: novel techniques in haemodynamic assessment. BMJ Case Rep 2018; pii: bcr-2018-225707. https://doi.org.10.1136/bcr-2018-225707; PMID: 29960972. 29. Warnes CA, Williams RG, Bashore TM, et al. ACC/AHA 2008 guidelines for the management of adults with congenital heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (writing committee to develop guidelines on the management of adults with congenital heart disease). Circulation 2008;118:e714–833. https://doi.org.10.1136/bcr2018-225707; PMID: 18997169. 30. Angelini P, Uribe C. Symptomatic right coronary anomaly with dynamic systolic intramural obliteration and isolated right ventricular ischemia. Catheter Cardiovasc Interv 2018;93:445-447 https://doi.org.10.1002/ccd.28028; PMID: 30585420. 31. Van Hare GF, Ackerman MJ, Evangelista JA, et al. Eligibility and disqualification recommendations for competitive athletes with cardiovascular abnormalities: Task Force 4: Congenital Heart Disease: A Scientific Statement from the American Heart Association and American College of Cardiology. J Am Coll Cardiol 2015;66:2372–84. https://doi.org/10.1016/ j.jacc.2015.09.036; PMID: 26542660.

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Coronary 32. K othari SS, Talwar KK, Venugopal P. Septal course of the left main coronary artery from right aortic sinus and ventricular tachycardia. Int J Cardiol 1998;66:207–9. https://doi. org/10.1016/S0167-5273(98)00218-6; PMID: 9829337. 33. Krasuski RA, Magyar D, Hart S, et al. Long-term outcome and impact of surgery on adults with coronary arteries originating from the opposite coronary cusp. Circulation 2011;123:154–62. https://doi.org/10.1161/CIRCULATIONAHA.109.921106; PMID: 21200009. 34. Mery CM, De Leon LE, Molossi S, et al. Outcomes of surgical intervention for anomalous aortic origin of

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a coronary artery: A large contemporary prospective cohort study. J Thorac Cardiovasc Surg 2018;155:305–19.e4. https://doi.org/10.1016/j.jtcvs.2017.08.116; PMID: 29074047. 35. Angelini P, Uribe C, Monge J, et al. Origin of the right coronary artery from the opposite sinus of Valsalva in adults: characterization by intravascular ultrasonography at baseline and after stent angioplasty. Catheter Cardiovasc Interv 2015;86:199–208. https://doi.org/10.1002/ccd.26069; PMID: 26178792. 36. Bixby MB. Successful medical management of a patient with

an anomalous right coronary artery who declined surgery. Am J Crit Care 1998;7:393–4. PMID: 9740890. 37. N ees SN, Flyer JN, Chelliah A, et al. Patients with anomalous aortic origin of the coronary artery remain at risk after surgical repair. J Thorac Cardiovasc Surg 2018;155:2554–64.e3. https://doi.org/10.1016/j.jtcvs.2017.12.134; PMID: 29526358. 38. Brothers JA, McBride MG, Seliem MA, et al. Evaluation of myocardial ischemia after surgical repair of anomalous aortic origin of a coronary artery in a series of pediatric patients. J Am Coll Cardiol 2007;50:2078–82. https://doi.org/10.1016/ j.jacc.2007.06.055; PMID: 18021877.

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Coronary Artery Vasospasm Induced by 5-fluorouracil: Proposed Mechanisms, Existing Management Options and Future Directions Jun Hua Chong 1 and Arjun K Ghosh 1,2 1. Cardio-Oncology Service, Barts Heart Centre, St Bartholomew’s Hospital, London, UK; 2. Cardio-Oncology Service, University College London Hospital, Hatter Cardiovascular Institute, London, UK

Abstract Cardiovascular disease and cancer are leading contributors to the global disease burden. As a result of cancer therapy-related cardiotoxicities, cardiovascular disease results in significant morbidity and mortality in cancer survivors and patients with active cancer. There is an unmet need for management of cardio-oncology conditions, which is predicted to reach epidemic proportions, and better understanding of their pathophysiology and treatment is urgently required. The proposed mechanisms underlying cardiotoxicity induced by 5-fluorouracil (5-FU) are vascular endothelial damage followed by thrombus formation, ischaemia secondary to coronary artery vasospasm, direct toxicity on myocardium and thrombogenicity. In patients with angina and electrocardiographic evidence of myocardial ischaemia due to chemotherapy-related coronary artery vasospasm, termination of chemotherapy and administration of calcium channel blockers or nitrates can improve ischaemic symptoms. However, coronary artery vasospasm can reoccur with 5-FU re-administration with limited effectiveness of vasodilator prophylaxis observed. While pre-existing coronary artery disease may increase the ischaemic potential of 5-FU, cardiovascular risk factors do not appear to completely predict the development of cardiac complications. Pharmacogenomic studies and genetic profiling may help predict the occurrence and streamline the treatment of 5-FU-induced coronary artery vasospasm. Echocardiographic measures such as the Tei index may help detect subclinical 5-FU cardiotoxicity. Further research is required to explore the cardioprotective effect of agents such as coenzyme complex, GLP-1 analogues and degradation inhibitors on 5-FU-induced coronary artery vasospasm.

Keywords 5-fluorouracil, capecitabine, coronary artery vasospasm, calcium channel blockers, verapamil, diltiazem Disclosure: The authors have no conflicts of interest to declare. Received: 25 February 2019 Accepted: 17 April 2019 Citation: Interventional Cardiology Review 2019;14(2):89–94. DOI: https://doi.org/10.15420/icr.2019.12 Correspondence: Arjun K Ghosh, Barts Heart Centre, St Bartholomew’s Hospital, West Smithfield, London, EC1A 7BE, UK. E: arjun.ghosh@bartshealth.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.

Cardiovascular disease is the leading cause of morbidity and mortality worldwide.1 The WHO estimates that 17 million people die each year of cardiovascular disease, about 30% of all deaths.2 Cancer is the second leading cause of death globally and is associated with 9 million deaths each year.3 According to the WHO, the incidence of cancer is expected to rise by about 70% over the next 20 years.4 Half of those diagnosed with cancer will survive for at least a decade, but this survival rate is expected to increase significantly in future and worsen the burden of cancer-related complications experienced by the global population.5,6 Significant progress in cancer therapy has greatly improved the mortality of cancer patients, with non-malignant comorbid conditions becoming important determinants of their quality of life and overall survival.7 Among this heterogeneous group of comorbid conditions, cardiovascular diseases are a major contributor to overall morbidity and mortality in cancer survivors and patients with active cancer.8

Factors Contributing to the Clinical Entity of Cardio-oncology Heart disease and cancer share common risk factors in an ageing population and are further linked through cardiotoxic effects of

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contemporary cancer treatment.9–11 Many cancer patients have subclinical cardiovascular disease, which can be worsened by the pro-inflammatory and hypercoagulable states associated with cancer, although precisely defining cardiotoxicity can be a challenge.12–15

Pathophysiology of Accelerated Atherosclerosis and Plaque Rupture in Cardio-oncology Many cancer therapies cause acute endothelial damage, vasospasm, platelet-platelet activation and aggregation, and attraction of elevated low-density lipoprotein cholesterol particles.16 This can lead to formation of potentially unstable lipid-rich coronary plaques and to the initiation and acceleration of the atherosclerosis process.17 When these lipid-rich plaques result in haemodynamically significant flow-limiting stenosis, symptoms of cardiovascular ischaemia such as angina can ensue.16 Vulnerable plaques, composed of a thin fibrous cap and large lipid cores (also known as thin-cap fibroatheromas), are also more susceptible to rupture with acute thrombus formation, resulting in acute coronary syndromes (ACS).17–19 Optimum management of ischaemic heart disease is necessary for this complex group of cardio-oncology patients to improve their overall outcome and quality of life.

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Coronary The relatively new, unmet medical need for management of chemotherapy- and radiotherapy-induced cardiovascular disease is predicted to reach epidemic proportions in the near future.6,20,21

Cardiotoxicity Secondary to 5-fluorouracil and Capecitabine Cardiac ischaemia associated with chemotherapy has been linked to several antineoplastic agents and is multifactorial in aetiology.22 Coronary artery vasospasm is one of the most commonly reported effects of cancer therapy that can lead to myocardial ischaemia or infarction.23,24 The chemotherapy agent 5-fluorouracil (5-FU) or its oral pro-drug capecitabine can result in coronary vascular endothelial dysfunction causing coronary artery spasm, and possibly coronary thrombosis, with a wide range of reported incidence between 1% and 68%.25,26 These agents are used to treat solid cancers, including gastrointestinal, breast, head, neck and pancreatic cancers.27 These drugs have also been shown to be associated with myocardial infarction or malignant ventricular arrhythmias.28 Capecitabine is converted to 5-FU in a three-step process involving several enzymes.29 The last stage is catalysed by thymidine phosphorylase.29 Many body tissues express thymidine phosphorylase, but this enzyme is expressed in higher concentrations in some carcinomas than in the surrounding normal tissues.29 Based on this theory, the concentration of 5-FU at the tumour site should be increased compared to the concentration of 5-FU in healthy tissues, resulting in fewer side-effects involving healthy tissue.29 The incidence of capecitabine-associated cardiac side-effects is 3–35%, gathered from the few studies of capecitabine cardiotoxicity.26,28,30–32 Case reports of cardiotoxicity after administration of capecitabine are similar to intravenous 5-FU treatment, with the predominant symptom being chest pain.33–35 Other less frequent adverse effects are cardiac arrhythmias, myocardial infarction, heart failure, cardiogenic shock and sudden death.36–38 Chest pain onset is often abrupt during infusion of 5-FU, but can also be delayed, presenting within the first 72 hours after 5-FU administration.38,39 Often, angina is accompanied by ECG changes including ST depression and prolonged repolarisation abnormalities.38 Cardiac enzymes are infrequently elevated in angina (12% of cases),and echocardiography can show regional or global hypokinesis that usually return to baseline within 48 hours of 5-FU cessation.38 Significant coronary artery disease and acute plaque rupture is usually ruled out on coronary angiography, which leads to the consideration of coronary artery vasospasm.33,40 In a review of 377 patients with 5-FU-induced cardiotoxicity, cardio vascular risk factors such as smoking, diabetes, hypercholesterolaemia and family history of heart disease were found in 37% of the patients. Smoking was the most common risk factor among these groups of patients.38 Previous or concomitant radiation therapy may play a role in 5-FU-induced cardiac toxicity as radiation can cause small-vessel thrombosis. 5-FU is a radiosensitiser and may enhance radiationinduced thrombosis.41,42 There is a higher incidence of angina with administration through continuous infusion compared to bolus infusion.38,43 It is unclear if

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this effect is dose-dependent, and although cessation of 5-FU results in resolution of angina, symptoms have been reported to last up to 12 hours.44 Re-initiation of 5-FU has been associated with increased incidence of angina with serious complications including acute coronary syndrome, hypotension, cardiac failure, and even death.38,43 While the causative relationship is unclear, endothelin-1 levels have been noted to be elevated in angina patients with 5-FU infusion.43 Patients with known pre-existing history of coronary artery disease also have a higher incidence of angina,and are considered to have an increased risk of developing cardiac ischaemia.16,45 In addition to high doses of 5-FU, prior mantle radiation, or simultaneous administration of another cardiotoxic chemotherapeutic agent are factors that can contribute to development of cardiac ischaemia in patients treated with antimetabolite drugs.46,47 In one large study, myocardial ischaemia was reported in 4% of patients receiving highdose, continuous infusion of 5-FU.48 However, the failure of ergonovine and 5-FU to produce direct vasospasm during cardiac catheterisation has questioned the hypothesis of abnormal vasoreactivity being the predominant mechanism causing 5-FU associated myocardial ischaemia.24,49 Age of the patient did not seem to influence the occurrence of cardiotoxicity.45

Proposed Pathophysiological Mechanisms of 5-fluorouracil-induced Cardiotoxicity The pathophysiological mechanisms underlying 5-FU-induced cardiotoxicity remain undefined.36,50,51 Several mechanisms have been proposed, including vascular endothelial damage followed by coagulation, ischaemia secondary to coronary artery spasm, direct toxicity on the myocardium and thrombogenicity.27 The theory of 5-FU-induced vasospasm resulting in myocardial ischaemia has been proposed in the context of failure of coronary angiography in general to show fixed stenoses in patients with acute 5-FU-induced cardiotoxicity.52–55 In a few cases, coronary artery vasospasm has been demonstrated during coronary angiography.55–58 In the study of the effect of 5-FU on the peripheral vasculature, vasoconstriction of the brachial artery was noted to appear immediately after 5-FU injection.59,60 While vasoconstriction has been observed immediately after 5-FU injection, clinical cardiotoxicity often presents at the end of the infusion, or even hours to days later.36 Moreover, cardiotoxicity may occur only after several cycles of 5-FU or its oral pro-drug capecitabine. Cwikiel et al. examined the endothelium of small arteries from rabbits after incubation with 5-FU.61 Vessel wall and endothelial cell contraction, cell oedema, cytolysis, occurrence of denuded areas, platelet adhesion/aggregation and fibrin formation were evaluated. The findings support the hypothesis that direct cytotoxic mechanisms on endothelial cells predominate, whereas thrombogenic features play a minor role.62

Endothelial Nitric Oxide Synthase One proposed mechanism for the pathophysiology of 5-FU-induced coronary spasm is that it exerts toxic effects on the vascular endothelium through endothelial nitric oxide synthase (eNOS), leading to coronary spasm and endothelium-independent vasoconstriction via protein kinase C.63 Nitric oxide (NO) produced by eNOS and its

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Coronary Artery Vasospasm Induced by 5-fluorouracil interaction with serine/threonine protein kinase Akt/PKB, with caveolin and calmodulin is a key determinant of cardiovascular tone.64–66

Endothelin-1 Raised plasma levels of endothelin-1 were observed by Thyss et al. in patients receiving 5-FU, especially in those experiencing 5-FU-induced cardiotoxicity.67 This observation may support the hypothesis of 5-FU-induced vasoconstriction.27 Endothelin-1 is a potent vasoconstrictor, which is produced by endothelial cells, cardiomyocytes and cardiac fibroblasts, as well as several noncardiac tissues such as the lungs.68,69 Endothelin-1 plays a regulatory role in coronary vascular resistance and myocardial capillary blood flow in coronary artery disease states.69–71 Hypoxia, ischaemia or shear stress induces vascular endothelial cells to synthesise and secrete endothelin-1.68 Endothelin-1 in turn is synthesised from the precursor peptide big endothelin.68 Salepci et al. found a trend towards increased big endothelin levels in the plasma of 5-FU treated patients, but this trend was not restricted to patients who experienced vasoconstriction.59 To further understand the role of endothelins in 5-FU-induced cardiotoxicity, the cellular source of endothelin-1 and the effect of endothelin-1 on vasomotor tone during the infusion of 5-FU should be further studied.27

This clinical effect is, in turn, inconsistent in 5-FU-induced coronary artery vasospasm. In a study by Mosseri et al., rabbit aorta rings were pre-treated in vitro with verapamil and diltiazem prior to 5-FU exposure.72 Of note, there was no observed effect of the calcium channel blockers verapamil and diltiazem on vasospasm.72 The clinical translation of this study remains to be determined.

Treatment Options for 5-fluorouracil-induced Coronary Artery Spasm While pre-existing coronary artery disease may increase the ischaemic potential of 5-FU, the presence of cardiac risk factors does not appear to completely predict the development of adverse cardiac sideeffects.78 Nitrates and calcium channel blockers have been used to treat and prevent coronary artery spasm in high-risk patients.79 In patients with angina and electrocardiographic evidence of myocardial ischaemia due to coronary artery vasospasm while receiving chemotherapy, termination of therapy and administration of calcium channel blockers or oral nitrates can improve the ischaemic symptoms.16 These patients might have clinical reoccurrence of coronary vasospasm with subsequent 5-FU re-exposure.16 Although treatment with vasodilators have been proposed as prophylaxis against coronary artery vasospasm, limited effectiveness of this prophylactic therapy has been observed.80

Protein Kinase C Staurosporine is a protein kinase C (PK-C) inhibitor and pre-treatment with it reduced 5-FU-induced vasoconstriction.72 Phorbol 12,13-dibutyrate is an activator of PK-C and pre-treatment with it increased the magnitude of 5-FU-induced vasoconstriction by 23 times.72

Acetylcholine Acetylcholine induces vasodilation through the NO-cGMP pathway.73 Acetylcholine is endothelium-dependant and hence intact endothelial cells are a requirement for acetylcholine-induced vasodilation.73 In fact, in the absence of endothelial cells, acetylcholine actually leads to vasoconstriction.73 It seems unlikely that the mechanism through which 5-FU causes functional vasoconstriction is through impaired vasodilatory response, as it has been observed that both acetylcholineinduced vascular relaxation and vascular relaxation by glyceryl nitrate were intact during 5-FU infusion.27 More research is required in this area to further delineate pathophysiological mechanisms behind proposed 5-FU-induced coronary artery vasospasm.

Proposed Management of 5-fluorouracil-induced Cardiotoxicity Controversy Over the Use of Calcium Channel Blockers Prophylactic nitrates and calcium channel blockers do not appear to reduce chest pain incidence, and vasospasm has not been clearly seen on coronary angiography.38 5-FU has been found to increase the expression of thioredoxininteracting protein (TXNIP).74 A number of studies have shown that verapamil and diltiazem suppress TXNIP expression.75 Chen et al. reported that verapamil and diltiazem reduced TXNIP transcription and protein levels in cultured cardiomyocytes in the presence of raised glucose concentrations.76 Subsequently, the same group also demonstrated the attenuation of the pro-apoptotic effects of TXNIP by verapamil.77 It may be appropriate therefore to determine whether TXNIP suppression might contribute to the clinical effectiveness of calcium channel blockers in inhibiting coronary artery spasm.75

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Due to the potential for arrhythmias, ECG monitoring is recommended if there is any evidence for cardiac side-effects during treatment.81 Subsequent to non-invasive testing and risk stratification for the presence of coronary artery disease, coronary angiography should be considered in patients who develop coronary artery vasospasm. Prophylactic treatment with verapamil and nitrates could be considered for patients with coronary artery disease and patients who had already been symptomatic following 5-FU administration.82 Due to the severity of cardiac side-effects, including sudden cardiac death, early discontinuation of 5-FU and modification of the therapeutic regimen should be taken into account.47,57,83,84 Kinhult et al. showed that antithrombotic treatment with dalteparin can protect against thrombogenic effects of 5-FU, secondary to its direct toxic effect on the vascular endothelium.51 Spasmogenic drugs, e.g. beta-blockers, should be avoided. This hypothesis is supported by a few reports.85–89 Taking haematological disorders into account, inhibition of platelet aggregation potentially could be helpful as well. Patients developing ischaemic events usually have recurrences if the drug is subsequently administered, so consideration must be given to withholding future 5-FU therapy if a patient develops ischaemic events while on the drug.47,90

Developing and Experimental Treatment Options In a 54-patient study by Zhang et al., coenzyme complex was found to decrease cardiotoxicity when combined with chemotherapy in treating elderly patients with gastrointestinal cancer.91 Coenzyme complex was postulated to confer cardioprotection through cell membrane stabilisation, enhanced mitochondrial energy production, antioxidant action and favourable effects on metabolism of longchain fatty acids. Further research is required in this area to explore the cardioprotective effect of coenzyme complex on 5-FU-induced coronary artery vasospasm.

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Coronary In a cell-based study by Altieri et al., GLP-1 counteracted 5-FU-initiated endothelial cell senescence and reduced eNOS and SIRT-1 expression, with this protection being mediated by GLP-1 receptor, ERK1/2 and, possibly, PKA and PI3K.92 This group noted that 5-FU caused endothelial cell senescence and dysfunction, which may contribute to its cardiovascular side-effects.92 5-FU-induced endothelial cell senescence was found to be prevented by GLP-1, raising the possibility of using GLP-1 analogues and GLP-1 degradation inhibitors to treat 5-FU and capecitabine induced cardiotoxicity.92 Since it is known that the complex system of eNOS regulation is crucial for the vascular tone, Hayward et al. addressed the hypothesis that regular physical activity may help improve endothelium-dependent vasodilation after exposure to 5-FU.93 Rats were stratified into one group with regular exercise training and one sedentary group. After 8 weeks of physical training, aortic rings were obtained and used to assess contractile and relaxation characteristics. Exercise training resulted in increased maximal endothelium-dependent vasorelaxation to acetylcholine after norepinephrine-induced vasoconstriction. Rings obtained from exercise-trained animals demonstrated enhanced vasorelaxation in response to acetylcholine after 5-FU-induced vasoconstriction when compared with rings obtained from sedentary animals. In addition, exercise training enhanced eNOS protein content and eNOS enzyme activity. Thus, exercise training enhanced endothelium-dependent vasorelaxation after 5-FU-induced vasoconstriction. This could have clinical implications if translated into human studies.

Future Directions Heart-type fatty acid-binding protein (h-FABP) and the myocardial performance index have been suggested to have the potential to be useful in the early detection of ischaemic coronary vasospasm induced by 5-FU.94 h-FABP is a small unbound cytoplasmic protein that is present at high levels in myocardial cells and released into the blood circulation within minutes of ischaemia.94 Myocardial performance index, also known as the Tei index, is a Doppler index that can evaluate left ventricular systolic and diastolic functions concurrently and can assist in detecting subtle changes in cardiac function.94 Turan et al. studied 32 cancer patients receiving their first 5-FU-based chemotherapy were studied.94 Prior to chemotherapy and 24 hours after the initiation of chemotherapy, all patients underwent echocardiography. The authors measured h-FABP and troponin I (TnI) levels at different time points during the first 24 hours of 5-FU administration. Post-infusion echocardiography revealed worsening in the Tei index. Clinically overt cardiotoxicity was evident in four members (12.5%) of the study group. h-FABP and TnI levels were within normal ranges throughout. These results suggest that the Tei index can be proposed as a sensitive indicator of occult 5-FU cardiotoxicity. Pharmacogenomics studies have shed insight into the correlations of drug efficacy and toxicity with patient genome variations.95 5-FU cardiotoxicity can potentially be modulated by being selective in

enjamin EJ, Muntner P, Alonso A, et al. Heart disease and B stroke statistics-2019 update: a report from the American Heart Association. Circulation 2019;139:e56-e528. https://doi. org/10.1161/CIR.0000000000000659; PMID: 30700139. Balukumar P, Maung-U K, Jagadeesh G. Prevalence and prevention of cardiovascular disease and diabetes mellitus. Pharmacol Res 2016;113:600–9. https://doi.org/10.1016/j.

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the treatment regimen administered in each patient with the help of genetic profiling.95 Several studies have highlighted genetic polymorphisms in DPYD, TYMS, MTHFR and OPRT as potential risk factors for serious toxicity.95 Determination of polymorphisms in xenobiotic metabolising enzymes through genetic profiling before 5-FU administration might suggest new and individualised strategies for optimising chemotherapy safety.95 Oral derivatives and pro-drugs have been developed to provide an alternative route of 5-FU administration.95 Differences have been reported regarding the adverse effect profiles of intravenous 5-FU and its oral pro-drug. The impact of genetic variations on the risk of severe toxicity may potentially differ between the two administration forms.95 Further investigation is required to understand the relationship between individual DPYD variants and the different 5-FU-based chemotherapy regimens.95

Conclusion Cardiovascular disease and cancer are the two leading causes of disease burden in the world. As a result of cardiotoxicities of cancer therapies and the prevalence of cardiovascular comorbidity, cardiovascular diseases are a major contributor to overall morbidity and mortality in cancer survivors and patients with active cancer. There is an unmet medical need for management of cancer therapyinduced cardiovascular disease which is predicted to reach epidemic proportions in the near future and better understanding of the pathophysiology and treatment of cardio-oncology conditions are urgently required. High-dose 5-FU or its oral pro-drug capecitabine is thought to cause coronary vascular endothelial dysfunction resulting in coronary artery spasm, and possibly coronary thrombosis. The pathophysiological mechanisms underlying 5-FU-induced cardiotoxicity remain undefined with several proposed mechanisms being vascular endothelial damage followed by coagulation, ischaemia secondary to coronary artery spasm, direct toxicity on the myocardium and thrombogenicity. In patients with angina and electrocardiographic evidence of myocardial ischaemia due to coronary artery vasospasm while receiving chemotherapy, termination of therapy and administration of calcium channel blockers or oral nitrates can improve the ischaemic symptoms. Coronary artery spasm can, however, reoccur with 5-FU re-administration with limited effectiveness of vasodilator prophylaxis observed. While pre-existing coronary artery disease may increase the ischaemic potential of 5-FU, the presence of cardiac risk factors does not appear to completely predict the development of adverse cardiac side-effects. Pharmacogenomic studies and genetic profiling may help predict the development of 5-FU-induced coronary artery vasospasm. Further research is required to explore the cardioprotective effect of agents such as coenzyme complex, GLP-1 analogues and degradation inhibitors on 5-FU-induced coronary artery vasospasm.

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Takotsubo syndrome: an underdiagnosed complication of 5-fluorouracil mimicking acute myocardial infarction. Blood Coagul Fibrinolysis 2013;24:90– 4. https://doi.org/10.1097/MBC.0b013e3283597605; PMID: 23249567. Kim SM, Kwak CH, Lee B, et al. A case of severe coronary spasm associated with 5-fluorouracil chemotherapy. Korean J Intern Med 2012;27:342–5. https://doi.org/10.3904/ kjim.2012.27.3.342; PMID: 23019400. Tsiamis E, Synetos A, Stefanidis C. Capecitabine may induce coronary artery vasospasm. Hellenic J Cardiol 2012;53:320–3. PMID: 22796820. Shah NR, Shah A, Rather A. Ventricular fibrillation as a likely consequence of capecitabine-induced coronary vasospasm. J Oncol Pharm Pract 2012;18:132–5. https://doi. org/10.1177/1078155211399164; PMID: 21321041. Alter P, Herzum M, Soufi M, et al. Cardiotoxicity of 5-fluorouracil. Cardiovasc Hematol Agents Med Chem 2006;4:1–5. PMID: 16529545. Shoemaker LK, Arora U, Rocha Lima CM. 5-fluorouracilinduced coronary vasospasm. 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Coronary

Thrombus Embolisation: Prevention is Better than Cure Fizzah A Choudry, 1,2 Roshan P Weerackody, 1 Daniel A Jones 1,2 and Anthony Mathur 1,2 1. Department of Cardiology, Barts Health NHS Trust, London, UK. 2. Queen Mary University of London, London, UK

Abstract Thrombus embolisation complicating primary percutaneous coronary intervention in ST-elevation myocardial infarction is associated with an increase in adverse outcomes. However, there are currently no proven recommendations for intervention in the setting of large thrombus burden. In this review, we discuss the clinical implications of thrombus embolisation and angiographic predictors of embolisation, and provide an update of current evidence for some preventative strategies, both pharmacological and mechanical, in this setting.

Keywords Percutaneous coronary intervention, thrombus, embolisation Disclosure: The authors have no conflicts of interest to declare. Received: 26 February 2019 Accepted: 23 April 2019 Citation: Interventional Cardiology Review 2019;14(2):95–101. DOI: https://doi.org/10.15420/icr.2019.11 Correspondence: Anthony Mathur, Department of Cardiology, Barts Heart Centre, St Bartholomew’s Hospital, West Smithfield, London EC1A 7BE, UK. E: a.mathur@qmul.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.

Over the last few decades, primary percutaneous coronary intervention (PCI) has revolutionised the treatment of ST-elevation myocardial infarction (STEMI) with rapid recanalisation of the infarct-related epicardial vessel, resulting in smaller infarct size and a substantial reduction in adverse clinical endpoints.1,2 However, suboptimal myocardial reperfusion is documented to occur in a relatively large proportion of patients undergoing primary PCI for STEMI, despite optimal restoration of epicardial flow, with unfavourable short- and long-term outcomes.3 STEMI patients are at particularly high risk of thrombus embolisation due to elevated thrombotic burden and prothrombotic milieu.4 Thrombus embolisation, either spontaneously or as a consequence of instrumentation, is associated with reduced levels of procedural success. While this is most commonly related to embolisation into the distal coronary tree, it also includes retrograde embolisation either into non-culprit vessels or systemic emboli, which could further complicate primary PCI. Distal embolisation can lead to re-occlusion of the culprit vessel or its downstream branches and is a major contributor to slow and no re-flow by occlusion of distal microvasculature, leading to ongoing ischaemia despite a patent epicardial artery. Thereby, evidence of distal embolisation is quantified by thrombolysis in MI (TIMI) flow, myocardial blush grade and ST segment resolution. While angiographic signs of distal embolisation occur in 6–18% of cases of primary PCI in STEMI,5–11 the true incidence may be much higher, demonstrated by retrieval of visible debris in up to 73% patients in studies such as the Enhanced Myocardial Efficacy and Recovery by Aspiration of Liberated Debris (EMERALD) trial.12 Thrombus embolisation is associated with adverse procedural results and a greater frequency of adverse outcomes, including larger infarct size, reduced left ventricular ejection fraction, larger enzyme rises and

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increased rates of recurrent MI and mortality.5,6,13 A high thrombus burden has been associated with incidence of distal embolisation and in itself is associated with PCI failure and adverse outcome in STEMI.14–16 Due to the prognostic implication of thrombus embolisation, management of lesions with high thrombotic burden remains a challenge in the setting of primary PCI for STEMI.

Case A 49-year-old man presented with a history of chest pain and worsening breathlessness over the previous 3 days. He had a history of hypertension and smoking. On arrival he had on-going chest pain and was in mild pulmonary oedema. He was Kilip class II with a systolic blood pressure of 120 mmHg. His ECG showed a late presenting anterior STEMI with Q waves and a bedside echocardiogram demonstrated moderate to severely impaired LV function with anterior wall hypokinesia. A coronary angiogram demonstrated a chronic occlusion of the right coronary artery with an ostial occlusion of the left anterior descending (LAD) artery (Figure 1A). A standard workhorse wire was taken to the distal LAD with no restoration of flow. A 2.5 × 15 mm balloon was inflated at the site of occlusion (Figure 1B). The next image showed retrograde thrombus embolisation into a large obtuse marginal branch (Figure 1C). This was accompanied by a drop in blood pressure requiring IV metaraminol and rapid deterioration to pulseless electrical activity (PEA) arrest. Cardiopulmonary resuscitation was initiated, an AutoPulse® device applied, and the patient was intubated. A second wire was passed to the circumflex vessel and after predilatation a 3.0 × 28 mm drugeluting stent (DES) was deployed with a further 3.0 × 38 mm DES deployed in the LAD. Despite TIMI 3 flow in both vessels (Figure 1D), there was no return of spontaneous circulation and resuscitation was discontinued after 38 cycles of CPR.

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Coronary Figure 1: Case of Thrombus Embolisation A

important bifurcation; protecting both branches with wires may help to prevent occlusion and facilitate treatment in the event of thrombus embolisation. Assessment of thrombus burden and composition, and anatomical risk of embolisation in patients with STEMI undergoing primary PCI may optimise percutaneous treatment of these highly thrombotic lesions, guiding utilisation of pharmacological agents or interventional strategies, to reduce thrombus burden and improve both epicardial and myocardial perfusion.

Pharmacological Strategies in Prevention of Thrombus Embolisation P2Y12 Inhibitors C

A: Occlusion of ostial left anterior descending artery. B: 2.5 × 15 mm balloon inflation. C: Retrograde thrombus embolisation into obtuse marginal; D: Result of percutaneous coronary intervention.

This case demonstrates retrograde thrombus embolisation into a nonculprit vessel with a large amount of myocardium at risk due to chronic occlusion of the right coronary artery. To our knowledge, there are only two other published case reports in the literature. However, the outcomes are poor. This case highlights some technical considerations hat could have been considered, including passage of a second wire to the circumflex artery, thrombus aspiration upfront (with deep intubation of the guide catheter), use of glycoprotein (GP) IIb/IIIa inhibitors, and supportive measures, such as use of mechanical support either upfront due to the large area of myocardium at risk or at the point of thrombus embolisation; however, these can often be overlooked with the need for rapid restoration of TIMI 3 flow in the culprit vessel.

All STEMI guidelines have recommended early upstream administration of oral P2Y12 inhibitors or at the latest at the time of PCI given their delay in onset of action.19 However, this is not evidenced by randomised trials. Upstream oral antiplatelet absorption may not always be achievable in situations of intubated patients or in patients with delayed absorption (e.g. morphine) or if associated vomiting. The only evidence currently available is from the 30 Day Study to Evaluate Efficacy and Safety of Pre-hospital vs In-hospital Initiation of Ticagrelor Therapy in STEMI Patients Planned for PCI (ATLANTIC) trial, which compared the upstream prehospital and periprocedural administration of ticagrelor in 1,862 STEMI patients with a mean time difference of 31 minutes. There was no difference in the rates of ST segment resolution or TIMI 3 flow between the two groups.20 Given that less than 50% patients with prasugrel and ticgarelor have optimal platelet inhibition at 2 hours and the problems with gastric absorption in specific patient groups anecdotally, these cases may be covered with GPIIb/IIIa inhibition.21 Recent guidelines recommend that cangrelor may be considered in patients who have not received P2Y12 inhibitors (IIb/A).19 Cangrelor is administered intravenously and has a faster onset of action. While there are no specific randomised trials in STEMI, pooled analysis from STEMI patients included in the Clinical Trial to Demonstrate the Efficacy of Cangrelor in PCI (CHAMPION PCI) and Clinical Trial Comparing Cangrelor to Clopidogrel Standard Therapy in Subjects Who Require PCI (CHAMPION-PHOENIX) showed a significant reduction in stent thrombosis at 30 days.22

Glycoprotein Inhibitors Thrombus embolisation, both distal and retrograde, is associated with increased morbidity and mortality in primary PCI and its management is still debated. Here we review current data for pharmacological and interventional strategies to prevent thrombus embolisation and suggest an optimal therapeutic strategy in the setting of large thrombus burden in primary PCI.

Angiographic Predictors of Thrombus Embolisation in Primary PCI The main predictor of embolisation is thrombus burden. Thrombus burden may be classified angiographically using the TIMI thrombus grade in Table 1.17 Since there is a high incidence of coronary occlusion in STEMI and large thrombus burden, in this setting thrombus grade 5 is reclassified after wire crossing and balloon passage/inflation.14 Other predictors of embolisation include thrombus composition, TIMI flow, lesion length and large vessel diameter.5–7,18 The anatomical risk of embolisation should also be assessed before deciding on therapeutic strategy. This allows for adjunctive therapies, such as mechanical support (intra-aortic balloon pump, Impella [Abiomed], extracoroporeal membrane oxygenation) to be considered where large areas of myocardium are at risk or if large thrombus is located close to an

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Despite some evidence to suggest that adjunctive administration of GPIIb/IIIa inhibitors in STEMI may reduce mortality and re-infarction23 there is no evidence to suggest benefit over risk of bleeding with routine facilitated use of GPIIb/IIIa inhibitors in STEMI.24–28 Although initial non-randomised trials suggested benefit of localised intracoronary delivery of GPIIb/IIIa inhibitor over intravenous delivery in terms of TIMI flow and short-term mortality, no overall mortality benefit has been demonstrated.29 There also appears to be a signal for use of intracoronary GPIIb/IIIa use from theIntracoronary Abciximab and Aspiration Thrombectomy in Patients With Large Anterior MI (INFUSEAMI) trial where abciximab was delivered using the ClearWay™ (Atrium Medical) infusion catheter where there was a reduction in infarct size in the intracoronary arm compared with intravenous of 2.3%, but this did not reach significance.30 However, the larger Abciximab IV Versus IC in ST-elevation MI (AIDA STEMI) trial (n=2065) did not show any reduction in clinical endpoints by intracoronary abciximab administration and this again was demonstrated in a more recent meta-analysis.31,32 Current guidelines suggest that while there is no evidence to recommend routine use of GP IIb/IIIa inhibitors, they may be considered in the event of

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Thrombus Embolisation angiographic evidence of large thrombus, slow- or no-reflow, and other thrombotic complications. It is important to note that this strategy has not yet been tested in randomised trials.

Table 1: Thrombolysis in Myocardial Infarction Thrombus Scale Grade

Description

Anticoagulant Therapy

No angiographic evidence of thrombus

While there has been no randomised trial assessing unfractionated intraprocedural heparin in primary PCI there is a substantial body of experience and its use is recommended in current guidance (I/C).19 There have been some randomised trials evaluating bivalirudin in the setting of STEMI with a recent meta-analysis demonstrating no mortality advantage and concerns over excess rates of early stent thrombosis in the bivalirudin treated arms.25,33–37 Further, the most recent large randomised study on the impact of bivalirudin during primary PCI for STEMI, Bivalirudin versus Heparin in ST-Segment and Non-STSegment Elevation MI in Patients on Modern Antiplatelet Therapy in the Swedish Web System for Enhancement and Development of Evidencebased Care in Heart Disease Evaluated according to Recommended Therapies Registry (VALIDATE-SWEDEHEART) trial randomising 3,005 patients with STEMI showed no benefit conferred by bivalirudin use in rates of myocardial infarction, bleeding and death at 180 days compared to unfractionated heparin.38 Therefore, current guidance has downgraded recommendation of bivalirudin use from I/B preferred to IIa/A (consider). Bivalirudin is also recommended in heparin-induced thrombocytopaenia.19

Angiographic features suggestive of thrombus • decreased contrast density • haziness of contrast • irregular lesion contour • a smooth convex meniscus at the site of a total occlusion • suggestive, but not firmly diagnostic of thrombus

Definite thrombus presents in multiple angiographic projections • marked irregular lesion contour with a significant filling defect • greatest dimension is <1/2 vessel diameter

Definite thrombus appears in multiple angiographic views • greatest dimension from >1/2 to <2 vessel diameters

Definite large size thrombus present • greatest dimension >2 vessel diameters

Definite complete thrombotic occlusion of a vessel • a convex margin that stains with contrast, persisting for several cardiac cycles

Intracoronary Thrombolysis Early small studies of local delivery of fibrinolytics as an adjunct to primary PCI showed promising results with improvement in myocardial reperfusion and TIMI flow in the infarct-related artery, suggesting that this may be beneficial adjunctive treatment in STEMI patients at high risk of thrombus embolisation, without the known systemic adverse effects.39,40 The first randomised trial, Delivery of Thrombolytics Before Thrombectomy in Patients With ST-Segment Elevation Myocardial Infarction Undergoing primary Percutaneous Coronary Intervention [DISSOLUTION]), where 102 patients with STEMI and large thrombus burden were randomised to either intracoronary urokinase delivered by microcatheter or placebo prior to thrombectomy demonstrated increased rate of TIMI 3 flow, myocardial blush grade, ST segment resolution as well as improvement in 6-month major adverse cardiac events.41 However, the recently reported Trial of Low-dose Adjunctive alTeplase During prIMary PCI (T-TIME), which randomised 440 patients with STEMI to either placebo, 10 mg alteplase or 20 mg alteplase after the first device in primary PCI (37–42% use of thrombectomy), showed no difference in the primary endpoint of extent of microvascular obstruction on cardiac MRI at 2–7 days.42 There are currently two ongoing Phase III trials to evaluate intracoronary low-dose alteplase, the Adjunctive Low-dose tPA in Primary PCI for STEMI (STRIVE, NCT03335839) study, and tenecteplase, the Restoring Microcirculatory Perfusion in STEMI (RESTORE-MI; ACTRN12618000778280) trial.

Mechanical Strategies in Prevention of Thrombus Embolisation Thrombectomy Thrombectomy devices have been developed in an attempt to prevent thrombotic complications in STEMI by reducing thrombus burden and thereby enhancing the benefits of primary PCI. These have been evaluated for routine use in STEMI in some studies. Mechanical devices include the AngioJet® (MEDRAD), X-SIZER® System (Covidien) and Rinspiration (eV3) that actively fragment and aspirate

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thrombus, and the TVAC® (Nipro) and Rescue (Boston Scientific) that aspirate thrombus only without fragmentation. Several trials using different mechanical devices have led to conflicting results. Both the AngioJet Rheolytic Thrombectomy In Patients Undergoing Primary Angioplasty for Acute MI (AIMI) trial randomising 480 STEMI patients to thrombectomy with Angiojet versus standard primary PCI and a second study randomising 215 patients to thrombectomy with the Rescue catheter versus standard primary PCI paradoxically demonstrated large infarct sizes in the treated arms.43,44 Conversely, the AngioJet Rheolytic Thrombectomy Before Direct Infarct Artery Stenting in Patients Undergoing Primary PCI for Acute MI (JETSTENT) trial where the Angiojet was tested in a cohort with large thrombus burden showed significant improvements in ST segment resolution, and 6-month major adverse cardiac event despite no difference in infarct size.45 A meta-analysis of mechanical thrombectomy in STEMI showed no improvement in reperfusion or mortality despite a benefit in ST segment resolution.46 Most of the current available thrombectomy data pertains to manual thrombus aspiration using the Export® Aspiration Catheter (Medtronic) or the Diver® (Invatec). These devices are simpler to use compared to mechanical devices. However, they are limited by the inability to aspirate large amounts of thrombus rendering them theoretically less effective in reducing thrombus load. Manual thrombectomy devices have shown benefits compared with standard primary PCI using surrogate endpoints, such as TIMI flow, ST segment resolution, myocardial blush grade, infarct size and LV function.47 However, evidence regarding clinical endpoints such as re-infarction, mortality and MACE as well as concerns regarding safety have meant that current guidance has downgraded the use of routine thrombectomy from recommended (IIa/B) to not recommended (III/A).19 The Thrombus Aspiration during Percutaneous coronary intervention in Acute MI Study (TAPAS) trial, where more than 1,000 STEMI patients were randomised to either routine thrombus aspiration (Export Aspiration Catheter) or conventional primary PCI, showed significant improvement in myocardial blush grade and ST segment resolution as well as increased 1-year survival.9

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Coronary However, recently, two large-scale randomised trials of manual powered to evaluate hard clinical endpoints comparing routine manual thrombus aspiration with standard primary PCI have definitely demonstrated no beneficial effect of routine thrombectomy.48,49 The Thrombus Aspiration During ST-Segment Elevation Myocardial Infarction in Scandinavia (TASTE) trial recruited over 7,000 patients and showed no difference in mortality between the two groups at 30 days or 1 year.48,50 The Trial of Routine Aspiration Thrombectomy With PCI Versus PCI Alone in Patients With STEMI (TOTAL) trial with over 10,000 patients corroborated this result with no difference in cardiovascular death, MI, cardiogenic shock, or heart failure at 1 year, despite improvements in surrogate markers of rate of distal embolisation and ST segment resolution.49,51 Importantly, TOTAL showed a clear safety signal with an increase in incidence of stroke at 1 year in the thrombectomy arm compared with primary PCI alone.52 The mechanism of this is presumed to be proximal or systemic embolisation of thrombus via the extraction of the device and it is therefore recommended that the guide be deeply engaged into the coronary ostium during thrombus aspiration and device removal as a preventative strategy; alternatively, a guide catheter extension may be used. A recent meta-analysis combined data from 18,306 patients from the TAPAS, TASTE and TOTAL trials showed overall no differences between the two treatment groups in terms of mortality at 30 days, or incidence of stroke.53 Subgroup analysis demonstrated that in patients with the highest thrombus burden defined by TIMI thrombus grade ≥3 there were fewer cardiovascular deaths as well; however, this group also had increased incidence of stroke/transient ischaemic attack; this could suggest that if systemic embolisation could be prevented then benefit could be seen in this high thrombus burden subgroup of patients. Taken together, this would suggest that patients with a high thrombus burden benefit the most from thrombectomy by reducing the incidence of distal embolisation. Current guidelines have suggested that while routine thrombus aspiration is not recommended, it may be considered in specific cases where there is a high thrombus burden and risk of embolisation.19 Innovations in device technology should now focus on mitigating risk of systemic embolisation and stroke during thrombectomy. Further trials are required to evaluate the utility and benefit of thrombus aspiration in cohorts with large thrombus burden; however, this would require large patient numbers to be powered to detect differences in hard clinical outcomes.

(PROMISE) trial which randomised 200 patients with STEMI to the FilterWire EZ or conventional primary PCI.55 An analysis of all trials of distal protection devices involving 1,353 patients showed that while there was some benefit in terms of myocardial blush grade there was no improvement in 30-day mortality.56 The only studied proximal protection device is the Proxis Embolic Protection System (Velocimed) which theoretically confers complete protection from distal embolisation by deployment proximal to the lesion interrupting antegrade flow and therefore has the benefit of protecting all distal branches while thrombus is aspirated. The PRoximal Embolic Protection in Acute MI and Resolution of ST-Elevation trial, the only trial to date evaluating this device in STEMI, showed no benefit conferred in either surrogate or clinical outcomes.57 Considering the paucity of data for embolic protection devices, they have not been recommended in current practice guidelines.

Excimer Laser Coronary Atherectomy Excimer laser coronary atherectomy (ELCA) is potentially effective in reducing the size of coronary thrombus by inducing shock waves that can separate thrombus from the vessel wall, dissolve clot by acoustic waves within the thrombus structure and vaporise procoagulant mediators.58,59 Laser also has an inhibitory effect on platelet aggregation due to interaction with the 308-nm ultraviolet beam leading to ‘stunned platelet phenomenon’.60 Despite the theoretical potential, there are limited data to support its use in primary PCI. The Cohort of Acute Revascularization of Myocardial infarction with Excimer Laser (CARMEL) multicentre registry, enrolled 151 AMI patients, 65% of whom had large thrombus burden in the culprit artery who gained most benefit.61 TIMI grade flow was significantly improved and there was a low rate of major adverse cardiac event (8.6%). Recently, another large registry (Utility of Laser for Transcatheter AtherectomyMulticenter Analysis around Naniwa [ULTRAMAN]) has reported on 175 STEMI patients treated with ELCA, again showing similar TIMI flow improvement, a 92.8% success rate, and major adverse cardiac event rate of 3.3%.62 The only randomised trial reported to date is the Excimer Laser Versus Manual Thrombus Aspiration in Acute Myocardial Infarction (LASER-AMI) trial where 27 STEMI patients were randomised to adjunctive ELCA or conventional primary PCI demonstrating safety of the device and similar outcomes in terms of TIMI grade flow, and myocardial blush in both groups.63

Stenting Strategy Embolic Protection Devices Embolic protection devices include both proximal and distal devices. Distal devices are either occlusive, such as the PercoSurge (Medtronic) whereby an occlusive balloon is inflated distal to the lesion with debris aspirated prior to deflation or filters such as the FilterWire EZ (Boston Scientific), which is a non-occlusive, filter-based distal protection device. While there is evidence to support embolic protection devices in the prevention of thrombus embolisation vein graft PCI, these have not been replicated in the setting of STEMI. Both the Exploring the MEchanism of Plaque Rupture in Acute Coronary Syndrome Using Coronary CT Angiography and computationaL Fluid Dynamic (EMERALD) trial and ASPiration of Liberated Debris in Acute MI with GUardWire Plus System (ASPARAGUS) trials comparing adjunctive PercoSurge to conventional primary PCI in 501 and 341 patients, respectively, demonstrated safety of the devices but failed to show benefit in terms of infarct size.12,54 These results were reflected in the PROspective Multicenter Imaging Study for Evaluation of chest pain

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A direct stenting strategy reduces the incidence of distal embolism and no-reflow in cases of high thrombus burden by trapping thrombus behind the stent. It has been validated by several studies that have demonstrated superiority over angioplasty with predilatation and stenting. In Harmonizing Outcomes with Revascularization and Stents in Acute MI (HORIZON-AMI) trial, the reperfusion indices (ST resolution, TIMI 3 flow, and no-reflow incidence) were better and the 1-year mortality was lower with this technique.64 However, the anticipated benefits need to be balanced alongside possible risks with this technique, including problematic stent delivery, incomplete lesion preparation and inaccurate stent sizing secondary to poor visualisation and vasoconstriction. In terms of stent choice in cases of large thrombus burden, the MGuard™ (InspireMD) and STENTYS™ (STENTYS SA) stents have recently been evaluated in randomised trials. The MGuard is a covered stent with a bare metal stent platform with a fine outer mesh with the aim

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Thrombus Embolisation to trap thrombus without prolapse through stent struts and prevent thrombus embolisation. The MASTER I trial randomising 433 STEMI patients to either MGuard or conventional stenting demonstrated promising results with improvement in ST segment resolution and improved mortality at 1 year.65,66 However, the MASTER II trial, which aimed to recruit 1,114 patients, was terminated early due to a high rate of stent dislodgement. The STENTYS is a self-apposing and self-expanding nitinol stent with its design offering several benefits in thrombus management. First, as the maximal expansion diameters of each of the stent sizes is at least 1 mm greater than the balloon size, a smaller diameter may be chosen than that of the artery, enabling a gentler and atraumatic deployment which limits the direct mechanical fragmentation of the atherothrombotic material. Second, the tight mesh allows better retention of the thrombotic mass against the wall. Third, the risk of late malapposition is reduced as expansion may continue with the stent conforming to the shape of the vessel as vasodilatation and thrombus lysis occur. This stent has been evaluated in a series of studies (APPOSITION IV).67–70 While use of this stent has not been studied in cases of large thrombus burden, APPOSITION IV randomised 152 STEMI patients to STENTYS or to conventional DES and reported a rate of malapposition at 4 months less with the STENTYS than with the comparator.70 Despite this, their clinical effectiveness in comparison to other stent designs still needs to be confirmed in large-scale, randomised clinical trials. Deferred stenting implantation in primary PCI is also an option to reduce embolisation of thrombotic material in the presence of high thrombus burden once antegrade flow has been restored. This can allow 24–48 hours of intense antithrombotic therapy, including prolonged intravenous GPIIb/IIIa inhibition. Subsequent angiography frequently shows reduced thrombus burden such that PCI may be performed with a significantly lower risk of distal embolisation.71 While the randomised Deferred Stenting Versus Immediate Stenting to Prevent No- or Slow-Reflow in Acute ST-Segment Elevation Myocardial Infarction (DEFER-STEMI) trial showed significantly lower rates of no-reflow in a high risk population,72 the MIMI trials showed no difference in rate of microvascular obstruction seen on cardiac MRI between immediate invasive treatment compared with deferred PCI.73 This signal was confirmed in the larger Deferred Versus Conventional Stent Implantation in Patients with ST-segment Elevation Myocardial Infarction (DANAMI 3-DEFER) study in which deferred stenting 48 hours after the index procedure had no effect on a composite clinical outcome of mortality and revascularisation of non-culprit vessels. However, it did demonstrate a higher rate of target vessel revascularisation.74 On the basis of the available data, deferred stenting is not recommended in the current guidelines (III/A).19

Therapeutic Strategy for Prevention of Thrombus Embolisation in Primary PCI There is conflicting evidence as to the ideal management strategy in cases of large thrombus burden in STEMI. Based on the evidence presented here we propose an interventional algorithm in these cases (Figure 2). For all cases, potent antiplatelet activity must be ensured to minimise the risk of thrombus expansion and new thrombus formation including consideration as to gastric absorption of oral aspirin/P2Y12 agents. If there is any doubt in this the patient may be covered with either IV cangrelor or GPIIb/IIIa inhibition upfront. Furthermore, anticoagulation should be maintained with either heparin or bivalirudin. Often wire crossing or balloon passage without inflation

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Figure 2: Proposed Algorithm for Primary PCI in the Presence of Large Thrombus Burden Wire passage

TG 3–5

TG 0–2

Direct stent Balloon/stent

Ischaemia/ TIMI flow <3

No ischaemia/ TIMI flow 3

Thrombus aspiration (or excimer laser)

Consider: GPIIb/IIIa 48 h/ deferred angiography ±PCI

Direct stent Balloon/stent Consider: Mguard/ STENTYS/embolic protection GPIIb/IIIa inhibition

Consider risk of embolisation: mechanical support/branch protection Ensure adequate oral dual antiplatelets/IV cangrelor/IV GPIIb/IIIa Ensure adequate anticoagulation during procedure

GP = glycoprotein; PCI = percutaneous coronary intervention; TG = thrombolysis in MI thrombus grade; TIMI = thrombolysis in MI.

can restore flow. Assessment of thrombus burden may then be made using the TIMI thrombus grading.14 As thrombus grade increases more benefit may be yielded from administration of GP IIb/IIIa inhibition. Further, consideration should be given to anatomical risk of thrombus aspiration in terms of need for supportive measures such as mechanical support as well as protection of branches especially in ostial stenosis. If the TIMI thrombus grade is ≥3 as described as large thrombus burden,14 aspiration thrombectomy should be considered and multiple runs may be necessary (or excimer laser if available although this is based on limited evidence). Thrombus aspiration if performed should either be with deep guide catheter engagement or a guide catheter extension to decrease risk of retrograde embolisation. Moreover, suction should be maintained until the thrombectomy catheter is removed from the guide catheter. Thereafter, balloon angioplasty and stenting may be performed, although there may be benefit in the setting of large thrombus load for direct stenting and consideration of either the MGuard or STENTYS stents. If antegrade flow is restored and large thrombus burden remains without ongoing ischaemia one other option to consider in preventing thrombus embolisation would be to defer further intervention by 24–48 hours with intense antithrombotic therapy, including prolonged GPIIb/IIIa inhibition.

Conclusion Large thrombus burden in STEMI can further complicate primary PCI due to spontaneous or mechanical embolisation, either distally or retrograde, into a non-culprit vessel or systemically. In the context of no proven recommendation in this setting, we discuss some adjunctive and preventative pharmacological and interventional strategies and propose a management algorithm in the primary PCI setting.

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Coronary 1.

10.

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14.

15.

16.

17.

18.

19.

20.

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Unfractionated heparin versus bivalirudin in primary percutaneous coronary intervention (HEAT-primary PCI): an open-label, single centre, randomised controlled trial. Lancet 2014;384:1849–58. https:// doi.org/10.1016/S0140-6736(14)60924-7; PMID: 25002178. 35. Schulz S, Richardt G, Laugwitz K-L, et al. Prasugrel plus bivalirudin vs. clopidogrel plus heparin in patients with ST-segment elevation myocardial infarction. Eur Heart J 2014;35:2285–94. https://doi.org/10.1093/eurheartj/ehu182; PMID: 24816809. 36. Valgimigli M, Frigoli E, Leonardi S, et al. Bivalirudin or unfractionated heparin in acute coronary syndromes. N Engl J Med 2015;373:997–1009. https://doi.org/10.1056/ NEJMoa1507854; PMID: 26324049. 37. Capodanno D, Gargiulo G, Capranzano P, et al. Bivalirudin versus heparin with or without glycoprotein IIb/IIIa inhibitors in patients with STEMI undergoing primary PCI: An updated meta-analysis of 10,350 patients from five randomized clinical trials. Eur Hear J Acute Cardiovasc Care 2016;5:253–62. https://doi. org/10.1177/2048872615572599; PMID: 25746943. 38. Erlinge D, Omerovic E, Fröbert O, et al. Bivalirudin versus heparin monotherapy in myocardial infarction. N Engl J Med 2017;377:1132–42. https://doi.org/ 10.1056/NEJMoa1706443; PMID: 28844201. 39. Kelly RV, Crouch E, Krumnacher H, et al. Safety of adjunctive intracoronary thrombolytic therapy during complex percutaneous coronary intervention: Initial experience with intracoronary tenecteplase. Catheter Cardiovasc Interv 2005;66:327–32. https://doi.org/10.1002/ccd.20521; PMID: 16208711. 40. Sezer M, Oflaz H, Gören T, et al. Intracoronary streptokinase

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Rheolytic thrombectomy with percutaneous coronary intervention for infarct size reduction in acute myocardial infarction: 30-day results from a multicenter randomized study. J Am Coll Cardiol 2006;48:244–52. https://doi.org/10.1016/j.jacc.2006.03.044; PMID: 16843170. Kaltoft A, Bøttcher M, Nielsen SS, et al. Routine thrombectomy in percutaneous coronary intervention for acute ST-segmentelevation myocardial infarction: a randomized, controlled trial. Circulation 2006;114:40–7. https://doi.org/10.1161/ CIRCULATIONAHA.105.595660; PMID: 16801464. Migliorini A, Stabile A, Rodriguez AE, et al. Comparison of AngioJet rheolytic thrombectomy before direct infarct artery stenting with direct stenting alone in patients with acute myocardial infarction. The JETSTENT trial. J Am Coll Cardiol 2010;56:1298–306. https://doi.org/10.1016/j.jacc.2010.06.011; PMID: 20691553. De Luca G, Navarese EP, Suryapranata H. A meta-analytic overview of thrombectomy during primary angioplasty. Int J Cardiol 2013;166:606–12. https://doi.org/10.1016/j. ijcard.2011.11.102; PMID: 22284272. Burzotta F, De Vita M, Gu YL, et al. Clinical impact of thrombectomy in acute ST-elevation myocardial infarction: an individual patient-data pooled analysis of 11 trials. Eur Heart J 2009;30:2193–203. https://doi.org/10.1093/eurheartj/ehp348; PMID: 19726437. Fröbert O, Lagerqvist B, Olivecrona GK, et al. Thrombus aspiration during ST-segment elevation myocardial infarction. N Engl J Med 2013;369:1587–97. https://doi.org/ 10.1056/ NEJMoa1308789; PMID: 23991656. Jolly SS, Cairns JA, Yusuf S, et al. Randomized Trial of primary PCI with or without Routine Manual Thrombectomy. N Engl J Med 2015;372:1389–98. https://doi.org/ 10.1056/ NEJMoa1415098; PMID: 25853743. Lagerqvist B, Fröbert O, Olivecrona GK, et al. Outcomes 1 year after thrombus aspiration for myocardial infarction. N Engl J Med 2014;371:1111–20. https://doi.org/10.1056/ NEJMoa1405707; PMID: 25176395. Jolly SS, Cairns JA, Yusuf S, et al. Outcomes after thrombus aspiration for ST elevation myocardial infarction: 1-year follow-up of the prospective randomised TOTAL trial. Lancet 2016;387:127–35. https://doi.org/10.1016/S01406736(15)00448-1; PMID: 26474811. Jolly SS, Cairns JA, Yusuf S, et al. Stroke in the TOTAL trial: a randomized trial of routine thrombectomy vs. percutaneous coronary intervention alone in ST elevation myocardial infarction. Eur Heart J 2015;36:2364–72. https://doi.org/10.1093/ eurheartj/ehv296; PMID: 26129947. Jolly SS, James S, Džavík V, et al. Thrombus aspiration in ST-segment–elevation myocardial infarction. Circulation 2017;135:143–52. https://doi.org/10.1161/ CIRCULATIONAHA.116.025371; PMID: 27941066. Muramatsu T, Kozuma K, Tsukahara R, et al. Comparison of myocardial perfusion by distal protection before and after primary stenting for acute myocardial infarction: angiographic and clinical results of a randomized controlled trial. Catheter Cardiovasc Interv 2007;70:677–82. https://doi.org/10.1002/ ccd.21190; PMID: 17621653. Gick M, Jander N, Bestehorn HP, et al. Randomized evaluation of the effects of filter-based distal protection on myocardial perfusion and infarct size after primary percutaneous catheter intervention in myocardial infarction with and without ST-segment elevation. Circulation 2005;112:1462–9. https://doi.org/10.1161/CIRCULATIONAHA.105.545178; PMID: 16129793. De Luca G, Suryapranata H, Stone GW, et al. Adjunctive mechanical devices to prevent distal embolization in patients undergoing mechanical revascularization for acute myocardial infarction: a meta-analysis of randomized trials. Am Heart J 2007;153:343–53. https://doi.org/10.1016/j. ahj.2006.11.020; PMID: 17307410. Haeck JDE, Koch KT, Bilodeau L, et al. Randomized comparison of primary percutaneous coronary intervention with combined proximal embolic protection and thrombus aspiration versus primary percutaneous coronary intervention alone in ST-segment elevation myocardial infarction: the PREPARE (PRoximal Embolic Protection in Acute myocardial infarction and Resolution of ST-Elevation) study. JACC Cardiovasc Interv 2009;2:934–43. https://doi.org/10.1016/j. jcin.2009.07.013; PMID: 19850252. Rawlins J, Talwar S, Green M, O’Kane P. Optical coherence tomography following percutaneous coronary intervention

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with Excimer laser coronary atherectomy. Cardiovasc Revascularization Med 2014;15:29–34. https://doi.org/10.1016/j. carrev.2013.10.002; PMID: 24238883. Fracassi F, Roberto M, Niccoli G. Current interventional coronary applications of excimer laser. Expert Rev Med Devices 2013;10:541–9. https://doi.org/10.1586/17434440.2013. 811846; PMID: 23895080. Topaz O, Minisi AJ, Bernardo NL, et al. Alterations of platelet aggregation kinetics with ultraviolet laser emission: the “stunned platelet” phenomenon. Thromb Haemost 2001;86:1087–93. PMID: 11686328. Topaz O, Ebersole D, Das T, et al. Excimer laser angioplasty in acute myocardial infarction (the CARMEL multicenter trial). Am J Cardiol 2004;93:694–701. https://doi.org/10.1016/j. amjcard.2003.11.050; PMID: 15019871. Nishino M, Mori N, Takiuchi S, et al. Indications and outcomes of excimer laser coronary atherectomy: Efficacy and safety for thrombotic lesions-The ULTRAMAN registry. 2017;69:314–9. https://doi.org/10.1016/j.jjcc.2016.05.018; PMID: 27381939. Dörr M, Vogelgesang D, Hummel A, et al. Excimer laser thrombus elimination for prevention of distal embolization and no-reflow in patients with acute ST elevation myocardial infarction. Int J Cardiol 2007;116:20–6. https://doi.org/10.1016/j. ijcard.2006.03.024; PMID: 16891005. Möckel M, Vollert J, Lansky AJ, et al. Comparison of direct stenting with conventional stent implantation in acute myocardial infarction. Am J Cardiol 2011;108:1697–703. https://

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doi.org/10.1016/j.amjcard.2011.07.040; PMID: 21906709. 65. S tone GW, Abizaid A, Silber S, et al. Prospective, randomized, multicenter evaluation of a polyethylene terephthalate micronet mesh-covered stent (MGuard) in ST-segment elevation myocardial infarction: The MASTER Trial. J Am Coll Cardiol 2012;60:1975–84. https://doi.org/10.1016/j. jacc.2012.09.004; PMID: 23103033. 66. Dudek D, Dziewierz A, Brener SJ, et al. Mesh-covered embolic protection stent implantation in ST-segment–elevation myocardial infarction. Circ Cardiovasc Interv 2015;8:e001484. https://doi.org/10.1161/CIRCINTERVENTIONS.114.001484; PMID: 25603802. 67. Koch KT, Grundeken MJ, Vos NS, et al. One-year clinical outcomes of the STENTYS Self-Apposing coronary stent in patients presenting with ST-segment elevation myocardial infarction: results from the APPOSITION III registry. EuroIntervention 2015;11:264–71. https://doi.org/10.4244/ EIJY15M02_08; PMID: 25692610. 68. van Geuns R-J, Tamburino C, Fajadet J, et al. Self-expanding versus balloon-expandable stents in acute myocardial infarction: Results From the APPOSITION II Study. JACC Cardiovasc Interv 2012;5:1209–19. https://doi.org/10.1016/j. jcin.2012.08.016; PMID: 23257368. 69. Amoroso G, van Geuns R-J, Spaulding C, et al. Assessment of the safety and performance of the STENTYS self-expanding coronary stent in acute myocardial infarction: results from the APPOSITION I study. EuroIntervention 2011;7:428–36. https:// doi.org/10.4244/EIJV7I4A71; PMID: 21764660.

70. v an Geuns R-JM, Yetgin T, La Manna A, et al. STENTYS Self-Apposing® sirolimus-eluting stent in ST-segment elevation myocardial infarction: results from the randomised APPOSITION IV trial. EuroIntervention 2016;11:e1267–74. https:// doi.org/10.4244/EIJV11I11A248; PMID: 26865444. 71. Echavarría-Pinto M, Lopes R, Gorgadze T, et al. Safety and efficacy of intense antithrombotic treatment and percutaneous coronary intervention deferral in patients with large intracoronary thrombus. Am J Cardiol 2013;111: 1745–50. https://doi.org/10.1016/j.amjcard.2013.02.027; PMID: 23528026. 72. Carrick D, Oldroyd KG, McEntegart M, et al. A randomized trial of deferred stenting versus immediate stenting to prevent no- or slow-reflow in acute st-segment elevation myocardial infarction (DEFER-STEMI). J Am Coll Cardiol 2014;63:2088–98. https://doi.org/10.1016/j.jacc.2014.02.530; PMID: 24583294. 73. Belle L, Motreff P, Mangin L, et al. Comparison of immediate with delayed stenting using the minimalist immediate mechanical intervention approach in acute ST-segment–elevation myocardial infarction. Circ Cardiovasc Interv 2016;9:e003388. https://doi.org/10.1161/ CIRCINTERVENTIONS.115.003388; PMID: 26957418. 74. Kelbæk H, Høfsten DE, Køber L, et al. Deferred versus conventional stent implantation in patients with ST-segment elevation myocardial infarction (DANAMI 3-DEFER): an openlabel, randomised controlled trial. Lancet 2016;387:2199–206. https://doi.org/10.1016/S0140-6736(16)30072-1; PMID: 27053444.

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Lessons Learned from RADIOSOUND-HTN: Different Technologies and Techniques for Catheter-based Renal Denervation and Their Effect on Blood Pressure Philipp Lurz and Karl Fengler Department of Cardiology, Heart Center Leipzig, University of Leipzig, Leipzig, Germany

Abstract The interest in renal denervation (RDN) as a treatment for arterial hypertension has returned with three proof of principle trials that have shown recently RDN to be superior to sham treatment. Nevertheless, many questions about this treatment remain open, including those around the optimal interventional technique and technology. To clarify this important question, the authors designed and conducted the Randomized Trial of Different Renal Denervation Devices and Techniques in Patients with Resistant Hypertension (RADIOSOUND-HTN) trial, which compared three RDN treatment arms in a prospective randomised clinical trial. In this article, they comment on the background and results of this trial, and discuss which conclusions can be drawn from the trial, and which questions remain open for future studies in this field.

Keywords Renal denervation, sympathetic nervous system, ultrasound ablation, resistant hypertension, renal nerves Disclosure: PL received fees as a consultant for ReCor Medical and Medtronic. KF has no conflicts of interest to declare. Received: 10 January 2019 Accepted: 23 April 2019 Citation: Interventional Cardiology Review 2019;14(2):102–6. DOI: https://doi.org/10.15420/icr.2019.03.R1 Correspondence: Philipp Lurz, Department of Cardiology, Heart Center Leipzig at University of Leipzig, Strümpellstrasse 39, 04289 Leipzig, Germany. E: Philipp.Lurz@medizin.uni-leipzig.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 rise and fall of interventional renal sympathetic denervation (RDN) as a treatment for arterial hypertension is a remarkable chapter in the scientific history of the 21st century. This once promising therapy has been abandoned by most clinicians after the neutral results of the Renal Denervation in Patients With Uncontrolled Hypertension (SYMPLICITY-HTN3) trial.1 It would have been easy to drop further efforts into the development of this technology, given this unsuccessful double-blind, sham controlled randomised controlled trial (RCT) of more than 500 patients. On the other hand, as the incidence and prevalence of arterial hypertension remain high and patient adherence to medical treatment and lifestyle modification is, at best, suboptimal, the desire for a nonpharmaceutical treatment of arterial hypertension persists. First, we will take a closer look at the history of RDN and specifics of the SYMPLICITY-HTN3 trial. Interventional RDN is based on the paradigm of an elevated sympathetic activity in people with hypertension.2,3 The clinical relevance of this paradigm is supported by the blood pressure (BP) lowering effects of thoracolumbar sympathectomy in the first half of the 20th century.4,5 While the role of sympathetic overactivity in elevating BP is well established, this does not necessarily mean any interventional RDN is successful in any hypertensive patient. There is a constant proportion of patients in whom BP cannot be reduced by RDN, who are called non-responders. In almost every major trial on RDN, including the

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latest proof-of-principle Renal Denervation With the Symplicity Spyral™ Multi-electrode Renal Denervation System in Patients With Uncontrolled Hypertension (SPYRAL-HTN) and Endovascular Ultrasound Renal Denervation To Treat Hypertension (RADIANCE-HTN SOLO) trials, the rate of patients with a significant BP response (usually ≥5 mmHg change in daytime BP from ambulatory measurements) ranges between 60% and 70%.6–9 In early surgical trials, responder rates were even lower (45%), in spite of a marked reduction in mortality following treatment.5 The reasons for this non-response are not fully clear yet, but can be thought of as a mixture of three important factors.10 First, non-response can be explained by the absence of a substrate for RDN. Elevated sympathetic activity cannot be found in all patients with hypertension, especially elderly people.2,3 In this group, biomechanical components such as vascular stiffening and increased wave reflections might outweigh the sympathomimetic contributors to an elevated BP.11,12 Second, interference with antihypertensive medication, medication adherence and changes in treatment influence the effects of RDN on BP. Third, procedural factors, such as an unsuccessful or incomplete denervation procedure, could lead to a reduced or absent treatment effect. This final issue warrants thorough study to better understand the results of SYMPLICITY-HTN3 and of RDN in general.

Anatomical and Procedural Aspects of Renal Sympathetic Denervation One frequently raised concern regarding SYMPLICITY-HTN3 was that it included a large number of centres with little practical experience

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Catheter-based Renal Denervation in RDN. This is important, as to achieve a fully circumferential ablation pattern using a unipolar radiofrequency catheter requires some training and can be a challenge even for a skilled interventionalist. Achieving ablation of all four quadrants of the renal arteries is necessary to ensure complete destruction of the adjacent sympathetic fibres (Figure 1). Consequently, in a post-hoc analysis of the study, patients with a higher number of ablations had a more pronounced reduction in BP.13 These thoughts led to the development of newer RDN catheters that apply four ablations in a circumferential or spiral pattern using radiofrequency energy, simultaneous perivascular application of ethanol at three different points or even a fully circumferential ultrasound ablation pattern to facilitate the procedure itself.10,13–15

Figure 1: Incomplete and Full Circumferential Ablation Runs and Affected Nerve Fibres Incomplete ablation

Full circumferential ablation

Preserved area

Notably, with all these devices, RDN is a black box treatment, as they do not allow direct feedback of treatment success to the interventionalist. In addition, the belief in the superiority of these newer generation catheters over previous technologies is based on technical considerations, but has never been proven in randomised clinical trials. Another major paradigm shift following SYMPLICITY-HTN3 was related to anatomical considerations. Initially, RDN was carried out in the main renal arteries only. As it had been postulated that the distribution of renal nerve fibres along the main renal artery is uniform, it was assumed the exact location of the ablation points would not be decisive. RDN would affect the fibres at any point of the renal arteries’ course. A later anatomical study revealed that this assumption was wrong. Renal nerve fibres were not only found more frequently in the superior and ventral areas of the renal arteries, but were also closer to the vessel’s lumen in its distal sections and even more in its side branches.16 Therefore, ablation of the distal sections of the renal arteries and even side branch ablation might help to extend the ablation process and, ultimately, lead to a greater BP reduction. This hypothesis has been supported by animal studies.17,18 Notably, an additional ablation of the renal arteries’ side branches would require a longer procedural time and a greater volume of contrast agent. Side branch ablation would also require catheters that are small enough to enter these small (3–4 mm) vessels. When using a denervation system that is small enough to reach into the renal side branches, it would be wise to use it on accessory renal arteries too. In the earlier SYMPLICITY trials, patients with accessory arteries were excluded, and a smaller retrospective study suggests a the effect of RDN is blunted when accessories are present.19 Another aspect that might have been underestimated in previous RDN trials is that the penetration depth of radiofrequency energy into adjacent tissue is limited to 3–4 mm.20 Particularly in the main renal arteries, this might not be deep enough to affect a significant number of sympathetic fibres.16 Therefore, increasing tissue penetration depth by using technologies with energy forms other than radiofrequency currents might increase the efficacy of RDN procedures. One such technology is the Paradise™ (ReCor Medical) ablation catheter. This catheter uses ultrasound energy to create a circumferential thermal ablation pattern. As the system is placed inside a cooling balloon, the directly adjacent vessel’s intima layer is protected, which allows a higher amount of energy to be applied. With this technology, an

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ablation depth of 6–7 mm into the tissue can be achieved, which theoretically affects around 90% of the adjacent nerves. Again, the superiority of this technology over previous approaches has not been proven in randomised trials. On the other hand, in a smaller trial in patients not responding to radiofrequency ablation, this technology significantly reduced BP.21 These considerations led to the design and conduction of the Global Clinical Study of Renal Denervation With the Symplicity Spyral™ Multielectrode Renal Denervation System in Patients With Uncontrolled Hypertension in the Absence of Antihypertensive Medications (SPYRALHTN-OFF-MED) and Global Clinical Study of Renal Denervation With the Symplicity Spyral™ Multi-electrode Renal Denervation System in Patients With Uncontrolled Hypertension on Standard Medical Therapy (SPYRAL HTN-ON MED) studies and the RADIANCE-SOLO trial.8,9,22 In the SPYRAL-HTN-OFF-MED and RADIANCE-SOLO trials, drug-naive patients underwent RDN; the SPYRAL-HTN-ON-MED trial investigated RDN in patients taking 1–3 antihypertensive drugs. In these studies, the latest state-of-the-art ablation catheters and techniques were used by RDNexperienced interventionalists following a rigorous protocol. All three trials found RDN had superior BP reductions than a sham treatment. Nevertheless, a direct head-to-head comparison of different ablation techniques and technologies was not available. This led to the design of the three-arm Randomized Trial of Different Renal Denervation Devices and Techniques in Patients with Resistant Hypertension (RADIOSOUND-HTN) study.23

RADIOSOUND-HTN This trial was designed as a three-arm randomised controlled trial to compare the BP lowering effects of radiofrequency ablation of the main renal arteries using the Symplicity Spyral™ catheter (Medtronic) as considered reference standard with either an additional ablation of the renal side branches and accessories using the same device or an ultrasound-based ablation of the main renal arteries using the Paradise™ ablation system in people with therapy-resistant hypertension. To avoid the high variability and higher likelihood of regression to the mean from office BP measurements, ambulatory blood pressure measurements (ABPM) were used. The primary end point was mean change in daytime average from ABPM 3 months after the procedure. Patients’ inclusion and exclusion criteria were broad to allow a better transfer of the results to everyday clinical practice. The main inclusion criterion was resistant hypertension (systolic daytime BP >135 mmHg despite ≥3 different classes of antihypertensive drugs on at least 50% of maximum dosage) with stable antihypertensive drug

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Proximal

B Proximal Distal

Previous concept of uniform radial distribution (A) and current concept (B). Source: Sakakura et al. 2014.16 Adapted with permission from Elsevier.

Figure 3: Changes to Ambulatory Blood Pressure Following Different Types of Ablation

Change in daytime ambulatory blood pressure (mmHg)

A 0

Diastolic

Radiofrequency ablation main artery Radiofrequency ablation main artery and branches

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Radiofrequency ablation main artery 30 20

66% responder

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20 10 0

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67% responder

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Blood pressure changes and responder rates per group receiving different types of ablation in the RADIOSOUND-HTN trial. Source: Fengler et al. 2019.23 Reproduced with permission from Wolters Kluwer Health.

−15 −NS−

−NS−

−20

B Change in 24 h ambulatory blood pressure (mmHg)

Systolic

Change in systolic daytime ambulatory blood pressure (mmHg)

Distal

Change in systolic daytime ambulatory blood pressure (mmHg)

Figure 4: Changes to Daytime Systolic Blood Pressure Following Different Types of Ablation

Change in systolic daytime ambulatory blood pressure (mmHg)

Figure 2: Distribution of Renal Nerves Around the Renal Arteries

−NS−

p=0.043

Systolic

p=0.025

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Radiofrequency ablation main artery Radiofrequency ablation main artery and branches

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−15 −NS−

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−20

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p=0.029

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Mean blood pressure change for daytime (A) and 24 h (B) ambulatory measurement values in the RADIOSOUND-HTN trial. Source: Fengler et al. 2019.23 Reproduced with permission from Wolters Kluwer Health. NS = not significant (p>0.05).

treatment for at least 4 weeks. An additional key inclusion criterion was the presence of at least one larger renal artery (≥5.5 mm), because the anatomical considerations discussed above can be thought to be more distinct in larger vessels, so significant differences in treatment outcome would be easier to assess. Key exclusion criteria were being aged <18 or >75 years, having a life expectancy <6 months, pregnancy, secondary hypertension and any main renal artery diameter being <4 mm, as this would be the minimum diameter needed for treatment with the ultrasound balloon. After 3 months, BP was reduced in all three treatment groups, with an average reduction of −9.5 ± 12.3 and −6.3 ± 7.8 mmHg for daytime

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systolic and diastolic ABPM values. The amount of BP reduction was significantly larger in the ultrasound ablation group than in the radiofrequency ablation group undergoing main renal artery ablation only (−13.2 ± 13.7 versus −6.5 ± 10.3 mmHg, mean difference −6.7 mmHg), while additional side-branch and accessory artery ablation was not superior to radiofrequency main artery treatment (−8.3 ± 11.7 mmHg for additional side branch ablation, mean difference −1.8 mmHg). Also, despite the numerical difference, ultrasound ablation was not found to be superior to combined main and side branch ablation in this trial (mean difference −4.9 mm Hg; Figure 3). While the magnitude of BP change differed between the treatment groups, to our surprise the frequency of BP response did not (Figure 4).

Lessons from RADIOSOUND-HTN Three major conclusions can be drawn from RADIOSOUND-HTN: First, there was a significant BP reduction in all three treatment groups. This underlines the overall efficacy of RDN in hypertension that was also found in the recently published proof of principle trials.8,9,22 Second, the use of newer ablation techniques and technologies seems to result in a greater reduction in BP but does not affect the frequency of patients not responding to the treatment. Third, while the ultrasound-based system was clearly superior to radiofrequency denervation when applied to the main renal arteries only, it is less clear if an additional side branch ablation would be beneficial.

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Catheter-based Renal Denervation The last finding is against expectations, as a previous non-randomised study and one randomised trial found additional side branch and accessory ablation was superior to isolated main renal artery treatment.24,25 Also, given the anatomical considerations, this more extensive ablation should have affected a markedly increased number of nerve fibres. On the other hand, this might be a cue for further investigation of renal nerve distribution and function: it is still not clear if ablation of afferent or efferent renal nerve fibres are key for RDN to work. Interrupting central afferences would reduce BP by downregulation of systemic sympathetic activity, and destroying central efferences could regulate BP by local renal diuretic and humoral function. It is likely that afferent renal fibres follow a different course to efferent ones.26 Possibly, ultrasound ablation of the main artery affects a different proportion of afferent and efferent fibres than distal and side branch radiofrequency ablation. Whichever of these fibres is the key effector of RDN, this might be one explanation for the diverging results in the treatment groups. Another explanation for the non-superiority of side branch ablation over isolated main artery treatment is related to the specific treatment. While the ablation points were placed more distally in the main renal arteries than in previous trials and ablations were relatively extensive in this group, the number of ablation points in the combined main and side branch ablation group was numerically smaller than it had been in the SPYRAL-HTN trials.8,22 It will remain unclear whether additional side branch ablation is a useful extension of radiofrequency denervation until larger, adequately powered trials are conducted. In the meantime, investigators should consider whether, on balance, the increased amount of contrast agent and fluoroscopy times necessary for this procedure can be justified. The observed BP responder frequencies in this study are counterintuitive. Our trial design was based on the assumption that more extensive ablation would lead to an increased number of BP responders, as fewer patients would receive an incomplete renal nerve ablation. This assumption was wrong. Instead, responder rates are comparable to those

hatt DL, Kandzari DE, O’Neill WW, et al. A controlled trial B of renal denervation for resistant hypertension. N Engl J Med 2014;370:1393–401. https://doi.org/10.1056/NEJMoa1402670; PMID: 24678939. Esler M, Jennings G, Lambert G. Noradrenaline release and the pathophysiology of primary human hypertension. Am J Hypertens 1989;2:140S–6S. https://doi.org/10.1093/ ajh/2.3.140S; PMID: 2647104. Sever PS, Osikowska B, Birch M, Tunbridge RD. Plasmanoradrenaline in essential hypertension. Lancet 1977;1:1078– 81. https://doi.org/10.1016/S0140-6736(77)92335-2; PMID: 68182. Parkes WE. Thoracolumbar sympathectomy in hypertension. Br Heart J 1958;20:249–52. https://doi.org/10.1136/hrt.20.2.249; PMID: 13523020. Smithwick RH, Thompson JE. Splanchnicectomy for essential hypertension; results in 1,266 cases. J Am Med Assoc 1953;152:1501–4. https://doi.org/10.1001/ jama.1953.03690160001001; PMID: 13061307 Mahfoud F, Böhm M, Azizi M, et al. Proceedings from the European clinical consensus conference for renal denervation: considerations on future clinical trial design. Eur Heart J 2015;36:2219–27. https://doi.org/10.1093/eurheartj/ ehv192; PMID: 25990344. Böhm M, Mahfoud F, Ukena C, et al. First report of the Global SYMPLICITY Registry on the effect of renal artery denervation in patients with uncontrolled hypertension. Hypertension 2015;65:766–74. https://doi.org/10.1161/ HYPERTENSIONAHA.114.05010; PMID: 25691618. Townsend RR, Mahfoud F, Kandzari DE, et al. Catheter-based renal denervation in patients with uncontrolled hypertension in the absence of antihypertensive medications (SPYRAL HTNOFF MED): a randomised, sham-controlled, proof-of-concept trial. Lancet 2017;390:2160–70. https://doi.org/10.1016/S01406736(17)32281-X; PMID: 28859944.

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found in previous RDN trials or even below this level when applying the office BP response used in the first SYMPLICITY trials.7,27,28. As responder frequencies are not higher in the SPYRAL-HTN and RADIANCE-SOLO trials using the same treatment methods, a statistical outlier is an unlikely explanation.8,9,22. Instead, this highlights the importance of wise patient selection when enrolling for RDN trials. It is likely that the rate of responders will not be improved unless only patients with an elevated sympathetic tone are enrolled, which is essential for RDN to work. In those patients, a more extensive ablation procedure will likely lead to a pronounced reduction of this overactivity, resulting in a greater lowering of BP. As other, non-invasive methods are not available, assessment of renal sympathetic activity requires invasive measurement of renal norepinephrine spillover. This is difficult to perform under the circumstances of clinical trials and will be even more challenging in clinical practice. In addition, norepinephrine spillover has never been investigated as a predictor for BP response after RDN. Therefore, future trials should focus on this issue. In the meantime, other potent predictors, such as elevated vascular stiffness could be used as surrogate markers for a biomechanical contribution to hypertension instead.11,12,29–31

Tasks for Future Trials While improvement of the ablation technology itself might have already reached its peak, several open questions remain to be answered by future RDN trials. In particular, three topics will be of interest in the next few years. First, despite research in catheter-based RDN for decades, a direct feedback mechanism that can assure whether ablation was successful during the procedure is still lacking. This will be an important task for future research. Second, the role and anatomical distribution of afferent and efferent renal fibres for RDN need to be clarified. Third, the mechanism(s) by which RDN results in BP reduction is/are still unclear. Uncovering this secret will certainly open new possibilities to optimise patient selection and medical co-treatment. All in all, RADIOSOUND-HTN allows insights into technical aspects of RDN and can thereby help in optimising future RDN trial design.

zizi M, Schmieder RE, Mahfoud F et al. Endovascular A ultrasound renal denervation to treat hypertension (RADIANCE-HTN SOLO): a multicentre, international, single-blind, randomised, sham-controlled trial. Lancet. 2018;391:2335–45. https://doi.org/10.1016/S01406736(18)31082-1; PMID: 29803590. Kandzari DE, Kario K, Mahfoud F, et al. The SPYRAL HTN Global Clinical Trial Program: Rationale and design for studies of renal denervation in the absence (SPYRAL HTN OFF-MED) and presence (SPYRAL HTN ON-MED) of antihypertensive medications. Am Heart J 2016;171:82–91. https://doi. org/10.1016/j.ahj.2015.08.021; PMID: 26699604. Fengler K, Rommel KP, Blazek S, et al. Cardiac magnetic resonance assessment of central and peripheral vascular function in patients undergoing renal sympathetic denervation as predictor for blood pressure response. Clin Res Cardiol 2018;107:945–55. https://doi.org/10.1007/s00392-0181267-6; PMID: 29744617. Fengler K, Rommel KP, Hoellriegel R, et al. Pulse wave velocity predicts response to renal denervation in isolated systolic hypertension. J Am Heart Assoc 2017;6:e005879. https://doi. org/10.1161/JAHA.117.005879; PMID: 28515119. Kandzari DE, Bhatt DL, Brar S, et al. Predictors of blood pressure response in the SYMPLICITY HTN-3 trial. Eur Heart J 2015;36:219–27. https://doi.org/10.1093/eurheartj/ehu441; PMID: 25400162. Worthley SG, Tsioufis CP, Worthley MI, et al. Safety and efficacy of a multi-electrode renal sympathetic denervation system in resistant hypertension: the EnligHTN I trial. Eur Heart J 2013;34:2132–40. https://doi.org/10.1093/eurheartj/eht197; PMID: 23782649. Mabin T, Sapoval M, Cabane V, et al. First experience with endovascular ultrasound renal denervation for the treatment of resistant hypertension. EuroIntervention 2012;8:57–61. https://doi.org/10.4244/EIJV8I1A10; PMID: 22580249.

16. S akakura K, Ladich E, Cheng Q, et al. Anatomic assessment of sympathetic peri-arterial renal nerves in man. J Am Coll Cardiol 2014;64:635–43. https://doi.org/10.1016/j.jacc.2014.03.059; PMID: 25125292. 17. Henegar JR, Zhang Y, Hata C, et al. Catheter-based radiofrequency renal denervation: location effects on renal norepinephrine. Am J Hypertens 2015;28:909–14. https://doi. org/10.1093/ajh/hpu258; PMID: 25576624. 18. Mahfoud F, Tunev S, Ewen S, et al. Impact of lesion placement on efficacy and safety of catheter–based radiofrequency renal denervation. J Am Coll Cardiol 2015;66:1766–75. https:// doi.org/10.1016/j.jacc.2015.08.018; PMID: 26483099. 19. Id D, Kaltenbach B, Bertog SC, et al. Does the presence of accessory renal arteries affect the efficacy of renal denervation? JACC Cardiovasc Interv 2013;6:1085–91. https://doi. org/10.1016/j.jcin.2013.06.007; PMID: 24156968 20. Al Raisi SI, Pouliopoulos J, Barry MT, et al. Evaluation of lesion and thermodynamic characteristics of Symplicity and EnligHTN renal denervation systems in a phantom renal artery model. EuroIntervention 2014;10:277–84. https://doi. org/10.4244/EIJV10I2A46; PMID: 24952062. 21. Stiermaier T, Okon T, Fengler K, et al. Endovascular ultrasound for renal sympathetic denervation in patients with therapyresistant hypertension not responding to radiofrequency renal sympathetic denervation. EuroIntervention 2016;12:e282–9. https://doi.org/10.4244/EIJV12I2A43; PMID: 27290688. 22. Kandzari DE, Bohm M, Mahfoud F, et al. Effect of renal denervation on blood pressure in the presence of antihypertensive drugs: 6-month efficacy and safety results from the SPYRAL HTN-ON MED proof-of-concept randomised trial. Lancet 2018;391:2346–55. https://doi.org/10.1016/S01406736(18)30951-6; PMID: 27290688. 23. Fengler K, Rommel KP, Blazek S, et al. A three-arm randomized trial of different renal denervation devices and techniques in patients with resistant hypertension

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Renal Denervation (RADIOSOUND-HTN). Circulation 2019;139:590-600. https://doi. org/10.1161/CIRCULATIONAHA.118.037654; PMID: 30586691. 24. Fengler K, Ewen S, Höllriegel R, et al. Blood pressure response to main renal artery and combined main renal artery plus branch renal denervation in patients with resistant hypertension. J Am Heart Assoc 2017;6:e006196. https://doi.org/10.1161/JAHA.117.006196; PMID: 28862930. 25. Pekarskiy SE, Baev AE, Mordovin VF, et al. Denervation of the distal renal arterial branches vs. conventional main renal artery treatment: a randomized controlled trial for treatment of resistant hypertension. J Hypertens 2017;35:369–75. https:// doi.org/10.1097/HJH.0000000000001160; PMID: 28005705. 26. Fudim M, Sobotka AA, Yin YH, et al. Selective vs. global renal denervation: a case for less is more. Curr Hypertens Rep

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2018;20:37. https://doi.org/10.1007/s11906-018-0838-2; PMID: 29717380. 27. Symplicity HTN-2 Investigators; Esler MD, Krum H, Sobotka PA, et al. Renal sympathetic denervation in patients with treatment-resistant hypertension (The Symplicity HTN-2 Trial): a randomised controlled trial. Lancet 2010;376:1903–9. https://doi.org/10.1016/S0140-6736(10)62039-9; PMID: 21093036. 28. Krum H, Schlaich M, Whitbourn R, et al. Catheter-based renal sympathetic denervation for resistant hypertension: a multicentre safety and proof-of-principle cohort study. Lancet 2009;373:1275–81. https://doi.org/10.1016/S01406736(09)60566-3; PMID: 19332353. 29. Courand PY, Pereira H, Del Giudice C, et al. Abdominal aortic calcifications influences the systemic and renal hemodynamic

response to renal denervation in the DENERHTN (Renal Denervation for Hypertension) Trial. J Am Heart Assoc 2017;6:pii: e007062. https://doi.org/10.1161/JAHA.117.007062; PMID: 29018027. 30. Sata Y, Hering D, Head GA, et al. Ambulatory arterial stiffness index as a predictor of blood pressure response to renal denervation. J Hypertens 2018;36:1414–22. https://doi.org/10.1097/HJH.0000000000001682; PMID: 29465712. 31. Mahfoud F, Bakris G, Bhatt DL, et al. Reduced blood pressurelowering effect of catheter-based renal denervation in patients with isolated systolic hypertension: data from SYMPLICITY HTN-3 and the Global SYMPLICITY Registry. Eur Heart J 2017;38:93–100. https://doi.org/10.1093/eurheartj/ ehw325; PMID: 28158510.

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