USC 11.2 by Radcliffe Cardiology

US Cardiology Review

Volume 11 • Issue 2 • Fall 2017

www.USCjournal.com

Volume 11 • Issue 2 • Fall 2017

Controversies in Antiplatelet and Anticoagulation Therapy in Patients Presenting with Acute Coronary Syndrome Colin T Phillips, MD and Michael C Gavin, MD

Clinical Practice Update: Who Should Be Referred for Transcatheter Aortic Valve Replacement in 2017? Colin M Barker, MD and Michael J Reardon, MD

Advances in Coronary Physiology: Update for 2017 Morton J Kern, MD, MSCAI, FAHA, FACC and Katherine M Yu, MD

Proprotein Convertase Subtilisin/kexin Type 9 Inhibitors in Clinical Practice: A Focused Update Evan A Stein, MD, PhD

ISSN: 1758-3896 • eISSN: 1758-390X

3D rendered medically accurate illustration of the aortic valve

New drugs for the treatment of heart failure

Human heart with cardiogram

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ESC Congress Munich 2018 25-29 August Where the world of cardiology comes together

Spotlight: Valvular Heart Disease

Key dates: Mid Dec – 14 Feb

Abstract submission

Mid Jan – 1 March

Clinical Case submission

Mid March – 21 May

Late-Breaking Science submission

31 May

Early registration deadline

31 July

Late registration deadline

www.escardio.org/ESC2018 #ESCcongress

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Volume 11 • Issue 2 • Fall 2017

www.USCjournal.com

Editor in Chief Professor Donald E Cutlip, MD Harvard Medical School, Boston, MA

Section Editor (Interventional/Structural)

Section Editor (Imaging)

Section Editor (Heart Failure)

Carey Kimmelstiel, MD

Warren Manning, MD

Leway Chen, MD, MPH

Tufts Medical Center, Boston, MA

Harvard Medical School, Boston, MA

University of Rochester, Rochester, NY

Deputy Editors Kashish Goel, MBBS

Chad A Kliger, MD, MS, FACC, FSCAID

Rajalakshmi Santhanakrishnan, MBBS

Mayo Clinic, Rochester, MN

Lenox Hill Heart and Vascular Institute, New York, NY

Wright State University, Dayton, OH

Ankur Kalra, MD, FACP, FACC, FSCAI Case Western Reserve University School of Medicine, Cleveland, OH

Ronnie Ramadan, MD Harvard Medical School, Boston, MA

Bruce Stambler, MD Piedmont Healthcare, Atlanta, GA

Editorial Board Uma Mahesh R Avula, MD

C Michael Gibson, MS, MD

Columbia University, New York, NY

Beth Israel Deaconess Medical Center, Boston, MA

Ralph G. Brindis, MD

Bill Gogas, MD, PhD

Emory University School of Medicine, Atlanta, GA

University of California, San Francisco, CA

Michael R Gold, MD

Todd Brown, MD, MSPH

University of Alabama, Birmingham, AL

Medical University of South Carolina, Charleston, SC

Leo Buckley, PharmD

Barry H Greenberg, MD

Virginia Commonwealth University, Richmond, VA

Robert Chait, MD, FACC, FACP

Thomas A Haffey, MD, DO

JFK Medical Center, Atlantis, FL

Western University of Health Sciences, Pomona, CA

Gregory J Dehmer, MD, MACC, FACP, FAHA, MSCAI Texas A&M University College of Medicine, Bryan, TX, USA

Elizabeth Kaufman, MD

Case Western Reserve University, Cleveland, OH

Morton J Kern, MD

University of California at Irvine, Orange, CA

NA Mark Estes III, MD

Tufts University School of Medicine, Boston, MA

Bernard J Gersh, MB, ChB, DPhil Mayo Clinic, Rochester, MN

University of California San Diego School of Medicine, La Jolla, CA

Richard Kones, MD, FAHA, FESC, FCCP, FRSM, FAGS Cardiometabolic Research Institute, Houston, TX

Roberto M Lang, MD

University of Chicago, Chicago, IL

Jackson J Liang, MD, DO

Hospital of the University of Pennsylvania, Philadelphia, PA

Sylvia Mamby, MD, FACC, FASE Emeritus Staff, Mayo Clinic

Patrick T O’Gara, MD

Brigham and Women's Hospital, Boston, MA

Duane Pinto, MD, MSc

Harvard Medical School, Boston MA

Krishna Pothineni, MD

University of Arkansas for Medical Sciences, Little Rock, AR

Elizabeth Ross, MD, FACC

Emeritus Member, American College of Cardiology

W Douglas Weaver, MD

Wayne State University, Detroit, MA

Managing Editor Rosie Scott • Production Jennifer Lucy • Design Tatiana Losinska Sales & Marketing Executive William Cadden • New Business & Partnership Director Rob Barclay Business Development Manager, USA Mark Watson • Publishing Director Liam O’Neill Managing Director David Ramsey • Commercial Director David Bradbury •

Editorial Contact Rosie Scott commeditor@radcliffecardiology.com Circulation & Commercial Contact David Ramsey david.ramsey@radcliffecardiology.com •

Cover image

3d rendered illustration - heart attack by Sebastian Kaulitzki | www.istockphoto.com

Radcliffe Cardiology

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Published by Radcliffe Cardiology. All information obtained by Radcliffe Cardiology and each of the contributors from various sources is as current and accurate as possible. However, due to human or mechanical errors, Radcliffe Cardiology and the contributors cannot guarantee the accuracy, adequacy or completeness of any information, and cannot be held responsible for any errors or omissions, or for the results obtained from the use there of. Where opinion is expressed, it is that of the authors and does not necessarily coincide with the editorial views of Radcliffe Cardiology. Statistical and financial data in this publication have been compiled on the basis of factual information and do not constitute any investment advertisement or investment advice. Radcliffe Cardiology, Unit F, First Floor, Bourne End Business Park, Cores End Road, Bourne End, Buckinghamshire, SL8 5AS © 2017 All rights reserved ISSN: 1758-3896 • eISSN: 1758-390X

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Established: March 2016 Frequency: Bi-annual Current issue: Fall 2017

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

• Once the authors have amended a manuscript in accordance with the reviewers’ comments, the manuscript is returned to the reviewers to ensure the revised version meets their quality expectations. Once approved, the manuscript is sent to the Editor-in-Chief for final approval prior to publication.

Submissions and Instructions to Authors

• US Cardiology Review is a bi-annual journal comprising review articles and editorials. • The structure and degree of coverage of the journal is determined by the Editor-in-Chief, with the support of the Editorial Board. • Articles are fully referenced, providing a comprehensive review of existing knowledge and opinion. • Each edition of US Cardiology Review is replicated in full online at www.USCjournal.com

• Contributors are identified and invited by the Commissioning Editor with guidance from the Editorial Board. • Following acceptance of an invitation, the author(s) and Commissioning Editor formalise the working title and scope of the article. • Subsequently, the Commissioning Editor provides an ‘Instructions to Authors’ document and additional submission details. • The journal is always keen to hear from leading authorities wishing to discuss potential submissions, and will give due consideration to any proposals. Please contact the Commissioning Editor for further details. The ‘Instructions to Authors’ information is available for download at www.USCjournal.com.

Editorial Expertise

Reprints

US Cardiology Review is supported by various levels of expertise: • Overall direction from an Editor-in-Chief, supported by an Editorial Board comprising leading authorities from a variety of related disciplines. • Invited contributors are recognised authorities from 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.

All articles included in US Cardiology Review are available as reprints. Please contact Liam O’Neill at liam.oneill@radcliffecardiology.com

Structure and Format

Peer Review • On submission, all articles are assessed by the Editor-in-Chief to determine their suitability for inclusion. • The Commissioning Editor, following consultation with the Editor-in-Chief, and/or a member of the Editorial Board, sends the manuscript to members of the Peer Review Board, 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 either 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.

Distribution and Readership US Cardiology Review is distributed bi-annually through controlled circulation to senior professionals in the field.

Copyright and Permission Radcliffe Cardiology is the sole owner of all articles and other materials that appear in US Cardiology Review unless otherwise stated. Permission to reproduce an article, either in full or in part, should be sought from the publication’s Managing Editor, Lindsey Mathews commeditor@radcliffecardiology.com.

Online All manuscripts published in US Cardiology Review are available free-to-view at www.USCjournal.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, Interventional Cardiology Review and European Cardiology Review. n

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Contents

Foreword Donald E Cutlip, MD

Acute Coronary Syndrome

Controversies in Antiplatelet and Anticoagulation Therapy in Patients Presenting with Acute Coronary Syndrome Colin T Phillips, MD and Michael C Gavin, MD

Clinical Trial Perspective: Optimizing Crossover From Ticagrelor to Clopidogrel in Patients with Acute Coronary Syndrome (CAPITAL OPTICROSS) Donald E Cutlip, MD

Heart Failure

New Drugs for the Treatment of Heart Failure Amarinder Bindra, MD and Shelley A Hall, MD

Valvular Disease

Clinical Practice Update: Who Should Be Referred for Transcatheter Aortic Valve Replacement in 2017? Colin M Barker, MD and Michael J Reardon, MD

Adult Congenital Heart Disease

The Impact of an Atrial Septal Defect on Hemodynamics in Patients With Heart Failure

Update on the Management of Patent Foramen Ovale in 2017: Indication for Closure and Literature Review

Saumil R. Shah, MD, Sergio Waxman, MD and William H. Gaasch, MD

Kimberly Atianzar, MD, Peter Casterella, MD, Ming Zhang, MD, PhD, Rahul Sharma, MD and Sameer Gafoor, MD

Interventional Cardiology

Advances in Coronary Physiology: Update for 2017

Left Ventricular Assisting Devices in Percutaneous Coronary Intervention

Morton J Kern, MD, MSCAI, FAHA, FACC1,2 and Katherine M Yu, MD

Ahmed M Alabbady, MD, Ahmed S Abdul-Al and Kimberly A Skelding, MD, FACC, FSCAI

Electrophysiology

Clinical Significance of Idiopathic Frequent Premature Ventricular Complexes Rakesh Latchamsetty, MD

Risk Prevention

98 105

Novel Pharmacologic Treatments for Cardiovascular Disease: A Practical Update Leo F. Buckley, PharmD and Ahmed Aldemerdash, BScPhm, PharmD, BCPS

Proprotein Convertase Subtilisin/kexin Type 9 Inhibitors in Clinical Practice: A Focused Update Evan A Stein, MD, PhD

Perspective

110

Early Retirement Elizabeth Ross MD FACC

ÂŠ RADCL IFFE CA RD IO LO G Y 2017

USC 11.2_Contents NEW.indd 47

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UPCOMING 2018 CRF EDUCATIONAL EVENTS

SAVE THE DATES

2017 ICI

Pulse

Innovations in Cardiovascular Systems December 3-5, 2017 Tel-Aviv, Israel

Pulse of the City Gala December 8, 2017 New York, NY A CRF Event

2018 TTT in Partnership With TCT Transcatheter Taiwan Therapeutics January 13-14, 2018 Taipei City, Taiwan

CHIP Florida CHIP: Complex Higher-Risk (and Indicated) Patients – Step-by-Step Approach January 19-20, 2018 Boca Raton, FL A CRF Event

BIT (TCT Highlights Session) Bangla Interventional Therapeutics February 10-11, 2018 Kolkata, India

CTO Chronic Total Occlusion Summit 2018: A Live Case Demonstration Course February 15-16, 2018 New York, NY A CRF Event

CADECI in Partnership With TCT Sociedad Mexicana de Electrofisiología y Estimulación Cardiaca February 21-24, 2018 Guadalajara, Mexico

JIM in Partnership With TCT Joint Interventional Meeting February 22-24, 2018 Milan, Italy

TVT

CHIP at ACC The Interventional Toolbox for Complex Higher-Risk (and Indicated) Patients (CHIP) March 9, 2018 Orlando, FL A CRF Event

Transcatheter Valve Therapies (TVT): Featuring Clinical Workshops June 21-23, 2018 Chicago, IL A CRF Event

CIT in Partnership With TCT

SOLACI in Partnership With TCT

Chinese Interventional Therapeutics March 22-25, 2018 Suzhou, China

Sociedad Latinoamericana de Cardiología Intervencionista August 1-3, 2018 Puebla, Mexico

Fellows Interventional Cardiology Fellows Course April 12-15, 2018 Orlando, FL A CRF Event

Echo

CHIP Seattle Expanding Your Practice to Include CHIP: An Interactive Workshop August 2018 Seattle, WA A CRF Event

TCT

Echocardiography Conference: State-of-the-Art 2018 April 18-20, 2018 New York, NY A CRF Event

CVREP in Partnership With TCT

Transcatheter Cardiovascular Therapeutics (TCT) September 21-25, 2018 San Diego, CA A CRF Event

April 19-21, 2018 Cairo, Egypt

GISE (TCT Highlights Session)

Cardiovascular Summit-TCTAP

October 2018 Milan, Italy

April 28-May 1, 2018 Seoul, Korea

CACI in Partnership With TCT

TCT Russia May 18-20, 2018 Moscow, Russia

Colegio Argentino de Cardioangiólogos Intervencionistas October 2018 Buenos Aires, Argentina

Information subject to change.

Please visit crf.org to get the latest info.

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TOGETHER WE

SHARE SCIENCE TOGETHER WE ARE

Mark your calendars! The Heart Rhythm Society returns to Boston, MA, May 9–12, 2018, for its Annual Scientific Sessions. Heart Rhythm 2018 will bring the global EP community together to discover the latest breakthroughs, discuss cutting-edge science, & build long-lasting relationships.

Abstract Deadline Member Registration Opens

December 1, 2017 December 12, 2017

Nonmember Registration Opens

January 9, 2018

Heart Rhythm 2018

May 9–12, 2018

Learn More at HRSsessions.org

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Supporting life-long learning for interventional cardiovascular professionals Led by Editor-in-Chief Donald E Cutlip and underpinned by an editorial board of renowned physicians, US Cardiology is a peer-reviewed journal that publishes reviews. Available in print and online, US Cardiology articles are free-to-access, and aim to support continuous learning for physicians within the field.

Call for Submissions US Cardiology Review publishes invited contributions from prominent experts, but also welcomes speculative submissions of a superior quality. For further information on submitting an article, or for free access to the journal, please visit:

www.USCjournal.com

Radcliffe Cardiology US Cardiology Review is part of the Radcliffe Cardiology family. For further information, including access to thousands of educational reviews from across the speciality, visit:

www.radcliffecardiology.com

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09/10/2016 18:07

Foreword

Donald E Cutlip MD is the Editor in Chief of US Cardiology Review journal, the Director of the Cardiac Catheterization Laboratory at The Cardiovascular Institute, Beth Israel Deaconess Medical Center, and Professor of Medicine at Harvard Medical School, Boston, MA.

he Editorial Board and staff are pleased to present the latest issue of US Cardiology Review. Ten timely reviews and a clinical trial perspective represent six different subspecialty sections, and the issue concludes with a special personal perspective on the pros and cons of early retirement from medical practice by Elizabeth Ross. Perhaps everyone has had that thought at one time or another! The issue leads off with a state-of-the-art review in the Acute Coronary Syndrome section by Colin Phillips and Michael Gavin on controversies in antiplatelet and anticoagulation therapy. This is followed by a clinical trial perspective from the CAPITAL OPTI-CROSS trial that discusses the frequent issue of converting from ticagrelor to clopidogrel after coronary stenting in these patients. Next, in the Heart Failure section, Shelley Hall and Amarinder Bindra provide a review on new pharmacologic agents for the management of heart failure. Understanding these new agents and their appropriate use will be essential as we strive for the balance of quality and costs in value-based health care. Colin Barker and Michael Reardon follow with a review on the selection of patients for transcatheter aortic valve replacement. As evidence from clinical trials continues to expand the potential population, it is helpful to have this expert perspective on case selection. In the Adult Congenital section, Saumil Shah et al. discuss the complex hemodynamics of left heart failure in the presence of an atrial septal defect. Understanding this pathophysiology may have implications for novel therapies of heart failure. Kimberly Atianzar et al. provide an update on the optimal management of patent foramen ovale, including the most recent evidence on the role for percutaneous closure. Moving on to Interventional Cardiology, there are two very relevant reviews on the contemporary practice of percutaneous coronary intervention. First, Morton Kern and Katherine Yu provide experts’ perspective on the use of fractional flow reserve. Although the value of this technology to guide case selection and optimize outcomes is clear, it is also important to understand its use and limitations in specific scenarios. This is followed by Kimberley Skelding et al.’s review of left ventricular support devices for percutaneous coronary intervention, a practice that has become increasingly common as more complex patients and lesions are referred for treatment. Next, in the Electrophysiology section, Rakesh Latchamsetty reviews the clinical implications of frequent isolated premature ventricular contractions, a problem whose clinical significance as a contributor to adverse cardiac outcomes may be often underappreciated. In the closing Risk Prevention section, there are two pharmacology reviews. Leo Buckley and Ahmed Aldemerdash address several recently approved drugs and their potential use in the management of cardiovascular disease, and Evan Stein provides a focused update on PCSK9 inhibitors. Timely guidance on patient selection and the use of novel therapies will continue to be an important concern for patient-centered care. As usual, we thank the authors and our reviewers for their efforts in assembling this variety of topics that we hope will be useful to you in the care of your patients. n

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Acute Coronary Syndrome

Controversies in Antiplatelet and Anticoagulation Therapy in Patients Presenting with Acute Coronary Syndrome Colin T Phillips, MD and Michael C Gavin, MD Division of Cardiology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA

Abstract Multiple, large-scale pharmaceutical and device trials have greatly improved the outcomes of patients with acute coronary syndrome (ACS). The expanding arsenal of antiplatelets, anticoagulants, and coronary stents has simultaneously generated debate over how to best optimize ischemic outcomes while mitigating bleeding risk for individual patients. This manuscript reviews the data supporting current practice, and highlights areas where the data are weak and controversies abound. After introducing the background and pathophysiology of patients presenting with ACS, five clinical controversies relevant to the everyday care of the ACS patient are discussed: (1) choice initial antiplatelet and anticoagulant combination; (2) decision to start second oral antiplatelet before or after coronary angiography; (3) transition between antiplatelets; (4) duration of dual antiplatelet therapy; and (5) management of patients on oral anticoagulants.

Keywords Acute coronary syndrome, antiplatelets, anticoagulants, bleeding, triple therapy Disclosure: The authors report no financial relationships or conflicts of interest. Received: March 23, 2017 Accepted: June 14, 2017 Citation: US Cardiology Review 2017;11(2):52–8. DOI: 10.15420/usc.2017:8:1 Correspondence: Colin T Phillips, Division of Cardiology, Department of Medicine, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA 02215, USA. E: ctphilli@bidmc.harvard.edu

Acute coronary syndrome (ACS) occurs most often when a vulnerable intracoronary plaque ruptures or erodes to expose a prothrombotic core, precipitating thrombus formation by way of platelet activation,1–3 The spectrum of ACS includes non-ST segment-elevation (NSTE) ACS, where a vulnerable plaque threatens downstream coronary perfusion manifest as an increase in symptom frequency and/or duration (unstable angina), and includes biomarker-proven myocardial necrosis from an NSTE myocardial infarction. Transmyocardial injury from complete thrombotic occlusion of the coronary artery results in an ST-segment elevation myocardial infarction (STEMI).4,5

Central to the controversy in treating patients presenting with an ACS is balancing safety and efficacy, which poses challenges for the practicing clinician. For example, there are nearly 3 million combinations of oral medications at different durations in patients who have a concurrent need for anticoagulation.8 This review utilizes landmark studies to address five clinical questions central to the controversy of balancing safety and efficacy: (1) which treatment to give; (2) when to start treatment; (3) how to switch between oral medications; (4) how long to treat; and (5) how to manage antiplatelets in patients on systemic anticoagulation. A timeline of these landmark studies is provided in Figure 1.

The spectrum of adverse outcomes in ACS includes ischemic complications of the index event, recurrent ischemic events after initial treatment, and complications from guideline-directed pharmaceutical and procedural interventions.

Which Treatment to Give

Patients identified as likely or definite ACS are typically managed following either an “early invasive” or “ischemia-guided” strategy. Patients in both groups receive similar upstream oral and parenteral medications, while patients following an early invasive strategy undergo coronary angiography and provisional percutaneous coronary intervention (PCI) based on immediately-available clinical, electrocardiogram, and laboratory data. Utilizing risk scores, and considering the patient’s clinical presentation, helps guide selection of the two strategies, where patients with a thrombolysis is myocardial infarction (TIMI) risk score ≥3 or a Global Registry of Acute Coronary Events score >140 benefit from an early invasive strategy.4–7

Access at: www.USCjournal.com

USC_Phillips_FINAL.indd 52

Parenteral Anticoagulants Consensus does not exist on the appropriate combination of medications. For example, the European Society of Cardiology (ESC) recommends against upstream use of a glycoprotein IIb/IIIa inhibitor prior to defining the coronary anatomy, whereas the American Heart Association (AHA)/ American College of Cardiology (ACC) suggests that it is reasonable to use prior to angiography in high-risk patients.9,10 Data support the use of unfractionated heparin (UFH), enoxaparin, and fondaparinux to reduce ischemic events in both ischemia-guided and early invasive strategies. Consideration can be given to using bivalirudin or adding a glycoprotein IIb/IIIa inhibitor to heparin in patients treated with an early invasive strategy. In clinical practice, UFH is most often selected initially because of its low cost, short half-life, ease of monitoring, lack of renal clearance, and ability to quickly reverse with protamine.

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Antiplatelet and Anticoagulation Therapy in ACS Figure 1: Timeline of major trials discussed

Year

1997

Which treatment

ESSENCE

1998

2001

2002

2003

CURE

Preloading

CURE

CREDO

ISARCOOL

2004

2006

2007

2009

2010

2012

SYNERGY

OASIS-5/ ACUITY

TRITONTIMI 38

EARLY ACS/ PLATO

CURRENT OASIS7

TRILOGY ACS

ACUITY

PLATO/ TIMACS

2013

ACCOAST/ CHAMPION

Reloading

2015

2016

MOJITO

SWAP 2

Duration Triple Therapy

2014

CREDO

STARS

PRODIGY/ EXCELLENT/ RESET

OPTIMIZE

ATLAS

WOEST

DAPT

ZEUS

PIONEER

ACCOAST = Comparison of Prasugrel at the Time of Percutaneous Coronary Intervention or as Pretreatment at the Time of Diagnosis in Patients with Non-ST Elevation Myocardial Infarction; ACS = acute coronary syndrome; ACUITY = Acute Catheterization and Urgent Intervention Triage StrategY; ATLAS = Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with Acute Coronary Syndrome; CHAMPION = Cangrelor versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition; CREDO = Clopidogrel for the Reduction of Events During Observation; CURE = Clopidogrel in Unstable Angina to Prevent Recurrent Events; CURRENT = Clopidogrel and Aspirin Optimal Dose Usage to Reduce Recurrent Events; DAPT = dual antiplatelet therapy; EARLY = Early Glycoprotein IIb/IIIa Inhibition; ESSENCE = Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-Wave Coronary Events; EXCELLENT = Efficacy of Xience/ Promus Versus Cypher to Reduce Late Loss After Stenting; ISAR-COOL = Intracoronary Stenting With Antithrombotic Regimen Cooling-Off; MOJITO = Mashed Or Just Integral pill of TicagrelOr; OASIS = Organization to Assess Strategies in Ischemic Syndromes; OPTIMIZE = Optimized Duration of Clopidogrel Therapy Following Treatment With the Zotarolimus-Eluting Stent in Real-World Clinical Practice; PIONEER = Study Exploring Two Treatment Strategies of Rivaroxaban and a Dose-Adjusted Oral Vitamin K Antagonist Treatment Strategy in Subjects with Atrial Fibrillation who Undergo Percutaneous Coronary Intervention; PLATO = Platelet Inhibition and Patient Outcomes; PRODIGY = Prolonging Dual Antiplatelet Treatment After Grading Stent-Induced Intimal Hyperplasia Study; RESET = Real Safety and Efficacy of 3-Month Dual Antiplatelet Therapy Following Endeavor Zotarolimus-Eluting Stent Implantation; STARS = Stent Anticoagulation Restenosis Study; SWAP-2 = Switching Anti Platelet-2; SYNERGY = Superior Yield of the New Strategy of Enoxaparin, Revascularization, and Glycoprotein IIb/IIIa Inhibitors; TIMACS = Timing of Intervention in Acute Coronary Syndromes; TRILOGY = TaRgeted platelet Inhibition to cLarify the Optimal strategy to medically manage Acute Coronary Syndromes; TRITON-TIMI = Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel–Thrombolysis in Myocardial Infarction; WOEST = What is the Optimal antiplatelet and anticoagulation therapy in patients with oral anticoagulation and coronary StenTing; ZEUS = Zotarolimus-eluting Endeavor Sprint Stent in Uncertain DES Candidates.

In the era before routine oral treatment with dual antiplatelet therapy (DAPT), a meta-analysis of the TIMI 11b and Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-Wave Coronary Events trials demonstrated that enoxaparin reduced the risk of death or myocardial infarction by 20 % when compared to UFH. Part of the explanation of this benefit was that enoxaparin has a higher affinity for factor Xa than IIa compared to UFH, and therefore, greater inhibition of thrombin generation by interrupting the coagulation cascade closer to its root.11 It is important to note that most patients were treated with an ischemiaguided strategy, and fewer than 10 % of patients in the TIMI 11b trial underwent urgent revascularization within the first 8 days.11

A meta-analysis of over 30,000 patients from six randomized, controlled trials undergoing an ischemia-guided strategy found that routine use of glycoprotein IIb/IIIa inhibitors reduced the odds of death or myocardial infarction by 9 % prior to PCI, particularly in patients at the highest ischemic risk.14 Patients in these trials were rarely treated upstream with DAPT, and as the practice of DAPT has increased, upfront IIb/IIIa inhibitors have become less popular.

The Superior Yield of the New Strategy of Enoxaparin, Revascularization, and Glycoprotein IIb/IIIa Inhibitors trial compared enoxaparin to UFH in 10,027 patients treated with an early invasive strategy, and found no difference in mortality between the groups.12 In this trial, nearly 60 % of patients were treated with a P2Y12 inhibitor and a glycoprotein IIb/ IIIa inhibitor. Investigators additionally found that patients who switched between arms had a higher rate of bleeding, which was thought to be due to the difficulty of dosing and the rapid monitoring of enoxaparin levels around the time of PCI because of its long half-life.12

The introduction the direct thrombin inhibitor bivalirudin further pushed IIb/IIIa inhibitors out of favor. The Acute Catheterization and Urgent Intervention Triage strategY (ACUITY) trial demonstrated in nearly 14,000 patients with ACS that bivalirudin was not inferior to heparin and a IIb/IIIa inhibitor for ischemic outcomes at 30 days, with the benefit of reduced major bleeding events (3.0 % versus 5.7 %). In one study, 64 % of patients were pretreated with a P2Y12 inhibitor.15 The reduction in bleeding events had the strongest interaction with ACS patients who underwent PCI by femoral access.16

In the Organization to Assess Strategies in Ischemic Syndromes (OASIS) 5 trial, 20,078 patients were randomized in a double-blind fashion to the factor Xa inhibitor fondaparinux or enoxaparin, with 60 % of the study population treated with an early invasive strategy and over 40 % treated with either PCI or coronary artery bypass grafting (CABG) while hospitalized. There was no difference in death or myocardial infarction at 9 days, but after 30 days, the fondaparinux group had a lower rate of bleeding (2.2 % versus 4.1 %) and death at 30 days (295 versus 352 patients).13 There was an increased incidence of catheter thromboses (0.9 % versus 0.3 %) among the patients who underwent coronary angiography, which raised concern about its use in patients undergoing

The Early Glycoprotein IIb/IIIa Inhibition ACS trial further supported avoiding routine, upfront eptifibatide in patients treated with clopidogrel (75 % of population), by demonstrating no added benefit of the IIb/IIIa inhibitor and an increased risk of bleeding.9

US CARDIOLOGY REVIEW

USC_Phillips_FINAL.indd 53

a routine invasive strategy. The ESC recommends fondaparinux as the first-line anticoagulant agent in ischemia-guided strategies, whereas the AHA/ACC makes no preference.4,10

In a Bayesian analysis of 18 randomized, controlled trials comparing heparin to bivalirudin, the overall unadjusted mortality was not different between the groups. Patients treated with bivalirudin had fewer bleeding events, but a higher rate of early stent thrombosis. The bleeding advantage of bivalirudin was reduced when the results were stratified by transradial access, planned glycoprotein IIb/IIIa use with bivalirudin,

22/10/2017 14:18

Acute Coronary Syndrome Table 1: Choice of antiplatelet therapy Use Dose Metabolism

Onset of action

Clopidogrel ACS

2 hours 6 hours 5 days (2 days if no load)

75 mg daily (300–600 mg load)

Prasugrel After 10 mg daily PCI (60 mg load)

Prodrug: must be converted

Half-life

Washout period

Special considerations Avoid if previous stent thrombosis; irreversible binding

Prodrug: 30 minutes 7 hours 7 days Avoid if >75 years, weigh quick <60 kg, h/o TIA/stroke; metabolism irreversible binding

Ticagrelor ACS 90 mg twice Direct acting 30 minutes 9 hours 5 days Avoid if COPD, CKD, Daily (180 mg gout, bradyarrhythmias; load) reversible binding ACS = acute coronary sydrome; ‘CKD = chronic kidney disease; COPD = chronic obstructive pulmonary disease; h/o = history of; PCI = percutaneous coronary intervention; TIA = transient ischemic attack.

or administering ticagrelor or prasugrel. Interestingly, the use of ticagrelor or prasugrel did not reduce the risk of stent thrombosis in patients randomized to bivalirudin.17 In current practice, parenteral anticoagulation for ACS is typically a decision between heparin and provisional IIb/IIIa inhibitors versus bivalirudin if proceeding to PCI.

Oral Antiplatelet Medications While its utility in the primary prevention of cardiovascular events is subject to debate, in patients not on systemic anticoagulation, aspirin is accepted as the standard of care in the treatment of ACS.18 Oral P2Y12 inhibitors (clopidogrel, ticagrelor, and prasugrel) now serve as mandatory support to protect against stent thrombosis in ACS, as well as to reduce all-cause ischemic events post-ACS. Guidelines recommend 1 year of DAPT, regardless of whether a stent is placed in a patient with NSTE-ACS.4 Clopidogrel and prasugrel are thienopyridines that irreversibly block the adenosine diphosphate (ADP) binding site on the P2Y12 receptor and inhibit platelet aggregation. Ticagrelor is a cyclopentyl-triazolo-pyrimidine agent that binds directly on the P2Y12 receptor (apart from the ADP binding site) without enzymatic conversion, and likewise, inhibits ADPinduced platelet aggregation.19,20 The characteristics of these antiplatelets are represented in Table 1. Evidence supporting the use of DAPT in ACS stems from the Clopidogrel in Unstable angina to prevent Recurrent ischemic Events (CURE) trial, which demonstrated the benefit of adding clopidogrel with a loading dose of 300 mg to aspirin in ACS, regardless of whether PCI was pursued.21 A 600 mg dose of clopidogrel at least 2 hours prior to PCI is further associated with improved platelet inhibition compared to 300 mg.22 The Clopidogrel and Aspirin Optimal Dose Usage to Reduce Recurrent Events–OASIS 7 demonstrated that loading with 600 mg of clopidogrel followed by 150 mg daily on days 2–7, compared to 300 mg followed by 75 mg, reduced the risk of stent thrombosis by 32 % at the expense of a 24 % increase in major bleeds among patients undergoing PCI for ACS.23 While stent thrombosis risk was reduced, there was no difference in the primary outcome of cardiovascular death, myocardial infarction, or stroke at 30 days between the clopidogrel high- and low-dose arms.24 This trial also demonstrated that, after an initial load of >300 mg aspirin, a low dose is equivalent to continued high dose on days 2–30.23

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Ticagrelor was compared to clopidogrel in the PLATelet inhibition and patient Outcomes (PLATO) trial, which demonstrated a reduced rate of death, myocardial infarction, or stroke, without an increase in the rate of overall major bleeding, but at the expense of a slightly higher risk of nonprocedure-related bleeding. This was true for patients undergoing both ischemia-guided and early invasive treatment strategies. Ticagrelor also conferred a 33 % relative risk reduction in stent thrombosis compared with clopidogrel.25,26 Regional variability with improved performance of clopidogrel (and no benefit of ticagrelor) in North America was seen in the trial, perhaps related to the increased use of high-dose aspirin in the US.27 As a result, the Food and Drug Administration (FDA) recommends <100 mg aspirin given concurrently with ticagrelor. Prasugrel reduced the rates of ischemic events, including stent thrombosis, in patients undergoing PCI for ACS compared with clopidogrel at the expense of increased major bleeding, including fatal bleeding in the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel (TRITON)-TIMI 38 trial.25 In the trial, 55 % of patients were treated with a glycoprotein IIb/IIIa inhibitor, and 3 % with bivalirudin, compared with 26 % and 2 %, respectively, in the PLATO trial. Other differences between these trials include clopidogrel loading dose (600 mg in the PLATO trial and 300 mg in the TRITON trial) and timing of drug loading relative to PCI (4 hours on average before PCI in the PLATO trial and at the time of PCI or immediately post in the TRITON trial). In a follow-up study, investigators found a greater inhibition of platelet aggregation measured in vitro with a 60 mg loading dose of prasugrel compared to a 600 mg loading dose of clopidogrel.28 Of note, no benefit or potential harm was seen among patients treated with prasugrel who were older than 75 years, weighed less than 60 kg, or who had a prior cerebrovascular accident.29 A black-box warning advises against use in these groups. Prasugrel is also superior to clopidogrel in preventing stent thrombosis.30 In patients with ACS who do not undergo revascularization, treatment with prasugrel versus clopidogrel resulted in similar rates of death from cardiovascular causes, myocardial infarction, or stroke in patients under the age of 75 years in the TaRgeted platelet Inhibition to cLarify the Optimal strategy to medically manage Acute Coronary Syndromes ACS Trial.31 In summary, current guidelines agree with a loading dose of aspirin at THE time of presentation, and a maintenance low dose in patients after ACS. Treatment with dual antiplatelet therapy is recommend for patients with ACS, regardless of treatment strategy, but prasugrel is approved only

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Antiplatelet and Anticoagulation Therapy in ACS among patients undergoing PCI.4,5 The timing of initiation of the P2Y12 inhibitor in the management of ACS remains a subject of much debate, and is discussed next.

primary endpoint of stroke, myocardial infarction, or death at 30 days; however, the majority of patients (>90 %) were treated with a loading dose of clopidogrel prior to PCI.7

When to Start a Second Antiplatelet Agent in NSTE-ACS: Preloading

Despite questions raised by these trials, there has not been a prospective, randomized trial examining optimal timing of clopidogrel or ticagrelor loading.41 The Comparison of Prasugrel at the Time of Percutaneous Coronary Intervention or as Pretreatment at the Time of Diagnosis in Patients with Non-ST Elevation Myocardial Infarction trial randomized patients to pretreatment with prasugrel (30 mg prior to PCI and 30 mg after) versus loading after PCI. The trial was stopped early, given no benefit of the pretreatment arm, and increased bleeding events.42 These randomized data have tempered enthusiasm for preloading.33

Despite solid agreement in the guidelines, and support for preloading from both the ESC and AHA/ACC, resistance to preloading with either clopidogrel or ticagrelor persists.10,32,33 Frequently-cited concerns about preloading with P2Y12 inhibitors are the need to delay CABG in ACS patients with surgical disease and/or increased CABG-related bleeding. However, the need for in-hospital CABG in patients presenting with ACS ranged from 4.5 % to 11.1 % in the CURE, ACUITY, and PLATO trials. While it occurs in a minority of patients, there is a wide range of CABG-related major bleeding, which is reported to occur 7.0–52.9 % of the time.25,34,35 Conversely, there is also fear that administration of the oral medications might not be metabolized effectively, and treatment could be ineffective in the period shortly after oral administration.36 This controversy drives at the crux of balancing safety and efficacy. Early data from the CURE trial demonstrated the benefit of early antiplatelet treatment with P2Y12 inhibitors, where a dose of clopidogrel reduced the risk of the primary combined endpoint of death, myocardial infarction, or stroke (PCI median was 6 days). With clopidogrel pretreatment, the event curves diverged early and prior to PCI.21 Furthermore, in the ACUITY trial of bivalirudin versus heparin and a glycoprotein IIb/IIIa, 68 % of patients were pretreated with a thienopyridine prior to PCI, and had a trend toward fewer ischemic events compared to those not pretreated.16 In the PLATO trial, all patients were preloaded with ticagrelor, and while the benefit occurred when treatment was initiated prior to PCI, the differences in timing of initiation were not analyzed.25 In a meta-analysis of patients undergoing an early invasive strategy, clopidogrel pretreatment was not associated with a reduction of death nor increased risk of major bleeding, but did show a decreased rate of major coronary events or myocardial infarctions.37 There is overall less benefit to pretreatment when there is a shorter time to angiography, likely due to delayed transit and absorption of the swallowed tablets.36 The Mashed Or Just Integral pill of TicagrelOr trial circumvents this concern, and demonstrated improved function (reduced platelet reactivity) in STEMI patients within 1 hour of administering crushed ticagrelor, suggesting a pharmacokinetic advantage over whole tablets.38 Direct evidence showing that delaying angiography for preloading P2Y12 inhibitors is lacking. The hypothesis generated from evidence based on the Clopidogrel for the Reduction of Events During Observation (CREDO) trial was that pretreatment with 300 mg clopidogrel 3–24 hours prior to PCI reduced event rates, but only in the subgroup of patients treated at least 6 hours prior to PCI.39 However, the Intracoronary Stenting with Antithrombotic Regimen Cooling-Off trial found that pretreatment with antithrombotic therapy, including clopidogrel, for 3–5 days increased mortality compared with early (<6 hours) angiography (Tirofiban was used in all patients).40 In contrast, the Timing of Intervention in Acute Coronary Syndromes trial compared early (<24 hours) versus delayed (>3 days) coronary angiography, and found no overall difference in the

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Patients undergoing PCI who have not been pretreated with an oral P2Y12 inhibitor are often given IIb/IIIa inhibitors during the PCI, following data demonstrating a reduction in ischemic events in these patients.43 Cangrelor is a recently FDA-approved parenteral P2Y12 inhibitor that offers rapid platelet inhibition.5 When started a median of 4.4 hours before PCI in a pooled analysis of nearly 25,000 patients, cangrelor reduced the combined endpoint of death, myocardial infarction, revascularization, and stent thrombosis (3.8 % versus 4.7 %), without an increase in Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries severe/life-threatening bleeding, but with an increase in TIMI mild and ACUITY major bleeding. A majority of patients were given a loading dose of clopidogrel immediately prior to PCI, with 75 % of patients treated with unfractionated heparin, and 25 % with bivalirudin.44 A reasonable strategy for the practicing cardiologist involves loading patients presenting with ACS with a P2Y12 inhibitor, and utilizing radial access and a short course of IIb/IIIa inhibitors (3 hours, not 12–24 hours), if needed, to minimize bleeding and maximize efficacy.

How to Switch Oral Medications: Reloading After initiating treatment with an oral P2Y12 inhibitor, often patients need to switch to an alternative medicine due to insurance coverage or adverse events, including upper gastrointestinal bleeding with prasugrel or dyspnea with ticagrelor.29,41 Due to differences in kinetics and the mechanism of action, switching medicines is not as simple as starting one and stopping another. Guidelines do not currently support a method of switching, and clinical outcome data are sparse. Both prasugrel and clopidogrel irreversibly bind to the ADP receptor binding site on the platelet. Clopidogrel has a delayed effect for full platelet inhibition, and along with prasugrel, must be metabolically activated (Table 1).19,39 Ticagrelor binds reversibly and independently from ADP outcompetes binding with prasugrel or clopidogrel.19 Due to its 9-hour half-life and reversible binding, platelet function recovers quickly with the cessation of ticagrelor. Unless a loading dose is given to allow continued exposure, prasugrel and clopidogrel are only transient in the circulation, and new platelets remain activated (since no longer bound by ticagrelor), as they are released into the circulation. The Switching Anti Platelet-2 trial demonstrated the return of platelet reactivity when switching from ticagrelor to prasugrel, which was reduced, but not fully resolved with a reloading of prasugrel.45

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Acute Coronary Syndrome While clinical outcomes are unknown, and anecdotal reports of adverse patient events abound, when an alternative antiplatelet is required, it is reasonable to reload with either clopidogrel or prasugrel when switching from ticagrelor. Alternatively, initiating ticagrelor or switching between clopidogrel or prasugrel does not require reloading.2,19,28 If a patient requires increased efficacy in their antiplatelet regimen, reloading with prasugrel or ticagrelor from clopidogrel is reasonable to strengthen the antiplatelet effect. Another consideration discussed below is that if patients require the initiation of anticoagulation due to atrial fibrillation, it is generally advised to switch to clopidogrel from a more potent P2Y12 inhibitor to limit bleeding.41

Treatment Duration While guidelines have long supported 1 month of DAPT for bare-metal stents, and 12 months for drug-eluting stents, a decade of trials has pushed the acceptable duration of dual antiplatelet therapy in both directions, based on the patient’s clinical condition, complicating a universal approach to therapy. A recent update to the AHA/ACC guidelines now recommends a minimum of 6 months of dual antiplatelet therapy following the placement of a drug-eluting stent, but practice variability exists.46 The threat of late stent thrombosis (occurring between 1–12 months) with the discontinuation of dual antiplatelet therapy drives prolonged treatment.47 Early real-world reports with sirolimus and paclitaxel-eluting stents demonstrated a 1.3 % risk of stent thrombosis in three hospitals and a 45 % mortality. Early discontinuation of antiplatelet therapy emerged as a major predictor of stent thrombosis.48 The CREDO trial emphasized the importance of 12 months versus 1 month of clopidogrel treatment after elective bare-metal stent implantation, with a 26.9 % relative risk reduction of the combined endpoint of death, myocardial infarction, or stroke.39 The DAPT trial tested continuing dual antiplatelet therapy (65 % clopidogrel, 35 % prasugrel) beyond 12 months after coronary stenting, and demonstrated reduced ischemic endpoints, including stent thrombosis and major adverse cardiovascular and cerebral events.49 Additional benefits included a reduction in myocardial infarction. More than half of the total benefit was unrelated to stent thrombosis, reaffirming the role of DAPT in reducing non-target vessel ischemic events. These benefits, however, came at a 1 % absolute increase in major bleeding events. A bleeding risk calculator to assist in clinical decision-making was derived and validated, with scores above 2 associated with a greater benefit of continuing dual antiplatelet therapy beyond 12 months.50 Numerous trials demonstrate non-inferiority for the shorter duration of dual antiplatelet therapy in specific scenarios. The Prolonging Dual Antiplatelet Treatment After Grading Stent-Induced Intimal Hyperplasia Study trial tested 6 months versus 24 months of clopidogrel in patients treated with a mix of bare-metal and drug-eluting stents, and found no difference in the risk of death, myocardial infarction, or cerebrovascular accident, but an increased risk of hemorrhage in the 24-month clopidogrel group.51 The Efficacy of Xience/Promus Versus Cypher to Reduce Late Loss After Stenting trial demonstrated that 6-month dual antiplatelet therapy did not increase the risk of target vessel failure at 12 months compared with a 12-month dual antiplatelet strategy. This trial has been criticized because of the wide non-inferiority margin that some consider clinically unaceptable.52

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The Zotarolimus-eluting Endeavor Sprint Stent in Uncertain DES Candidates trial demonstrated superiority of 1 month of dual antiplatelet therapy in patients receiving a zotarolimus-eluting stent with a fast-release profile versus a bare-metal stent in reducing myocardial infarction and target vessel revascularization.53 Utilizing the same Endeavor zotarolimus-eluting stent, the Real Safety and Efficacy of 3-Month Dual Antiplatelet Therapy Following Endeavor Zotarolimus-Eluting Stent Implantation trial demonstrated noninferiority of a 3-month dual antiplatelet strategy versus 12 months, without an excess risk of stent thrombosis after cessation of clopidogrel in the 3-month group.54 In addition, the Optimized Duration of Clopidogrel Therapy Following Treatment With the Zotarolimus-Eluting Stent in Real-World Clinical Practice trial demonstrated non-inferiority of 3 months versus 12 months of DAPT in stable, low-risk patients treated with a zotarolimus-eluting stent.55 When considering the duration of dual antiplatelet therapy, balancing the risk of bleeding and benefit of preventing ischemia is difficult and calls for the development of decision tools, such as the DAPT score, to help guide individual treatment deicsions.50

How to Address Triple Therapy Over 5 % of patients referred for PCI have concurrent atrial fibrillation. Patients treated with dual antiplatelet therapy, as well as anticoagulation (so-called “triple therapy”), have an excess risk of major bleeding beyond 10 % per year,56,57 While there is guidance from multiple groups on the management of these patients, until recently, there have been little randomized, controlled data.58–60 Warfarin is effective post-ACS at decreasing recurrent myocardial infarction from a meta-analysis of nearly 6,000 patients treated without stents, but at an increased rate of bleeding.61 For preventing ischemic complications following stent placement, DAPT with ticlopidine is superior to aspirin and warfarin, based on the Stent Anticoagulation Restenosis Study trial.62 The Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with Acute Coronary Syndrome ACS-TIMI 51 trial demonstrated secondary risk reduction with a low-dose rivaroxaban treatment shortly after ACS. This highlights the role of factor Xa in thrombosis in patients with ACS, and the benefits of Xa inhibition, but also the risk of bleeding. While triple therapy is often inevitable, practice has centered around limiting the duration of treatment with triple therapy by either using bare-metal stents or balancing the risk of stroke and stent thrombosis and lowering the international normalized ratio goals to 2.0–2.5.57 The What is the Optimal antiplatelet and anticoagulation therapy in patients with oral anticoagulation and coronary StenTing trial tested the innovative idea of dropping aspirin from the triple-therapy cocktail in patients with atrial fibrillation and a stent. The major finding was a 64 % relative risk reduction in any bleeding event (not just major bleeding) at 1 year in patients treated with a vitamin K antagonist and clopidogrel versus triple therapy.63 While the trial was small (573 patients), there was no evidence of increased thrombotic risk of dropping aspirin. Recent data from the Study Exploring Two Treatment Strategies of Rivaroxaban and a Dose-Adjusted Oral Vitamin K Antagonist Treatment Strategy in Subjects with Atrial Fibrillation who Undergo Percutaneous Coronary Intervention (PIONEER) trial demonstrated the improved safety of dropping aspirin in favor of low-dose rivaroxaban (15 mg daily) in addition

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Antiplatelet and Anticoagulation Therapy in ACS to a P2Y12 inhibitor versus standard triple therapy.64 Randomization of the 2,124 patients occurred in a 1:1:1 ratio, and included a group of patients also treated with very low-dose rivaroxaban (2.5 mg twice daily). In the group of patients treated with 15 mg rivaroxaban and a P2Y12 inhibitor, there was a 41 % relative risk reduction of clinically-significant bleeding. Likewise, there was a 37 % relative risk reduction when comparing 2.5 mg rivaroxaban twice daily with triple therapy with warfarin. Patients were excluded if they had a recent gastrointestinal bleed, anemia of unknown cause, recent transient ischemic attack or stroke, or if the creatinine clearance was <30 mL/min.64 In addition to the PIONEER trial, three other trials assessing other oral anticoagulants are ongoing to help further elucidate the question of minimizing both bleeding and thrombotic risks in these patients.65 These trials are designed to assess safety. Demonstration of non-inferiority or superiority for bleeding will be expected, given the high risk of bleeding with triple therapy and the relative low risk of embolic events. Proving efficacy is limited by the large number of patients required, and therefore, the efficacy of dropping aspirin will likely remain an area of controversy.

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Conclusion Patients undergoing coronary stenting have numerous medical therapies to help minimize adverse events, including stent thrombosis, while balancing the risk of bleeding. The practicing cardiologist faces numerous uncertainties as they treat patients with ACS. This review explored the controversies, including the choice initial antiplatelet and anticoagulant combination, decision of when to load with a second P2Y12 inhibitor and how to transition between them, how long to treat after a stent, and how to manage patients on oral anticoagulants. Navigating the different treatment possibilities remains a daunting task. Within a vast knowledge base and excellent trials, controversy still exists in how to best manage patients presenting with ACS. While guidelines and assistance exist, ultimately many of these questions are best answered when considering the totality of the patient’s presentation. Tailoring the therapy for each patient combines the art and science of clinical medicine, with the emphasis on the individual patient. n

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54. DOI: 10.1161/CIRCULATIONAHA.111.047498; PMID: 21709065. Wiviott SD, Trenk D, Frelinger AL, et al. Prasugrel compared with high loading- and maintenance-dose clopidogrel in patients with planned percutaneous coronary intervention: the Prasugrel in Comparison to Clopidogrel for Inhibition of Platelet Activation and Aggregation-Thrombolysis in Myocardial Infarction 44 trial. Circulation 2007;116(25):2923–32. DOI: 10.1161/ CIRCULATIONAHA.107.740324; PMID: 18056526. Wiviott SD, Braunwald E, McCabe CH, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007;357(20):2001–15. DOI: 10.1056/NEJMoa0706482. Wiviott SD, Braunwald E, McCabe CH, et al. Intensive oral antiplatelet therapy for reduction of ischaemic events including stent thrombosis in patients with acute coronary syndromes treated with percutaneous coronary intervention and stenting in the TRITON-TIMI 38 trial: a subanalysis of a randomised trial. Lancet 2008;371(9621):1353–63. DOI: http://dx.doi.org/10.1016/ S0140-6736(08)60422-5; PMID: 18377975. Roe MT, Armstrong PW, Fox KAA, et al. Prasugrel versus clopidogrel for acute coronary syndromes without revascularization. N Engl J Med 2012;367(14):1297–309. DOI: 10.1056/NEJMoa1205512; PMID: 22920930. Valgimigli M. Pretreatment with P2Y12 inhibitors in non-STsegment-elevation acute coronary syndrome is clinically justified. Circulation 2014;130(21):1891–903. DOI: 10.1161/ CIRCULATIONAHA.114.011319; PMID: 25403595. Collet J-P, Silvain J, Bellemain-Appaix A, Montalescot G. Pretreatment with P2Y12 inhibitors in non-ST-Segmentelevation acute coronary syndrome: an outdated and harmful strategy. Circulation 2014;130(21):1904–14. DOI: 10.1161/ CIRCULATIONAHA.114.011320; PMID: 25403596. Fox KAA, Mehta SR, Peters R, et al. Benefits and risks of the combination of clopidogrel and aspirin in patients undergoing surgical revascularization for non-ST-elevation acute coronary syndrome: the Clopidogrel in Unstable angina to prevent Recurrent ischemic Events (CURE) Trial. Circulation 2004;110(10):1202–8. DOI: 10.1161/01.CIR.0000140675.85342.1B; PMID: 15313956. Stone GW, Clayton TC, Mehran R, et al. Impact of major bleeding and blood transfusions after cardiac surgery: analysis from the Acute Catheterization and Urgent Intervention Triage strategY (ACUITY) trial. Am Heart J 2012;163(3):522–9. DOI: 10.1016/j. ahj.2011.11.016; PMID: 22424026. Ghobrial J, Gibson CM, Pinto DS. Delayed clopidogrel transit during myocardial infarction evident on angiography. J Invasive Cardiol 2015;27(5):E68–9. PMID: 25929306. Bellemain-Appaix A, O’Connor SA, Silvain J, et al. Association of clopidogrel pretreatment with mortality, cardiovascular events, and major bleeding among patients undergoing percutaneous coronary intervention: a systematic review and meta-analysis. JAMA 2012;308(23):2507–16. DOI: 10.1001/jama.2012.50788; PMID: 23287889. Parodi G, Xanthopoulou I, Bellandi B, et al. Ticagrelor crushed tablets administration in STEMI patients: the MOJITO study. J Am Coll Cardiol 2015;65(5):511–2. DOI: 10.1016/j.jacc.2014.08.056; PMID: 25660931. Steinhubl SR, Berger PB, Mann JT, et al. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. JAMA

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Acute Coronary Syndrome 2002;288(19):2411–20. PMID: 12435254. 40. N eumann F-J, Kastrati A, Pogatsa-Murray G, et al. Evaluation of prolonged antithrombotic pretreatment (“cooling-off” strategy) before intervention in patients with unstable coronary syndromes: a randomized controlled trial. JAMA 2003;290(12):1593–9. DOI: 10.1001/jama.290.12.1593; PMID: 14506118. 41. Collet J-P, Roffi M, Mueller C, et al. Questions and answers on antithrombotic therapy: a companion document of the 2015 ESC guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation. Eur Heart J 2015;37(3):e1–7. DOI: 10.1093/ eurheartj/ehv407; PMID: 26320115. 42. Montalescot G, Bolognese L, Dudek D, et al. Pretreatment with Prasugrel in Non–ST-Segment Elevation Acute Coronary Syndromes. N Engl J Med 2013;369(11):999–1010. DOI: 10.1056/ NEJMoa1308075; PMID: 23991622. 43. EPILOG Investigators. Platelet glycoprotein IIb/IIIa receptor blockade and low-dose heparin during percutaneous coronary revascularization. N Engl J Med 1997;336(24):1689–96. DOI: 10.1056/NEJM199706123362401; PMID: 9182212. 44. Steg PG, Bhatt DL, Hamm CW, et al. Effect of cangrelor on periprocedural outcomes in percutaneous coronary interventions: a pooled analysis of patient-level data. Lancet 2013;382(9909): 1981–92. DOI: 10.1016/S0140-6736(13)61615-3; PMID: 24011551. 45. Angiolillo DJ, Curzen N, Gurbel P, et al. Pharmacodynamic evaluation of switching from ticagrelor to prasugrel in patients with stable coronary artery disease: Results of the SWAP-2 Study (Switching Anti Platelet-2). J Am Coll Cardiol 2014;63(15):1500–9. DOI: 10.1016/j.jacc.2013.11.032; PMID: 24333493. 46. Levine GN, Bates ER, Bittl JA, et al. 2016 ACC/AHA Guideline focused update on duration of dual antiplatelet therapy in patients with coronary artery disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Thorac Cardiovas Surg 2016;152(5):1243–75. DOI: 10.1016/j.jtcvs.2016.07.044; PMID: 27751237. 47. McFadden EP, Stabile E, Regar E, et al. Late thrombosis in drugeluting coronary stents after discontinuation of antiplatelet therapy. Lancet 2004;364(9444):1519–21. DOI: 10.1016/S01406736(04)17275-9; PMID: 15500897. 48. Iakovou I, Schmidt T, Bonizzoni E, et al. Incidence, predictors, and outcome of thrombosis after successful implantation of drug-eluting stents. JAMA 2005;293(17):2126–30. DOI: 10.1001/ jama.293.17.2126; PMID: 15870416.

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49. M auri L, Kereiakes DJ, Yeh RW, et al. Twelve or 30 months of dual antiplatelet therapy after drug-eluting stents. N Engl J Med 2014;371(23):2155–66. DOI: 10.1056/NEJMoa1409312; PMID: 25399658. 50. Yeh RW, Secemsky EA, Kereiakes DJ, et al. Development and validation of a prediction rule for benefit and harm of dual antiplatelet therapy beyond 1 year after percutaneous coronary intervention. JAMA 2016;315(16):1735–49. DOI: 10.1001/ jama.2016.3775; PMID: 27022822. 51. Valgimigli M, Campo G, Monti M, et al. Short- versus long-term duration of dual-antiplatelet therapy after coronary stenting: a randomized multicenter trial. Circulation 2012;125(16):2015–26. DOI: 10.1161/CIRCULATIONAHA.111.071589; PMID: 22438530. 52. Gwon H-C, Hahn J-Y, Park KW, et al. Six-month versus 12-month dual antiplatelet therapy after implantation of drug-eluting stents: the Efficacy of Xience/Promus Versus Cypher to Reduce Late Loss After Stenting (EXCELLENT) randomized, multicenter study. Circulation 2012;125(3):505–13. DOI: 10.1161/ CIRCULATIONAHA.111.059022; PMID: 22179532. 53. Valgimigli M, Patialiakas A, Thury A, et al. Zotarolimus-eluting versus bare-metal stents in uncertain drug-eluting stent candidates. J Am Coll Cardiol 2015;65(8):805–15. DOI: 10.1016/j. jacc.2014.11.053; PMID: 25720624. 54. Kim B-K, Hong M-K, Shin D-H, et al. A new strategy for discontinuation of dual antiplatelet therapy: the RESET Trial (REal Safety and Efficacy of 3-month dual antiplatelet Therapy following Endeavor zotarolimus-eluting stent implantation). J Am Coll Cardiol 2012;60(15):1340–8. DOI: 10.1016/j.jacc.2012.06.043; PMID: 22999717. 55. Feres F. Three vs twelve months of dual antiplatelet therapy after zotarolimus-eluting stents. JAMA 2013;:1–13. DOI: 10.1001/ jama.2013.282183; PMID: 24177257. 56. Sørensen R, Hansen ML, Abildstrom SZ, et al. Risk of bleeding in patients with acute myocardial infarction treated with different combinations of aspirin, clopidogrel, and vitamin K antagonists in Denmark: a retrospective analysis of nationwide registry data. Lancet 2009;374(9706):1967–74. DOI: 10.1016/S01406736(09)61751-7; PMID: 20006130. 57. Paikin JS, Wright DS, Crowther MA, Mehta SR, Eikelboom JW. Triple antithrombotic therapy in patients with atrial fibrillation and coronary artery stents. Circulation 2010;121(18): 2067–70. DOI: 10.1161/CIRCULATIONAHA.109.924944; PMID: 20458022. 58. Task Force Members, Lip GYH, Windecker S, et al. Management

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of antithrombotic therapy in atrial fibrillation patients presenting with acute coronary syndrome and/or undergoing percutaneous coronary or valve interventions: a joint consensus document of the European Society of Cardiology Working Group on Thrombosis, European Heart Rhythm Association (EHRA), European Association of Percutaneous Cardiovascular Interventions (EAPCI) and European Association of Acute Cardiac Care (ACCA) endorsed by the Heart Rhythm Society (HRS) and Asia-Pacific Heart Rhythm Society (APHRS). Eur Heart J 2014;35(45):3155–79. DOI: 10.1093/ eurheartj/ehu298; PMID: 25154388. Patrick WL, Patel C, Guddeti R, et al. Is there a need for “triple therapy?” Role of anticoagulation with dual antiplatelet therapy in acute coronary syndromes (ATLAS Study & TRAP Study). Curr Cardiol Rep 2013;15(10):411–7. DOI: 10.1007/s11886-013-0411-1; PMID: 24022544. Lamberts M, Gislason GH, Olesen JB, et al. Oral anticoagulation and antiplatelets in atrial fibrillation patients after myocardial infarction and coronary intervention. J Am Coll Cardiol 2013;62(11):981–9. DOI: 10.1016/j.jacc.2013.05.029; PMID: 23747760. Rothberg MB, Celestin C, Fiore LD, Lawler E, Cook JR. Warfarin plus aspirin after myocardial infarction or the acute coronary syndrome: meta-analysis with estimates of risk and benefit. Ann Intern Med 2005;143(4):241–50. PMID: 16103468. Leon MB, Baim DS, Popma JJ, et al. A clinical trial comparing three antithrombotic-drug regimens after coronaryartery stenting. Stent Anticoagulation Restenosis Study Investigators. N Engl J Med 1998;339(23):1665–71. DOI: 10.1056/ NEJM199812033392303; PMID: 9834303. Dewilde WJM, Oirbans T, Verheugt FWA, et al. Use of clopidogrel with or without aspirin in patients taking oral anticoagulant therapy and undergoing percutaneous coronary intervention: an open-label, randomised, controlled trial. Lancet 2013;381(9872):1107–15. DOI: 10.1016/S0140-6736(12)62177-1; PMID: 23415013. Gibson CM, Mehran R, Bode C, et al. Prevention of bleeding in patients with atrial fibrillation undergoing PCI. N Engl J Med 2016;375(25):2423–34. DOI: 10.1056/NEJMoa1611594; PMID: 27959713. Angiolillo DJ, Goodman SG, Bhatt DL, et al. Antithrombotic therapy in patients with atrial fibrillation undergoing percutaneous coronary intervention: a North American perspective-2016 update. Circ Cardiovasc Interv 2016;9(11): e004395. DOI: 10.1161/CIRCINTERVENTIONS.116.004395; PMID: 27803042.

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Acute Coronary Syndrome

Clinical Trial Perspective: Optimizing Crossover From Ticagrelor to Clopidogrel in Patients with Acute Coronary Syndrome (CAPITAL OPTICROSS) Donald E Cutlip, MD Division of Cardiology and Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA

Abstract Guideline-recommended treatment in patients with acute coronary syndrome is dual anti-platelet therapy (DAPT) with aspirin and a P2Y12 inhibitor, with clopidogrel or ticagrelor the preferred options for initial therapy. Ticagrelor has been demonstrated to have improved efficacy, and is preferred over clopidogrel in the absence of contraindications or the need for oral anticoagulation. However, it is not uncommon that patients are switched to clopidogrel after starting on ticagrelor. Reasons for this may be related to recognition of the increased risk of bleeding, the higher costs of ticagrelor, or adverse effects such as adenosine-mediated dyspnea. It is therefore important to understand the optimal dosing strategy in patients undergoing a switch from ticagrelor to clopidogrel. A loading dose of clopidogrel is standard when initiating therapy for acute coronary syndrome or before coronary stenting. However, whether this is required in patients who have already achieved adequate platelet inhibition with ticagrelor is unknown. Owing to the short half-life of the unbound active metabolite of clopidogrel at standard doses, there are concerns of high on-treatment platelet activity for a period of time following switching. However, this must be balanced against concerns of an increased risk of bleeding if a loading dose is used. To investigate this, the Optimizing Crossover From Ticagrelor To Clopidogrel In Patients With Acute Coronary Syndrome (CAPITAL OPTICROSS) clinical trial was conducted to compare a clopidogrel bolus dose with no bolus among patients currently treated with ticagrelor and whose treating physician had decided to switch therapy to clopidogrel. This review summarizes the CAPITAL OPTICROSS trial and its findings, and discusses the implications for clinical practice.

Keywords Bleeding, MI, anti-platelet therapy Disclosure: Contracted research support paid to institution from CeloNova, Medtronic and Boston Scientific. Received: 17 June 2017 Accepted: 19 July 2017 Citation: US Cardiology Review 2017;11(2):59–61. DOI: 10.15420/ucs.2017:10:1 Correspondence: Professor Donald E Cutlip, 185 Pilgrim Road, Boston, MA. E: dcutlip@bidmc.harvard.edu

Dual anti-platelet therapy (DAPT) with aspirin and a P2Y12 inhibitor reduces recurrent ischemic events in patients with acute coronary syndrome and is recommended by guidelines for patients treated with either an early invasive or ischemia-guided strategy.1,2 For initial therapy, either clopidogrel or ticagrelor are the preferred options, with prasugrel also an option at the time of percutaneous coronary intervention in some patients. Based on improved efficacy demonstrated in the randomized Platelet Inhibition And Patient Outcomes (PLATO) trial, ticagrelor is preferred over clopidogrel in the absence of contraindications or a requirement for oral anticoagulants.2,3 In PLATO, the primary endpoint of cardiovascular death, MI or stroke (10.0 versus 12.3 %; p=0.0013) as well as all-cause mortality (4.3 versus 5.8 %; p=0.0020) and cardiovascular mortality (3.7 versus 4.9 %; p=0.0070) were significantly lower for ticagrelor compared with clopidogrel. There was a slight increase for ticagrelor in major bleeding not related to coronary artery bypass surgery (4.8 versus 3.8 %; p=0.0139), but no difference in lifethreatening or fatal bleeds. The favorable efficacy and safety profile for ticagrelor is related in part to differences in pharmacokinetics. Unlike clopidogrel or prasugrel, ticagrelor is a reversible non-competitive inhibitor of the P2Y12 receptor.

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It is active as the parent compound and is (also) rapidly converted to an active metabolite that has similar pharmacokinetics; thus has more rapid onset as well as more potent platelet inhibition than clopidogrel.4 Despite these advantages and the intent to use ticagrelor as part of a DAPT strategy, it is not uncommon that a switch to clopidogrel is necessitated after initiation of ticagrelor. Common reasons for this switch include recognition of increased bleeding risk, requirement for initiation of oral anticoagulation, issues with added cost and insurance coverage for ticagrelor, and development of adenosine-mediated dyspnea as an adverse effect of ticagrelor. It is unknown whether a loading dose of clopidogrel, as is standard with initiation of therapy for acute coronary syndrome or before coronary stenting, is required when switching from ticagrelor in patients who have achieved therapeutic platelet inhibition. Continued inactivation of the P2Y12 receptor at the time of clopidogrel dosing and the extremely short half-life of the unbound clopidogrel active metabolite following a standard daily dose raise concerns of high on-treatment platelet activity for a period of time after switching. Whether a loading dose of clopidogrel mitigates this concern or may increase bleeding risk is uncertain. These strategies were compared in the Optimizing Crossover From Ticagrelor

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Acute Coronary Syndrome To Clopidogrel In Patients With Acute Coronary Syndrome (CAPITAL OPTICROSS) clinical trial.5

Clinical Trial Summary The CAPITAL OPTICROSS trial was a single-center, randomized, openlabel study designed to compare a clopidogrel bolus dose (600 mg) with no bolus among patients who were currently being treated with ticagrelor (180 mg bolus and at least 24 hours of maintenance 90 mg twice daily) and whose physician had decided to switch therapy to clopidogrel. The primary endpoint was P2Y12 reactivity units (PRU) at 72 hours and secondary endpoints included PRU at 12 hour intervals after initial clopidogrel dosing, the incidence of high on-treatment platelet reactivity, (defined as PRU ≥208) major adverse cardiac events (MACE) at 30 days, and thrombolysis in myocardial infarction (TIMI) minor or major bleeding at 30 days. Patients randomized to bolus dose received clopidogrel 600 mg 12 hours after last ticagrelor dose and then clopidogrel 75 mg daily. Patients randomized to no bolus received clopidogrel 75 mg daily beginning 12 hours after last ticagrelor dose. Sixty patients were randomized, with 30 patients in each group. At 72 hours, there was no difference in PRU for bolus versus no bolus (165.8 ± 71.0 versus 184.1 ± 67.7; p=0.19). During earlier time intervals there was a gradual separation in PRU such that there was a significant difference at 48 hours (114.1 ± 73.1 versus 165.1 ± 70.5; p=0.0076), followed by convergence of the groups thereafter. The frequency of high on-treatment platelet reactivity was also significantly lower in the bolus group (26.7 % versus 56.7 %; p=0.02). There were no differences in MACE (one event in each group), TIMI major bleeding (no events) or TIMI minor bleeding (one versus two events).

Discussion of Results The results of the CAPITAL OPTICROSS trial suggest that a 600 mg bolus of clopidogrel 12 hours after ticagrelor is associated with early reduction in platelet reactivity compared with no bolus, but that by 72 hours this difference is attenuated. Furthermore, the risk of high on-treatment platelet reactivity was significantly lower after a bolus dose. Although there was not an increase in risk of ischemic or bleeding events with either strategy, the numbers were too small to draw conclusions. Based on the pharmacokinetics of ticagrelor and clopidogrel, the results are not unexpected. As a non-competitive reversible inhibitor of the P2Y12 receptor, ticagrelor continues to inactivate platelets for a limited period of time after the last dose. In pharmacodynamic studies, the offset is rapid with inhibition of platelet aggregation <50 % by 24–36 hours after discontinuation of ticagrelor.4 The ticagrelor binding site on the P2Y12 receptor is distinct from the adenosine diphosphate (ADP) site bound by thienopyridines.6 However, binding by ticagrelor at the remote site renders the receptor locked in an inactive state and prevents ADP signaling. As ticagrelor dissociates from the receptor, it returns to active state. ADP is able to bind and initiate signaling for platelet aggregation. If the active metabolite of clopidogrel is unable to bind to its site on the P2Y12 receptor, it is rapidly cleared and thus ineffective. Given the rapid offset of ticagrelor there would be an expected loss of platelet inhibition during this transition

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until a steady state is achieved by repeat clopidogrel dosing. Previous studies have shown that effective inhibition of platelet activity requires several days with daily dosing of 75 mg,7 but is achieved within several hours after a 600 mg loading dose. The data from CAPITAL OPTICROSS indicate that an initial loading dose provides more effective platelet inhibition during the first 48 hours compared with initiating therapy with clopidogrel 75 mg daily. The increase in PRU after 24–48 hours in the bolus group raises the question whether an additional clopidogrel bolus dose after 24 hours may have provided a longer duration of effective platelet inhibition as the concentration and inhibitory effect of ticagrelor continue to decrease and more P2Y12 receptor binding sites become available. This hypothesis, of course, was not tested in this study. The absence of an increase in bleeding is of limited value given the small number of patients included in the study. Nevertheless, given the known differences in efficacy between ticagrelor and clopidogrel for platelet inhibition it is unlikely that a bolus dose of clopidogrel 12 hours after the last ticagrelor dose would increase bleeding.

Study Limitations There are several limitations in generalizing these data to clinical practice. First, the study was a single-center pharmacodynamic study conducted in the acute setting. Although this is the most common time to initiate a change from ticagrelor, the findings may not apply to later time periods. For example, PRU at baseline and on-treatment may be higher in patients in the acute setting and the impact of a loading dose may be greater. The platelet function results are limited to 72 hours. This is reasonable for testing the effect of an initial bolus dose, but does include a window where there is possible residual effect of ticagrelor and does not allow estimates for a steady state of clopidogrel platelet inhibition. For example, depending on the observations between 3–7 days, it may be reasonable to question the value of a subsequent clopidogrel bolus dose. The primary endpoint at 72 hours was not met and the significance in a secondary endpoint at 48 hours is subject to type 1 error. However, the trends in the assessments before 48 hours are consistent, and support the finding at 48 hours. Finally, the study is underpowered to make inference on clinical outcomes of MACE or bleeding. This does not, however, lessen the importance of the pharmacodynamic results.

Clinical Practice Implications A planned switch from a more potent P2Y12 inhibitor to clopidogrel is common, with a frequency of 5–14 % in registry reports.8 In the acute phase after acute coronary syndrome presentation, a bolus dose of clopidogrel 600 mg given 12 hours after the last dose of ticagrelor is associated with improved platelet inhibition at 48 hours and reduces the risk for high on-treatment platelet reactivity during the 72 hours after switching. In this setting, when a switch from ticagrelor to clopidogrel is required for clinical or economic reasons, it seems reasonable to initiate the switch with an initial 600 mg bolus followed by a daily dose thereafter. Whether subsequent bolus dosing for switching early after acute coronary syndrome may be even more effective or if similar bolus dosing is required for later time of switching is not known. n

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Optimizing Crossover From Ticagrelor to Clopidogrel

msterdam EA, Wenger NK, Brindis RG, et al. 2014 AHA/ACC A guideline for the management of patients with non-ST-elevation acute coronary syndromes: A report of the American College of Cardiology/American Heart Association task force on practice guidelines. Circulation 2014;130:e344–426. DOI: 10.1161/ CIR.0000000000000134; PMID: 25249585 Roffi M, Patrono C, Collet JP, et al. 2015 ESC guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: Task force for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation of the European Society of Cardiology (ESC). Eur Heart J 2016;37: 267–315. DOI: 10.1093/eurheartj/ehv320; PMID: 26320110

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Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2009;361:1045–57. DOI: 10.1056/NEJMoa0904327; PMID: 19717846 Gurbel PA, Bliden KP, Butler K, et al. Randomized double-blind assessment of the onset and offset of the antiplatelet effects of ticagrelor versus clopidogrel in patients with stable coronary artery disease: The onset/offset study. Circulation 2009;120: 2577–85. DOI: 10.1161/CIRCULATIONAHA.109.912550; PMID: 19923168 Pourdjabbar A, Hibbert B, Chong AY, et al. A randomised study for optimising crossover from ticagrelor to clopidogrel in patients with acute coronary syndrome. The CAPITAL

OPTI-CROSS study. Thromb Haemost 2017;117:303–10. DOI: 10.1160/TH16-04-0340; PMID: 27761582 Husted S, van Giezen JJ. Ticagrelor: the first reversibly binding oral P2Y12 receptor antagonist. Cardiovasc Ther 2009;27:259–74. DOI: 10.1111/j.1755-5922.2009.00096.x; PMID: 19604248 Savcic M, Hauert J, Bachmann F, et al. Clopidogrel loading dose regimens: Kinetic profile of pharmacodynamic response in healthy subjects. Semin Thromb Hemost 1999;25 Suppl 2:15–9. PMID: 10440417 Rollini F, Franchi F, Angiolillo DJ. Switching p2y12-receptor inhibitors in patients with coronary artery disease. Nat Rev Cardiol 2016;13:11-27. DOI: 10.1038/nrcardio.2015.113; PMID: 26283269

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Heart Failure

New Drugs for the Treatment of Heart Failure Amarinder Bindra, MD and Shelley A Hall, MD Baylor University Medical Center, Dallas, TX; Texas A&M Health Science Center, College of Medicine, Dallas, TX

Abstract Angiotensin receptor-neprilysin inhibitor, Entresto® (Novartis), a combination of sacubitril and valsartan, and funny channel inhibitor of the sinoatrial node, Corlanor® (Amgen), are two new drugs that have been Food and Drug Association-approved for treatment of symptomatic heart failure patients. Their mechanisms of action differ from each other and from the heart failure drugs available prior to their approval. Reduction in mortality is the hallmark of Entresto, while reduction in hospitalizations was the common denominator of both Entresto and Corlanor. These drugs are generally well tolerated and are widely used by heart failure cardiologists. Another promising agent, omecamtiv mecarbil, a myosin activator, is currently under trials, while RLX030, a relaxin receptor agonist, did not meet primary endpoints in a study.

Keywords Heart failure, pharmaceutical preparations, angiotensin receptor-neprilysin inhibitor, ARNI, sinus node modulator, funny channel, myosin activation, relaxin Disclosure: AB and SAH are on speakers bureaus for Novartis Received: 23 August 2017 Accepted: 4 October 2017 Citation: US Cardiology Review 2017;11(2):62–6. DOI: 10.15420/usc.2017:17:1 Correspondence: Amarinder Bindra, MD, Center for Advanced Heart and Lung Disease, Baylor University Medical Center, 3410 Worth Street, Suite 250, Dallas, TX 75246, USA. E: Amarinder.Bindra@BSWHealth.org

After a drought in viable new therapies for more than a decade, two new drugs for use in heart failure patients were approved by the US Food and Drug Administration (FDA) in 2015. These drugs represent two new classes of agents in the heart failure space: a combined angiotensin receptor-neprilysin inhibitor (ARNI) (sacubitril/valsartan; brand name Entresto®, Novartis) and a sinoatrial node modulator (ivabradine; brand name Corlanor®, Amgen). Both drugs are recommended for use as part of a comprehensive medical therapy regimen. The clinical trials for, respectively, Novartis’ Entresto and Amgen’s Corlanor were so strong in their positive results for heart failure patients, that the American College of Cardiology/American Heart Association/Heart Failure Society of America (HFSA) and the European Society of Cardiology produced focused updates in 2016 highlighting the use of both drugs and adding criteria to their respective guideline documents.1,2 ARNI received a class I, level of evidence B-R recommendation, while ivabradine was given a class IIa, level of evidence B-R recommendation.

Sacubitril/valsartan ARNI (sacubitril/valsartan; or LCZ696) is a combination drug of neprilysin inhibitor and valsartan, and is indicated for use in symptomatic heart failure patients with reduced ejection fraction (HFrEF) with ejection fraction (EF) ≤35 %. (In the early days of the trial, the EF cutoff was ≤40 % and revised later to the current ≤35 %.) The ARNI trial (Prospective Comparison of ARNI with Angiotensin Converting Enzyme Inhibitors to Determine Impact on Global Mortality and Morbidity in Heart Failure; PARADIGM-HF) was published in September 2014.3 The trial was stopped early at 27 months of a projected 4-year duration. In light of the dramatic benefit with use of ARNI, the data safety and monitoring

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board decided it would be unethical to continue the trial with patients in the standard-of-care arm. The primary objective of PARADIGM-HF was to determine whether Entresto was superior to a renin-angiotensin system inhibitor (enalapril) alone in reducing the risk of the combined endpoint of cardiovascular (CV) death or hospitalization for heart failure. After discontinuing their existing angiotensin-converting enzyme (ACE) inhibitor or angiotensin II receptor blocker (ARB) therapy, patients entered sequential single-blind run-in periods during which they received enalapril 10 mg twice daily, followed by Entresto 100 mg twice daily, increasing to 200 mg twice daily. It is important to note the dropout rate was equal in the two treatment groups, reflecting that no matter how effective a medication, there will always be a percentage of the patient population intolerant to target doses. Patients who successfully completed the sequential run-in periods were randomized to receive either Entresto 200 mg (n=4,209) twice daily or enalapril 10 mg (n=4,233) twice daily. The median follow-up duration was 27 months and patients were treated for up to 4.3 years. PARADIGMHF was the largest trial in heart failure history, screening over 10,000 patients and ultimately randomizing 8,442 patients to the gold standard ACE inhibitor as the control arm versus ARNI. Enalapril was chosen to represent the ACE category because it is the most studied drug in heart failure trials. An ACE inhibitor, and not ARB, was chosen in the standardof-care arm because the data for ACE inhibitors are stronger, and ACE inhibitors are still considered first-line therapy over ARBs for heart failure. The primary endpoint was CV death or hospitalization for heart failure. Entresto had a 20 % incremental reduction in CV death beyond that achieved with enalapril and an absolute risk reduction of 4.7 %.

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New Drugs for the Treatment of Heart Failure Figure 1: Kaplan–Meier curves for key study outcomes of PARADIGM-HF trial according to study group: probabilities of the primary composite endpoint (death from cardiovascular causes or first hospitalization for heart failure; A), death from cardiovascular causes (B), first hospitalization for heart failure (C), and death from any cause (D). PARADIGM-HF = Prospective Comparison of Angiotensin Receptor-neprilysin Inhibitor with Angiotensin Converting Enzyme Inhibitors to Determine Impact on Global Mortality and Morbidity in Heart Failure A Primary endpoint

B Death from cardiovascular causes 1.0

Hazard ratio, 0.80 (95 % Cl, 0.73–0.87) p<0.001

0.6

Cumulative probability

1.0

0.5 0.4

Enalapril

0.3 LCZ696

0.2 0.1

Hazard ratio, 0.80 (95 % Cl, 0.71–0.89) p<0.001

0.6 0.5 0.4 0.3

Enalapril

0.2

LCZ696

0.1

0.0

0.0 0

180

360

540

720

900

1080

1260

180

No. at risk LCZ696 Enalapril

4187 4212

3922 3883

3663 3579

3018 2922

2257 2123

1544 1488

896 853

249 236

C Hospitalization for heart failure

No. at risk LCZ696 Enalapril

4187 4212

4056 4051

1.0

Hazard ratio, 0.79 (95 % Cl, 0.71–0.89) p<0.001

0.6 0.5 0.4 0.3 Enalapril

0.2 0.1

720

900

3891 3860

3282 3231

2478 2410

1716 1726

1080

1260

1005 994

280 279

Hazard ratio, 0.84 (95 % Cl, 0.76–0.93) p<0.001

0.6 0.5 0.4 0.3

Enalapril

0.2 LCZ696

0.1

LCZ696

0.0

0.0 0

180

360

540

720

900

1080

1260

180

Days since randomization No. at risk LCZ696 Enalapril

540

D Death from any cause

Cumulative probability

1.0

360

Days since randomization

4187 4212

3922 3883

3663 3579

3018 2922

2257 2123

1544 1488

360

540

720

900

1080

1260

1005 994

280 279

Days since randomization 896 853

249 236

No. at risk LCZ696 Enalapril

4187 4212

4056 4051

3891 3860

3282 3231

2478 2410

1716 1726

Source: McMurray, et al., 2014.3 Reprinted with permission from Massachusetts Medical Society.

Figure 1 presents an overview of the key results in the original article.3 Using patient-level data, the PARADIGM-HF investigators estimated that treatment with sacubitril/valsartan prolongs life by an average of 1–2 years. The aggressive uptitration of dosages is reflected in a moderate percentage of patients withdrawing from the trial because of intolerance to the drugs. More patients dropped off in the enalapril arm (12.2 %) than in the ARNI arm (10.7 %). Dosing in the trial was based on the total amount of both components of sacubitril/valsartan. The PARADIGM-HF trial demonstrated that Entresto was superior to enalapril in reducing the risk of the combined endpoint of CV death or hospitalization for heart failure, based on a time-to-event analysis (p<0.0001). The treatment effect reflected a reduction in both CV death and heart failure hospitalization. Sudden death accounted for 45 % of CV deaths, followed by pump failure, which accounted for 26 %. Entresto also improved overall survival

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(p=0.0009). However, patients with severe HF were underrepresented in the PARADIGM-HF trial, as were African American patients, common in most first trials for heart failure. Also, the use of sacubitril alone for the treatment of HFrEF has not been evaluated.4 A recent analysis presented at this year’s HFSA Annual Scientific Meeting has now shown improved quality of life in the ARNI LCZ696 group over the enalapril group, especially in the overall Kansas City Cardiomyopathy Questionnaire clinical score.5 Concerns have been raised about neprilysin inhibition in regard to LCZ696. Neprilysin inhibition in mice does result in elevation of amyloidbeta peptide and plaque-like deposits, which are 30–50 times as high as normal levels in the brain.6 Cognition, memory, and dementia-related

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Heart Failure Figure 2: Kaplan–Meier cumulative event curves for death from heart failure (A) and all-cause death in the Systolic Heart Failure Treatment with the I f Inhibitor Ivabradine (SHIFT) trial (B). HR = hazard ratio. Source: Swedberg, et al., 2010. 14 Reprinted with permission from Elsevier. B

Placebo (151 events)

Placebo (552 events)

Ivabradine (503 events)

Ivabradine (113 events) HR 0.74 (95 % CI 0.58–0.94), p=0.014

Patients with all-cause death (%)

Patients with death from heart failure (%)

HR 0.90 (95 % CI 0.80–1.02), p=0.092

0 0 Number at risk Placebo group 3264 Ivabradine group 3241

Months 3094 3085

2817 2818

2391 2428

1318 1376

534 531

Months 2391 2428

1318 1376

534 531

3264 3241

3094 3085

2817 2818

HR = hazard ratio. Source: Swedberg, et al., 2010.14 Reprinted with permission from Elsevier

adverse events were not increased in the LCZ696 group in PARADIGM-HF. Indeed, it is possible that cognitive decline related to vascular disease might be reduced by LCZ696. A trial of LCZ696 versus valsartan, which includes repeated measurements of cognitive function in patients who have heart failure and a preserved EF, is ongoing (Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction (PARAGON-HF), ClinicalTrials identifier NCT01920711). Neprilysin also inhibits prostate cancer cell invasion in vitro,7 and neprilysin overexpression has been associated with improved disease-free survival among women with breast cancer.8 Protection derives from the inactivation of mitogenic peptides, including endothelin-1 and bradykinin. No increase in the risk of cancer was associated with LCZ696, and 2-year carcinogenicity studies involving rodents that received the neprilysin inhibitor component of LCZ696 did not show an increase in the incidence of tumors. Entresto is supplied as a tablet for oral administration. The recommended starting dose is 100 mg (49 mg sacubitril/51 mg valsartan) twice daily. Similar to current clinical practice with ACE and ARB uptitration, the dose of Entresto can be increased every 2–4 weeks with the objective to reach the target maintenance dose of 97/103 mg twice daily, as tolerated by the patient. While most patients will tolerate a simple doubling of dose, some will be more sensitive and require starting at the lower 24/26 mg twice daily dose combined with smaller increments and/or longer time periods between dose-change titration. This is important for patients not currently taking an ACE inhibitor or an ARB, who have lower systolic blood pressure or who have moderate renal or hepatic dysfunction. Entresto is a combination of sacubitril, a neprilysin inhibitor, and valsartan, an ARB drug. Entresto inhibits neprilysin (neutral endopeptidase) via LBQ657, the active metabolite of the prodrug sacubitril, and blocks the angiotensin II type-1 (AT1) receptor via valsartan. Neprilysin inhibition

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leads to decreased metabolism of endogenous vasoactive peptides (e.g. natriuretic peptides, adrenomedullin, bradykinin, substance P, and calcitonin gene-related peptide).9–12 This inhibition produces elevated levels of these endogenous vasoactive peptides, and thus augmentation of their beneficial effects, including a decrease in adverse neurohormonal activation, lower vascular tone, decreased cardiac fibrosis, less hypertrophy, and decreased sodium retention. The CV and renal effects of Entresto in heart failure patients are attributed to the increased levels of peptides that are degraded by neprilysin, such as natriuretic peptides (by LBQ657) and the simultaneous inhibition of the effects of angiotensin II (by valsartan). Valsartan inhibits the effects of angiotensin II by selectively blocking the AT1 receptor, and also inhibits angiotensin II-dependent aldosterone release. The FDA approval of Entresto was based on the impressive results of the PARADIGM-HF trial for patients with symptomatic chronic heart failure (New York Heart Association [NYHA] class II–IV) and left ventricular EF ≤40 %.

Ivabradine Ivabradine is the first drug of its kind with a novel mechanism of action. It selectively inhibits the pacemaker ‘funny’ (lf) channel, which is responsible for the autonomic capacity of the sinoatrial node. In patients with heart failure, If channels are upregulated in the atrial tissue.13 Ivabradine decreases the heart rate by direct sinus node inhibition without affecting blood pressure, myocardial contractility, or intracardiac conduction. The drug is approved for patients with stable, symptomatic, chronic heart failure with EF ≤35 % who are in sinus rhythm and have a resting heart rate >70 BPM, and are also taking beta-blockers at the highest tolerated doses. Ivabradine was studied in an industrysponsored clinical trial (Amgen) of 6,505 participants. The Systolic Heart Failure Treatment with the If Inhibitor Ivabradine (SHIFT) trial was a multinational, randomized, double-blinded, placebo-controlled trial published in 2010, which showed that ivabradine significantly reduced

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New Drugs for the Treatment of Heart Failure the primary composite endpoint of CV death and hospitalization for worsening heart failure by as much as 18 % (Figure 2).14 The finding was mainly attributable to ivabradine’s favorable effect on heart failure hospitalizations (16 % versus 21 %; hazard ratio [HR] 0.74, 0.66–0.83; p<0.0001) and less to heart failure deaths (3 % versus 5 %; HR 0.74, 0.58–0.94; p=0.014). Note, that CV deaths and all-cause mortality were not affected by ivabradine. In the SHIFT trial, only 26 % of subjects were on target doses of betablocker and only 56 % of patients were on at least half-target doses of beta-blocker. Although this is presumably due to beta-blocker intolerance, an element of beta-blocker underuse may have overestimated the benefit of ivabradine. The effects of ivabradine were attenuated in a group of patients on at least 50 % target dose of beta-blocker, raising the question of whether the benefit of ivabradine may be limited to patients with complete or partial beta-blocker intolerance. Corlanor is supplied as tablets for oral administration. The recommended starting dose is 5 mg twice daily. After 2 weeks of treatment the dose should be adjusted based on heart rate, with a maximum dose of 7.5 mg twice daily. In patients with conduction defects, or in whom bradycardia could lead to hemodynamic compromise, the initiate dosing is 2.5 mg twice daily. Part of the challenge, as well described in recent publication by Bhatt et al.15 is how to determine “maximal beta-blocker tolerated” prior to initiation of ivabradine.

Discussion Amgen’s Corlanor and Novartis’ Entresto are both twice-a-day pills that currently cost approximately $4,500 per year, with Medicare and most private insurers covering the drugs. A new study published in Annals of Internal Medicine concluded these drugs are cost-effective in patients with NYHA class II–IV heart failure at a cost of $47,000 per quality-adjusted life year (QALY).16 Using a hypothetical cohort based on the characteristics of patients in the PARADIGM-HF trial, the costeffectiveness and cost per QALY gained of sacubitril/valsartan relative to enalapril was estimated.17 The average medication and heart failure hospitalization costs for patients in the sacubitril/valsartan and enalapril groups were $60,391 and $21,758, respectively. The use of sacubitril/ valsartan yielded 6.59 QALYs (9.48 life years), while enalapril yielded 5.83 QALYs (8.40 life years). This resulted in an incremental cost-effectiveness ratio for sacubitril/valsartan versus enalapril of $50,959 per QALY gained. Recent further analysis released at HFSA18 demonstrated the costeffectiveness is continuing to improve for sacubitril/valsartan to under $50,000 per life year gained and under $18,000 for ivabridine per life year gained, both being well within the range of what is considered acceptable financial cost. A continual theme in the medical community is the underutilization of guideline-directed medical therapy; high costs and the need for more studies are often cited as the reason for not using optimum medications. Unfortunately, simply starting a medication is regarded as adequate. Advancement of effective medications takes time and effort which can be difficult in today’s reality of too many patients and too little provider time. Appropriate infrastructures need to be built so patients can be effectively treated in the ways identified and demonstrated by science as most successful.

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Not all new drugs have been successful. RLX030 (serelaxin) in patients with acute heart failure (AHF) was studied in the Efficacy, Safety and Tolerability of Serelaxin When Added to Standard Therapy in AHF (RELAX-AHF-2) trial,19 but did not meet the primary endpoints of reduction in CV death through day 180 or reduced worsening heart failure through day 5 when added to standard therapy in patients with AHF. RLX030, a relaxin receptor agonist, is a recombinant form of the naturally-occurring human relaxin-2 hormone. Human relaxin-2 is present in both men and women; elevated levels in pregnant women are thought to help the body cope with the additional CV demands during pregnancy. There is enthusiasm for future heart failure therapies, including omecamtiv mecarbil, a novel cardiac myosin activator. Cardiac myosin is the cytoskeletal motor protein in the cardiac muscle cell that is directly responsible for converting chemical energy into the mechanical force resulting in cardiac contraction. Cardiac myosin activators are thought to accelerate the rate-limiting step of the myosin enzymatic cycle and shift the enzymatic cycle in favor of the force-producing state. Preclinical research has shown that cardiac myosin activators increase contractility in the absence of changes in intracellular calcium in cardiac myocytes. The Chronic Oral Study of Myosin Activation to Increase Contractility in Heart Failure (COSMIC-HF) trial was a double-blind, randomized, placebo-controlled, multicenter, phase II trial designed to evaluate an oral formulation of omecamtiv mecarbil in chronic HFrEF.20 In the study, 448 chronic HFrEF were dosed with the selected oral formulation of omecamtiv mecarbil for 20 weeks and followed for a total of 24 weeks. Patients were randomized 1:1:1 to receive either placebo or treatment with omecamtiv mecarbil 25 mg twice daily or 25 mg with dose escalation to 50 mg twice daily, depending on plasma concentrations of omecamtiv mecarbil after 2 weeks of treatment. The primary endpoints for the expansion phase were to assess the maximum and predose plasma concentration of omecamtiv mecarbil. The secondary endpoints were to assess changes from baseline in systolic ejection time, stroke volume, left ventricular end-systolic diameter, left ventricular end-diastolic diameter, heart rate, and N-terminal pro-brain natriuretic peptide (NT-proBNP; a biomarker associated with the severity of heart failure) at week 20, as well as the safety and tolerability of omecamtiv mecarbil, including incidence of adverse events from baseline to week 24. Following 20 weeks of treatment, statistically significant improvements were observed in all prespecified secondary endpoint measures of cardiac function in the dose titration group, compared with placebo. Systolic ejection time increased by 25.0 ms (p<0.0001), stroke volume increased by 3.6 ml (p=0.0217), and heart rate decreased by 3.0 BPM (p=0.0070). Left ventricular end-systolic and end-diastolic dimensions decreased by 1.8 mm (p=0.0027) and 1.3 mm (p=0.0128), respectively, and were associated with statistically significant reductions in left ventricular endsystolic and end-diastolic volumes. NT-proBNP decreased by 970 pg/ ml (p=0.0069). In prespecified exploratory analyses of the dose titration group, placebo-corrected reductions in NT-proBNP persisted 4 weeks after stopping omecamtiv mecarbil, decreasing further to 1,306 pg/ml (p=0.0006). The data also showed increases in fractional shortening at week 20 compared with placebo in the dose titration group. COSMICHF, conducted by Amgen in collaboration with Cytokinetics, was not designed to assess the impact of omecamtiv mecarbil on CV outcomes in heart failure patients. New trials to assess clinical efficacy are underway.

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Heart Failure Changing a clinical paradigm takes time, and the clinical community must retain a desire to always be open for new discoveries. If we look back at one of the greatest breakthroughs in heart failure medicine, betablockers, we are reminded that what we think we know is not always true. When beta-blockers were introduced, as now with these new drugs, there was resistance to changing patients’ medication profiles. Who remembers the days of office visits with vital sign checks every

ancy CW, Jessup M, Bozkurt B, et al. 2016 ACC/AHA/HFSA Y focused update on new pharmacological therapy for heart failure: an update of the 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association task force on clinical practice guidelines and the Heart Failure Society of America. J Am Coll Cardiol 2016;68:1476–88. DOI: 10.1016/j.jacc.2016.05.011; PMID: 27216111 Oeing CU, Tschöpe C, Pieske B. [The new ESC guidelines for acute and chronic heart failure 2016]. Herz 2016;41:655–63 [in German]. DOI: 10.1007/s00059-016-4496-3; PMID: 27858115 McMurray JJ, Packer M, Desai AS, et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med 2014;371:993–1004. DOI: 10.1056/NEJMoa1409077; PMID: 25176015 Yandrapalli S, Aronow WS, Mondal P, Chabbott DR. Limitations of sacubitril/valsartan in the management of heart failure. Am J Ther 2017;24:e234–9. DOI: 10.1097/MJT.0000000000000473; PMID: 27574931 Chandra A, Lewis EF, Claggett BL, et al. The effects of sacubitril/ valsartan on physical and social activity limitations in patients with heart failure: the PARADIGM-HF. Presented at Heart Failure Society of America 21st Annual Scientific Meeting, Dallas, Texas, 19 Sep 2017. Miners JS, Barua N, Kehoe PG, et al. Abeta-degrading enzymes: potential for treatment of Alzheimer disease. J Neuropathol Exp Neurol 2011;70:944–59. DOI: 10.1097/NEN.0b013e3182345e46; PMID: 22002425 Dawson LA, Maitland NJ, Turner AJ, Usmani BA. Stromal-epithelial interactions influence prostate cancer cell invasion by altering the

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10.

11.

12.

13.

15 minutes to make sure the patient would be okay with carvedilol 6.25 mg dosage? If this pattern was the directive today, would we even have explored beta-blockers further? Can you imagine a heart failure patient today not being offered beta-blockers? Change is difficult, but we must remember that we clinicians are only as good as our next discovery. We must embrace the new, respect that prior truths are not always forever, and offer our patients the best we have in the moment. n

balance of metallopeptidase expression. Br J Cancer 2004;90: 1577–82. DOI: 10.1038/sj.bjc.6601717; PMID: 15083188 Smollich M, Götte M, Yip GW, et al. On the role of endothelinconverting enzyme-1 (ECE-1) and neprilysin in human breast cancer. Breast Cancer Res Treat 2007;106:361–9. DOI: 10.1007/ s10549-007-9516-9; PMID: 17295044 D’Elia E, Iacovoni A, Vaduganathan M, et al. Neprilysin inhibition in heart failure: mechanisms and substrates beyond modulating natriuretic peptides. Eur J Heart Fail 2017;19:710–7. DOI: 10.1002/ ejhf.799; PMID: 28326642 Jhund PS, McMurray JJ. The neprilysin pathway in heart failure: a review and guide on the use of sacubitril/valsartan. Heart 2016;102:1342–7. DOI: 10.1136/heartjnl-2014-306775; PMID: 27207980 McMurray JJ, Packer M, Desai AS, et al. Dual angiotensin receptor and neprilysin inhibition as an alternative to angiotensin-converting enzyme inhibition in patients with chronic systolic heart failure: rationale for and design of the Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure trial (PARADIGM-HF). Eur J Heart Fail 2013;15:1062–73. DOI: 10.1093/ eurjhf/hft052; PMID: 23563576 von Lueder TG, Atar D, Krum H. Current role of neprilysin inhibitors in hypertension and heart failure. Pharmacol Ther 2014;144:41–9. DOI: 10.1016/j.pharmthera.2014.05.002; PMID: 24836726 Cerbai E, Pino R, Porciatti F, et al. Characterization of the hyperpolarization-activated current, I(f), in ventricular myocytes from human failing heart. Circulation 1997;95:568–71. DOI: 10.1161/01.CIR.95.3.568; PMID: 9024140

14. S wedberg K, Komajda M, Böhm M, et al. Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study. Lancet 2010;376:875–85. DOI: 10.1016/ S0140-6736(10)61198-1; PMID: 20801500 15. Bhatt AS, DeVore AD, DeWald TA, et al. Achieving a maximally tolerated beta-blocker dose in heart failure patients: is there room for improvement? J Am Coll Cardiol 2017;69:2542–50. DOI: 10.1016/j.jacc.2017.03.563; PMID: 28521892 16. Sandhu AT, Ollendorf DA, Chapman RH, et al. Cost-effectiveness of sacubitril-valsartan in patients with heart failure with reduced ejection fraction. Ann Intern Med 2016;165:681–9. DOI: 10.7326/ M16-0057; PMID: 27571284 17. King JB, Shah RU, Bress AP, et al. Cost-effectiveness of sacubitrilvalsartan combination therapy compared with enalapril for the treatment of heart failure with reduced ejection fraction. JACC Heart Fail 2016;4:392–402. DOI: 10.1016/j.jchf.2016.02.007; PMID: 27039128 18. Heidenreich PA. Update on utilization and financial impact of new heart failure therapies: impact of MACRA. Presented at Heart Failure Society of America 21st Annual Scientific Meeting. Dallas, Texas, 16 Sep 2017. 19. Teerlink JR, Voors AA, Ponikowski P, et al. Serelaxin in addition to standard therapy in acute heart failure: rationale and design of the RELAX-AHF-2 study. Eur J Heart Fail 2017;19:800–9. DOI: 10.1002/ejhf.830; PMID: 28452195 20. Teerlink JR, Felker GM, McMurray JJ, et al. Chronic Oral Study of Myosin Activation to Increase Contractility in Heart Failure (COSMIC-HF): a phase 2, pharmacokinetic, randomised, placebocontrolled trial. Lancet 2016;388:2895–903. DOI: 10.1016/S01406736(16)32049-9; PMID: 27914656

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Valvular Disease

Clinical Practice Update: Who Should Be Referred for Transcatheter Aortic Valve Replacement in 2017? Colin M Barker, MD and Michael J Reardon, MD Houston Methodist DeBakey Heart & Vascular Center, Houston Methodist Hospital, Houston, TX

Abstract Transcatheter aortic valve replacement (TAVR) was initially envisioned as a less invasive option for patients with severe symptomatic aortic stenosis (AS) either not candidates or very high-risk candidates for surgical aortic valve replacement (SAVR). Based on data from the original Placement of Aortic Transcatheter Valves (PARTNER) trial and CoreValve® US Pivotal trials, TAVR is now approved and accepted in the treatment for severe symptomatic AS in extreme-, high-, and intermediate-risk patients. Thus far, the randomized controlled trial data for TAVR have been non-inferior or even superior to both medical therapy and SAVR. Given all the data, the logical next step is to study low-risk patient groups. Anecdotal and non-randomized data have been conflicting when comparing TAVR with SAVR in low-risk patients. Two low-risk randomized trials have started in the US, and ultimately, these trials will determine the feasibility of TAVR as an acceptable alternative to SAVR in low-risk patients with severe AS. Thus, in 2017, any patient with AS should be referred to a multidisciplinary valve team to be evaluated for TAVR, SAVR, or nothing, depending on risk and availability of ongoing clinical trials.

Keywords Transcatheter aortic valve replacement, TAVR, risk, clinical trials, heart team, durability Disclosure: CMB is a consultant and member of the advisory board for Medtronic and Boston Scientific; MJR has received a grant and research support from Medtronic and Boston Scientific Received: 2 Sep 2017 Accepted: 21 Sep 2017 Citation: US Cardiology Review 2017;11(2):67–71. DOI: 10.15420/usc.2017:22:1 Correspondence: Colin M Barker, MD, FACC, FSCAI, Assistant Professor of Cardiology, Houston Methodist DeBakey Heart & Vascular Center, Department of Cardiology, 6550 Fannin Street, Suite 1901, Houston, TX 77030 USA. E: cmbarker@houstonmethodist.org

Aortic stenosis (AS) has a long latent period and then rapid progression with high mortality once symptoms appear.1 The absence of an effective medical therapy for symptomatic severe AS led to a class I indication for aortic valve replacement (AVR) in both the US and European guidelines.2,3 Unfortunately, a study by Bach et al. in 2009 found that up to half of patients with symptomatic severe AS were not offered surgical aortic valve replacement (SAVR) as they were not considered reasonable surgical candidates based on age, comorbidities, frailty, or other anatomic risks.4 Transcatheter aortic valve replacement (TAVR) was developed as a less invasive alternative to SAVR to allow treatment in this higher-risk patient population. Since the first successful TAVR in 20025 more than 250,000 procedures have been performed worldwide with a steadily decreasing patient-risk profile (Table 1).

started in the US, and ultimately, these trials will determine the feasibility of TAVR as an acceptable alternative to SAVR in low-risk patients with severe AS.

Based on data from the original Placement of Aortic Transcatheter Valves (PARTNER) trials and CoreValve® US Pivotal trials, TAVR is now approved and accepted in the treatment for severe symptomatic AS in extreme-, high-, and intermediate-risk patient populations. Thus far, the randomized controlled trial data for TAVR have been non-inferior or even superior to both medical therapy and SAVR. Given the evolution of the data, the next step is to study low-risk patient groups. Anecdotal and non-randomized data have been conflicting when comparing TAVR with SAVR in low-risk patients. Two low-risk randomized trials have

Cohort B of the PARTNER trial was the first and only trial in nonoperative patients to randomize TAVR using the valve against best medical therapy, which could include BAV.7 The primary endpoint was all-cause death. At 1 year there was a 20 % survival advantage to TAVR,7 and this advantage persisted for the 5-year life of the trial.8 The Extreme Risk Iliofemoral study of the CoreValve US Pivotal trial started after the reported 1-year endpoint of the PARTNER B trial; by then it was no longer considered reasonable to randomize against medical therapy due to the clinically significant advantage of TAVR. The US CoreValve Extreme Risk Pivotal Trial

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Extreme-risk Patients The onset of symptoms in severe AS heralds the usually rapid clinical deterioration and high mortality seen in the original survival curves of Ross and Braunwald1 and confirmed by contemporary authors such as Otto et al.6 If operated upon, extreme-risk patients are considered to have a >50 % chance of death or permanent disability at 30 days. Balloon aortic valvuloplasty (BAV) was developed to address this group of patients who could not undergo SAVR. Although BAV could decrease the gradient and improve flow dynamics, it did not improve survival.

Access at: www.USCjournal.com

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Valvular Disease Table 1: Summary of Transcatheter Aortic Valve Replacement Clinical Trials in Patients with Severe Symptomatic Aortic Stenosis Trial

Population (n)

Intervention

Comparator

Outcome

PARTNER B7 Inoperable (358) TAVR with Edwards SAPIEN Valve Standard medical care, including via transfemoral approach balloon aortic valvuloplasty

The mortality rate was reduced with TAVR at 1 year (30.7 % versus 50.7 %), 2 years (43.4 % versus 68 %), 3 years (54.1 % versus 80.9 %) and five years (71.8 % versus 93.6 %)

Extreme surgical TAVR with the self-expanding CoreValve® US Pivotal Trial risk (489) CoreValve Extreme Risk Iliofemoral Study9

In those treated with the CoreValve transcatheter heart valve, the rate of all-cause mortality or major stroke at 12 months was 26 %, which was significantly lower than the prespecified performance goal of 43 %

Prespecified estimate of 12-month mortality or major stroke with medical therapy (43 %, based upon results of a meta-analysis and data from PARTNER cohort B)

High-risk SAVR (699). Balloon-expandable TAVR SAVR PARTNER A15 Mean STS PROM (by transfemoral or transapical was 11.7 % approach)

Mortality rates in the TAVR and surgical groups were similar at 30 days (3.4 % versus 6.5 %, p=0.07), 1 year (24.3 % versus 26.8 %), 2 years (33.9 % versus 35 %), and 5 years (67.8 % versus 62.4 %)

CoreValve US High-risk SAVR (795). Self-expanding TAVR SAVR Pivotal Trial Mean STS PROM High Risk was 7.4 % Study10

Mortality rate was lower in the TAVR group at 1 year (14.2 % versus 19.1 %) and 2 years (22.2 % versus 28.6 %). The rate of death or major stroke was significantly lower with TAVR at 1 year (16.3 % versus 22.5 %), 2 years (24.2 % versus 32.5 %), and 3 years (35.0 % versus 41.6 %)

Intermediate-risk Balloon-expandable TAVR SAVR PARTNER IIA22 SAVR (2032). (by transfemoral or transapical Mean STS PROM approach) score 5.8 %

The rate of death from any cause or disabling stroke was similar in both groups. At 2 years, the Kaplan-Meier event rates were similar: 19.3 % in the TAVR group and 21.1 % in the SAVR group. In the transfemoral access cohort, TAVR resulted in a lower event rate than SAVR (HR 0.79; 95 % CI [0.62-1.00]). In the transthoracic access cohort, outcomes were similar in the TAVR and SAVR groups (HR 1.21; 95 % CI [0.79-1.65]).

Intermediate-risk Self-expanding TAVR; SAVR SAVR (1746). CoreValve in 84 % and Evolut Mean STS PROM R™ in 16 % 4.5 %

The incidence of the primary composite endpoint of death from any cause or disabling stroke at 24 months was similar in the TAVR and SAVR groups (12.6 % and 14.0 %)

SURTAVI23

Low-risk SAVR, all Self-expanding TAVR SAVR NOTION25 comers (280). Mean STS PROM 3 %

There was no difference in the TAVR and SAVR groups in the primary outcome, the composite rate of death from any cause, stroke, or MI at 1 year (13.1 % versus 16.3 %, p=0.43 for superiority)

High- or extreme-risk TAVR with Lotus™ Valve using TAVR with self-expanding valve REPRISE III12 TAVR (912). a mechanical expansion platform (CoreValve) Mean STS PROM 6.4 %

Primary Safety: Composite of all-cause mortality, stroke, life-threatening and major bleeding events, acute kidney injury (stage II/III), and major vascular complications at 30 days (Lotus 19.0 %, CoreValve 16.2 %, noninferiority p=0.001). Primary Effectiveness: Composite of allcause mortality, disabling stroke, and moderate or greater paravalvular leak (core lab assessment) at 1 year (Lotus 15.8 %, CoreValve 26.0 %, superiority p<0.001). Secondary: Moderate or greater PVL (core lab assessment) at 1 year (Lotus 0.9 %, CoreValve 6.9 %, p<0.001)

HR = hazard ratio; NOTION = Nordic Aortic Valve Intervention trial; PARTNER = Placement of Aortic Transcatheter Valves trial; PROM = predicted risk of 30-day mortality; PVL = paravalvular leak; REPRISE III = Repositionable Percutaneous Replacement of Stenotic Aortic Valve Through Implantation of Lotus Valve System trial; SAVR = surgical aortic valve replacement; STS = Society of Thoracic Surgeons; SURTAVI = Surgical Replacement and Transcatheter Aortic Valve Implantation trial; TAVR = transcatheter aortic valve replacement.

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Who should be referred for TAVR was a non-randomized registry comparing TAVR with the self-expanding valve against a performance goal based on the 95 % lower margin of survival for the medical arm of PARTNER B and five contemporary BAV series.9 TAVR with the self-expanding valve easily exceeded this goal at both 1 and 2 years.9,10 The Repositionable Percutaneous Replacement of Stenotic Aortic Valve Through Implantation of Lotus Valve System (REPRISE III) trial extreme-risk arm randomized TAVR with a mechanicallyexpandable valve against the self-expanding valve in a 2:1 fashion. The results were recently presented and found the Lotus™ Valve (Boston Scientific) to be safe and effective compared to commercially available self-expanding TAVRs (CoreValve and Evolut™, Medtronic).12

years TAVR maintains a 6.4 % absolute survival advantage.18 In the trial the worry about stroke reversed as TAVR had less strokes than SAVR. Hemodynamic flow parameters by echo were statistically superior for TAVR over SAVR at all time points while PVL remained significantly higher in TAVR. Pacemaker implantation was higher with TAVR at 30 days and 1 year (19.8 % versus 7.1 %, p<0.001; 22.3 % versus 11.3 %, p<0.001). Like the PARTNER A trial, QoL increased dramatically and equally in both groups. The data led to commercial approval of both valves in the US and guideline recommendation for TAVR as an alternative to SAVR in this highrisk patient group.

Intermediate-risk Patients An issue that has become a challenge for valve teams in the management of extreme-risk patients is determining when a TAVR is futile and not appropriate in a patient with severe AS. There remains a sizable group of patients who die or lack improvement in quality of life (QoL) soon after TAVR.13 In this very elderly population (mean < 80 years) a number of factors in addition to traditional risk stratification need to be considered, including comorbidities, disability, frailty, and cognition, in order to assess the anticipated benefit of TAVR as well as the risk of an invasive procedure. Evaluation by a multidisciplinary heart valve team with broad areas of expertise is critical for assessing likely benefit from TAVR. Moreover, these complicated decisions should take place with clear communication around desired health outcomes on behalf of the patient and provider. Expectations need to be clear and realistic. For example, TAVR will not cure dementia and age-related cognitive decline.14 The approach should include a multidisciplinary evaluation. When there is concern regarding futility and expectations, additional members from the team are included in the consultation. Ultimately, the assessment to move forward with a TAVR must be a consensus opinion. The decision that treatment with TAVR is futile should include alternative plans to optimize the patient’s health state or, in some cases, discussions related to end-of-life care.

High-risk Patients Cohort A of the PARTNER trial randomized patients with AS and a high risk of operative mortality to treatment with either SAVR or the SAPIEN (Edwards Lifesciences Corp) transcatheter valve. High risk was defined as either a Society of Thoracic Surgeons (STS) predicted risk of 30-day mortality (PROM) of at least 10 % or an expected risk of mortality of at least 15 % for SAVR as determined by two cardiac surgeons. The PARTNER A trial randomized patients with symptomatic severe AS as high risk for SAVR to TAVR versus SAVR.15 Survival at 1 year was equivalent and remained so for the 5-year term of the study.16 One question raised in the trial was the higher risk of stroke in TAVR compared with SAVR. The difference disappeared and strokes actually became numerically greater in SAVR by 2.5 years. Hemodynamic flow parameters measured by echo were equivalent but paravalvular leak (PVL) was substantially more common in TAVR than SAVR. Subsequently, the PVL rate in TAVR has substantially decreased as a result of more accurate annulus sizing using computer tomomgraphy angiogram better technique, and improved annular sealing using external skirts. QoL improved greatly and equivalently in both groups. The randomized CoreValve US Pivotal Trial High Risk study tested TAVR with a self-expanding valve against SAVR in a high-risk population.9 The trial had the provocative finding of actual superior survival for TAVR over SAVR at 1 and 2 years.9,17 At 3

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A number of reports from Europe for intermediate-risk patient populations for TAVR versus SAVR in propensity-matched studies have shown equivalent survival that suggested equipoise in the intermediate-risk population.19–21 This lead to randomized trials for TAVR versus SAVR in the intermediate-risk population in the US. The PARTNER II trial cohort A randomized 2,032 patients for SAVR against TAVR with the secondgeneration balloon-expandable TAVR valve.22 The trial had separate arms for transfemoral (TF) and non-transfemoral (non-TF) access. The trial used an STS PROM of ≥4 but <10 to define intermediate risk. The primary endpoint was a non-hierarchical composite of all-cause mortality or disabling stroke at 2 years. The primary analysis was intent-to-treat but analysis of the as-treated and TF subgroups where prespecified. Over 1,000 patients were randomized into the TAVR and SAVR group with 789 and 716 available at 2 years for analysis in the TAVR and SAVR cohorts, respectively. The mean age was 81.5 and 81.7 years in the TAVR and SAVR groups, respectively, with corresponding mean STS score of 5.8 % in both arms. Anesthesia time, procedure time, intensive care unit time, and length of stay were all significantly shorter in the TAVR group. The primary endpoint in the intent-to-treat group of all-cause mortality or disabling stroke for TAVR versus SAVR at 1, 12 and 24 months was 6.1 %, 14.5 %, and 19.3 % versus 8.0 %, 16.4 %, and 21 %, respectively (p=0.253), easily reaching non-inferiority at p=0.001. The as-treated numbers were similar with a p=0.180. Subgroup analysis suggested that non-TF access trended towards favoring SAVR at p=0.06. When looking at the prespecified TF-only intent-to-treat group for the primary endpoint, TAVR versus SAVR at 1, 12 and 24 months was 4.9 %, 12.3 %, and 16.8 % versus 7.7 %, 15.9 %, and 20.4 %, respectively, (p=0.05). This reached statistical superiority for TAVR in the as-treated TF group with TAVR versus SAVR at 2 years (16.3 % versus 20.0 %, p=0.04). Major vascular complications were more common in TAVR versus SAVR (7.9 % versus 5.0 %, p=0.006), while life-threatening and disabling bleeding (10.4 % versus 43.4 %, p <0.001), acute kidney injury (1.3 % versus 3.1 %, p=0.02), and new atrial fibrillation (9.1 % versus 26.4 %, p< 0.001) were all significantly more common in SAVR. Aortic valve area by echo was significantly better in TAVR at all time points. The trial supported the use of the second-generation balloonexpandable TAVR valve in the intermediate-risk population. The Surgical Replacement and Transcatheter Aortic Valve Implantation trial (SURTAVI) trial was a prospective randomized trial of TAVR with the self-expanding valve versus SAVR in an intermediate-risk population.23 The trial randomized TAVR to SAVR 1:1 with each group having subgroups of patients requiring revascularization or not. Intermediate risk in the trial is defined as an estimated 30-day surgical mortality of 3–15 % according to the criteria of the STS PROM. The primary endpoint was

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Valvular Disease all-cause mortality or disabling stroke at 24 months. A total of 1,746 patients underwent randomization at 87 centers. Of these patients, 1,660 underwent an attempted TAVR or surgical procedure. The mean (± SD) age of the patients was 79.8 ± 6.2 years, and all were at intermediate-risk for surgery (STS PROM 4.5 ± 1.6 %). At 24 months the estimated incidence of the primary endpoint was 12.6 % in the TAVR group and 14.0 % in the surgery group (95 % credible interval [Bayesian analysis] for difference, -5.2–2.3 %; posterior probability of non-inferiority >0.999). Surgery was associated with higher rates of acute kidney injury, atrial fibrillation, and transfusion requirements, whereas TAVR had higher rates of residual aortic regurgitation and need for pacemaker implantation. TAVR resulted in lower mean gradients and larger aortic valve areas compared with surgery. Structural valve deterioration at 24 months did not occur in either group. The conclusion was TAVR was a non-inferior alternative to surgery in patients with severe AS at intermediate surgical risk, with a different pattern of adverse events associated with each procedure. The Safety and Performance Study of the Edwards SAPIEN 3 Transcatheter Heart Valve (SAPIEN3) trial was a non-randomized registry for TAVR using the third-generation balloon-expandable valve in an intermediate-risk population defined as an STS score of 4–8 %.24 A prespecified comparison to the surgical arm of PARTNER IIA was planned using a prespecified propensity score analysis with patient level data. The trial recruited 1,078 patients who were divided into TF and non-TF access (transapical and transaortic). The design was a non-inferiority primary endpoint composite of all-cause mortality, all stroke, and moderate or greater PVL with a hierarchical prespecified superiority test if non-inferiority was met. The mean age for TAVR and SAVR was 81.9 and 81.6 years with a mean STS of 5.2 and 5.4, respectively. The trial reached non-inferiority for the composite primary endpoint at p<0.001 followed by superiority at p<0.001. Looking at the individual components of the endpoint, TAVR reached superiority for mortality (p<0.001) and stroke (p=0.004) but SAVR was superior for PVL (p=0.0149). All-cause death and all stroke for TAVR versus SAVR at 30 days and 1 year were 1.1 % and 7.4 % versus 4.0 % and 13.0 %; 2.7 % and 4.6 % versus 6.1 % and 8.2 %, respectively, showing an extremely low mortality and stroke rate for TAVR in this elderly population. Moderate or greater PVL in the TAVR cohort in this trial was only 1.5 % at 1 year. Both TAVR platforms are currently Food and Drug Administration approved in the US for the use in treating intermediate-risk patients with severe symptomatic AS. All patients who meet this profile should be evaluated by a heart team and offered TAVR as an alternative to SAVR with an understanding of the advantages and disadvantages of each modality.

Low-risk Patients The Nordic Aortic Valve Intervention (NOTION) trial compared TAVR with SAVR in predominantly low-risk patients.25 Patients ≥70 years with severe AS and no significant coronary artery disease were randomized 1:1 to TAVR using a self-expanding bioprosthesis versus SAVR. The primary outcome was the composite rate of death from any cause, stroke, or MI at 1 year. A total of 280 patients were randomized with a mean age of 79.1 years, and 81.8 % were considered low-risk patients. In the intention-to-treat population, no significant difference in the primary endpoint was found

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(13.1 % versus 16.3 %, p=0.43 for superiority). The result did not change in the as-treated population. No difference in the rate of cardiovascular death or prosthesis reintervention was found. Compared with SAVR, TAVR had more conduction abnormalities requiring pacemaker implantation, larger improvement in effective orifice area, more total aortic valve regurgitation, and higher New York Heart Association functional class at 1 year. SAVR had more major or life-threatening bleeding, cardiogenic shock, acute kidney injury (stage II or III), and new-onset or worsening atrial fibrillation at 30 days compared with TAVR. This study had several limitations as it was a small trial and not fully reflective of the population of low-surgicalrisk patients with AS. Low-risk patients are determined by the heart team to have <3 % surgical risk or an STS PROM score of <4 %. Two low-risk prospective randomized trials are currently enrolling in the US: the PARTNER III trial of the balloon-expandable valve (The Safety and Effectiveness of the SAPIEN 3 Transcatheter Heart Valve in Low-risk Patients with Aortic Stenosis, NCT02675114) and the Evolut R low-risk randomized trial for the selfexpanding valve (Medtronic Transcatheter Aortic Valve Replacement in Low-risk Patients, NCT02701283). Low-risk patients in the US should be referred to a center with a heart team and evaluated for participation in a randomized clinic trial comparing TAVR and SAVR. Alternatively, in 2017, whether these patients should be treated with SAVR as TAVR has not yet been completely evaluated. Many who are evaluated as low risk via screening may have a bicuspid aortic valve. These patients are currently excluded from the current protocols. For TAVR to be considered as an alternative to SAVR in low-risk patients it would need to show equivalent or better mortality, morbidity, hemodynamics, QoL, patient acceptance, and durability. The available data would support equivalent or better mortality, hemodynamics, and QoL. A continuing challenge and limitation of TAVR remains conduction disturbances requiring a permanent pacemaker. As younger and lowerrisk patients are treated this will become less acceptable. Although little directly-measured data on patient acceptance exists, valve clinic practitioners understand patients overwhelmingly desire TAVR as their treatment choice. The morbidity of TAVR has improved substantially. The data on stroke now suggest it is higher in SAVR than TAVR and PVL has improved substantially through valve design in the short period that TAVR has existed. SAVR continues to show higher rates of severe bleeding, AKI, and atrial fibrillation in multiple randomized trials.

Durability Long-term valve durability concerns have remained a limitation in the expansion of TAVR to lower-risk patients. The 5-year follow-up data from PARTNER16,26 are reassuring in that no episodes of structural deterioration requiring replacement were observed, and valve hemodynamics (gradient and effective orifice areas) remained stable. Furthermore, biomechanical stresses are likely lower in transcatheter patients than surgical patients due to the lower residual mean gradients and the effective orifice area in transcatheter patients. Regardless, additional follow-up data in transcatheter valves will be required in the future to declare equivalence with the most durable surgical bioprosthetic valves.27 The transcatheter valves currently used in practice appear equivalent in the short to intermediate term. Perhaps the uncertainty of long-term durability becomes less concerning with the possibility

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Who should be referred for TAVR of transcatheter valve-in-valve therapy to extend the duration of nonsurgical valve treatment.

Conclusion Current data suggest TAVR is not just an alternative but the best choice for nonoperative patients with severe symptomatic AS in both extreme- and high-risk patients with anatomy suitable for TAVR. In addition, TAVR is a reasonable alternative in the intermediate-risk

1. 2.

Ross J Jr, Braunwald E. Aortic stenosis. Circulation 1968;38:61–7. DOI: 10.1161/01.CIR.38.1S5.V-61; PMID: 4894151 Nishimura RA, Otto CM, Bonow RO, et al. 2014 AHA/ACC guideline for the management of patients with valvular heart disease: a report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2014;63:e57–185. DOI: 10.1016/j.jacc.2014.02. 536; PMID:24603191 Vahanian A, Alfieri O, Andreotti F, Antunes MJ, Baron-Esquivias G, Baumgartner H, et al. [Guidelines on the management of valvular heart disease (version 2012). The joint task force on the management of valvular heart disease of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS)]. G Ital Cardiol (Rome) 2013;14:167–214 [in Italian]. DOI: 10.1714/1234.13659; PMID: 23474606 Bach DS, Siao D, Girard SE, et al. Evaluation of patients with severe symptomatic aortic stenosis who do not undergo aortic valve replacement: the potential role of subjectively overestimated operative risk. Circ Cardiovasc Qual Outcomes 2009;2:533–9. DOI: 10.1161/CIRCOUTCOMES.109.848259; PMID: 20031890 Cribier A, Eltchaninoff H, Bash A, et al. Percutaneous transcatheter implantation of an aortic valve prosthesis for calcific aortic stenosis: first human case description. Circulation 2002;106:3006–8. DOI: 10.1161/01.CIR.0000047200.36165.B8; PMID: 12473543 Otto CM, Pearlman AS, Gardner CL. Hemodynamic progression of aortic stenosis in adults assessed by Doppler echocardiography. J Am Coll Cardiol 1989;13:545–50. DOI: 10.1016/0735-1097(89)90590-1; PMID: 2918158 Leon MB, Smith CR, Mack M, et al. Transcatheter aortic-valve implantation for aortic stenosis in patients who cannot undergo surgery. N Engl J Med 2010;363:1597–607. DOI: 10.1056/ NEJMoa1008232; PMID: 20961243 Kapadia SR, Tuzcu EM, Makkar RR, et al. Long-term outcomes of inoperable patients with aortic stenosis randomly assigned to transcatheter aortic valve replacement or standard therapy. Circulation 2014;130:1483–92. DOI: 10.1161/ CIRCULATIONAHA.114.009834; PMID: 25205802 Popma JJ, Adams DH, Reardon MJ, et al. Extreme risk Corevalve transcatheter aortic valve replacement using a self-expanding bioprosthesis in patients with severe

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group with appropriate anatomy. Two low-risk randomized trials have started in the US (PARTNER III and Evolut low-risk randomized trials) to determine the feasibility of TAVR as an acceptable alternative to SAVR in low-risk patients with severe AS. In 2017, all patients with severe symptomatic AS should be referred to a valve center that can offer the entire spectrum of treatment modalities including TAVR and SAVR as part of routine care or the opportunity to participate in a clinical trial to answer some of the remaining questions surrounding TAVR. n

aortic stenosis at extreme risk for surgery. J Am Coll Cardiol 2014, March 13. Adams DH, Popma JJ, Reardon MJ, et al. Transcatheter aorticvalve replacement with a self-expanding prosthesis. N Engl J Med 2014;370:1790–8. DOI: 10.1056/NEJMoa1400590; PMID: 24678937 Yakubov SJ, Adams DH, Watson DR, et al. 2-year outcomes after iliofemoral self-expanding transcatheter aortic valve replacement in patients with severe aortic stenosis deemed extreme risk for surgery. J Am Coll Cardiol 2015;66:1327–34. DOI: 10.1016/j.jacc.2015.07.042; PMID: 26383718 Feldman T, Reardon MJ, Rajagopol V, et al. A prospective investigation of a novel transcatheter aortic valve implantation system: the REPRISE III trial. Presented at: EuroPCR 2017; Paris, 16 May 2017. Lindman BR, Alexander KP, O’Gara PT, Afilalo J. Futility, benefit, and transcatheter aortic valve replacement. JACC Cardiovasc Interv 2014;7:707–16. DOI: 10.1016/j.jcin.2014.01.167; PMID: 24954571 Auffret V, Campelo-Parada F, Regueiro A, et al. Serial changes in cognitive function following transcatheter aortic valve replacement. J Am Coll Cardiol 2016;68:2129–41. DOI: 10.1016/ j.jacc.2016.08.046; PMID: 27692728 Smith CR, Leon MB, Mack MJ, et al. Transcatheter versus surgical aortic-valve replacement in high-risk patients. N Engl J Med 2011;364:2187–98. DOI: 10.1056/NEJMoa1103510; PMID: 21639811 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. DOI: 10.1016/S0140-6736(15)60308-7; PMID: 25788234 Reardon MJ, Adams DH, Kleiman NS, et al. 2-year outcomes in patients undergoing surgical or self-expanding transcatheter aortic valve replacement. J Am Coll Cardiol 2015;66:113–21. DOI: 10.1016/j.jacc.2015.05.017; PMID: 26055947 Deeb GM, Reardon MJ, Chetcuti S, et al. 3-year outcomes in high-risk patients who underwent surgical or transcatheter aortic valve replacement. J Am Coll Cardiol 2016;67:2565–74. DOI: 10.1016/j.jacc.2016.03.506; PMID: 27050187 Piazza N, Kalesan B, van Mieghem N, et al. A 3-center comparison of 1-year mortality outcomes between

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transcatheter aortic valve implantation and surgical aortic valve replacement on the basis of propensity score matching among intermediate-risk surgical patients. JACC Cardiovasc Interv 2013;6:443–51. DOI: 10.1016/j.jcin.2013.01.136; PMID: 23702009 D’Errigo P, Barbanti M, Ranucci M, et al. Transcatheter aortic valve implantation versus surgical aortic valve replacement for severe aortic stenosis: results from an intermediate risk propensity-matched population of the Italian OBSERVANT study. Int J Cardiol 2013;167:1945–52. DOI: 10.1016/j.ijcard.2012.05.028; PMID: 22633667 Latib A, Maisano F, Bertoldi L, et al. Transcatheter vs surgical aortic valve replacement in intermediate-surgical-risk patients with aortic stenosis: a propensity score-matched case-control study. Am Heart J 2012;164:910–7. DOI: 10.1016/j.ahj.2012.09.005; PMID: 23194492 Leon MB, Smith CR, Mack MJ, et al. Transcatheter or surgical aortic-valve replacement in intermediate-risk patients. N Engl J Med 2016;374:1609–20. DOI: 10.1056/NEJMoa15 14616; PMID:27040324 Reardon MJ, Van Mieghem NM, Popma JJ, et al. Surgical or transcatheter aortic-valve replacement in intermediaterisk patients. N Engl J Med 2017;376:1321–31. DOI: 10.1056/ NEJMoa1700456; PMID: 28304219 Thourani VH, Kodali S, Makkar RR, et al. Transcatheter aortic valve replacement versus surgical valve replacement in intermediate-risk patients: a propensity score analysis. Lancet 2016;387:2218–25. DOI: 10.1016/S0140-6736(16)30073-3; PMID: 27053442 Thyregod HG, Steinbrüchel DA, Ihlemann N, et al. Transcatheter versus surgical aortic valve replacement in patients with severe aortic valve stenosis: 1-year results from the all-comers NOTION randomized clinical trial. J Am Coll Cardiol 2015;65:2184–94. DOI: 10.1016/j.jacc.2015.03.014; PMID: 25787196 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. DOI: 10.1016/S0140-6736(15)60290-2; PMID: 25788231 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. DOI: 10.1016/ j.athoracsur.2014.10.070; PMID: 25662439

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Adult Congenital Heart Disease

The Impact of an Atrial Septal Defect on Hemodynamics in Patients With Heart Failure Saumil R. Shah, MD, Sergio Waxman, MD and William H. Gaasch, MD From the Department of Cardiovascular Medicine, Lahey Hospital and Medical Center, Burlington, MA and Tufts University School of Medicine, Boston, MA

Abstract In patients with left ventricular (LV) dysfunction, a large atrial septal defect (ASD) provides an alternate pathway for left atrial emptying and prevents abnormal elevation of left atrial and LV filling pressures. In such patients, closure of the ASD can cause an increase in LV diastolic pressure with pulmonary venous hypertension and congestion. The protective effect of an ASD is attenuated or abolished in the presence of right ventricular (RV) dysfunction. Thus, an elevated LV diastolic pressure in the presence of an ASD indicates dysfunction or failure of both ventricles. In this situation, pharmacologic or mechanical unloading of the left ventricle may result in right to left shunting with arterial hypoxemia. In the absence of RV failure, creation of an ASD can reduce LV filling pressures. Management of patients with heart failure and an ASD requires accurate assessment of atrial pressures and shunt flows as well as consideration of the functional state of both ventricles.

Keywords Atrial septal defect, heart failure, hemodynamics, interventional cardiology, intracardiac shunts, left atrial pressure, left ventricular diastolic pressure, pulmonary venous pressure Disclosure: The authors have no conflicts of interest to declare. Received: 29 June 2017 Accepted: 21 July 2017 Citation: US Cardiology Review 2017;11(2):72–4. DOI: 10.15420/ucs.2017:9:2 Correspondence: William H. Gaasch, MD, Lahey Clinic Cardiovascular Medicine, 14 Mall Road Burlington, MA 01805. E: William.H.Gaasch@lahey.org

Pulmonary venous hypertension and congestion that occurs with left ventricular (LV) failure is generally not seen in the presence of a large atrial septal defect (ASD). As long as right ventricular (RV) function and distensibility are not impaired, the ASD provides an alternate pathway for atrial emptying, thus preventing or attenuating elevated LV filling pressures. When RV dysfunction develops and right atrial pressure increases, this ‘protective’ effect of the ASD is reduced, the left to right shunt flow declines, and the LV filling pressures increase.1–6 These observations indicate that the hemodynamic consequences of ASD closure (or the creation of an ASD) are influenced by the functional state and the interaction of the two ventricles. In this brief review, we emphasize pulmonary venous, left atrial (LA), and LV diastolic pressures, and consider the impact of an ASD on the hemodynamics of heart failure.

Closure of an Atrial Septal Defect Symptomatic patients with uncomplicated ASD generally show an improvement in functional capacity after closure of an ASD. However, some patients require special consideration. For example, in the presence of an abnormal left ventricle, closure of an ASD removes its protective effect, and contributes to the poor clinical outcome that is occasionally seen.4,5 A modest increment in LA pressure is often seen after closure of an ASD, but large changes in pressure are uncommon and seen primarily in older patients with hypertension and/or LV dysfunction.5,7–10 Before proceeding with ASD closure in such patients, consideration should be given to test occlusion of the ASD to evaluate the potential for a deleterious increase in LA pressure.

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An example of the effect of ASD closure in a patient with RV and LV dysfunction and mitral stenosis (valve area = 1.1 cm2) is shown in Figure 1. Transient occlusion of the ASD resulted in an increase in pulmonary capillary wedge pressure (PCWP) from 18 to 23 mmHg. The increase developed gradually over several minutes, stabilizing after 3 minutes. The pressure returned to baseline after removal of the occluding balloon catheter. Some authorities suggest that an LA pressure increase exceeding 3 mmHg during test occlusion should prompt a consideration of the use of a fenestrated occluder that reduces, but does not abolish, the left-toright interatrial shunt.7 This approach should decrease the shunt flow and reduce the volume load on the right heart, and would potentially provide a lower LA pressure than would be expected with a complete closure.9 Others use an LA pressure increment of 10 mmHg (during test occlusion) to identify high-risk patients.8 Test occlusion of the ASD in patients at risk of a significant increment in LA pressure is relatively easy to recommend, but the exact partition pressure that would optimally identify patients who might benefit from a fenestrated occluder is not known.

Creation of an Atrial Septal Defect as a Therapeutic Measure In 1948 Harkin and associates recognized the infrequency of pulmonary edema in patients with mitral stenosis and ASD (Lutembacher’s syndrome) and they considered the creation of an ASD as a protective measure against the increasing LA pressure in patients with mitral stenosis.11

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Impact of Atrial Septal Defect on Hemodynamics Bland and Sweet also recognized this potential benefit and created an ‘extracardiac shunt to provide an outlet from the high-pressure left auriclepulmonary vein area into the systemic venous bed.’12,13 The anastomosis of a right pulmonary vein to the azygous vein produced a significant reduction in LA pressure and clinical improvement in their patients with end-stage mitral stenosis and severe pulmonary hypertension. Partial opening of a closed ASD has been reported in patients with refractory pulmonary edema after surgical closure of the defect.5 This being the case, it would seem appropriate to consider the creation of an ASD in some patients with recurrent hospitalization for acute pulmonary edema, particularly those with hypertension and diastolic heart failure.14 In the presence of LV diastolic dysfunction, a relatively small reduction in LV and LA volume could produce a large reduction in LA and pulmonary venous pressure.15 Ideally, the ASD should be made small enough to limit the left-to-right shunt when LA pressure is not significantly elevated, but large enough to provide the protective unloading discussed above.5,7 The feasibility and potential value of implanting an interatrial device that provides a left-to-right shunt in patients with LV dysfunction has been confirmed in a well-designed observational study.16 The study included 64 symptomatic patients with an LV ejection fraction >40 %, and an elevated PCWP (>15 mmHg at rest or >25 mmHg during supine exercise). In the presence of a normal LV end diastolic volume, most of such patients have significant diastolic dysfunction or diastolic heart failure.15 After implantation of the shunt device there was a modest reduction in the pressure gradient between the left and right atria, in association with a barely detectable left-to-right shunt (Qp/Qs = 1.25). These changes were accompanied by symptomatic improvement. A most important result was an improvement in exercise capacity that was achieved without an increase in the PCWP. There is little reason to believe that these salutary results would be different in patients with systolic heart failure, but it should be recognized that similar benefits should not be expected in patients with RV failure. Patients with severe pulmonary hypertension and right heart failure have undergone atrial septostomy in an attempt to blunt the progression of right heart failure and promote blood flow to the systemic circulation.17 The increase in systemic flow may promote increased oxygen delivery to the periphery despite the arterial hypoxemia that accompanies creation of a right-to-left interatrial shunt. A percutaneous balloon atrial septostomy might be considered in patients with refractory heart failure, but before the procedure is carried out some caveats deserve mention. First, the creation of an ASD in such patients can cause a decrease in right heart filling pressures and venous congestion, but only if the LV filling pressures are not elevated. Second, it is difficult, if not impossible, to reliably identify patients who are likely to benefit from atrial septostomy, and it should be recognized that some patients may not benefit and some may worsen after creation of an ASD.

Atrial Septal Defect With a Right-to-Left Shunt It has long been recognized that a right-to-left shunt can develop as a consequence of RV overload. More recently, LV mechanical support systems have been shown to precipitate right-to-left shunting and arterial hypoxemia in patients with heart failure with previously unrecognized ASD, patent foramen ovale, and iatrogenic/acquired defects.18–21 The

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Figure 1: ASD Closure in a Patient with RV and LV Dysfunction and Mitral Stenosis

50 45

ASD Occlusion (3 min)

Baseline

40 35 30

19 19 21 18

21 18

LV 7

PCW

10 5

24 1919

22 21

24 21

LV 10

Baseline LV, left atrial and PCWP measurements show elevated LVEDP (17 mmHg) and elevated PCWP (mean PCWP = 18 mmHg). The RV pressure (not shown) was 35/15 mmHg. After occlusion of the ASD the pulmonary artery oxygen saturation decreased from 76 to 65 %, there was an increase in LVEDP from 17 to 21 mmHg and the mean PCWP increased from 18 to 23 mmHg. ASD = atrial septal defect; LA = left atrial; LV = left ventricular; LVEDP = LV end-diastolic pressure; PCW = pulmonary capillary wedge; PCWP = pulmonary capillary wedge pressure; RV= right ventricular.

mechanical reduction in LV filling pressures in the presence of elevated right atrial pressure promotes right-to-left shunting. One report included measurement of central venous pressure and arterial PO2 over a range of right atrial pressures.21 This report documented arterial hypoxemia (PO2 = 40 mmHg) that improved dramatically (PO2 = 430 mmHg) when central venous pressure was reduced from 23 to 12 mmHg. These reports further illustrate the concepts of ventricular interaction discussed above and they emphasize the importance of considering the diagnosis of rightto-left intracardiac shunting in critically ill patients who develop arterial hypoxemia while on an LV-assist device.

Pressure Measurement Caveats The management of patients discussed above generally requires right heart catheterization and accurate pressure measurements. First, it should be acknowledged that significant interatrial shunting may occur with little or no detectable pressure gradient across the atrial septum, and that large gradients are usually a consequence of artifacts in the PCWP recordings. Second, the pulmonary artery balloon occlusion pressure, widely used as a surrogate for the PCWP, does not always accurately reflect pulmonary venous pressure. This issue can be addressed by evaluating the relation of the pulmonary artery (PA) diastolic pressure to the balloon occlusion pressure. If the balloon occlusion pressure exceeds the PA diastolic pressure, the accuracy of the occlusion pressure should be questioned. In the absence of pulmonary vascular disease, at end-diastole the PA pressure is equal to or only slightly higher than the pulmonary venous pressure, and there is virtually no forward blood flow. At end-diastole, the pulmonary venous pressure never exceeds the PA diastolic pressure; however, the mean PCWP may exceed the PA diastolic pressure in severe mitral regurgitation. Finally, it should be mentioned that an accurate mean PCWP reflects the mean LV filling pressure, but LV end-diastolic pressure can exceed the mean pressure in patients with a forceful atrial contraction (e.g. patients with LV diastolic dysfunction with or without heart failure). Thus, the mean PCWP is not always equal to the LV end-diastolic pressure.

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Adult Congenital Heart Disease Summary ASD closure in patients with suspected LV or RV dysfunction should be performed only after consideration of the hemodynamic effects of closing the defect. A careful assessment of changes in filling pressures should be performed with test balloon occlusion of the ASD. Conversely,

1. 2.

3. 4.

5. 6. 7.

Dexter L. Atrial septal defect. Br Heart J 1956;18:209–25. PMID: 13315850. Roven RB, Crampton RS, Case RB. Effect of compromising right ventricular function in left ventricular failure by means of interatrial and other shunts. Am J Cardiol 1969;24:209–19. PMID: 5799082. Tikoff G, Schmidt AM, Kuida H, Hecht HH. Heart failure in atrial septal defect. Am J Med 1965;39:533–51. PMID: 5831898. Davies H, Oliver CO, Rappoport WJ, Gazetopoulos N. Abnormal left heart function after operation in atrial septal defect. Br Heart J 1970;32:747–53. PMID: 5212346. Beyer J. Atrial septal defect: acute left heart failure after surgical closure. Ann Thoracic Surg 1978;25:36–43. PMID: 619810. Lutembacher R. De la stenose mitrale avec cummunication intrauriculaire. Arch Mal Coeur 1916;9:237–60. Holzer R, Qi-Ling C, Hijazi ZM. Closure of a moderately large atrial septal defect with a self-fabricated fenestrated amplatz septal occluder in an 85 year old patient with reduced diastolic elasticity of the left ventricle. Cath Cardiovasc Interv 2001;52: 177–80. Humbenberger M, Rosenhek R, Gabriel H, et al. Benefit of atrial septal defect closure in adults: impact of age. Eur Heart J 2011;32:533–60. PMID: 20943671.

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10.

11.

12. 13. 14.

15.

creation of an ASD with the purpose of unloading the left ventricle may offer therapeutic promise in select patients with LV dysfunction and symptomatic heart failure. The hemodynamic consequences of either closure or creation of an ASD are intimately dependent on the functional state and interaction of the two ventricles. n

ruch L, Winkelmann A, Sonntag S, et al. Finestrated occluders B for treatment of ASD in elderly patients with pulmonary hypertension and/or right heart failure. J Interv Cardiol 2008; 21:44–9. DOI: 10.1111/j.1540-8183.2007.00324.x; PMID: 18086135. Ewert P, Berger F, Nagdyman N, et al. Masked left ventricular restriction in elderly patients with atrial septal defects: a contraindication for closure? Catheter Cardiovasc Interv 2001;52:177–80. PMID: 11170324. Harken DE, Ellis LB, Ware PF, Norman LR. The surgical treatment of mitral stenosis: I. Valvuloplasty. N Engl J Med 1948;239:801–9. DOI: 10.1056/NEJM194811252392201; PMID: 18890600. Bland EF, Sweet RH. A venous shunt for advanced mitral stenosis. JAMA 1949;140:1259–65. PMID: 18137277. Bland EF. Surgery for mitral stenosis: a review of progress. Circulation 1952;5:290–9. PMID: 14896476. Gandi SK, Powers JC, Abdel-Mohsen N, et al. The pathogenesis of acute pulmonary edema associated with hypertension. N Engl J Med 2001;344:17–22. DOI: 10.1056/NEJM200101043440103; PMID: 11136955. Gaasch WH. Deliberations on diastolic heart failure. Am J Cardiol 2017;119:138–44. DOI: 10.1016/j.amjcard.2016.08.093; PMID: 28029360.

16. K aye DM, Hasenfus G, Petr Neuzil P, et al. One-year outcomes after transcatheter insertion of an interatrial shunt device for the management of heart failure with preserved ejection fraction. Circ Heart Fail 2016;9:1–6. DOI: 10.1161/ CIRCHEARTFAILURE.116.003662; PMID: 27852653. 17. Hopkins W, Rubin LJ. Treatment of pulmonary hypertension in adults. In: Post TW (ed), UpToDate. Waltham, MA: UpToDate. Available at: www.uptodate.com/contents/treatment-ofpulmonary-hypertension-in-adults (accessed on July 30, 2017). 18. Baldwin RT, Duncan JM, Frazier OH, Wilansky S. Patient foramen ovale: a cause of hypoxemia in patients on left ventricular support. Ann Thorac Surg 1991:52:865–7. PMID: 1929645. 19. Nguyen DQ, Das GS, Grubbs BC, et al. Transcatheter closure of patient foramen ovale for hypoxemia during left ventricular assist devide support. J Heart Lung Transplant 1999;19:1021–3. PMID: 10561114. 20. Sur JP, Pagani FD, Moscucci M. Percutaneous closure of an iatrogenic atrial septal defect. Catheter Cardiovasc Interv 2009;73:267–71. DOI: 10.1002/ccd.21768; PMID: 19156898. 21. Loyalka P, Idelchik GM, Kar B. Percutaneous left ventricular assist device complicated by a patent foramen ovale: importance of identification and management. Catheter Cardiovasc Interv 2007:70:383–6. DOI: 10.1002/ccd.21185; PMID: 17563095.

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Adult Congenital Heart Disease

Update on the Management of Patent Foramen Ovale in 2017: Indication for Closure and Literature Review Kimberly Atianzar, MD, 1 Peter Casterella, MD, 1 Ming Zhang, MD, PhD, 1 Rahul Sharma, MD 1,2 and Sameer Gafoor, MD 1,3 1. Swedish Heart and Vascular Institute, Seattle, WA; 2. Carilion Clinic, Roanoke, VA; 3. Cardiovascular Center Frankfurt, Frankfurt, Germany

Abstract Patent foramen ovale (PFO) is a common congenital abnormality with a high prevalence of approximately 25 % in the general population and an even higher incidence of about 40 % in the cryptogenic stroke population. PFO closure in cryptogenic stroke patients as a treatment modality for the secondary prevention of recurrent stroke has been much debated and studied. Several completed randomized clinical trials sought to answer the question of whether PFO closure is beneficial for cryptogenic stroke patients. Until the most recent of these trials, no significant benefit had been demonstrated. Based on newer evidence, in October 2016 the US Food and Drug Administration approved the first dedicated closure device for PFO. This review article describes the association between PFO and cryptogenic stroke, reviews current diagnostic modalities of PFO assessment, discusses management approaches, and reviews randomized clinical trials, practice guidelines, and consensus statements. Associations between PFO and other conditions such as migraine headaches, platypnea-orthodeoxia syndrome, and decompression sickness in divers are also briefly reviewed.

Keywords Patent foramen ovale; patent foramen ovale closure; cryptogenic stroke; recurrent stroke; migraine; decompression sickness; platypneaorthodeoxia; obstructive sleep apnea Disclosure: Sameer Gafoor has consulting and proctoring disclosures with Abbott Vascular. The other authors have no conflicts of interest to disclose. Received: 22 August 2017 Accepted: 9 October 2017 Citation: US Cardiology Review 2017;11(2):75–9. DOI: 10.15420/usc.2017:18:1 Correspondence: Sameer Gafoor, Swedish Heart and Vascular, 550 17th Avenue Suite 680, Seattle, WA 98122; E: sameergafoor@gmail.com

The foramen ovale is an important fetal structure that is integral to fetal circulation. During fetal development days 30–37, intra-atrial endothelial cells proliferate to form the septum primum and the ostium primum. The overlap between the these structures forms the inter-atrial passage known as the foramen ovale,1,2 which allows the fetal lungs to be bypassed by facilitating fetal blood movement from the right to the left atrium. The initiation of lung function and increase in left-sided pressures, both of which occur at birth, result in functional closure of the foramen ovale. In most people, spontaneous anatomical closure of the foramen ovale occurs in the first few months of life. However, based on several large autopsy studies, approximately 25 % of healthy adults in the general population have a patent foramen ovale (PFO),3–5 with equal prevalence between men and women. Most individuals with a PFO are asymptomatic. However, when the right atrial pressure increases so it is greater than the left atrial pressure, whether transiently (for example during a Valsalva maneuver) or permanently, a right-to-left shunt occurs across the PFO allowing the venous circulation to be in direct contact with the arterial circulation. This potential for a PFO to be open and have right-to-left flow means that paradoxical embolization may occur through the PFO, leading to cerebral, coronary or other systemic arterial embolization, with the potential for serious adverse outcomes. Additional PFO-related conditions of concern include migraine headaches, decompression sickness, platypnea-orthodeoxia, exacerbation of right–left shunting with obstructive sleep apnea (OSA), and myocardial infarction due to

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paradoxical embolism to the coronary arteries.6–10 This article provides a focused up-to-date review of the association between cryptogenic stroke and PFO, diagnostic methods, recurrent stroke risk, clinical assessment scores, management approaches, and current guidelines.

PFO Association with Stroke In the US, approximately 800,000 people suffer from a stroke annually, with around 185,000 being recurrent attacks. Stroke is the fifth leading cause of death, and the third leading cause of disability in the US.11 Eighty percent of all strokes are ischemic and 20–30 % are cryptogenic, meaning no obvious etiology is detected despite a detailed and thorough etiological work-up.12 PFO prevalence in cryptogenic stroke patients is greater (about 40 %) than in the general population, and even higher in cryptogenic stroke patients <55 years of age (about 55 %).13 The Risk of Paradoxical Embolism (RoPE) study devised a predictive model to determine the likelihood that an initial stroke was due to a PFO and recurrent stroke risk. However, observational studies suggest that stroke development in PFO patients is likely multifactorial.14–16 For example, atrial fibrillation and atrial flutter are established preventable ischemic stroke risk factors; therefore, the development of these arrhythmias in cryptogenic stroke patients with a PFO may increase the likelihood of stroke recurrence.17 In the 30 Day Event Monitoring Belt for Recording Atrial Fibrillation After a Cerebral Ischemic Event (EMBRACE) randomized controlled trial, cryptogenic stroke patients were monitored for atrial

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Adult Congenital Heart Disease fibrillation using a 30-day event-triggered loop recorder versus a 24-hour ECG Holter monitor.18 The authors found a significantly higher prevalence of atrial fibrillation in the cryptogenic stroke patients monitored for 30 days versus those monitored for only 24 hours after stroke (16.1 % versus 3.2 %; 95 % CI: 8.0–17.6; p<0.001).18 Thus, whether a PFO is present or not, it is important to carefully monitor for paroxysmal atrial fibrillation in cryptogenic stroke patients and initiate appropriate anticoagulation for the prevention of recurrent stroke. Multiple studies have established an association between PFO and cryptogenic stroke. The Risk of Paradoxical Embolism (RoPE) study devised a predictive model to determine the likelihood of initial stroke being due to the presence of PFO and to predict recurrent stroke risk. The premise of the RoPE study was that patients with a high RoPE score and significant stroke recurrence risk would benefit the most from PFO closure for secondary stroke prevention.19,20 Using the Trial of ORG 10172 in Acute Stroke Treatment (TOAST) classification of cryptogenic stroke,21 Kent and Thaler used data from 3,023 cryptogenic stroke patients from 12 independent databases to derive a RoPE score calculator utilizing six patient characteristics (hypertension, diabetes mellitus, prior stroke/ transient ischemic attack (TIA), non-smoker, cortical infarct on brain imaging, and age) to predict the probability that the stroke is PFO-related as opposed to the PFO being an incidental finding. While RoPE score is not advocated as a definitive tool to determine PFO management, it is a validated model that predicts the extent of PFO contribution to stroke causation. Stroke patients with RoPE scores of seven or greater have a paucity of traditional stroke risk factors, and therefore are more likely to benefit from PFO closure as a means to reduce the risk of recurrent stroke.

tunnel and traversing into the left atrium during the bubble study. Color flow Doppler during TEE is also used to directly visualize the shunting of blood. Schneider et al. determined a sensitivity and specificity of 100 % for color Doppler TEE as well as 89 % sensitivity and 100 % specificity for contrast-enhanced TEE.4,5 The American Academy of Neurology recommends the use of a contrastenhanced TEE for the detection of a PFO and inter-atrial shunting for the potential cause of stroke.24 Other imaging modalities that may be considered for the detection of a PFO include transcranial Doppler with bubble contrast injection (which is less frequently used), multi-detector computed tomography, or cardiac MRI. Several anatomical features accompanying PFO have been associated with recurrent stroke. Inter-atrial septal aneurysm (ASA) is a hypermobile atrial septum that results in significant movement of at least 10 mm from the plane of the septum into either the right or left atrium.25 While ASA occurs in 2.2 % of the general population, it occurs in approximately 60 % of cryptogenic stroke patients with PFO.26,27 However, it is not clear what the exact mechanism is by which an ASA affects cryptogenic stroke risk in the setting of a PFO. The anatomical size and physiological shunt size of the PFO are also potential predictors of stroke recurrence. A PFO of >4 mm on TEE has been associated with a greater odds ratio for stroke.28,29 TEE defines PFO size as the maximal height of separation between the septum primum and secundum.30 The physiological shunt size of a PFO is determined by the number of bubbles that cross the PFO, with large PFO shunts being defined as ≥20 microbubbles. However, evidence of a correlation between PFO anatomical size, physiological shunt size and stroke risk varies.31–35

Diagnosis A PFO is rarely detected on a routine transthoracic echocardiogram (TTE) unless one is specifically looking for it. Findings suggestive of PFO on a TTE include hypermobility of the inter-atrial septum (atrial septal aneurysm), and color flow Doppler findings of left–right or bi-directional flow across the atrial septum. Confirmation of a PFO is routinely accomplished by TTE with bubble contrast injection. In this study, agitated saline injected intravenously at rest and during the release of the strain phase of the Valsalva maneuver is performed during 2D echocardiographic imaging focused on the inter-atrial septum. With visualization of the entire heart with 2D echocardiography, the injected saline increases blood pool echodensity and creates visible microbubbles, first seen in the right atrium. In a normal individual, no microbubbles will be seen in the left atrium. If a PFO is present, the saline microbubbles will subsequently be seen in the left atrium within the first three cardiac cycles at rest, with release of a Valsalva maneuver, or in both instances. The prompt appearance of contrast in the left atrium following venous injection is considered a positive bubble study for intra-cardiac shunting. The size of the PFO is often determined by the number of microbubbles visualized in the left atrium during the first three initial cardiac cycles. Saline microbubbles seen after five to six cardiac cycles after injection or release of Valsalva strain usually indicate the presence of pulmonary arteriovenous malformations. The sensitivity for PFO detection with a TTE bubble study is 50 %.22,23 The gold standard for the identification and diagnosis of a PFO is a transesophageal echocardiogram (TEE). This is because it enables direct visualization of the PFO anatomy and the microbubbles entering the PFO

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Management of PFO After Stroke Based on the results of three completed clinical trials, the recurrence rate of ischemic stroke in patients with PFO and medically-treated cryptogenic stroke ranges between 0.6 % and 1.5 % per year.36–38 There are limited data comparing antiplatelet therapy with anticoagulation in cryptogenic stroke patients with PFO. The PFO in Cryptogenic Stroke Study (PICSS)39 was a sub-study of the Warfarin-Aspirin Recurrent Stroke Study (WARSS), a multi-center study in which stroke patients were randomized to either warfarin or aspirin and monitored for stroke recurrence or death over a 24-month period. Of the 2,206 stroke patients, 630 underwent TEE evaluation for clinical purposes including cryptogenic stroke. These 630 patients were then enrolled in the 42-center PICSS study and randomly assigned to treatment with warfarin or aspirin. Their TEE images were evaluated for the presence of PFO. The two primary endpoints of the study were recurrent ischemic stroke or death from any cause. In the study, 312 patients were randomized to warfarin and 318 to aspirin. Of the participants, approximately one-third (203 patients) were diagnosed with a PFO. Only 98 of the 203 patients were diagnosed with cryptogenic stroke. In this small group of PFO patients, a high recurrent event rate was observed on medical therapy, with no significant difference in time to primary endpoints between the warfarin- and the aspirin-treated patients (hazard ratio [HR] 1.29; 95 % CI: 0.63–2.64; 2-year event rates 16.5 % versus 13.2 %; p=0.49). More patients taking warfarin reached the primary endpoint, however the difference was not significant.40 The updated 2014 American Heart Association/American Stroke Association (AHA/ASA) guidelines have a Class I, Level of Evidence (LOE) B indication

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Management of Patent Foramen Ovale for antiplatelet therapy in ischemic stroke/TIA patients with a PFO as well as a Class I, LOE A for anticoagulation in patients with an ischemic stroke/ TIA with a PFO and an established PFO.41,42 Despite medical therapy, the stroke recurrence rate in ischemia stroke patients with PFO is estimated at 4.5 % within a 4-year period.40 In PICSS, the incidence of recurrent stroke in PFO patients with ischemic stroke was substantially higher, being 14.8 % at 2 years.43 Therefore, in addition to medical therapy, the utility of secondary preventative treatment options such as percutaneous PFO closure has been a topic of debate. Observational data, including meta-analysis of observational studies on PFO closure therapy, point to the safety and low stroke recurrence rate compared to medical treatment alone.43–47 As controversy exists over the preferred management strategy for secondary prevention in patients with PFO and prior stroke, randomized clinical trials (RCTs) have been performed to evaluate the safety and efficacy of percutaneous PFO closure in this patient population. There are three well-known completed multi-center RCTs comparing PFO closure using one of two devices – the umbrella occlude (STARFlex®, NMT Medical, Inc.) or the disc occlude (AMPLATZERTM PFO Occluder, AGA Medical/St. Jude Medical) – to medical therapy alone for the prevention of recurrent ischemic stroke in patients with a history of cryptogenic ischemic stroke.36,37,43 The Closure I trial36 evaluated the STARFlex PFO closure system against the administration of warfarin, aspirin, or combined aspirin and warfarin. The Randomized Evaluation of Recurrent Stroke Comparing PFO Closure to Established Current Standard of Care Treatment (RESPECT) trial37 compared the AMPLATZER PFO Occluder with four treatment regimens: monotherapy with warfarin, aspirin or clopidogrel, or a combination of aspirin with extended-release dipyridamole. The percutaneous closure trial38 compared the AMPLATZER PFO Occluder with any antiplatelet or anticoagulation therapy of the physician’s choice. At the time of completion and initial data evaluation, none of these trials had found a statistically significant benefit of PFO closure over medical therapy for ischemic stroke recurrence. Additionally, there was a significantly higher incidence of atrial fibrillation development in the patients who received the STARFlex closure device, but not the AMPLATZER PFO Occluder, compared to medication. Based on these three RCTs, the 2014 AHA/ ASA guidelines did not recommend PFO closure in cryptogenic stroke (Class III, LOE A).42 The American Academy of Neurology maintained a strong position against routine PFO closure in cryptogenic stroke patients outside of research trials until July 2016, when an updated statement was issued discouraging its use.48 However, it is important to note that the statement was made prior to the publication of positive data on PFO closure from the three trials in September 2017,47,48 and further update of their position on the topic is likely. The final long-term results of the RESPECT trial were presented at the 2016 Transcatheter Technologies Annual Scientific Meeting in Washington, DC, and have since been published.49 The investigators noted a relatively low incidence of recurrent stroke in both treatment groups during the initial follow-up period.35 In the intention-to-treat cohort, a total of 25 primary endpoint events occurred (nine in the closure group and 16 in the medical therapy group), all of which were recurrent nonfatal stroke (0.66 events per 100 patient-years, HR with closure = 0.49, 95 % CI: 0.22–1.11; p=0.08).37 The investigators followed the study population for longer to assess for divergent results. The investigators reported

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that after 10 years, in an intention-to-treat analysis, PFO closure with the AMPLATZER PFO Occluder resulted in a 62 % relative risk reduction (RRR) for recurrent ischemic stroke compared to medical management (HR 0.38; 95 % CI: 0.18–0.79; 10-year event rates 2.3 % versus 11.1 %; p=0.007).47 Similar results were seen in patients <60 years of age (58 % RRR; HR 0.42; 95 % CI: 0.21–0.83; 10-year event rates 3.0 % versus 13.2 %; p=0.01).50 The rates of atrial fibrillation, major bleeding, and death from any cause were comparable or lower in the device study arm. In October 2016, the US Food and Drug Administration approved the AMPLATZER PFO Occluder for percutaneous transcatheter PFO closure to reduce the risk of recurrent ischemic stroke in patients, predominantly between 18 and 60 years, who have had a cryptogenic stroke due to presumed paradoxical embolism, as determined by a neurologist and cardiologist following evaluation excluding all other known causes of ischemic stroke. In May 2017, at the third European Stoke Organisation Scientific Meeting in Prague, Czech Republic, the primary results of two multicenter randomized controlled trials – Patent Foramen Ovale Closure or Anticoagulants Versus Antiplatelet Therapy to Prevent Stroke Recurrence (CLOSE) and GORE® HELEX® Septal Occlulder/GORE® CARDIOFORM Septal Occluder for PFO Closure in Stroke Patients (REDUCE) – evaluating PFO closure with antiplatelet therapy versus antiplatelet therapy alone were presented.51,52 Both trials provided new support for PFO closure in cryptogenic stroke by achieving their primary endpoints.39,53 Kasner presented the REDUCE trial, stating that through at least 2 years, PFO closure with the GORE HELEX or GORE CARDIOFORM (both W.L. Gore & Associates) septal occluder plus antiplatelet therapy was superior to antiplatelet treatment alone in reducing the risk of recurrent (77 % RRR; HR 0.23; 95 % CI: 0.09–0.62) and new clinical ischemic stroke or in silent brain infarct on MRI (49 % RRR; HR 0.51; 95 % CI: 0.29–0.91).48,51 As seen in some prior studies, the REDUCE trial showed that significantly more patients in the PFO closure group developed new-onset atrial fibrillation/flutter compared to the antiplatelet-only group (6.6 % versus 0.4 %; p<0.001).48 The CLOSE study, a multicenter randomized superiority trial, compared transcatheter PFO closure with any CE-mark PFO closure device plus antiplatelet therapy to antiplatelet therapy alone for the prevention of recurrent stroke in patients aged 16–60 years who had a recent cryptogenic ischemic stroke attributed to PFO with an associated atrial septal aneurysm or large right-to-left shunt.54 This trial also had positive results in which recurrent fatal or non-fatal stroke was significantly reduced in the PFO closure group as compared with the antiplatelet therapy alone group (97 % RR; HR 0.03; 95 % CI: 0.00–0.26; p<0.001).52,54 The CLOSE trial showed a significantly higher rate of new-onset paroxysmal atrial fibrillation in the PFO closure group compared to the antiplatelet only group (4.6 % versus 0.9 %; p<0.02).54 It is important to note that in both studies, the new-onset atrial fibrillation was peri-procedural (detection within 45 days of the procedure), with no atrial fibrillation recurrence noted in the CLOSE PFO patients at median follow-up of 4.4 years, and no detection of atrial fibrillation at 2 weeks from onset in 59 % of the PFO patients who developed the arrhythmia in the REDUCE study. However, it is important to note that these findings cannot yet determine the stroke risk attributable to atrial fibrillation induced by PFO closure. Although the Closure I trial, percutaneous closure trial, and early followup results of the RESPECT trial were not able to show the superiority of PFO closure over medical therapy alone in the prevention of stroke

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Adult Congenital Heart Disease recurrence in patients with PFO,36–38 the benefit of PFO closure compared to medical therapy alone for the secondary prevention of cryptogenic stroke laid the groundwork for the positive results from the CLOSE, REDUCE and RESPECT trials.48,51,52,54 These three trials have shown exciting, encouraging and compelling evidence that PFO closure reduces the risk of recurrent stroke and provide strong supportive data for the ongoing debate on PFO closure in cryptogenic stroke.

PFO and Unique Clinical Scenarios Migraines are common phenomena, with a prevalence of approximately 18 % and 6 % in women and men, respectively.44 Several studies have documented a high co-existence of migraine headaches and PFO: PFO is present in up to 60 % of migraine patients; and up to 50 % of patients with PFO suffer from migraines.55–58 A number of early trials evaluating PFO closure for secondary stroke prevention showed a trend of decreased migraine incidence after PFO closure.58,59 These observational studies suggested that patients with migraine were the most likely to experience complete resolution of migraine with PFO closure. Furthermore, a recent a meta-analysis found that after PFO closure, migraine improvement was greater in patients who had migraine with aura than in those without aura.60 Thus Shi et al. suggest the presence of aura serves as a predictor for symptom improvement after PFO closure. However, this is a retrospective analysis and prospective randomized controlled trials are necessary to show whether aura has a prognostic value for patient outcomes. Previously, three RCTs – Migraine Intervention with STARFlex Technology (MIST), Percutaneous Closure of PFO in Migraine with Aura (PRIMA), and Prospective, Randomized Investigation to Evaluate Incidence of Headache Reduction in Subjects With Migraine and PFO Using the AMPLATZER PFO Occluder to Medical Management (PREMIUM) – were performed to assess the potential benefit of PFO closure on reducing or eliminating migraines.61–63 All three studies had negative results, with no significant difference in the reduction or cessation of migraines between the treatment and control groups. Based on current evidence, PFO closure is not recommended as a preventive treatment for migraine. There is a known association between PFO and increased risk of decompression illness in scuba divers.64,65 Accordingly, professional divers or military personnel may undergo screening for PFO with a bubble contrast TTE or TEE study. The presence of a PFO is considered a contraindication to diving. PFO closure is not recommended in this scenario. Recreational scuba divers may choose to undergo screening for the presence of a PFO at their own discretion. Individuals with OSA may develop transient increases in right-sided heart pressure during periods of apnea/hypopnea. In such circumstances, transient increased right heart pressures may lead to increased right–left shunting and worsening hypoxemia.9,66 The concurrence of OSA and PFO is not an indication for PFO closure, but rather must be recognized as a scenario whereby the PFO may exacerbate hypoxia in OSA and lead to worsening sequelae from OSA.

1. Sadler WL. Langman’s Medical Embryology. 11th ed. Philadelphia, PA: Wolters Kluwer Lippincott Williams & Wilkins, 2010. 2. McCarthy K, Ho SAR. Defining the morphologic phenotypes of atrial septal defects and interarterial communications. Images Paediatr Cardiol 2003;5:1–24. 3. Hagen PT, Scholz DG, Edwards WD. Incidence and size of patent foramen ovale during the first 10 decades of life: an autopsy

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Platypnea-orthodeoxia is an unusual clinical scenario that is the inverse of orthopnea, whereby affected individuals develop hypoxia when assuming an upright position. The condition is created by circumstances wherein right–left shunting through a PFO or atrial septal defect is enhanced when the person is upright. The various scenarios associated with this condition typically result in transient increases in right atrial pressure and decreases in right ventricular compliance, favoring right-to-left shunting through a PFO or the atrial septal defect. The presence of intracardiac shunting, intrapulmonary shunting, ventilation– perfusion mismatch, or a combination of these conditions – as seen with kyphoscoliosis, tortuous aortic root and ascending aorta, aortic elongation, or hemidiaphragmatic paralysis – can lead to right–left shunting and hypoxemia.67 Platypnea-orthodeoxia is a rare condition with <100 cases reported worldwide. Isolated citations in the scientific literature detail case reports where atrial septal defect or PFO closure resulted in resolution of positional hypoxemia.67–69 The 2008 ACC/AHA guidelines for the management of adults with congenital heart disease have a Class IIa, LOE B indication for reasonable closure of an atrial septal defect, either percutaneously or surgically, in the presence of documented platypnea-orthodeoxia.70

Conclusion PFO is in and of itself a paradox, in that it is a very common remnant of the fetal circulation, present in up to 25 % of adults, and is usually associated with a benign clinical scenario and lack of adverse effects. However, the presence of a PFO defect in association with venous thromboembolism can lead to paradoxical embolism from the venous to arterial circulation, with serious consequences. While the majority of individuals with a PFO never experience adverse sequelae, it is the most likely contributing factor to cryptogenic stroke in those <55 years old and when common risk factors for stroke are absent. The RoPE score is an accurate, validated tool to help determine the likelihood that cryptogenic stroke is due to a PFO. The final decision about PFO management is not necessarily predicated by RoPE score results, and each case should be individually considered with input from cardiology and neurology about how best to treat a specific patient. Current AHA/ ASA guidelines recommend antiplatelet therapy in all cryptogenic stroke patients with PFO. In the past, early results from randomized PFO closure versus medical therapy trials showed no significant decrease in the rate of recurrent stroke with PFO closure in cryptogenic stroke patients. However, longer-term follow-up data and newer trials have shown a significant decrease in the incidence of recurrent ischemic stroke with PFO closure as compared to medical therapy alone. This has led to the US Food and Drug Administration approval of the AMPLATZER PFO Occluder in PFO-related cryptogenic stroke patients, and anticipation that the GORE HELEX device will be approved in the near future. Continued trials and long-term follow-up are needed to further solidify and clarify the benefit of PFO device closure in the cryptogenic stroke population. Patients will benefit the most from collaboration between cardiologists and neurologists in the management of this unique clinical situation. n

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Interventional Cardiology

Advances in Coronary Physiology: Update for 2017 Morton J Kern, MD, MSCAI, FAHA, FACC 1,2 and Katherine M Yu, MD 2,3 1. Division of Medicine, Veterans Administration Long Beach Health Care System, Long Beach, CA; 2. University of California, Irvine, CA; 3. Department of Cardiology, Veterans Administration Long Beach Health Care System, Long Beach, CA

Abstract Invasive coronary physiology is a key instrument in decision-making for the interventional cardiologist. Fractional flow reserve has been well validated in chronic stable coronary artery disease and its practical applications are expanding into other clinical situations including acute coronary syndrome, severe aortic stenosis, and post percutaneous coronary intervention. Instantaneous free ratio is a resting index used to assess severity of an intracoronary stenosis. This review will cover some of the most recent developments and controversies in invasive coronary physiology.

Keywords Coronary artery disease, coronary flow reserve, coronary hemodynamics, fractional flow reserve, angiography Disclosure: MJK is a consultant and speaker for Abbott/St. Jude, Philips/Volcano, Acist Medical, Inc., Opsens Inc., and Heartflow Inc. KMY has no conflict of interest to declare. Received: 25 July 2017 Accepted: 18 August 2017 Citation: US Cardiology Review 2017;11(2):80–5. DOI: 10.15420/usc.2017:13:1 Correspondence: Morton J Kern, MD, MFSCAI, FAHA, FACC, Professor of Medicine, University of California Irvine, Chief of Medicine, Veterans Administration Long Beach Health Care System, 5901 E 7th St., Long Beach, CA 90822, USA. E: mortonkern2007@gmail.com

Coronary artery disease (CAD), the most common cause of morbidity and mortality in the US, is frequently identified by coronary angiography. Decisions for treatment are often based on angiography alone, absent other clinical indicators for intervention. However, by angiography alone, conventional wisdom has suggested that a coronary stenosis is significant if there is at least a 50 % diameter reduction in the left main coronary artery, or at least a 70 % diameter reduction in any other epicardial artery. Over the past two decades, the use of in-lab coronary physiology has demonstrated that angiography alone is not accurate in determining ischemia for intermediate lesions. Compared with angiography aloneguided percutaneous coronary intervention (PCI), physiology-guided PCI is associated with improved clinical outcomes and cost-effectiveness. The most commonly used invasive physiologic indices include fractional flow reserve (FFR), coronary flow reserve (CFR), and instantaneous wave-free ratio (iFR). A solid understanding of coronary physiology and the tools for measuring it is paramount to good clinical decision-making for anyone practicing invasive and interventional cardiology. With this in mind, the purpose of this review will be to identify and explore some of the most recent developments and controversies in invasive coronary physiology.

Fractional Flow Reserve Foundations It is now well known that FFR is the ratio of the mean coronary pressure distal (Pd) to a stenosis to the mean aortic pressure (Pa) at maximal hyperemia or when myocardial resistance is at its presumed absolute minimum. This condition permits pressure and flow to be linearly related, and thus the ratio represents the fraction of normal coronary blood flow across a stenosis with a normal value being 1 (i.e. Pd=Pa). FFR requires the induction of maximal hyperemia, most commonly with an intravenous infusion or intracoronary bolus of adenosine. Studies have shown that

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FFR is comparable to noninvasive functional testing. Originally an FFR <0.75 was considered significant and indicates a reduction in coronary pressure by 25 % of normal. To improve the sensitivity of FFR the threshold has been raised to 0.80 and it is the threshold endorsed by the American College of Cardiology (ACC), American Heart Association (AHA), Society for Cardiovascular Angiography and Interventions (SCAI), and European Society of Cardiology (ESC) in their guidelines for PCI. This threshold has left a clinical decision-making “gray zone” FFR of 0.75–0.80. A recent study by Agarwal et al. found that among 238 patients with gray-zone FFR, revascularization was associated with a significantly reduced risk of major adverse cardiovascular events (MACE) compared with medical therapy alone (Figure 1).1,2 On the other hand, in the Interventional Cardiology Research Incooperation Society Fractional Flow Reserve (IRIS-FFR), a large prospective, multicenter registry, the risk of MACE was not significantly different between deferred and revascularized lesions for FFR ≥0.76 (including the gray zone).3 In these situations, the decision to revascularize based on the clinical context of the patient is still best left to the clinician.

Fractional Flow Reserve for STEMI Revascularization Guidance The utility of FFR to guide revascularization of intermediate lesions in patients with chronic stable multivessel coronary artery disease has been validated in several landmark clinical trials including the Fractional Flow Reserve to Determine the Appropriateness of Angioplasty in Moderate Coronary Stenosis (DEFER), FFR versus Angiography for Multivessel Evaluation (FAME 1), and FFR-guided Percutaneous Coronary Intervention Plus Medical Treatment Versus Medical Treatment Alone in

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Advances in Coronary Physiology

Traditional teaching has been to treat only the culprit vessel during STEMI because several meta-analyses and non-randomized registry studies showed that treating all vessels at the same time as the STEMI culprit was associated with more adverse events. Up until the most recent 2015 update, the 2013 ACC/AHA/SCAI STEMI guidelines gave a class III recommendation against intervening on a noninfarct-related artery at the time of primary PCI in patients who are hemodynamically stable.7 Since then several studies have shown the accuracy of FFR in ACS, including Fractional Flow Reserve Versus Angiography in Guiding Management to Optimize Outcomes in Non-ST-Elevation Myocardial Infarction Cardiac Magnetic Resonance (FAMOUS NSTEMI CMR) substudy that showed an excellent accuracy of FFR <0.80 for predicting perfusion defects on cardiac magnetic resonance.8 Furthermore, multiple trials including Preventive Angioplasty in Acute Myocardial Infarction (PRAMI), Complete Versus Lesion-Only Primary PCI Trial (CvLPRIT), and the Third Danish Study of Optimal Acute Treatment of Patients With STEMI: Primary PCI in Multivessel Disease (DANAMI3– PRIMULTI) have shown that revascularizing non-culprit arteries, either at the time of primary PCI or later in a staged manner, reduce risk of MACE by a relative 44–65 % compared with culprit-only PCI.9–11 DANAMI3–PRIMULTI was an open-label, randomized controlled trial that enrolled 627 patients with STEMI who had ≥1 clinically significant coronary stenosis in addition to the culprit lesion. After successful PCI to the culprit lesion, patients were randomized into no further invasive treatment or complete FFR-guided revascularization before discharge. A threshold of FFR <0.80 was used, and FFR was performed 2 days after primary PCI to avoid the risk of invalid FFR measurements inferred from acute changes in macrovascular tone or microvascular flow obstruction. The primary endpoint of a composite of all-cause mortality, non-fatal reinfarction, and ischemia-driven revascularization of lesions in noninfarct-related arteries was significantly lower in the complete revascularization group (13 %) compared with the infarct-related only group (22 %). The favorable effect was driven by significantly fewer revascularizations. A substudy of the DANAMI3–PRIMULTI trial found that the benefit of staged FFR-guided complete revascularization was observed primarily in patients with threevessel disease and at least one noninfarct-related stenosis with a ≥90 % diameter (Figure 2).12 In the Fractional Flow Reserve-Guided Multivessel Angioplasty in Myocardial Infarction - COMPARE-ACUTE trial 885 patients with STEMI and multivessel disease who had undergone primary PCI of

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Figure 1: MACE-free Survival (%) in Patients of the Medical Therapy Group Stratified by FFR Strata (log-rank, 15; P<0.001)

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Patients With Stable Coronary Artery Disease (FAME 2).4–6 The utility of FFR in acute coronary syndrome (ACS) has been controversial. During a ST-segment elevation myocardial infarction (STEMI), the degree of damage to the infarct-related or culprit myocardial bed makes FFR in this artery questionable. Furthermore, whether or not the non-culprit myocardial bed is impaired limiting the usefulness of FFR is unknown. Changes in microcirculation and coronary flow secondary to both the plaque activation and myocardial tissue infarction make the feasibility and accuracy of measuring FFR during STEMI (i.e. the ability to induce maximum hyperemia) unreliable. A subhyperemic response to adenosine would result in an underestimation of stenosis severity so that an FFR >0.80 at the time of STEMI may initially be considered nonsignificant, but it may decrease several days later as the injured myocardial bed recovers and flow increases to the area.

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Time to follow-up (months) In STEMI patients, the primary composite endpoint of all cause death, reinfarction, and ischemia-driven revascularization was lower in those who received FFR-guided complete revascularization compared to infarct-related PCI alone. The primary endpoint was further reduced in patients with at least 1 noninfarct-related stenosis ≥90 % compared to those with <90 %. FFR = fractional flow reserve; STEMI = ST-elevation myocardial infarction. Source: Lønborg, et al., 2017.12

the infarct-related artery were randomized to undergo FFR-guided complete revascularization of noninfarct-related coronary arteries or no revascularization of noninfarct-related arteries. Unlike DANAMI3– PRIMULTI, FFR of the noninfarct-related artery was done in the acute STEMI setting, during the time of primary PCI. At one year those who underwent FFR-guided complete revascularization of noninfarct-related arteries had a lower risk of death (1.4 % versus 1.7 %), MI (2.4 % versus 4.7 %), revascularization (6.1 % versus 17.5 %), and cerebrovascular events (0.0 % versus 0.7 %) compared with those who were treated for the infarct-related artery only.13 Approximately half of the noninfarctrelated artery lesions that were angiographically significant were not physiologically significant by FFR (≥0.80).

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Figure 3: Results from the DKCRUSH VII Registry Study A

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Patients with a post-drug-eluting stent FFR >0.88 had fewer rates of cardiac death, target vessel revascularization (TVR), and target vessel failure (TVF) at one year compared to those with an FFR ≤0.88 (Figures A–C). This beneficial trend continued at 3 years of follow up (Figures D–F). FFR = fractional flow reserve. Reprinted from Li, et al., 2017, with permission from Elsevier.16

The ideal threshold for FFR in the ACS population has been debated. The FFR threshold of 0.80, which is used to determine functional significance in the stable ischemic heart disease (SIHD) population, was applied to the ACS population in the above studies. Hakeem et al. found that using FFR for clinical decision-making in ACS patients using the standard FFR = 0.80 threshold was associated with a threefold increase in the risk of subsequent MI and target vessel failure compared with SIHD patients, and advised caution in using FFR-derived values for clinical decision-making in patients with ACS. They found that ACS patients had a higher FFR threshold of functional significance, and those with an FFR <0.85 had significantly higher event rates than those with FFR >0.85.14

Post-percutaneous Coronary Intervention Fractional Flow Reserve

values are associated with significantly lower risks of repeat PCI and MACE during follow up, and post-PCI FFR values of ≥0.90 are associated with a relative risk reduction of repeat PCI of 55 % and a relative risk reduction of MACE by 30 %.15 Results from the Randomized Study on Double Kissing Crush Technique Versus Provisional Stenting Technique for Coronary Artery Bifurcation Lesions (DKCRUSH VII Registry Study) showed that a post-drug-eluting stent (DES) FFR ≤0.88 strongly correlated with target vessel failure, and this was maintained after 3 years of follow up (Figure 3).16 Impaired post-DES FFR may be influenced by several independent factors including stent length, stent diameter, and disease in the left anterior descending artery. In one study among patients receiving long stents (defined as 30–49 mm), only 12.2 % were found to have an optimal post-PCI defined as an FFR >0.95. Among patients who received ultra-long stents (≥50 mm), none achieved an optimal post-PCI FFR.17

Implications and Importance In contrast to pre-PCI FFR, the clinical implications of post-PCI FFR have not been as well demonstrated in large, randomized clinical trials. In a meta-analysis of 105 studies between 1995 and 2005 reporting on post-PCI FFR and evaluating the relationship between post-PCI and clinical outcomes post-PCI, Rimac et al. found that higher post-PCI FFR

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Fractional Flow Reserve and Transcatheter Aortic Valve Implantation for Aortic Stenosis Many patients with severe aortic stenosis (AS) have concomitant CAD, but there are no clearly established guidelines on revascularization management in patients undergoing transcatheter aortic valve

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Advances in Coronary Physiology Figure 4: Among Patients with Coronary Artery Disease and Severe Aortic Stenosis Undergoing TAVI, the Overall Pre-TAVI FFR Values Did not Differ from the Post-TAVI FFR Values

Figure 5: Illustration of Plausible Anatomic and Physiological Explanation for FFR-CFR Discordance between Fractional Flow Reserve and Coronary Flow Reserve CFR≠

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implantation (TAVI). The utility of FFR in this patient population has been recently validated. In severe AS there is increased microcirculatory resistance and reduced vasodilatory reserve, which may influence FFR. In a study of 54 patients with severe AS and CAD undergoing TAVI, 154 lesions were assessed by FFR both before and after TAVI. There were no ischemic complications related to the administration of intracoronary adenosine during the FFR procedure or after one month of follow up, demonstrating that an FFR evaluation is safe to perform in severe AS patients. Overall, there were only minor changes in FFR values before and after TAVI, confirming the validity of FFR in this clinical scenario. In approximately 15 % of patients with CAD, the post-TAVI FFR assessment did change the indication to perform PCI, and this was mostly for angiographically intermediate lesions with unmasked functional significance (Figure 4).18

1 0.95 0.9 0.85 0

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When differentiated into positive (FFR ≤0.8) and negative (FFR >0.8), there was a trend for preTAVI positive FFR to decrease even further after TAVI. Blue lines represent patients with FFR >0.8 at baseline. The dashed black line represents the average trend of this subgroup. Red lines represent patients with FFR ≤0.8 at baseline. The dashed red line shows their average trend. FFR = fractional flow reserve; LAD = left anterior descending; LCx = left circumflex; RCA = right coronary artery; TAVI = transcutaneous aortic valve implantation. Source: Pesarini, et al., 2016.18

Preserved fractional flow reserve (FFR) and reduced coronary flow reserve (CFR) were related to increased microvascular resistance, while diminished FFR and preserved CFR showed moderately increased stenosis resistance with well-preserved microvascular function. The extent of atherosclerotic burden in the mid to proximal segments of the coronary artery assessed by intravascular ultrasound did not associate with their discordance in the present study. Variability of microvascular vasodilatory capacity is likely an important mechanism of discordance between FFR and CFR. HMR = hyperemic microvascular resistance; HSR = hyperemic stenosis resistance. Blue circles and red diamonds = concordant CFR and FFR, Red circles and blue diamonds = discordant CFR and FFRReprinted from Ahn, et al., 2017, with permission from Elsevier.20

0.05

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Fractional Flow Reserve and Coronary Flow Reserve CFR measures flow through both the epicardial resistance conduit and the microcirculation. It is another validated index of the functional significance of a coronary stenosis when the microcirculation is considered normal. In contrast to FFR, reduced CFR has been shown to be a prognostic marker of adverse outcomes in patients with and without epicardial disease. Pre-PCI CFR, and not post-PCI FFR, was shown to be an independent predictor of adverse cardiovascular events after PCI in one study.19 FFR and CFR values may be discordant, even in the same patient. The reason for discordance is not entirely clear (Figure 5). The amount of atherosclerotic burden may influence discordance. In a study of 94 patients with moderate coronary stenosis, intravascular ultrasound was used to measure degree of atherosclerosis. Among patients with preserved FFR, those with low CFR had similar plaque burden and

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25 Distance (mm)

5.3 mm 4.2 mm 3.2 mm 9.5 mm Estimated physiological length of stenoses Figure A shows a right coronary artery with four stenoses. Figure B shows an iFR intensity plot with sudden stepdowns that correspond to focal lesions, and gradual slopes that correspond to diffuse disease. iFR = instantatenous wave-free ratio. Reprinted from Niijjer, et al., 2015, with permission from Elsevier.23

higher microvascular resistance compared with those with preserved CFR. In patients with low FFR, those with preserved CFR had smaller plaque burden and lower microvascular resistance than those with low CFR.20

Instant Wave-free Ratio Outcomes iFR is a resting index used to assess severity of an intracoronary stenosis. It measures the ratio of Pd to the Pa during an isolated period of diastole (i.e. the “wave-free period”). It is an attractive alternative to FFR because it does not require hyperemia, and therefore has a lower incidence of patient discomfort, side effects, and shorter procedural time.

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Interventional Cardiology Figure 7: iFR Pullback Across Serial Stenosis in a Diffusely Diseased Left Anterior Descending

On the left, an angiogram shows diffuse disease along the LAD. On the right, an iFR pullback across the LAD shows an iFR of 0.85. There is a gradual slope upwards and a sudden stepup at the midLAD. Diffuse LAD is difficult to treat with stents. iFR pullback may help identify the location of a physiologically significant stenosis along the vessel. The patient went on to receive PCI of the midLAD. iFR = instant wave-free ratio; LAD = left anterior descending; PCI = percutaneous coronary reserve. Courtesy of Dr. Arnold Seto, Department of Cardiology, Veterans Administration Long Beach Health Care System, Long Beach, CA. University of California, Irvine, CA.

iFR has been shown to be non-inferior compared to FFR in two large, multicenter, randomized controlled trials. The Instantaneous Wave-free Ratio Versus Fractional Flow Reserve in Patients with Stable Angina Pectoris or Acute Coronary Syndrome (iFR-SWEDEHEART) trial included 2037 patients with stable angina or ACS, and randomly assigned them to undergo either iFR or FFR-guided revascularization. The rate of primary endpoint (composite of death from any cause, non-fatal MI, or unplanned revascularization within 12 months after the procedure) was not significantly different between the two groups.21 In the Functional Lesion Assessment of Intermediate Stenosis to Guide Revascularisation (DEFINE-FLAIR) trial, 2492 patients with CAD were randomized to have iFR-guided or FFR-guided coronary revascularization. The primary endpoint of a composite of death from any cause, non-fatal MI, or unplanned revascularization did not differ significantly between groups. Additionally, the number of patients in the iFR group had lower rates of adverse side effects from the procedure (3.1 % versus 30.8 %), and a shorter median procedural time (40.5 minutes versus 45.0 minutes) compared with the FFR group.22 Comparisons of iFR and FFR remain a hot topic. Critiques of iFRSWEDEHEART and DEFINE-FLAIR include the low-risk populations studied and the large non-inferiority margins used. The safety of using iFR instead of FFR in patients with higher-risk (i.e. more severe ischemic lesions with

garwal SK, Kasula S, Edupuganti MM, et al. Clinical decisionA making for the hemodynamic “gray zone” (FFR 0.75-0.80) and long-term outcomes. J Invasive Cardiol 2017; PMID: 28420802; epub ahead of press Adjedj J, De Bruyne B, Floré, et al. Significance of Intermediate Values of Fractional Flow Reserve in Patients With Coronary Artery Disease. Circulation 2016; 133:502–8. DOI: 10.1161/CIRCULATIONAHA.115.018747; PMID: 26733607 Ahn JM, Park DW, Shin ES, et al. Fractional flow reserve and cardiac events in coronary artery disease: data from a prospective IRIS-FFR registry (Interventional Cardiology Research Incooperation Society Fractional Flow Reserve). Circulation 2017;135:2241–51. DOI: 10.1161/ CIRCULATIONAHA.116.024433; PMID: 28356440

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low FFR) CAD is debatable as the average FFR in the two iFR studies was much higher than in FAME trials (FFR 0.83 versus 0.71). While IFR and FFR are generally concordant 80 % of the time, especially for severe and minimal stenoses, iFR and FFR discordance occurs in about 20 % of patients and raises a clinical decision-making dilemma – Which one is superior? That question is an ongoing area of active research. iFR has the potential to simplify treatment of serial lesions by pullback iFR measurements co-registered with the angiographic lesion locations (Figures 6 and 7).23 This technology will likely be a vanguard of future research into the interaction of resting and hyperemic flow across serial stenoses.

Conclusion Coronary physiology is now recognized as a key part of the clinical decisionmaking for interventional cardiologists. Exciting developments over the past few years have led to a renewed interest in the field. With strong data showing favorable outcomes associated with the use of measuring coronary physiology in the cardiac catheterization lab, especially FFR and iFR, the days of angiography alone-based PCI are over. The future lies in new methods of physiologic measurements including iFR, CFR, indices of microvascular resistance, index of microvascular resistance, and expanding the use of these methods to unique clinical scenarios. n

Z immermann FM, Ferrara A, Johnson NP, et al. Deferral vs performance of percutaneous coronary intervention of functionally non-significant coronary stenosis: 15-year follow-up of the DEFER trial. Eur Heart J 2015;36:3182–8. DOI: 10.1093/eurheartj/ehv452; PMID: 26400825 Tonino PA, De Bruyne B, Pijls NH, et al. Fractional flow reserve versus angiography for guiding percutaneous coronary intervention. N Engl J Med 2009;360:213–24. DOI: 10.1056/ NEJMoa0807611. PMID: 19144937 De Bruyne B, Pijls NHJ, Kalesan B, et al. Fractional flow reserveguided PCI versus medical therapy in stable coronary disease. N Engl J Med 2012;367:991–1001. DOI: 10.1056/NEJMoa1205361; PMID: 22924638 O’Gara PT, Kushner FG, Ascheim DD, et al. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial

infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2013;61:e78–e140. DOI: 10.1016/ j.jacc.2012.11.019; PMID: 23256914 8. Layland J, Rauhalammi S, Watkins S, et al. Assessment of fractional flow reserve in patients with recent non-STsegment-elevation myocardial infarction: comparative study with 3-T stress perfusion cardiac magnetic resonance imaging. Circ Cardiovasc Interv 2015;8:e002207. DOI: 10.1161/ CIRCINTERVENTIONS.114.002207; PMID: 26253733 9. Wald DS, Morris JK, Wald NJ, et al. Randomized trial of preventive angioplasty in myocardial infarction. N Engl J Med 2013;369:1115–23. DOI: 10.1056/NEJMoa1305520; PMID: 23991625 10. Gershlick AH, Khan JN, Kelly DJ, et al. Randomized trial of complete versus lesion-only revascularization in patients

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11.

12.

13.

14.

undergoing primary percutaneous coronary intervention for STEMI and multivessel disease: the CvLPRIT trial. J Am Coll Cardiol 2015;65:963–72. DOI: 10.1016/j.jacc.2014.12.038; PMID: 25766941 Engstrøm T. The third Danish study of optimal acute treatment of patients with ST-segment elevation myocardial infarction: Primary PCI in Multivessel disease. Presented at American College of Cardiology/i2 Scientific Session, San Diego, California, 16 March 2015. Lønborg J, Engstrøm T, Kelbæk H, et al. Fractional flow reserveguided complete revascularization improves the prognosis in patients with ST-segment-elevation myocardial infarction and severe nonculprit Disease: a DANAMI 3-PRIMULTI substudy (primary PCI in patients with ST-elevation myocardial infarction and multivessel Ddsease: treatment of culprit lesion only or complete revascularization). Circ Cardiovasc Interv 2017;10:e004460. DOI: 10.1161/CIRCINTERVENTIONS.116.004460; PMID: 28404623 Smits PC, Abdel-Wahab M, Neumann FJ, et al. Fractional flow reserve-guided multivessel angioplasty in myocardial infarction. N Engl J Med 2017;376:1234–44. DOI: 10.1056/NEJMoa1701067; PMID: 28317428 Hakeem A, Edupuganti MM, Almomani A, et al. Long-term prognosis of deferred acute coronary syndrome lesions

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15.

16.

17.

18.

based on nonischemic fractional flow reserve. J Am Coll Cardiol 2016;68:1181–91. DOI: 10.1016/j.jacc.2016.06.035; PMID: 27609680 Rimac G, Fearon WF, De Bruyne B, et al. Clinical value of post–percutaneous coronary intervention fractional flow reserve value: a systematic review and meta-analysis. Am Heart J 2017;183:1–9. DOI: 10.1016/j.ahj.2016.10.005; PMID: 27979031 Li SJ, Ge Z, Kan J, et al. Cutoff value and long-term prediction of clinical events by FFR measured immediately after implantation of a drug-eluting stent in patients with coronary artery disease: 1- to 3-year results from the DKCRUSH VII registry study. JACC Cardiovasc Interv 2017;10:986–95. DOI: 10.1016/j.jcin.2017.02.012; PMID: 28456699 Baranauskas A, Peace A, Kibarskis A, et al. FFR result post PCI is suboptimal in long diffuse coronary artery disease. EuroIntervention 2016;12:1473–80. DOI: 10.4244/EIJ-D-15-00514; PMID: 27998839 Pesarini G, Scarsini R, Zivelonghi C, et al. Functional assessment of coronary artery disease in patients undergoing transcatheter aortic valve implantation: influence of pressure overload on the evaluation of lesion severity. Circ Cardiovasc Interv 2016;9:e004088. DOI: 10.1161/CIRCINTERVENTIONS.116.004088; PMID: 27803040

19. M atsuda J, Murai T, Kanaji Y, et al. Prevalence and clinical significance of discordant changes in fractional and coronary flow reserve after elective percutaneous coronary intervention. J Am Heart Assoc 2016;5:e004400. DOI: 10.1161/JAHA.116.004400; PMID: 27899365 20. Ahn SG, Suh J, Hung O, et al. Discordance between fractional flow reserve and coronary flow reserve: insights from intracoronary imaging and physiological assessment. JACC Cardiovasc Interv 2017;10:999–1007. DOI: 10.1016/ j.jcin.2017.03.006; PMID: 28521932 21. Götberg M, Christiansen EH, Gudmundsdottir IJ, et al. Instantaneous wave-free ratio versus fractional flow reserve to guide PCI. N Engl J Med 2017;376:1813–23. DOI: 10.1056/ NEJMoa1616540; PMID: 28317438 22. Davies JE, Sen S, Dehbi HM, et al. Use of the instantaneous wave-free ratio or fractional flow reserve in PCI. N Engl J Med 2017;376:1824–34. DOI: 10.1056/NEJMoa1700445; PMID: 28317458 23. Niijjer SS, Sen S, Petraco R, et al. The instantaneous wave-free ratio pullback: a novel innovation using baseline physiology to optimise coronary angioplasty in tandem lesions. Cardiovasc Revasc Med 2015;16:167–71. DOI: 10.1016/j.carrev.2015.01.006; PMID: 25977227

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Left Ventricular Assisting Devices in Percutaneous Coronary Intervention Ahmed M Alabbady, MD, Ahmed S Abdul-Al and Kimberly A Skelding, MD, FACC, FSCAI Cardiology Department, Geisinger Medical Center, Danville, PA

Abstract Over the past four decades advances in the interventional cardiology field have led to growing indications for percutaneous coronary interventions (PCIs). With increasing numbers of complex and high-risk PCIs performed in today’s catheterization laboratories, cardiogenic shock is encountered more frequently than ever before emphasizing the need for proper knowledge of different adjunct hemodynamic support devices available on the market. We aim to review the percutaneously-placed left ventricular assisting devices available to catheterization laboratories in the US for use in high-risk PCIs, their indications, contraindications, limitations, and review of the most prominent literature.

Keywords Percutaneous coronary intervention, high-risk percutaneous intervention, acute myocardial infarction, cardiogenic shock, hemodynamic support devices, percutaneous left ventricular assist devices, balloon pump, extracorporeal membranous oxygenation Disclosure: The authors have no conflicts of interest to declare. Received: 9 August 2017 Accepted: 11 September 2017 Citation: US Cardiology Review 2017;11(2):86–94. DOI: 10.15420/usc.2017:14:2 Correspondence: Ahmed Alabbady, MD, Cardiology Department, Geisinger Medical Center, 100 N Academy Ave, Danville, PA 17822-2770, USA. E: amalabbady@geisinger.edu

The introduction of percutaneous coronary angioplasty in 1977 by Dr Andreas Grüntzig1 was one of the most remarkable achievements in the cardiology realm, opening the door to numerous advancements in percutaneous coronary interventions (PCIs). Due to advances in PCI techniques over the past four decades, catheters along with four generations of coronary stents have dramatically changed the natural history of acute myocardial infarction (AMI) management and brought hope of improved outcomes to more and more patients. Indications for PCI and demographics of such patients are changing to include increasingly critically ill patients.2 With increasing numbers of high-risk coronary procedures, rapid door-to-balloon times for critical ST-elevation myocardial infarction (STEMI) patients, and expanding PCI indications, cardiogenic shock is becoming a frequent encounter in today’s catheterization laboratory.3 We aim to review adjunct catheterization laboratory devices that support the left ventricular (LV) while undergoing high-risk PCI. Percutaneous LV assisting devices (pLVAD) include: the intra-aortic balloon pump (IABP), the Impella® (Abiomed, Inc), the TandemHeart™ (Cardiac Assist, Inc), the currently investigational HeartMate PHP™ (St Jude Medical) and extracorporeal membrane oxygenation (ECMO). The advancements of each of these devices have helped support patients’ weakened hearts, preparing them for the road to recovery. High mortality and morbidity are closely related to cardiogenic shock following a MI.4–5 However, these tools are critical to the support of thousands of patients each year, allowing many to move on to new therapy or even surgery.

the idea of counterpulsation, the timing of pressure events to enhance the hemodynamics of the heart. Acting as a circulatory support device, the IABP leads to diastolic augmentation during inflation and potentially contributes to coronary, cerebral, and systemic circulation (Figure 1). In 1967, the first clinical application of an IABP was successfully used on 45-yead-old women that had sustained a MI. By 1976, more than 5,000 patients had received IABP treatment in the US.6,7 Continuous evolution of the IABP led to the development of a percutaneous means of insertion. The adoption of this revolutionary method transformed the field of IABP helping more patients who are unresponsive to other forms of medical management. The IABP is a device that consists of a console and a balloon catheter that is filled with either helium or carbon dioxide, typically helium. (Figure 2) Its components include: a gas source, a valve for gas delivery, and a system to monitor blood pressure and acquisition of electrocardiogram. It is very critical that the appropriate size of the catheter is appropriate to the size, age, and weight of the patient. Incorrect sizing or placement can lead to very serious and even life-threatening complications. As for the positioning of the device, the closer the distance between the tip of the balloon and the aortic valve, the greater the diastolic pressure elevation. When considering the types of hemodynamic criteria for mechanical circulatory support one should consider the following: left atrial or right atrial pressure >20 mmHg, urine output <20 ml/h, systemic vascular resistance >2100, systolic arterial pressure <90 mmHg, cardiac index <1.8 l/min, and metabolic acidosis. “Relative exclusion” factors include severe peripheral vascular disease, infection, hepatic disease, stage IV cancer, and severe coagulopathy.9

Intra-aortic Balloon Pump Among the different approaches to the treatment of a failing heart, the intraaortic balloon pump is a frequently used mechanism in medicine today; however, it is an older device in this field of medical technology. It utilizes

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Despite the widespread use of the IABP, there are still numerous complications that can arise from the use of this device. Ranging from a mechanical error to anatomical risk factors. Cao et al. analyzes some of

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Left Ventricular Assisting Devices in Percutaneous Coronary Intervention these risk factors in a study observing the deaths of patients with AMI with IABP support.8 The study consisted of 572 IABP-supported patients with AMI in 72 hours. There were 81 non-survivors and 491 survivors in the study. The most prevalent complication arose from misplaced balloon catheters. Peripheral vascular disease, small size patients, use of sheath of IABP, and diabetes can all lead to difficulty of insertion and mispositioning. A mispositioned pump can augment the blood pressure incorrectly, impair the blood flow of the patient, and lead to infection. The acceptance of less-ideal placement of the balloon was indicative of the morbidity of the patient in most cases.9 The primary complication is arterial damage from the catheter; however, ischemia of the limbs, thrombosis, renal failure, balloon leaks, vessel perforations, and bleeding are all possible complications that can arise. There are several recent studies done to show the effectiveness of the IABP. A paper from the Society of Thoracic Surgeons observed 88 patients with congestive heart failure who received a subclavian-IABP.10 The goal of the study was to investigate whether the device was an acceptable method to bridge patients to other forms of treatments. Eighty patients could move to their intended goal or desired therapy/surgery. These results concluded this method was an excellent method to improve hemodynamic function, allow for extensive rehabilitation, and permit patients to receive their intended therapy. Although the device is by no means a cure to a patient’s heart failure, it certainly is an efficient approach to begin a road to recovery. Another study delves deeper, and comprehensively studies the effect the IABP has on diastole in 10 patients. Although there is a limitation regarding their small sample size, the researchers concluded IABP counterpulsation has a positive impact on diastolic function in patients undergoing urgent coronary artery bypass grafting (CABG), in addition to the previously-known beneficial effects on systolic dysfunction.11 A much larger study by the Québec Heart–Lung Institute, Laval University performed a meta-analysis utilizing the data of 22 different observational studies, including a total of 46,067 patients. It assessed the effect of IABP on hospital stay and 30-day mortality, while also looking at the length of stay of patients in the intensive care unit and the need for cardiac surgery. The study ultimately shows a significant reduction in mortality rates and length of stay using the IABP. Only 1 % of patients had some form of severe IABP-related complications. They also conclude that among other pLVADs it is the least costly option for patients.12

Figure 1: Intra-aortic Balloon Pump

Inflated

Deflated

Figure 2: Components of Intra-aortic Balloon Pump

Intra-aortic Balloon

A well-validated risk prediction score for short-term mortality in cardiogenic shock patients was developed from Intra-aortic Balloon Pump in Cardiogenic Shock (IABP-SHOCK II) trial.13 The score includes six variables: age >73, history of stroke, glucose >191 mg/dl (10.6 mmol/l) on admission, creatinine >1.5 mg/dl (132.6 μmol/l), thrombolysis in myocardial infarction, flow grade <2 after PCI, and lactic acid >5.0 mmol/l on admission. Each variable is assigned 1 or 2 points resulting in three risk categories with a maximum possible score of 9. Low-risk score of <2, intermediate score of 3–4, and a high-risk score of 5–9 correlated with 30-day mortality of 28.0 %, 49.2 % and 76.6 %, respectively (p<0.0001).

Impella In 1966 the first successful implantation of ventricular-assisting device was performed on a 37-year-old woman by Dr Michael E DeBakey.14 The external circuit could support this patient for 10 days following the operation. This marked the beginning of numerous advancements to the

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field of ventricular-assist devices. In 1988, Texas Heart Institute introduced “Hemopump”,15 the first small, percutaneously-inserted axial-flow pump

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Interventional Cardiology Figure 3: Impella Device

in unloading of the left ventricle (LV volume dependent), reducing left ventricular end diastolic pressure, decreasing LV work, and myocardial oxygen demand. The pump also increases coronary and systemic perfusion by increasing mean arterial pressure and diastolic pressure.16

Red Pressure Sidearm

Catheter Shaft

Plug

Clear Sidearm

Impella RP is designed for right-heart support. Having a similarly designed motor (22 Fr mounted on a 11 Fr), catheter is placed percutaneously with inlet in the inferior vena cava and across the tricuspid and pulmonary valves with outlet in the pulmonary artery bypassing the right atrium and right ventricle.17

Infusion Filter Pressure Reservoir Check Valve

Pigtail

Repositioning Unit

Inlet Area Cannula Outlet Area

Impella in High-risk Percutaneous Coronary Intervention

Open Pressure Area Motor Housing

Naidu SS. Novel percutaneous cardiac assist devices. Circulation. 2011 Feb 8;123(5):533-43. Published with permission from Wolters Kluwer Health.

Figure 4: The Impella (A) Aatheter Pumps and (B) Automated Impella Controller A

2.5

Percutaneous insertion

5.0

Surgical cutdown

Reprinted from International Journal of Cardiology, 201, Burzotta F et al. Impella ventricular support in clinical practice: collaborative viewpoint from a European expert user group, 684-91, 2015, with permission from Elsevier.

via femoral cut-down. The device was not successful commercially; however, it was the precursor to today’s Impella. The Impella is a non-pulsatile micro-axial ventricular pump (Figure 3). Its use has been growing since Food and Drug Administration (FDA) approval in 2008 to more than 50,000 patients supported with Impella in recent years. Impella (2.5L and CP) are placed percutaneously via peripheral arterial approach, typically femoral or possibly axillary arteries. However, bigger-sized ones like the Impella 5.0 require surgical arterial cut-down for placement. The pump is available in different sizes allowing for different flow rates and levels of circulatory support. Impella 2.5, CP and 5.0/LD have motors that are 12 Fr, 14 Fr, and 21 Fr with blood flow rates of 2.5, 4.0, and 5.0 l/m, respectively (Figure 4). The motors are mounted on 9-Fr catheters (Impella 2.5, CP and 5.0/LD) with pigtail tip, distal inlet and proximal outlet. The Impella is placed across the aortic valve with the inlet in the left ventricle and the outlet in the ascending aorta. The pump pulls blood from its inlet and expels it into the ascending aorta resulting

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The independency from cardiac rhythm gives the Impella advantage over the IABP; however, the need for experience in positioning and troubleshooting of a relatively new device continue to be a major disadvantage of the Impella.

After proving safe and potentially efficacious for use in patients undergoing high-risk PCI in A Prospective Feasibility Trial Investigating the Use of the Impella Recover LP 2.5 System in Patients Undergoing High Risk PCI (PROTECT I) trial,17 FDA approved in 2008 the use of Impella 2.5L for partial circulatory support for periods up to 6 hours during cardiac procedures. The A Prospective Randomized Clinical Trial of Hemodynamic Support with Impella 2.5TM versus Intra-Aortic Balloon Pump in Patients Undergoing High-Risk Percutaneous Coronary Intervention (PROTECT II) trial randomized 452 patients undergoing nonemergent PCI on an unprotected left main or last patent coronary vessel with a left ventricular ejection fraction (LVEF) <35 % and patients with three vessel diseases and LVEF <30 % to Impella versus IABP. The results failed to show superiority of Impella over IABP in reducing adverse events at 30 and 90 days but established Impella as an acceptable and safe hemodynamic support device during high-risk PCI, leading to FDA approval of Impella 2.5 for elective and high-risk PCI in 2015. Recently, in December 2016 the approval was extended to include Impella CP (4 l/min of blood flow) in the same settings.18 Despite failure of the Impella to prove superiority in large multicenter trials as a protective measure in high-risk PCI, several substudies and subanalysis from PROTECT II and registry data suggest more promising results. A substudy of PROTECT II trial examined the effect of periprocedural MI definition on trial outcomes. The investigators used the validated definition (new Q-waves or a creatine kinase-MB elevation more than eight times normal value) instead of the original protocol definition. Ninety-day major adverse events (MAE) and major adverse cardiac and cerebral events (MACCE) of death, stroke, MI, and repeat revascularization were compared. MAE and MACCE were lower in the Impella group compared with IABP. The study concluded that hemodynamic support with Impella 2.5 compared with IABP during high-risk PCI in PROTECT II trial resulted in improved event-free survival at 90 days.19 A subanalysis of PROTECT II trial evaluated the impact of device learning curve on the outcomes of PROTECT II trial. The analysis included 448 patients at 74 different sites. Among these, 58 patients were the first to receive Impella 2.5 at their site, 62 were the first to receive IABP. Significantly lower 90-day MAE rates were observed with the use of

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Left Ventricular Assisting Devices in Percutaneous Coronary Intervention Impella 2.5 compared with the use of IABP after excluding the first patient per group at each site, highlighting the new device learning curve as a potential confounding factor of the trial results.20

USpella, and cVAD, are showing better outcomes, lower incidence of AKI even in CKD patients, fewer post-procedure MIs, and fewer need for revascularizations.

Another substudy of PROTECT II evaluated the efficacy of hemodynamic support using Impella 2.5 versus IABP in patients with 3-vessel coronary disease (3VD) and LVEF <30 %. At 30 days after PCI, patients in the Impella group trended toward reduction in incidence of MAE compared with IABP group. Use of Impella 2.5 was an independent predictor of improved 90-day outcomes. Study concluded that patients with 3VD and reduced LVEF show improved outcomes when PCI is performed with Impella 2.5 hemodynamic support.21

Impella in Cardiogenic Shock After Myocardial Infarction

USpella registry is an observational ongoing multicenter voluntary registry of Impella use in which 47 sites in the US and two sites in Canada participated. A total of 637 high-risk PCI patients were identified from USpella registry and a further 339 patients who met eligibility criteria for enrollment in the PROTECT II trial, referred to as “PROTECT II-like” group, were identified, and then each of those groups were compared with the 216 patients randomized to the Impella arm of the PROTECT II trial. USpella registry were older, had higher incidence of chronic kidney disease, fewer prior CABG or MI, more prior PCI, more severe heart failure symptoms, and lower LVEF compared with PROTECT II trial patients. Despite higher risk profile, blood transfusions, vascular complications requiring surgery, and mortality were not statistically significant overall in the USpella registry patients and the PROTECT II-like patients when compared with the PROTECT II trial patients. However, vascular complications not requiring surgery where significantly lower in the overall USpella registry, but not the PROTECT II-like patients, when compared with the PROTECT II trial patients. MI was also significantly lower in the USpella registry as was repeat revascularizations concluding that USpella registry patients seem to do better than PROTECT II trial cohort despite having higher-risk profile.22 A retrospective, single-center study was conducted to analyze 230 patients (115 Impella-supported and 115 unsupported matched controls) undergoing high-risk PCI with LVEF <35 %. Primary outcome was incidence of in-hospital acute kidney injury (AKI). Impella support during high-risk PCI was independently associated with a significant reduction in AKI. Despite preexisting chronic kidney disease (CKD) or a lower LVEF, Impella support protection against AKI persisted. The study showed Impella to be protective against AKI during high-risk PCI even in preexisting CKD and decreased EF populations.23 A recently published, retrospective study using cVAD Registry (a global, observational, retrospective, multicenter registry of patients who have been treated with Impella devices) of 36 patients who underwent PCI on an upper left main coronary artery lesion and were supported by a pLVAD (Impella 2.5) found 55.6 % initiated pLVAD support before PCI and 44.4 % initiated pLVAD support after PCI. Overall, survival to discharge was 38.9 %, with patients who initiated pLVAD support before versus after PCI faring better (55 % versus 18.8 %; P=0.041).24 In conclusion, Impella use as a protective measure in high-risk PCI has shown to be non-inferior to IABP in PROTECT II trial. However, more recent substudies and subanalysis of PROTECT II trial, and registries

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The Efficacy Study of Left Ventricular Assist Device to Treat Patients With Cardiogenic Shock (ISAR-SHOCK) was a prospective, two-center, randomized study in cardiogenic shock patient aiming to test whether the Impella 2.5 device provides superior hemodynamic support compared with IABP. The study enrolled 26 patients with cardiogenic shock. The primary endpoint was the change of the cardiac index from baseline to 30 minutes after 30 days. Secondary endpoints included lactic acidosis, hemolysis, and mortality after 30 days. Study established Impella as feasible and safe, and provides superior hemodynamic support compared with standard treatment using IABP.25 The results of the above study lead to wider adoption of Impella use by interventionalists in the setting of cardiogenic shock complicating AMI. In 2014 the largest cohort at the time of USpella registry who received Impella 2.5 in the setting of cardiogenic shock complicating AMI were studied. The study included a total of 154 consecutive patients from 38 US hospitals and reviewed the timing of Impella placement (pre-PCI versus post-PCI) with primary endpoint survival to discharge, and secondary endpoints including assessment of patient’s hemodynamics and in-hospital complications. Both groups were comparable except for diabetes, peripheral vascular disease, chronic obstructive pulmonary disease, and prior stroke, all of which were more prevalent in the pre-PCI group. Patients in the pre-PCI group had more lesions and vessels treated. These patients also had significantly better survival to discharge compared with patients in the post-PCI group (65.1 % versus 40.7 %, P=0.003). The study showed that the initiation of support prior to PCI with Impella 2.5 was an independent predictor of in-hospital survival (OR 0.37; 95 % CI: 0.17–0.79, P=0.01) and concluded that early initiation of the hemodynamic support prior to PCI with Impella 2.5 is associated with more complete revascularization and improved survival in the setting of cardiogenic shock complicating AMI.26 The Impella CP Versus Intra-aortic Balloon Pump in Acute Myocardial Infarction Complicated by Cardiogenic Shock (IMPRESS) trial was a more recent randomized, prospective open-label, multicenter trial assessing whether the Impella CP can decrease 30-day mortality when compared with IABP in patients with severe cardiogenic shock complicating AMI. The trial enrolled a total of 48 patients (24 in each arm). The primary endpoint was 30-day all-cause mortality and results showed that routine treatment with Impella CP was not associated with reduced 30-day mortality compared with IABP. Given such a small study population the trial has limitations and continues to leave several unanswered questions regarding the use of Impella in cardiogenic shock population.27 A recent analysis of cVAD registry concluded that early initiation of hemodynamic support prior to PCI with Impella 2.5, in the setting of AMI complicated by cardiogenic shock was associated with a greater survival benefit to hospital discharge in women compared with men, despite a higher predicted risk of mortality and a greater revascularization failure rate for women.28

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Interventional Cardiology Figure 5: HeartMate PHP

and Impella LD) and the treatment of ongoing cardiogenic shock that occurs immediately (<48 hours) following AMI.17 The safe use of Impella requires low risk for vascular access complications (the most common complication) and relative structurally normal heart to safely introduce the device through peripheral vasculature, across the aortic valve into the left ventricle. Contraindications for Impella use include LV mural thrombus, significant atrial septal defect or ventricular septal defect, LV rupture, moderate to severe aortic insufficiency (graded as >+2 by echocardiography), mechanical aortic valve, and severe aortic stenosis (<0.6 cm2).17

Figure 6: The TandemHeart Kit A

In a case series of five patients with severe aortic stenosis (valve area of 0.6 cm2) and LVEF of 24 ± 5 % who needed Impella support for PCI, Impella catheter successfully traversed the aortic valve after a balloonassist technique was used in 4 out of the 5 patients. All procedures were well tolerated, with absence of arrhythmia, hypotension, pulmonary edema, stroke, or MI. One patient died 48 hours post-PCI of multiorgan failure. The four remaining patients were well at 30 days.29

HeartMate PHP HeartMate PHP is a new percutaneous temporary LV support device manufactured by St Jude Medical currently under investigational use in the US. The device is a low-profile catheter-based heart pump similar to Impella promising to deliver higher blood flow with smaller size compared with Impella.

TandemHeart (A) consists of a 21-Fr inflow cannula in the left atrium after femoral venous access and transseptal puncture (B) and a 15-Fr to 17-Fr arterial cannula in the iliac artery. The externalized centrifugal motor (C) rotates at maximal speed of 7500 rotations per minute, delivering 4 l/min of continuous flow. Naidu SS. Novel percutaneous cardiac assist devices. Circulation. 2011 Feb 8;123(5):533-43. Published with permission from Wolters Kluwer Health.

As of the date of this review, the FDA-approved indications for the Impella devices are: • Impella 2.5 and Impella CP for temporary (<6 hours) ventricular support during high-risk PCI performed in elective or urgent, hemodynamically stable patients with severe coronary artery disease and depressed LV ejection fraction as a potential prevention from hemodynamic instability during or shortly after the procedure.17 • Impella 2.5, Impella CP, Impella 5.0 and Impella LD for short-term use (<4 days for Impella 2.5 and Impella CP, and <6 days for Impella 5.0

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HeartMate PHP catheter (Figure 5) is inserted over a guide wire through femoral access via a 14 Fr femoral introducer sheath. Once in position across the aortic valve, the outer 14 Fr sheath is pulled back allowing for the 13 Fr cannula to expand to 24 Fr. The cannula has an integrated 3-blade impeller that begins to spin pulling blood from left ventricle into the ascending aorta with physiologic flow rate of 4-5 l/min. Introducing the sheath forward again will collapse the expanded cannula for easy retrieval. The Coronary Interventions in High-Risk Patients Using a Novel Percutaneous Left Ventricular Support Device (SHIELD II trial) is an ongoing, prospective, randomized, multicenter, open label, noninferiority study comparing HeartMate PHP to the Impella 2.5 in patients undergoing high-risk PCI. The study enrolled 425 patients as of February 2017 and the estimated primary completion date is October 2017 with study completion estimated to be in January 2018. The inclusion criteria included hemodynamically stable patients undergoing elective or urgent high-risk PCI. Patients indicated for revascularization of at least one de novo or restenotic lesion in a native coronary vessel or bypass graft. Complex coronary artery disease was defined as: LVEF <35 % and at least one of the following: last patent coronary vessel, unprotected left main artery, or triple vessel disease. Study excluded emergent PCI, recent history of revascularization in the prior 6 months and STEMI/non-STEMI patients.30

TandemHeart The TandemHeart Kit is manufactured by Cardiac Assist, Inc. It is an extracorporeal pLVAD that bypasses the left ventricle, reducing LV workload and myocardial oxygen demand. The kit (Figure 6) consists of: (1) an extracorporeal continuous flow centrifugal pump; (2) a trans-septal 21 Fr

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Left Ventricular Assisting Devices in Percutaneous Coronary Intervention cannula with a large end-hole and 14-side holes; (3) a femoral arterial line ranging in size from 15 Fr to 19 Fr and is the main determinant of flow rate; (4) a control consoles. It is FDA approved for circulatory support up to 6 hours and also has FDA approval to add an oxygenator to the circuit allowing for concomitant LV unloading and oxygenation.31 The trans-septal cannula is introduced via venous access into the right atrium then across the inter-atrium septum positioning the tip of the cannula into the left atrium to pull oxygenated blood to the extracorporeal pump. The outflow arterial line is placed through femoral line and introduced to the level of aortic bifurcation providing blood at a rate of 3.5 to 5.0 l/min (depending on the size of the outflow arterial line), resulting in reduction in LV preload, LV workload, filling pressures, and myocardial oxygen demand, and increasing arterial blood pressure and cardiac output (CO). TandemHeart function is largely dependent on right ventricular function to maintain left atrial volume. As with Impella, contraindications include severe peripheral vascular disease, profound coagulopathy, bleeding diathesis precluding safe arterial cannulization, major ventricular septal defect, severe aortic insufficiency and left atrial thrombus. The most common complications from TandemHeart use are limb ischemia and major bleeding. TandemHeart was studied for use in cardiogenic shock cohort after AMI with intended PCI of the infarcted artery. The study randomized 41 patients to either IABP (n=20) or TandemHeart support (n=21). Complications like severe bleeding or limb ischemia were encountered more frequently after TandemHeart support, whereas 30-day mortalities were similar in the two groups.32 TandemHeart started losing popularity likely owing to the need for trans-septal puncture, its high-profile kit and higher complication rate, specifically hemolysis and the need for more blood transfusions compared with IABP.33

Figure 7: Peripheral Extracorporal Membrane Oxygenation Cannulation

Venous cannula

Arterial cannula Reprinted from Heart, Lung and Circulation, Vol 17, Marasco SF, Lukas G, McDonald M, McMillan J, Ihle B., Review of ECMO (extra corporeal membrane oxygenation) support in critically ill adult patients., S41-47, Copyright (2008), with permission from Elsevier [OR APPLICABLE SOCIETY COPYRIGHT OWNER].”, with permission from Elsevier.

Figure 8: Central Extracorporal Membrane Oxygenation Cannulation

Extracorporal Membrane Oxygenation ECMO is a device that externally circulates a patient’s blood providing efficient gas exchange, allowing it to stabilize patients temporarily with heart or pulmonary failure using a semipermeable membrane technology that was first discovered in 1944 by Kloff and Berk.34 Typically, a surgeon would handle the implementation of central ECMO via open approach and peripheral ECMO via a cut-down (Figures 7 and 8). With early technologies, a caretaker could provide a few hours of circulation before hemolysis set in. This barred its use for long-term use; however, in the 1950s the first membrane oxygenator35 was permitted for prolonged cardio pulmonary bypass.35 In the 1960s and 1970s the National Heart, Lung, and Blood Institute organized a nine-hospital collaborative study36 to investigate ECMO therapy; however, errors in the study itself led to inconclusive evidence regarding the improvement of survival rates. Studies during this time reported a 90 % mortality rate with patients afflicted with respiratory failure. After vast technological advancements, ECMO therapy developed enough to improve survival rates up to 75 % in adults with cardiac failure.37 From the 1980s to the early 2000s there was very limited ECMO use due to poor outcomes from prospective studies. Since the early 2000s after much development and analysis there was an increase of ECMO use, utilizing its capabilities as a bridge to transplant or different therapies.

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Arterial cannula

Venous cannula

Reprinted from Heart, Lung and Circulation, Vol 17, Marasco SF, Lukas G, McDonald M, McMillan J, Ihle B., Review of ECMO (extra corporeal membrane oxygenation) support in critically ill adult patients., S41-47, Copyright (2008), with permission from Elsevier.

After dramatic evolutionary advancements to the technology, the promising outcomes of Efficacy and Economic Assessment of Conventional

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Interventional Cardiology Table 1: Comparison of Available Percutaneous Left Ventricular Assist Devices pLVAD

Access

Cardiac Output

Indications

Limitation

Contraindications

Support

IABP 8–9 Fr through femoral artery Up to 0.5 l/min -Cardiogenic shock Requires stable rhythm - High-risk PCI

-Aortic insufficiency -Aortic pathology (aneurysm/dissection)

12–21 Fr typically femoral 2.5 to 5.0 l/min -Cardiogenic shock Large cannula Impella® possible axillary artery following AMI -High-risk PCI

-LV mural thrombus - Significant ASD or VSD -Moderate to severe aortic stenosis

TandemHeart™

-RV failure -Significant VSD -PAD

15–19 Fr through femoral 3.5 to 5.0 l/min -Cardiogenic shock artery - High-risk PCI + 21 Fr through femoral vein

Requires two access sites and trans-septal puncture

VA-ECMO 15–23 Fr through femoral Up to 7.0 l/min -Acute, severe cardiac Requires two access artery and femoral vein failure/cardiogenic sites and usually requires shock with high risk venous/arterial cut-down of death. -Typically used for bridging to LVAD/ transplant

-non-recoverable cardiac disease -Unwitnessed arrest -Advanced malignancy

AMI = acute myocardial infarction; ASD = atrial septal defect; ECMO = extracorporeal membrane oxygenation; IABP = intra-aortic balloon pump; LV = left ventricular; LVAD = left ventricle assisting devices; PAD = peripheral arterial disease; PCI = percutaneous coronary intervention; pLVAD = percutaneous left-ventricle-assisting devices; RV = right ventricular; VSD = ventricular septal defect.

Ventilatory Support Versus Extracorporeal Membrane Oxygenation for Severe Adult Respiratory Failure (CESAR) trial38 and the role ECMO played in influenza A pandemic,39–40 it became one of the most effective forms of circulatory support. Driven by a rotor unit, the device will drain and return a patient’s blood through a cannula and tubbing. Once the blood is drained, the blood passes through the ECMO device where it is then oxygenated, decarboxylated, and warmed so it can then be returned into the patient. The standard technique of nonsurgical application in adults begins with the peripheral cannulation of the femoral or jugular vessels. The veno-venous ECMO drains and returns blood from the right atrium (Figure 8). Typically, this technique is performed on patients with respiratory distress syndrome. The focus of this paper will be directed towards the veno-arterial (VA) ECMO, which drains blood from the right atrium and returns to the arterial system. The VA-ECMO can reduce the preload of blood and increase aortic flow and end-organ perfusion. Typically, during this treatment, a sheath for antegrade perfusion of the cannulated leg is invoked to prevent leg ischemia. One advantage of this treatment is that the system and technology required is very accessible and mobile, if necessary. Once the device is implanted and operational, the patient can be transported anywhere with the whole unit. The ECMO can establish a right-to-left shunt by draining blood from a vein while returning it to the iliac artery. With large cannulas and rotors, the blood can flow up to 7 l/m, resulting in a significant increase of blood pressure if there is enough vascular resistance (pressure = flow × resistance). Although this device has an extensive variety of benefits and advantages, as is the case with any medical device, complications can arise. Despite having a quick set-up and sufficient hemodynamic support, the ECMO still has its own list of limitations, contraindications, and complications. Despite having lifesaving capabilities, this device should only be used when patients’ wishes or ethical aspects do not exclude mechanical support. There must be an outlined bridging strategy, or an end goal before the device is implemented. If a patient

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has severe peripheral artery disease in their iliac arteries, the ECMO may not be a viable option. Other contraindications arise in patients with aortic dissection, relative LV thrombus, or uncontrolled bleeding disorder. Among the complications, leg ischemia may arise so a sheath must be implemented to thwart the threat. Bleeding, LV distention, hyperfibrinolysis and embolism may all occur.41 Other conditions such as two-circulation syndrome and other vascular complications may also arise.42 It is possible to see severe aortic regurgitation caused from the retrograde flow support of the VA-ECMO, leading to the potential event of pulmonary edema or LV distention. Many of these complications occur when caretakers fail to notice specific indications prior to implantation.43 Typically, ECMO is used in patients with compromised ventilation or oxygenation status. If they have suffered a cardiac event such as a MI followed by cardiogenic shock, then implementation of the ECMO may also be used. Usage of the device is also common in cases where there is acute respiratory distress syndrome, viral, bacterial, or atypical pneumonia, barotrauma, and acute chronic interstitial pneumonitis.44 Before the device is used, it should be noted that patients with lifeshortening conditions, such as overwhelming sepsis, non-pulmonary multiorgan failure, irreversible neurological injury, terminal illness, or other life-limiting disease, should not have the ECMO device used. A common candidate for the ECMO may also have hypercapnic, hypoxic, and be unresponsive to optimal medical managements, including lowtidal volumes, bronchodilator treatment, administration of epoprostenol, paralytics administration, and appropriate diuresis.45 Clinical studies show evidence of the effectiveness of this device, depending on proper preprocedural assessments. Several recent studies pertaining to the ECMO shed some healthy light on the effectiveness of the device and its patients’ outcomes and treatment. In a recent study from the Journal of Cardiac Surgery,46

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Left Ventricular Assisting Devices in Percutaneous Coronary Intervention over 8 years of clinical observations 150 patients were categorized in four groups by specific indications: patients with post-cardiotomy, cardiogenic shock, requiring cardiopulmonary resuscitation (CPR), cardiogenic shock not requiring CPR, and respiratory failure. Among the 150 cases, 73 (41 %) were weaned off ECMO, 40 (23 %) were bridged to their healthcare goal of transplantation or mechanical-assist device insertion, and 63 (36 %) expired on ECMO. Mortality rates and length of stay in the hospital did not vary much between the four groups. The device duration was 4.9 days on average and the stay in the hospital was 40.3 days on average. With a survival rate of 64 % and a relatively small study population, further data to elaborate on the effectiveness of the device can be seen in another study from the Journal of Critical Care.47 Candidates for the study’s population were all high-risk patients in need of CABG surgery. The objective was to prove that ECMO is a viable option to act as a bridge before a large operation. Among their population 100 % received a successful ECMO insertion and 83 % of patients lived the next 6 months’ event free. The ECMO is a very useful percutaneous device that in some cases can provide a chance for survival or at least a bridge to a definitive treatment. Much research is required before it is clear whether this device reduces mortality.

Conclusion Despite large, randomized trials failing to show superiority of one device over the other, the IABP seem to be falling out of favor with most

1. 2. 3.

10.

11.

12.

13.

14.

Grüntzig A. Transluminal dilatation of coronary-artery stenosis. Lancet 1978;311:263. PMID: 74678 Rajani R, Lindblom M, Dixon G, et al. Evolving trends in percutaneous coronary intervention. Br J Cardiol 2011;18:73–6. Carnendran L, Abboud R, Sleeper LA, et al. Trends in cardiogenic shock: report from the SHOCK Study. Eur Heart J 2001;22:472–8. DOI: 10.1053/euhj.2000.2312; PMID: 11237542 Babaev A, Frederick PD, Pasta DJ, et al. Trends in management and outcomes of patients with acute myocardial infarction complicated by cardiogenic shock. JAMA 2005;294:448–54. DOI: 10.1001/jama.294.4.448; PMID: 16046651 Menon V, Hochman JS, Stebbins A, et al. Lack of progress in cardiogenic shock: lessons from the GUSTO trials. Eur Heart J 2000;21:1928–36. DOI: 10.1053/euhj.2000.2240; PMID: 11071798 Nanas JN, Moulopoulos SD. Counterpulsation: historical background, technical improvements, hemodynamic and metabolic effects. Cardiology 1994;84:156–67. PMID: 8205565 Parissis H, Graham V, Lampridis S, et al. IABP: history-evolutionpathophysiology-indications: what we need to know. J Cardiothorac Surg 2016;11:122. DOI: 10.1186/s13019-016-0513-0; PMID: 27487772 Cao J, Liu W, Zhu J, Zhao H. Risk factors and clinical characteristics of in-hospital death in acute myocardial infarction with IABP support. Int J Clin Exp Med 2015;8:8032–41. PMID: 26221368 Siriwardena M, Pilbrow A, Frampton C, et al. Complications of intra-aortic balloon pump use: does the final position of the IABP tip matter? Anaesth Intensive Care 2015;43:66–73. PMID: 25579291 Tanaka A, Tuladhar SM, Onsager D, et al. The subclavian intraaortic balloon pump: a compelling bridge device for advanced heart failure. Ann Thorac Surg 2015;100:2151–7. DOI: 10.1016/j.athoracsur.2015.05.087; PMID: 26228596 Nowak-Machen M, Hilberath JN, Rosenberger P, et al. Influence of intraaortic balloon pump counterpulsation on transesophageal echocardiography derived determinants of diastolic function. PloS One 2015;10:e0118788. DOI: 10.1371/ journal.pone.0118788; PMID: 25739068 Poirier Y, Voisine P, Plourde G, et al. Efficacy and safety of preoperative intra-aortic balloon pump use in patients undergoing cardiac surgery: a systematic review and meta-analysis. Int J Cardiol 2016;207:67–9. DOI: 10.1016/j.ijcard.2016.01.045; PMID: 26797334 Pöss J, Köster J, Fuernau G, et al. Risk stratification for patients in cardiogenic shock after acute myocardial infarction. J Am Coll Cardiol 2017;69:1913–20. DOI: 10.1016/j.jacc.2017.02.027; PMID: 28408020 Kirklin JK, Naftel DC. Mechanical circulatory support. Circ Heart Fail 2008;1:200–5. DOI: 10.1161/CIRCHEARTFAILURE.108.782599; PMID: 19808290

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interventionalists due to expanding registry data and substudy analysis showing promise in Impella. IABP’s lower CO augmentation (up to 0.5 l/min) and need for regular rhythm are major limitations. With ECMOs being largely managed by the surgeons and the need for septal perforation for TandemHeart placement, Impella offers better CO augmentation compared with IABP, and easier placement compared with TandemHeart. However, Impella is a relatively new device that has a learning curve compared with more established devices as suggested by a substudy analysis of PROTECT II trial.48 Also, technical support and troubleshooting are other considerations when prolonged support is needed. ECMO and TandemHeart have different roles in specific scenarios. Device choice depends on many factors including: patient’s profile (Table 1), nature of procedure (e.g. critical STEMI PCI versus elective high-risk PCI), time limitations, anticipated degree for hemodynamic compromise, anticipated duration of support, availability of the device, interventionalist’s experience with the device, and availability of resources for post-placement management. There is still much data to be collected and analyzed to determine the best choices in specific clinical scenarios. Each operator and center must determine their needs and skillsets in the setting of current evidencebased data. Clearly, patients benefit from the hemodynamic support in critical cases, whether planned or emergent. Ease of use, cost, and availability of local expertise must also be considered in order to best serve our cardiovascular patients. n

15. B aldwin RT, Radovancˇevic´ B, Duncan JM, et al. Management of patients supported on the Hemopump cardiac assist system. Tex Heart Inst J 1992;19:81–6. PMID: 15227419 16. http://www.abiomed.com 17. Dixon SR, Henriques JP, Mauri L, et al. A prospective feasibility trial investigating the use of the Impella 2.5 system in patients undergoing high-risk percutaneous coronary intervention (The PROTECT I Trial): initial US experience. JACC Cardiovasc Interv 2009;2:91–6. DOI: 10.1016/j.jcin.2008.11.005; PMID: 19463408 18. O’Neill WW, Kleiman NS, Moses J, et al. A Prospective, Randomized Clinical Trial of Hemodynamic Support With Impella 2.5 Versus Intra-Aortic Balloon Pump in Patients Undergoing High-Risk Percutaneous Coronary Intervention: The PROTECT II Study. Circulation 2012;126(14):1717–27. 19. Dangas GD, Kini AS, Sharma SK, et al. Impact of hemodynamic support with Impella 2.5 versus intra-aortic balloon pump on prognostically important clinical outcomes in patients undergoing high-risk percutaneous coronary intervention (from the PROTECT II randomized trial). Am J Cardiol 2014;113:222–8. DOI: 10.1016/j.amjcard.2013.09.008; PMID: 24527505 20. Henriques JP, Ouweneel DM, Naidu SS, et al. Evaluating the learning curve in the prospective randomized clinical trial of hemodynamic support with Impella 2.5 versus intra-aortic balloon pump in patients undergoing high-risk percutaneous coronary intervention: a prespecified subanalysis of the PROTECT II study. Am Heart J 2014;167:472–9. DOI: 10.1016/ j.ahj.2013.12.018; PMID: 24655695 21. Kovacic JC, Kini A, Banerjee S, et al. Patients with 3‐vessel coronary artery disease and impaired ventricular function undergoing PCI with Impella 2.5 hemodynamic support have improved 90‐day outcomes compared to intra‐aortic balloon pump: a sub‐study of the PROTECT II trial. J Interv Cardiol 2015;28:32–40. DOI: 10.1111/joic.12166; PMID: 25689546 22. Kahaly O, Boudoulas KD. Percutaneous left ventricular assist device in high risk percutaneous coronary intervention. J Thorac Dis 2016;8:298–302. DOI: 10.21037/jtd.2016.01.77; PMID: 27076921 23. Flaherty MP, Pant S, Patel SV, et al. Hemodynamic support with a microaxial percutaneous left ventricular assist device (Impella) protects against acute kidney injury in patients undergoing high-risk percutaneous coronary intervention. Circ Res 2017;120:692–700. DOI: 10.1161/CIRCRESAHA.116.309738; PMID: 28073804 24. Meraj PM, Doshi R, Schreiber T, et al. Impella 2.5 initiated prior to unprotected left main PCI in acute myocardial infarction complicated by cardiogenic shock improves early survival. J Interv Cardiol 2017;30:2562–63. DOI: 10.1111/joic.12377; PMID: 28419573

25. S eyfarth M, Sibbing D, Bauer I, et al. A randomized clinical trial to evaluate the safety and efficacy of a percutaneous left ventricular assist device versus intra-aortic balloon pumping for treatment of cardiogenic shock caused by myocardial infarction. J Am Coll Cardiol 2008;52:1584–8. DOI: 10.1016/j.jacc.2008.05.065; PMID: 19007597 26. O’Neill WW, Schreiber T, Wohns DH, et al. The current use of Impella 2.5 in acute myocardial infarction complicated by cardiogenic shock: results from the USpella Registry. J Interv Cardiol 2014;27:1–11. DOI: 10.1111/joic.12080; PMID: 24329756 27. Ouweneel DM, Eriksen E, Sjauw KD, et al. Impella CP versus intra-aortic balloon pump in acute myocardial infarction complicated by cardiogenic shock: The IMPRESS trial. J Am Coll Card 2016 Oct 31:23127 28. Joseph SM, Brisco MA, Colvin M, et al. Women with cardiogenic shock derive greater benefit from early mechanical circulatory support: an update from the cVAD registry. J Interv Cardiol 2016;29:248–56. DOI: 10.1111/joic.12298; PMID: 27229327 29. Spiro J, Venugopal V, Raja Y, et al. Feasibility and efficacy of the 2.5 L and 3.8 L Impella percutaneous left ventricular support device during high‐risk, percutaneous coronary intervention in patients with severe aortic stenosis. Catheter Cardiovasc Interv 2015;85:981–9. DOI: 10.1002/ccd.25355; PMID: 24408882 30. Spiro J, Venugopal V, Raja Y, et al. Feasibility and efficacy of the 2.5 L and 3.8 L impella percutaneous left ventricular support device during high‐risk, percutaneous coronary intervention in patients with severe aortic stenosis. Catheterization and Cardiovascular Interventions 2015 May 1;85(6):981–9. 31. Clinical Trails. Supporting patients undergoing high-risk PCI using a high-flow percutaneous left ventricular support device (SHIELD II). 2018. Available at: www.clinicaltrials.gov/show/ NCT02468778 (accessed 1 October 2017) 32. Khalife WI, Kar B. The TandemHeart® pVAD™ in the treatment of acute fulminant myocarditis. Texas Heart Institute Journal 2007;34(2):209. 33. Thiele H, Sick P, Boudriot E, et al. Randomized comparison of intra-aortic balloon support with a percutaneous left ventricular assist device in patients with revascularized acute myocardial infarction complicated by cardiogenic shock. European heart journal 2005 Feb 25;26(13):1276–83. 34. Cheng JM, den Uil CA, Hoeks SE, et al. Percutaneous left ventricular assist devices vs. intra-aortic balloon pump counterpulsation for treatment of cardiogenic shock: a meta-analysis of controlled trials. European heart journal 2009 Jul 18;30(17):2102–8. 35. Kolobow T, Bowman RL. Construction and evaluation of an alveolar membrane artificial heart-lung. Trans Am Soc Artif Intern Organs 1963;9:238–43. PMID: 14034415

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Interventional Cardiology 36. Z apol WM, Snider MT, Hill JD, et al. Extracorporeal membrane oxygenation in severe acute respiratory failure: a randomized prospective study. JAMA 1979;242:2193–6. PMID: 490805 37. Smedira NG, Moazami N, Golding CM, et al. Clinical experience with 202 adults receiving extracorporeal membrane oxygenation for cardiac failure: survival at five years. J Thorac Cardiovasc Surg 2001;122:92–102. DOI: 10.1067/ mtc.2001.114351; PMID: 11436041 38. Peek GJ, Mugford M, Tiruvoipati R, et al. Efficacy and economic assessment of conventional ventilatory support versus extracorporeal membrane oxygenation for severe adult respiratory failure (CESAR): a multicentre randomised controlled trial. Lancet 2009;374:1351–63. DOI: 10.1016/ S0140-6736(09)61069-2; PMID: 19762075 39. Davies A, Jones D, Bailey M, et al. Extracorporeal membrane oxygenation for 2009 influenza A(H1N1) acute respiratory distress syndrome. JAMA 2009;302:1888–95. DOI: 10.1001/ jama.2009.1535; PMID: 19822628

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40. Z angrillo A, Biondi-Zoccai G, Landoni G, et al. Extracorporeal membrane oxygenation (ECMO) in patients with H1N1 influenza infection: a systematic review and meta-analysis including 8 studies and 266 patients receiving ECMO. Crit Care 2013;17:R30. DOI: 10.1186/cc12512; PMID: 23406535 41. Zangrillo A, Landoni G, Biondi-Zoccai G, et al. A meta-analysis of complications and mortality of extracorporeal membrane oxygenation. Crit Care Resusc 2013;15:172–8. PMID: 23944202 42. García-Carreño J, Sousa-Casasnovas I, Díez-Delhoyo F, et al. Vein thrombosis after ECMO decannulation, a frequent and sometimes missed complication. Int J Cardiol 2016;223:538–39. DOI: 10.1016/j.ijcard.2016.08.137; PMID: 27552576 43. Thiagarajan RR, Brogan TV, Scheurer MA, et al. Extracorporeal membrane oxygenation to support cardiopulmonary resuscitation in adults. Ann Thorac Surg 2009;87:778–85. DOI: 10.1016/j.athoracsur.2008.12.079; PMID: 19231388 44. Hemmila MR, Rowe SA, Boules TN, et al. Extracorporeal life support for severe acute respiratory distress syndrome in adults. Ann Surg 2004;240:595–605. PMID: 15383787

45. B rodie D, Bacchetta M. Extracorporeal membrane oxygenation for ARDS in adults. N Engl J Med 2011;365:1905–14. DOI: 10.1056/ NEJMct1103720; PMID: 22087681 46. Chiu R, Pillado E, Sareh S, et al. Financial and clinical outcomes of extracorporeal mechanical support. J Card Surg 2017;32:215–21. DOI: 10.1111/jocs.13106; PMID: 28176385 47. Tomasello SD, Boukhris M, Ganyukov V, et al. Outcome of extracorporeal membrane oxygenation support for complex high-risk elective percutaneous coronary interventions: a single-center experience. Heart Lung 2015;44:309–13. DOI: 10.1016/j.hrtlng.2015.03.005; PMID: 25913808 48. Henriques JP, Ouweneel DM, Naidu SS, et al. Evaluating the learning curve in the prospective randomized clinical trial of hemodynamic support with Impella 2.5 versus intra-aortic balloon pump in patients undergoing high-risk percutaneous coronary intervention: a prespecified subanalysis of the PROTECT II study. Am Heart J 2014;167:472–9. DOI: 10.1016/ j.ahj.2013.12.018; PMID: 24655695

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Electrophysiology

Clinical Significance of Idiopathic Frequent Premature Ventricular Complexes Rakesh Latchamsetty, MD Michigan Medicine, University of Michigan, Ann Arbor, MI

Abstract Premature ventricular complexes (PVCs) in the absence of underlying structural heart disease are often benign. Most patients with this type of disease have an uneventful clinical course and can be treated based on symptoms. However, there exists a subset of patients with frequent PVCs that may develop cardiomyopathy and heart failure. This review describes the mechanisms and potential adverse effects of frequent PVCs, the prognosis and risk stratification of patients based on the nature and quantity of PVCs, and the clinical management and outcomes of these patients.

Keywords Premature ventricular complexes, heart failure, antiarrhythmic drugs, catheter ablation Disclosure: The author has no conflict of interest to declare. Received: August 26, 2017 Accepted: September 27, 2017 Citation: US Cardiology Review 2017;11(2):95–7. DOI: 10.15420/usc.2017:19:1 Correspondence: Rakesh Latchamsetty, MD, Cardiovascular Center, 1500 E Medical Center Dr SPC 5856, Ann Arbor, MI 48109-5856. E: rakeshl@med.umich.edu

Introduction Premature ventricular complexes (PVCs) in the absence of underlying structural heart disease have long been viewed as benign. Early studies with small population sizes and limited cardiac testing suggested that long-term prognosis in patients with idiopathic PVCs is similar to those in patients without other cardiac disease, and treatment was consequently limited to provide symptomatic improvement. While most patients with infrequent or moderate idiopathic PVCs have benign outcomes and can be managed based on symptoms, there exists a subset of patients with frequent PVCs that may develop cardiomyopathy and heart failure. Due to its rare occurrence, the nature and predictability of PVCs causing sudden cardiac death (SCD) is not well described and risk stratification and management of such patients remains a challenge. In this review, I first describe the mechanisms and potential adverse effects of frequent PVCs with a focus on the development of cardiomyopathy. I will subsequently discuss prognosis and risk stratification in patients based on the nature and quantity of PVCs. Finally, I will describe clinical management and outcomes.

Epidemiology and Mechanisms The prevalence of PVCs in the population inherently depends on the type and duration of screening. In a study of 122,043 men in the United States Air Force monitored by EKG for 48 s, <1 % were noted to have PVCs.1 When monitoring was extended to 6 h in 301 men, 62 % had PVCs.2 A PVC burden of >60/h was reported in 1–4 % of the general population.3 The natural history of PVCs is incompletely understood and it is not clear why some patients have spontaneous resolution or improvement in PVCs, others have maintenance of their PVC burden without compromise of cardiac function, and others develop cardiomyopathy and heart failure even with similar PVC burdens or origins.

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Initiation of PVCs can be due to any of the three primary arrhythmia mechanisms: re-entry, automaticity, or triggered activity. The autonomic nervous system also plays a significant role, and can affect PVC genesis due to automaticity or triggered activity in particular. Increased sympathetic tone can enhance automaticity in an ectopic focus or induce cAMP-mediated triggered activity.4 Vagal activity has been suggested to potentially facilitate early afterdepolarizations that can lead to increased ventricular arrhythmias.5 The influence of the autonomic nervous system was demonstrated in a recent analysis where idiopathic PVCs were identified as being either bradycardia or tachycardia dependent in 80 % of patients.5 This is evident in the variability of clinical presentation where some patients have exertional ventricular arrhythmia whereas others experience a higher PVC burden at rest. Treatment options are also affected, with patients demonstrating tachycardia-dependent PVCs being more likely to respond to sympatholytic therapies such as beta blockers.5

Prognosis The prognosis in patients with frequent PVCs is affected by the presence of underlying cardiac disease. In patients with a recent myocardial infarction, the presence of frequent PVCs is associated with worse outcomes, including increased mortality.6 In these patients, based on failure to improve outcomes with attempts at PVC suppression,7 it is suspected that PVCs likely serve more as a marker of the severity of underlying disease rather than a modifiable risk factor. In the absence of other cardiac disease, the prognosis of patients with frequent idiopathic PVCs is determined by a number of factors, including PVC frequency. A recent long-term prospective analysis over a mean follow-up of 13 years showed that patients in the upper quartile of PVC frequency (0.123–17.7 %) had a higher rate of cardiomyopathy, heart failure, and mortality.8 Although increased long-term presence of heart

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Electrophysiology failure symptoms was noted even at low PVC frequencies, the range of PVC frequencies at which increased cardiomyopathy and mortality were seen was quite large and it is not clear based on this study which specific patients warrant closer monitoring or more aggressive therapy. Furthermore, to what extent PVCs represented a reversible etiology of subsequent clinical events in this cohort versus a marker of the severity of another underlying process remains to be seen. The majority of data suggest that patients with low to moderate PVC burdens and without structural heart disease will have a benign clinical course, with treatment focussed on symptom management.9 In patients with very frequent PVCs, the risk for development as well as the reversibility of PVC-induced cardiomyopathy is well established. Risk factors for development of cardiomyopathy include long-term exposure to very frequent PVCs. In one study, patients with a PVC burden >24 % were found to be at a particularly high risk of developing a PVC-induced cardiomyopathy, but the presence of cardiomyopathy was seen even with a PVC burden of 10 %.10 The mechanisms for developing PVC-induced cardiomyopathy are likely multifactorial and not completely understood but may at least partially be explained by ventricular dysynchrony caused by the PVCs. Other factors associated with a higher risk of developing cardiomyopathy include longer duration of exposure to PVCs, asymptomatic status, epicardial PVC origin, increased QRS duration of the PVCs, interpolated PVCs, and lack of circadian PVC variation.11–14 There is also evidence to suggest that men may have a slightly higher risk of developing PVCinduced cardiomyopathy than women.15 Although patients with PVCinduced cardiomyopathy are certainly at risk of developing significant heart failure symptoms, whether they are at the same risk for SCD as other patients with ischemic or other forms of cardiomyopathy is not clear.

patients with cardiac resynchronization therapy and patients in whom PVCs are implicated in triggering sustained ventricular arrhythmias.

The occurrence of SCD in patients with idiopathic PVCs is low, although difficult to quantitate due to its rarity. Patients with such a presentation should be screened for occult cardiac disease such as sarcoidosis or arrhythmogenic right ventricular dysplasia. When PVCs are documented to trigger sustained ventricular arrhythymias, ablation may be effective in eliminating or reducing the PVCs and subsequent arrhythmias.16 When polymorphic ventricular tachycardia or ventricular fibrillation is documented, an ICD is also indicated.17 In other patients, the decision to implant an ICD should consider various clinical parameters including documentation of clinical ventricular tachycardia, left ventricular function, inducibility of ventricular tachycardia during electrophysiology study, success of catheter ablation, and presence of structural heart disease by advanced imaging.

Many patients with symptomatic PVCs without structural heart disease can be initially managed by their primary care physician. When advanced therapy such as antiarrhythmics or catheter ablation is necessary, or the presence of cardiomyopathy or other structural heart disease is present or suspected, referral to a cardiologist or cardiac electrophysiologist is appropriate.

In patients with frequent symptoms or frequent PVCs noted by 12-lead EKG, initial workup should include a 24–48-h Holter monitor and an echocardiogram. EKG monitoring can provide symptom correlation and identify PVC frequency. Twelve-lead Holter monitors are particularly useful in identifying the number of PVC foci. An echocardiogram should be used to evaluate ventricular function and dimensions as well as search for any other structural abnormalities. An initial search for secondary etiologies should be pursued and PVCs secondary to other cardiac or metabolic abnormalities may be reduced or eliminated with therapy addressing the underlying cause. Patients with symptoms on exertion should also have an exercise stress test including 12-lead EKG analysis. A positive stress test or symptoms consistent with ischemia, particularly in a patient with coronary risk factors, may prompt a coronary angiogram. While there are no specific criteria for obtaining a cardiac MRI, these are often obtained when it is necessary to further evaluate abnormalities detected on echocardiogram or in patients where symptoms or other findings suggest the potential presence of structural abnormalities not definitively evaluated by echocardiogram. There is little data on the appropriate management of asymptomatic patients with very frequent PVCs (>10–20 %) without evidence of ventricular dysfunction or dilation. These patients are at risk for future development of cardiomyopathy, but whether prophylactic therapy is warranted is not clear. At a minimum, these patients should be followed regularly with periodic assessment of cardiac function.

Treatment When behavioral triggers are identified, initial management may include an attempt to limit or eliminate these triggers. Although most patients do not experience a significant PVC reduction with behavioral modification such as reducing moderate caffeine, alcohol, or tobacco consumption,18,19 the secondary benefits of lifestyle modification can justify this as an initial strategy.

Presentation and Diagnostic Evaluation The two most common indications for therapy to reduce or eliminate PVCs are symptomatic improvement and reversal of a cardiomyopathy.17 Symptoms can vary greatly and be a result of individual PVCs or the cumulative hemodynamic effect of frequent PVCs. Symptoms from individual PVCs can be from the PVCs themselves, a following compensatory pause, or a subsequent hypercontractile beat. These symptoms can include palpitations, chest pain, dyspnea, and lightheadedness. When symptoms are due to the cumulative hemodynamic effect of frequent PVCs, they can range from mild fatigue or dyspnea with exertion to significant heart failure with or without left ventricular dysfunction. Less common scenarios where PVC elimination may be pursued include PVCs limiting adequate biventricular pacing in

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Pharmacotherapy Initial pharmacotherapy for idiopathic PVCs usually consists of beta blockers or calcium channel blockers.17 The overall efficacy of these agents in eliminating PVCs is poor, with reported rates of 10–24 %;20–22 however, additional patients can experience an alleviation of symptoms even without significant PVC elimination. Despite the low efficacy, beta blockers and calcium channel blockers remain the most common initial treatment modalities as risks with these medications are generally low. Beta blockers may also be indicated in patients with evidence of cardiomyopathy. Antiarrhythmic drugs to treat PVCs are more effective than beta blockers or calcium channel blockers, with a reported decease in

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Clinical Significance of Idiopathic Frequent PVCs PVC frequency and associated symptoms in 15–65 % of patients.20,23,24 Although efficacy is improved, this must be weighed against the potential risks and side effects of long-term exposure to antiarrhythmic medication. Antiarrhythmic therapy remains a useful option for patients refractory to other pharmacologic treatment, particularly those that are not ideal ablation candidates or have a preference for medical therapy.

Figure 1: Acute and long-term success rates after ablation of premature ventricular complexes (PVCs) with and without the use of antiarrhythmic drugs (AADs) 100 % 90 % RVOT

Catheter Ablation In appropriate patients, catheter ablation can offer the highest efficacy in the management of frequent PVCs. Factors that may favor attempts at ablation include a high frequency of PVCs, limited PVC foci, and favorable PVC locations. Ablation may be the preferred approach in patients with PVC-induced cardiomyopathy given the robust data showing favorable outcomes in these patients following ablation.

Cusp

80 %

PAP Epicardial Single PVC

70 %

Multiple PVCs Total

60 % 50 %

In one large-scale multicenter study, 1,185 patients referred for catheter ablation of frequent PVCs had a single procedural success rate of 84 %. Following an average of 1.3 ablations, 73 % of patients remained off antiarrhythmic drugs and maintained at least an 80 % PVC reduction at a mean follow-up of 1.9 years (Figure 1).15 Factors associated with a greater likelihood of success included right ventricular outflow tract origin and fewer PVC foci. The overall major complication rate in that study was 2.4 %, with access-related complications being the most common, and no procedural mortality observed. The reversibility of PVC-induced cardiomyopathy following successful ablation has been well established, with normalization of ejection fraction being reported in >80 % of patients undergoing successful ablation and at least some improvement in ejection fraction in 85 % of all patients with cardiomyopathy attempting ablation.15,25 It is also important to recognize that PVCs can contribute to a pre-existing cardiomyopathy from other causes and an improvement in ejection fraction following successful PVC ablation can be observed in these patients.26

Hiss RG, Lamb LE. Electrocardiographic findings in 122,043 individuals. Circulation 1962;25:947–61. DOI: 10.1161/01. CIR.25.6.947; PMID: 13907778 Hinkle LE, Carver ST, Stevens M. The frequency of asymptomatic disturbances of cardiac rhythm and conduction in middleaged men. Am J Cardiol 1969;24:629–50. DOI: 10.1016/00029149(69)90451-2 Kennedy HL, Whitlock JA, Sprague MK, et al. Long-term followup of asymptomatic healthy subjects with frequent and complex ventricular ectopy. N Engl J Med 1985;312:193–7. DOI: 10.1056/NEJM198501243120401; PMID: 2578212 Lerman BB, Belardinelli L, West GA, et al. Adenosine-sensitive ventricular tachycardia: evidence suggesting cyclic AMPmediated triggered activity. Circulation 1986;74:270–80. DOI: 10.1161/01.CIR.74.2.270; PMID: 3015453 He W, Lu Z, Bao M, Yu L, et al. Autonomic involvement in idiopathic premature ventricular contractions. Clin Res Cardiol 2013;102:361–70. DOI: 10.1007/s00392-013-0545-6; PMID: 23386255 Kostis JB, Byington R, Friedman LM, et al. Prognostic significance of ventricular ectopic activity in survivors of acute myocardial infarction. J Am Coll Cardiol 1987;10:231–42. DOI: 10.1016/S0735-1097(87)80001-3 Echt DS, Liebson PR, Mitchell LB, et al. Mortality and morbidity in patients receiving encainide, flecainide, or placebo. The Cardiac Arrhythmia Suppression Trial. N Engl J Med 1991;324:781–8. DOI: 10.1056/NEJM199103213241201; PMID: 1900101 Dukes JW, Dewland TA, Vittinghoff E, et al. Ventricular ectopy as a predictor of heart failure and death. J Am Coll Cardiol 2015;66:101–9. DOI: 10.1016/j.jacc.2015.04.062; PMID: 26160626 Niwano S, Wakisaka Y, Niwano H, et al. Prognostic significance of frequent premature ventricular contractions originating from the ventricular outflow tract in patients with normal left ventricular function. Heart 2009;95:1230–7. DOI: 10.1136/ hrt.2008.159558; PMID: 19429571

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Acute Procedural Success (n=1185)

Long-Term Success without AAD (n=490)

Long-Term Success Including AAD (n=490)

Acute procedural success data are for the entire cohort, whereas long-term success data are for 490 patients at centers where Holter monitoring was performed routinely after ablation. Results are shown by PVC location and single versus multiple PVC foci. PAP = papillary muscle; RVOT = right ventricular outflow tract. (Reproduced with permission from: Latchamsetty et al.15)

Summary Most patients with PVCs in the absence of structural heart disease have a benign clinical course and can be treated based on symptoms. Patients with frequent idiopathic PVCs are at a higher risk for development of cardiomyopathy and heart failure. Treatment modalities to eliminate or reduce PVC burden include pharmacotherapy and catheter ablation. In the case of PVC-induced cardiomyopathy, successful PVC elimination by ablation usually normalizes or significantly improves cardiac function. In asymptomatic patients with very frequent PVCs and preserved cardiac function, regular follow-up and monitoring of cardiac function is warranted. n

10. B aman TS, Lange DC, Ilg KJ, et al. Relationship between burden of premature ventricular complexes and left ventricular function. Heart Rhythm 2010;7:865–9. DOI: 10.1016/j. hrthm.2010.03.036; PMID: 20348027 11. Bas HD, Baser K, Hoyt J, et al. Effect of circadian variability in frequency of premature ventricular complexes on left ventricular function. Heart Rhythm 2016;13:98–102. DOI: 10.1016/j. hrthm.2015.07.038; PMID: 26247319 12. Yokokawa M, Kim HM, Good E, et al. Impact of QRS duration of frequent premature ventricular complexes on the development of cardiomyopathy. Heart Rhythm 2012;9:1460–4. DOI: 10.1016/j. hrthm.2012.04.036; PMID: 22542704 13. Olgun H, Yokokawa M, Baman T, et al. The role of interpolation in PVC-induced cardiomyopathy. Heart Rhythm 2011;8:1046–9. DOI: 10.1016/j.hrthm.2011.02.034; PMID: 21376837 14. Yokokawa M, Kim HM, Good E, et al. Relation of symptoms and symptom duration to premature ventricular complex-induced cardiomyopathy. Heart Rhythm 2012;9:92–5. DOI: 10.1016/j. hrthm.2011.08.015; PMID: 21855522 15. Latchamsetty RY, Morady M, Kim F, et al. Multicenter outcomes for catheter ablation of idiopathic premature ventricular complexes. JACC Clin Electrophysiol 2015;1:116–23. DOI: 10.1016/j. jacep.2015.04.005 16. Knecht S, Sacher F, Wright M, et al. Long-term follow-up of idiopathic ventricular fibrillation ablation: a multicenter study. J Am Coll Cardiol 2009;54:522–8. DOI: 10.1016/j.jacc.2009.03.065; PMID: 19643313 17. Pedersen CT, Kay GN, Kalman J, et al. EHRA/HRS/APHRS expert consensus on ventricular arrhythmias. Heart Rhythm 2014;11:e166–96. DOI: 10.1016/j.hrthm.2014.07.024; PMID: 25179489 18. DeBacker G, Jacobs D, Prineas R, et al. Ventricular premature contractions: a randomized non-drug intervention trial in normal men. Circulation 1979;59:762–9. DOI: 10.1161/01.CIR.59.4.762; PMID: 421317

19. P rineas RJ, Jacobs DR, Crow RS, Blackburn H. Coffee, tea and VPB. J Chronic Dis 1980;33:67–72. DOI: 10.1016/00219681(80)90029-6 20. Stec S, Sikorska A, Zaborska B, et al. Benign symptomatic premature ventricular complexes: short- and long-term efficacy of antiarrhythmic drugs and radiofrequency ablation. Kardiol Pol 2012;70:351–8. PMID: 22528707 21. Withagen AJ, Corbeij HM, Huige MC, et al. Effects of epanolol and metoprolol on the heart measured by 24-hour holter monitoring. Drugs 1989;38(Suppl 2):67–9. DOI: 10.2165/00003495198900382-00017; PMID: 2575985 22. Krittayaphong R, Bhuripanyo K, Punlee K, et al. Effect of atenolol on symptomatic ventricular arrhythmia without structural heart disease: a randomized placebo-controlled study. Am Heart J 2002;144:e10. DOI: 10.1067/mhj.2002.125516; PMID: 12486439 23. Hohnloser SH, Meinertz T, Stubbs P, et al. Efficacy and safety of d-sotalol, a pure class III antiarrhythmic compound, in patients with symptomatic complex ventricular ectopy. Results of a multicenter, randomized, double-blind, placebo-controlled dose-finding study. The d-Sotalol PVC Study Group. Circulation 1995;92:1517–25. DOI: 10.1161/01.CIR.92.6.1517; PMID: 7664435 24. Kubac G, Klinke WP, Grace M. Randomized double blind trial comparing sotalol and propranolol in chronic ventricular arrhythmia. Can J Cardiol 1988;4:355–9. PMID: 3067834 25. Bogun F, Crawford T, Reich S, et al. Radiofrequency ablation of frequent, idiopathic premature ventricular complexes: comparison with a control group without intervention. Heart Rhythm 2007;4:863–7. DOI: 10.1016/j.hrthm.2007.03.003; PMID: 17599667 26. Sarrazin JF, Labounty T, Kuhne M, et al. Impact of radiofrequency ablation of frequent post-infarction premature ventricular complexes on left ventricular ejection fraction. Heart Rhythm 2009;6:1543–9. DOI: 10.1016/j.hrthm.2009.08.004; PMID: 19879531

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Risk Prevention

Novel Pharmacologic Treatments for Cardiovascular Disease: A Practical Update Leo F. Buckley, PharmD 1 and Ahmed Aldemerdash, BScPhm, PharmD, BCPS 2 1. Department of Pharmacy Services and Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Boston, MA, USA; 2. Department of Clinical Pharmacy, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia

Abstract Cardiovascular disease is the leading cause of death in the US. Several new pharmacologic therapies have been developed to improve patient outcomes beyond the current standard of care. These novel agents target pathways related to atherogenic lipoprotein clearance, renal glucose and potassium handling, endogenous incretins, and coagulation. In addition, emerging targets include anti-atherogenic lipoproteins, inflammatory cytokines, and dual and triple antithrombotic therapy. This review outlines important updates in cardiovascular pharmacotherapy and provides guidance on practical use in clinical practice and an outlook to emerging therapeutics.

Keywords Pharmacotherapy, proprotein convertase subtilisin-kexin type 9, sodium-glucose cotransporter-2, glucagon-like peptide-1, idarucizumab, interleukin-1, cholesteryl ester transfer protein. Disclosure: The authors have no conflicts of interest to declare. Received: August 30, 2017 Accepted: September 19, 2017 Citation: US Cardiology Review 2017;11(2):98–104. DOI: 10.15420/usc.2017:20:2 Correspondence: Leo Buckley, PharmD, Division of Cardiovascular Medicine, Brigham and Women’s Hospital, 75 Francis Street, Boston, MA 02115, USA. E: lfbuckley@bwh.harvard.edu

Cardiovascular disease is the leading cause of death in the US.1,2 Although advances in the prevention and treatment of cardiovascular disease have contributed to a decline in mortality rates, this favorable trend has slowed over the past several years.3 Recently, however, a revival of cardiovascular drug development has introduced new treatment options to the market, with several promising therapies in various stages of preclinical and clinical development. In this review, we highlight important updates in the field of cardiovascular pharmacotherapy. We focus on currently available treatments but, given the rapidly evolving landscape, include an outlook on treatments in the development pipeline. Each section focuses on a specific drug class, provides an overview of the mechanism of action and outcomes, and finishes with a practical guide to their clinical application. Key considerations are summarized in Table 1.

Proprotein Convertase Subtilisin-Kexin Type 9 Inhibitors Overview Proprotein convertase subtilisin-kexin type 9 (PCSK9) marks low-density lipoprotein cholesterol (LDL-C) receptors (LDL-R) on the hepatocyte membrane for intracellular degradation and thereby regulates circulating levels of the atherogenic LDL-C.4 Two fully human monoclonal antibodies against PCSK9, evolocumab and alirocumab, have been approved for use in the US. The development of a third, humanized antibody, whose amino acid sequence retained 3 % of the murine sequence, was discontinued due to detection of neutralizing antibodies in a phase 3 outcomes trial.5 A small interfering RNA (siRNA) inhibitor6 and an AT04A vaccine7 promise more durable and long-lasting anti-PCSK9 effects than monoclonal antibodies, but remain early in development.

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PCSK9 monoclonal antibodies reduce circulating LDL-C by 60 % on average, in addition to their beneficial effects on other atherogenic lipoprotein species, such as lipoprotein(a), in patients without familial hypercholesterolemia. Depending on the genotype, PCSK9 inhibitors also have varying degrees of lipid-lowering efficacy in patients with familial hypercholesterolemias (FH).8 PCSK9 inhibitors reduce LDL-C by 60 % and 30 % in patients with heterozygous and homozygous FH, respectively.9–13 These effects may be blunted in FH patients with negative/negative LDL-R genotype status.10,11

Outcomes The effect of PCSK9 inhibition on clinical outcomes was evaluated in the FOURIER trial, which randomized 27,564 patients with atherosclerotic cardiovascular disease on maximally tolerated statin therapy and an LDL-C level of at least 70 mg/dL to receive either evolocumab, administered as 140 mg every 2 weeks or 420 mg monthly at the patient’s discretion, or placebo.14 Over a median follow-up duration of 26 months, evolocumab significantly reduced the risk of the composite of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization by 15 % compared with placebo (9.8 % versus 11.3 %; hazard ratio [HR] 0.85; 95 % CI [0.79–0.92]; p<0.001). The composite of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke was reduced by 20 % in evolocumabtreated patients compared with placebo (5.9 % versus 7.4 %; HR 0.80; 95 % CI [0.73–0.88]; p<0.001). These reductions in the primary and secondary composite endpoints were driven by significant reductions in both non-fatal myocardial

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Novel Treatments for Cardiovascular Disease Table 1: Overview of Novel, Approved Pharmacologic Treatments for Cardiovascular Disease Indication

Dosing

Therapeutic Drug Monitoring

Evolocumab PCSK9 inhibitor

Name

Mechanism

Patients with atherosclerotic cardiovascular disease or familial heterozygous/homozygous hypercholesterolemia who require additional LDL-C lowering despite maximal statin therapy (adjunct)

Heterozygous: 140 mg bimonthly or 420 mg once monthly Homozygous: 420 mg once monthly

LDL-C level 4–8 weeks after initiation and yearly thereafter

Alirocumab PCSK9 inhibitor

Patients with atherosclerotic cardiovascular disease or familial heterozygous hypercholesterolemia who require additional LDL-C lowering despite maximal statin therapy (adjunct)

75 mg bimonthly titrated to 150 mg bimonthly to achieve goal LDL-C

LDL-C level 4–8 weeks after initiation and yearly thereafter

Empagliflozin SGLT-2 inhibitor To reduce the risk of cardiovascular death 10 mg once daily titrated to 25 mg in patients with type 2 diabetes mellitus once daily to achieve glycemic and established cardiovascular disease control

Hemoglobin A1c level, plasma glucose concentration Discontinue if eGFR <45 mL/min/1.73 m2

Canagliflozin SGLT-2 inhibitor Improvement of glycemic control in type 2 100 mg once daily titrated to 300 mg diabetes mellitus once daily to achieve glycemic control

Hemoglobin A1c level, plasma glucose concentration Discontinue if eGFR <45 mL/min/1.73 m2

Liraglutide GLP-1 agonist Improvement of glycemic control in type 2 0.6 mg once daily titrated to 1.8 mg diabetes mellitus once daily to achieve glycemic control

Hemoglobin A1c level, plasma glucose concentration

Patiromer

8.4 g once daily to achieve goal serum potassium level

Serum potassium levels weekly until goal potassium achieved

5 g administered as two separate 2.5 g bolus infusions, not more than 15 min apart

Hemostasis

Cation potassium Treatment of hyperkalemia exchange polymer

Idarucizumab Monoclonal antibody fragment against dabigatran

Reversal of the anticoagulant effects of dabigatran for emergency surgery/urgent procedures or life-threatening or uncontrolled bleeding

eGFR = estimated glomerular filtration rate; GLP-1 = glucagon-like peptide-1; LDL-C = low-density lipoprotein cholesterol; PCSK9 = proprotein convertase subtilisin-kexin type 9; SGLT-2 = sodium–glucose co-transporter-2.

infarction and non-fatal stroke. Cardiovascular death was not significantly different between the two treatment arms, although the short followup duration may not have allowed for detection of cardiovascular deaths averted. A second cardiovascular outcomes trial using alirocumab has completed enrollment and is in long-term follow-up (clinicaltrials.gov NCT01663402). PCSK9 inhibitors are generally well tolerated. In FOURIER, injection site reactions were infrequent but did occur in significantly more evolocumab patients (2.1 % versus 1.6 %; p<0.001). Neutralizing antibodies were not detected in any evolocumab-treated patient in FOURIER. The neurocognitive effects of extremely low LDL-C levels are an area of interest, given the lack of available data. In the dedicated neurocognitive substudy of FOURIER (Evaluating PCSK9 Binding Antibody Influence on Cognitive Health in High Cardiovascular Risk Subjects or EBBINGHAUS), 1,974 patients underwent prospective cognitive function testing.15 The authors reported no significant differences in neurocognitive function between evolocumab and placebo. A Mendelian randomization study of Copenhagen Heart Study did not find a significant association between LDL-C level and the risk of Alzheimer’s disease, vascular dementia, or Parkinson’s disease in patients with life-long low LDL-C levels.16 Long-term follow-up of patients treated with anti-PCSK9 monoclonal antibodies will provide further reassurance to patients and clinicians. It is important to note that Mendelian randomization studies

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also have suggested an increased risk of developing type 2 diabetes mellitus for patients with the metabolic syndrome – an effect similar to that observed with statins.17

Practical Considerations Evolocumab and alirocumab are currently indicated for patients with established cardiovascular disease or FH who require additional lipid lowering beyond that achievable with maximally tolerated statin therapy. Evolocumab can be dosed subcutaneously either every other week (140 mg) with a pen injector or once monthly (420 mg). The 420 mg evolocumab dose can be administered as three successive subcutaneous pen injections or as a single, 9-min subcutaneous infusion using a dedicated single-use auto-infuser. Alirocumab dosing should begin with 75 mg every other week subcutaneously and, if necessary to achieve further LDL-C reduction, increased to 150 mg every other week. Both evolocumab and alirocumab must be stored in the refrigerator and warmed to room temperature prior to administration. Patients should be counseled about possible injection-site reactions and flu-like symptoms. LDL-C level should be checked 4–8 weeks after starting therapy, as 1–2 % of patients may be non-responders, possibly due to an undetected PCSK9 gain-of-function gene variant or non-adherence. The central issue related to PCSK9 monoclonal antibody use is cost. The current out-of-pocket cost for either alirocumab or evolocumab

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Risk Prevention approaches US$14,000 annually and cost-effectiveness analyses from the societal perspective have not found PCSK9 inhibitors to be favorable.18,19 Many insurance plans consider PCSK9 inhibitors to be Tier 3 medications, leaving patients with a significant co-pay. Patient assistance programs are sponsored by the manufacturers of alirocumab and evolocumab and can assist both clinicians and patients in navigating the insurance prior authorization approval process. These programs may also defray out-ofpocket costs for eligible patients.

fatal stroke by 14 % (EMPA REG OUTCOME: HR 0.86; 95 % CI [0.74–0.99]; p=0.04 for superiority; CANVAS: HR 0.86; 95 % CI [0.75–0.97]; p=0.02 for superiority). In both EMPA REG and CANVAS, heart failure events were reduced by nearly 40 % and additional studies will further investigate the effects of SGLT-2 inhibition in patients with heart failure and type 2 diabetes mellitus. The reader is referred to an in-depth discussion of possible mechanisms which mediate the cardioprotective effects of SGLT-2 inhibition.21

Ezetimibe, an orally available inhibitor of the gut cholesterol transport protein Niemann-Pick C1-like 1 protein, reduces LDL-C by approximately 20–30 % and modestly reduces the risk of cardiovascular outcomes without significant adverse effects. Ezetimibe may be considered for patients who choose to avoid subcutaneous administration of monoclonal antibodies or for whom the cost of a PCSK9 antibody is prohibitive. Ezetimibe went off patent in the US in December 2016 and the 6 month exclusivity period for the first generic expired in June 2017. With more generics entering the US market, it is anticipated that the cost will decrease significantly and rapidly in late 2017 or early 2018. PCSK9 inhibitors should be considered preferred over ezetimibe, provided patients are comfortable with the route of administration and can afford the difference in cost. A recent simulation analysis of a large claims database found that maximal statin therapy achieves goal lipid levels in the majority of patients and reinforces the need to maximize statin therapy prior to the addition of costly non-statin lipidlowering therapy.20

As a result of profound glucosuria induced by SGLT-2 inhibition, patients are at increased risk of genital infections. SGLT-2 inhibitors may also cause transient worsening of renal function due to prerenal volume depletion, but SGLT-2 inhibition preserves kidney function in the long term. In patients with pre-existing renal dysfunction (estimated glomerular filtration rate 45–60 mL/min per 1.73 m2), SGLT-2 inhibitors induce a lesser degree of glucosuria as a result of impaired glucose filtration but provide similar cardiovascular benefit.22,23 Reports of 20 cases of acidosis, which were described as diabetic ketoacidosis by the reporting clinician and occurred in the setting of risk factors for diabetic ketoacidosis, prompted the United States Food and Drug Administration to issue a warning that SGLT-2 inhibitors may cause diabetic ketoacidosis.24

Sodium–Glucose Co-Transporter-2 Inhibitors Overview The sodium–glucose co-transporter-2 (SGLT-2) is a protein that is responsible for up to 90 % of the sodium and glucose reabsorption in the proximal convoluted tubule of the nephron.21 The plasma glucose threshold that inhibits SGLT-2-mediated urinary glucose reabsorption is elevated in patients with type 2 diabetes mellitus. Thus, SGLT-2 inhibition induces glucosuria, natriuresis, and osmotic diuresis, which together decrease plasma glucose concentrations and lower blood pressure. SGLT-2-mediated effects level off after an initial profound response. SGLT-2 inhibitors also produce weight loss that is sustained over several years of treatment.22,23 Notably, SGLT-2 inhibitors have modest effects on hemoglobin A1c level, with a mean reduction of 0.3-0.4 % over 52 weeks. Most important, SGLT-2 inhibition does not cause hypoglycemia, unlike other glucose-lowering agents such as insulin and sulfonylureas.

Outcomes Two major clinical trials have demonstrated the beneficial effects of SGLT-2 inhibitors in patients with type 2 diabetes mellitus. The EMPA-REG OUTCOME trial compared empagliflozin against placebo added to optimal medical therapy in patients (n=7,028) with type 2 diabetes mellitus and established cardiovascular disease.22 In contrast, the CANVAS trial enrolled patients (n=10,142) with type 2 diabetes mellitus and either established cardiovascular disease or risk factors for cardiovascular disease and randomized them to canagliflozin or placebo added to optimal medical therapy.23 In both EMPA-REG OUTCOME and CANVAS, SGLT-2 inhibition reduced the risk of cardiovascular death, non-fatal myocardial infarction, or non-

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In the CANVAS trial, amputations of the toes, feet, or legs occurred at a rate of 0.6 events per 100 patient-years in canagliflozin patients compared with 0.3 events per 100 patient-years in placebo patients (p<0.001). Seventy-one percent of amputations were of the toe or metatarsal. The frequency of amputations was significantly greater in patients with prior amputations or peripheral vascular disease, although the effects of canagliflozin on amputations were not significantly different across these subgroups. Based on these findings, the United States Food and Drug Administration issued a boxed warning that canagliflozin increases the risk of leg and foot amputations.25 The risk of amputation did not appear to differ between empagliflozin and placebo in EMPA-REG OUTCOME.

Practical Considerations SGLT-2 inhibitors should be considered second-line therapies to metformin for patients with established or elevated risk for cardiovascular disease and type 2 diabetes mellitus.26 Patients with low blood pressure or orthostatic hypotension, severe renal impairment (estimated glomerular filtration rate <30 mL/min per 1.73 m2) or a history of urinary tract infections or genital infections should not receive an SGLT-2 inhibitor. Canagliflozin should be avoided in patients with a history of lower extremity amputation or peripheral vascular disease until further data are available. As evidence accumulates, SGLT-2 inhibitors may become first-line or co-first-line with metformin in patients with both established cardiovascular disease and type 2 diabetes mellitus. Dosing for both empagliflozin and canaglifozin should start at the lowest available dose (10 mg once daily and 100 mg once daily, respectively) and subsequently increased to 25 mg for empagliflozin or 300 mg for canagliflozin as needed to achieve the goal hemoglobin A1c level. The addition of an SGLT-2 inhibitor may decrease the need for glucose-lowering therapies and therefore the doses of insulin and sulfonylurea should be lowered as a precaution due to their hypoglycemic effects.

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Novel Treatments for Cardiovascular Disease Patients should be assessed for symptoms of urinary tract or genital infections while taking empagliflozin or canagliflozin. Periodic assessment of serum creatinine is warranted, with greater frequency in patients with baseline impairment in renal function. At the time of SGLT-2 inhibitor initiation, a decrease in the loop diuretic dose should also be considered, if applicable, to decrease the possibility of volume depletion. Out-ofpocket costs for these agents can exceed several hundred dollars per month without insurance coverage.

In general, GLP-1 agonists are well tolerated. Up to 40 % of patients may experience gastrointestinal side effects, such as nausea, vomiting, diarrhea, cramping, and flatulence. Patients should be counseled that these symptoms dissipate over several weeks. Dose de-escalation and re-challenge may be required for patients who experience gastrointestinal side effects. Sulfonylurea doses should be decreased by 50 % prior to starting a GLP-1 agonist, if applicable. Cautious use of GLP-1 agonists is warranted in patients with systolic heart failure based on the findings of a phase 2 clinical trial.34

Glucagon-like Peptide-1 Receptor Agonists Overview

Potassium-Lowering Agents

Glucagon-like peptide-1 (GLP-1) is an endogenous incretin that inhibits glucagon secretion, increases insulin secretion in response to postprandial or fasting hyperglycemia, slows gastric emptying, and increases satiety.27 GLP-1 receptor agonists decrease hemoglobin A1c levels by 0.3–1.4 % in addition to having weight-lowering and blood pressurelowering effects. A high dose of liraglutide is marketed with an indication for weight loss.28–30 GLP-1 agonists require hyperglycemia to exert insulinotropic effects and therefore cannot cause hypoglycemia.

Overview

Outcomes Long-acting GLP-1 agonists decrease cardiovascular outcomes in patients with established cardiovascular disease or risk factors for cardiovascular disease and concomitant type 2 diabetes mellitus. In the LEADER trial, 9,340 patients received once-daily liraglutide or placebo for a median duration of 3.8 years.31 Liraglutide significantly reduced the risk of cardiovascular death, non-fatal myocardial infarction, or nonfatal stroke by 13 % (13.0 % versus 14.9 %; HR 0.87; 95 % CI [0.78–0.97]; p=0.01 for superiority). In the SUSTAIN-6 trial, once-weekly semaglutide was compared against placebo in 3,297 patients with established cardiovascular disease or risk factors for cardiovascular disease and concomitant type 2 diabetes mellitus.32 Semaglutide met pre-specific criteria for non-inferiority with respect to cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke (6.6 % versus 8.9 %; HR 0.74; 95 % CI [0.58–0.95]; p<0.001 for non-inferiority). In addition, a post-hoc analysis demonstrated that the effect of semaglutide on cardiovascular outcomes achieved statistical significance compared with placebo (p=0.02 for superiority). The ELIXA trial tested the hypothesis that lixisenatide, a short-acting GLP-1 agonist, reduces cardiovascular outcomes in patients with recent acute coronary syndrome and type 2 diabetes mellitus. 33 Lixisenatide was neutral with respect to the primary outcome and each secondary outcome. The weaker effects of lixisenatide on hemoglobin A1c, weight loss, blood pressure, and heart rate as compared with liraglutide or semaglutide suggest that the results of ELIXA can be attributed to differences between short- and long-acting GLP-1 agonists (for a detailed review of GLP-1 biology and receptor pharmacology, see Meier). 27

Practical Considerations Although the starting dose in the LEADER trial was 1.8 mg once daily, clinicians should consider starting liraglutide at 0.6 mg once daily and then increasing, as tolerated by the patient, by 0.6 mg weekly to 1.8 mg daily to improve gastrointestinal tolerability. Semaglutide is not yet commercially available in the US.

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Hyperkalemia is frequently encountered in the management of patients with cardiovascular disease, in particular those with cardiovascular and renal disease, and is associated with an increased risk of adverse outcomes.35 Moreover, hyperkalemia is a dose-limiting side effect of many life-saving cardiovascular therapies, such as angiotensin-converting enzyme inhibitors and aldosterone antagonists. Hyperkalemia management strategies include dietary interventions, adjustment of hyperkalemia-causing medications, treatment with sodium polystyrene sulfate (SPS) and, in urgent situations, insulin– glucose therapy or hemodialysis. SPS is an orally administered sodium– potassium exchange resin that has been associated with significant gastrointestinal discomfort and risk of bowel obstruction, as the resin swells upon contact with water. Due to these adverse effects, SPS is not tolerable as a chronic-use medication. Patiromer is a cation-exchange polymer that is reconstituted in water to create an orally available potassium binder.35 Patiromer exchanges calcium ions for potassium ions in the distal colon without the adverse effect profile of SPS. Sodium zirconium cyclosilicate is a sodium–potassium exchanger that acts throughout the gut.35 ZS-9 has yet to be approved for use in the US due to manufacturing and production issues. Comparative data for patiromer and ZS-9 are not available.

Outcomes Patiromer has been shown to control potassium levels within a safe range in patients with hyperkalemia who were receiving renin– angiotensin–aldosterone system inhibitors. Time to first episode of hyperkalemia was significantly longer in patiromer-treated patients compared with control. The potassium-lowering effects of patiromer appear to be related to the baseline serum potassium level, with potassium-lowering effects greatest among those with the highest baseline potassium level. In the OPAL-HK trial, mean serum potassium decreased by 1.23 ± 0.04 mmol/L among patients with baseline serum potassium levels of 5.5–6.5 mmol/L compared with a decrease of -0.65 mmol/L among patients with baseline serum potassium levels of 5.1–5.5 mmol/L.36 In patients with heart failure who were starting treatment with an aldosterone antagonist, patiromer blunted the increase in serum potassium levels, which were 0.45 mmol/L higher in the placebo arm than patiromer after 8 weeks of treatment.37 A greater proportion of patiromer-treated patients were titrated to maximal spironolactone dose than placebo (91 % versus 74 %; p=0.02).

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Risk Prevention Figure 1: Anticoagulant Usage at the Time of Event in Patients Experiencing a Thrombotic Event in RE-VERSE AD and ANNEXA-4 Antithrombotic

No Antithrombotic

Number of Subjects

In the Pipeline

Interleukin-1 Blockers RE-VERSE AD

ANNEXA-4

The number of patients who were taking an anticoagulant medication at the time of a thrombotic event in RE-VERSE AD and ANNEXA-4 is depicted. Within 30 days of treatment, there were 24 thrombotic events among 503 patients (4.8 %) in RE-VERSE AD and 12 thrombotic events among 67 patients (18 %) in ANNEXA-4.

Practical Considerations Whether novel potassium-lowering agents have a role in routine clinical practice is unclear. The available evidence suggests that potassiumlowering agents may facilitate up-titration of renin–angiotensin–aldosterone system inhibitors. However, these data are derived from small sample sizes. In addition, side effects of potassium-lowering agents, including hypomagnesemia, may preclude tolerability in many patients.

Monoclonal Antibody Antidote for Dabigatran Although direct oral anticoagulants (DOACs) provide an improved safety profile and greater ease of use than vitamin K antagonists, the risk of major bleeding is 1.6–3.6 % per year.38,39 To date, four reversal agents have been developed to improve the safety margin of DOACs. The use of indirect reversal agents, such as coagulation factor replacement, has been reviewed in detail elsewhere.40 Idarucizumab is a humanized, murine monoclonal antibody Fab fragment that binds free and thrombin-bound dabigatran, an oral direct thrombin inhibitor.41 Idarucizumab’s affinity for dabigatran is 350 times greater than the affinity of dabigatran for thrombin. In the single-arm RE-VERSE AD trial, patients with uncontrolled or life-threatening bleeding (Group A, n=301) or who required an urgent procedure within 8 h of presentation (Group B, n=202) received two bolus infusions of idarucizumab 2.5 g within a 15 min period.42 Bleeding resolved within a median 2.5 h among Group A patients. Periprocedural hemostasis was graded as normal in 93.4 % of Group B patients. Among 24 patients (4.8 %) who experienced a thrombotic event within 30 days of idarucizumab, 16 were not taking anticoagulation or antiplatelet therapy at the time of the event (Figure 1). Idarucizumab was approved in late 2015 for marketing in the US.43

Practical Considerations A significant amount of work remains to refine the usage of DOAC reversal agents as well as ensure the successful development of pipeline compounds. Reversal agents are best reserved for life-threatening

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bleeding events or patients who require urgent surgery that cannot be delayed until the DOAC is cleared from circulation. The decision to utilize a reversal agent should be based on the location and severity of bleeding, as well as factors that influence the drug clearance, such as renal function, time of last dose, or drug–drug interactions. Patients who have non-life-threatening bleeding, have taken the last dose 3–4 halflives prior to presentation, and have preserved renal function are unlikely to benefit from a reversal agent. In contrast, patients with intracranial hemorrhage who took a dose within a few hours of presentation or who have acute kidney injury are good candidates for a reversal agent. Idarucizumab is indicated for patients who require urgent surgery, but andexanet alfa (see In the Pipeline) was not studied in this population and is unlikely to be approved for this indication.

Interleukin-1 (IL-1) is a cytokine regulator of the inflammatory response to myocardial insult and injury.44 IL-1 has been implicated in the pathogenesis of a wide range of cardiovascular diseases, including atherosclerotic cardiovascular disease, heart failure, and pericarditis.45,46 In the CANTOS trial, 10,061 patients with recent myocardial infarction and evidence of systemic inflammation, defined as a C-reactive protein level of at least 2 mg/L, were randomized to either canakinumab, a human monoclonal antibody directed against the beta isoform of IL-1, or placebo. Patients received either 50, 150, or 300 mg once every 3 months. The primary endpoint of non-fatal myocardial infarction, non-fatal stroke, or cardiovascular death was reduced by 15 % in the canakinumab 150 mg-treated patients compared with placebo (HR 0.85; 95 % CI [0.74–0.98]; p=0.021). In the 300 mg canakinumab group, the primary endpoint was similarly reduced (HR 0.86; 95 % CI 0.75–0.99; p=0.031), but this difference was not considered statistically significant after multipletesting adjustments. There was no significant difference in the primary endpoint between the 50 mg canakinumab group and placebo. Other notable results from this trial include a reduction in cancer-related mortality and an increased incidence of fatal infections. IL-1 blockade does not affect T-cell function but may mask the signs of infection, such as fever, and lead to delayed diagnosis and treatment.46 Indeed, IL-1 blockade has been studied in severe sepsis with no evidence of an increased risk of mortality.47–49 The most important implication of the CANTOS trial is the opening of a new avenue of investigation for the treatment of atherosclerotic cardiovascular disease. Indeed, CANTOS is the culmination of decades of work related to the inflammatory hypothesis of atherosclerotic cardiovascular disease and may mark the beginning of a new era in cardiovascular disease research.

Cholesteryl Ester Transfer Protein Inhibitors Cholesteryl ester transfer protein (CETP) inhibitors increase highdensity lipoprotein cholesterol and decrease LDL-C. The REVEAL trial compared anacetrapib against placebo in patients with atherosclerotic cardiovascular disease on maximally tolerated statin therapy.50 At a median follow-up duration of 4.1 years, anacetrapib-treated patients had a modest 9 % lower risk of the composite of coronary death, myocardial

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Novel Treatments for Cardiovascular Disease infarction, or coronary revascularization compared with placebo (HR 0.91; 95 % CI [0.85–0.97]; p=0.004). Considering the disappointing results of prior CETP inhibitor clinical trials,51–53 the modest benefit observed in the REVEAL trial is unlikely to lead to a change in clinical practice. In fact, it is uncertain whether the sponsor will seek marketing approval for this new therapy.54

Antithrombotic and Hemostatic Agents Both anticoagulant and antiplatelet agents have important roles in the acute and chronic management of many cardiovascular diseases, including acute coronary syndromes and stroke prevention in atrial fibrillation. As such, the use of “triple therapy” with two platelet inhibitors and an anticoagulant has increased in recent years. Due to a lack of evidence, the optimal antithrombotic strategy in a patient with indications for both antiplatelet and anticoagulant therapy is controversial. Several clinical trials have been designed to address this need, but additional efficacy data are required.55,56 Since many of these regimens compare dual versus triple antithrombotic therapy, reduced dose versus full dose or short versus long duration of therapy, an improved safety profile of these novel regimens is to be expected. However, these trials are not designed to thoroughly test the more uncertain question of efficacy. Also, the addition of anticoagulation to aspirin therapy in patients with stable coronary artery disease or peripheral arterial disease is an area of active research.57–59 Andexanet alfa is a recombinant protein decoy that binds direct and indirect Factor Xa inhibitors, including rivaroxaban, apixaban, edoxaban, and enoxaparin.60 Andexanet alfa lacks the catalytic domain of endogenous

a J, Ward EM, Siegel RL, et al. Temporal trends in mortality in M the United States, 1969–2013. JAMA 2015;314:1731. DOI: 10.1001/ jama.2015.12319; PMID: 26505597 2. Xu J, Murphy S, Kochanek K, Arias E. Mortality in the United States, 2015. NHS Data Brief No. 267. Available at: www.cdc. gov/nchs/products/databriefs/db267.htm (accessed September 26, 2017). 3. Sidney S, Quesenberry CP, Jaffe MG, et al. Recent trends in cardiovascular mortality in the United States and public health goals. JAMA Cardiol 2016;1:594. DOI: 10.1001/ jamacardio.2016.1326; PMID: 27438477 4. Dixon DL, Trankle C, Buckley L, et al. A review of PCSK9 inhibition and its effects beyond LDL-receptors. J Clin Lipidol 2016;10:1073–80. DOI: 10.1016/j.jacl.2016.07.004; PMID: 27678423 5. Ridker PM, Tardif J-C, Amarenco P, et al. Lipid-reduction variability and antidrug-antibody formation with bococizumab. N Engl J Med 2017;376:1517–26. DOI: 10.1056/NEJMoa1614062; PMID: 28304227 6. Fitzgerald K, White S, Borodovsky A, et al. A highly durable RNAi therapeutic inhibitor of PCSK9. N Engl J Med 2017;376:41–51. DOI: 10.1056/NEJMoa1609243; PMID: 27959715 7. Landlinger C, Pouwer MG, Juno C, et al. The AT04A vaccine against proprotein convertase subtilisin/kexin type 9 reduces total cholesterol, vascular inflammation, and atherosclerosis in APOE*3Leiden.CETP mice. Eur Heart J 2017;38:2499–507. DOI: 10.1093/eurheartj/ehx260; PMID: 28637178 8. Pec´in I, Hartgers ML, Hovingh GK, et al. Prevention of cardiovascular disease in patients with familial hypercholesterolaemia: the role of PCSK9 inhibitors. Eur J Prev Cardiol 2017;24:1383–401. DOI: 10.1177/2047487317717346; PMID: 28644091 9. Kastelein JJP, Ginsberg HN, Langslet G, et al. ODYSSEY FH I and FH II: 78 week results with alirocumab treatment in 735 patients with heterozygous familial hypercholesterolaemia. Eur Heart J 2015;36:2996–3003. DOI: 10.1093/eurheartj/ehv370; PMID: 26330422 10. Stein E, Honarpour N, Wasserman S, et al. Effect of the proprotein convertase subtilisin/kexin 9 monoclonal antibody, AMG 145, in homozygous familial hypercholesterolemia. Circulation 2013;128:2113–20. DOI: 10.1161/ CIRCULATIONAHA.113.004678; PMID: 24014831 11. Raal FJ, Honarpour N, Blom DJ, et al. Inhibition of PCSK9 with

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FXa as well as the prothrombinase complex binding domain. In the ANNEXA-4 trial, andexanet alfa, administered as a bolus followed by 2 h continuous infusion, rapidly decreased the unbound drug concentrations of rivaroxaban and apixaban.61 Thrombotic events occurred in 12 patients (18 %) within 30 days of andexanet alfa administration. Of these 12 patients, 11 were not receiving anticoagulation at the time of the event (Figure 1). Andexanet alfa has not received marketing approval in the US at the time of writing. A second recombinant Factor Xa decoy protein, which lacks the catalytic domain but retains the prothrombinase complex binding domain and therefore has prohemostatic properties, is in preclinical development.62 Ciraparantag (PER977) is a synthetic molecule that establishes noncovalent hydrogen bonds and charge–charge interactions with direct and indirect Factor Xa inhibitors, including rivaroxaban, apixaban, low molecular weight heparin, unfractionated heparin, fondaparinux, and the Factor IIa inhibitor dabigatran. Available data indicate that ciraparantag is inactive and lacks affinity for coagulation factors. Ciraparantag remains in development, but has been granted Fast Track review status by the United States Food and Drug Administration.63

Conclusions Cardiovascular disease remains the leading cause of death worldwide. The biological mechanisms leading to cardiovascular disease are complex and span several key biological systems. Cardiovascular drug development has led to several new treatment options and avenues for investigation. At present, the introduction of several new therapies promises immediate benefits for today’s patients and advances in basic and clinical science offer hope to tomorrow’s patients. n

evolocumab in homozygous familial hypercholesterolaemia (TESLA Part B): a randomised, double-blind, placebocontrolled trial. Lancet 2015;385:341–50. DOI: 10.1016/S01406736(14)61374-X Raal F, Scott R, Somaratne R, et al. Low-density lipoprotein cholesterol-lowering effects of AMG 145, a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 serine protease in patients with heterozygous familial hypercholesterolemia. Circulation 2012;126:2408–17. DOI: 10.1161/CIRCULATIONAHA.112.144055; PMID: 23129602 Raal FJ, Stein EA, Dufour R, et al. PCSK9 inhibition with evolocumab (AMG 145) in heterozygous familial hypercholesterolaemia (RUTHERFORD-2): a randomised, doubleblind, placebo-controlled trial. Lancet 2015;385:331–40. DOI: 10.1016/S0140-6736(14)61399-4 Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med 2017;376:1713–22. DOI: 10.1056/NEJMoa1615664; PMID: 28304224 Giugliano RP, Mach F, Zavitz K, et al. Cognitive function in a randomized trial of evolocumab. N Engl J Med 2017;377:633–43. DOI: 10.1056/NEJMoa1701131; PMID: 28813214 Benn M, Nordestgaard BG, Frikke-Schmidt R, Tybjærg-Hansen A. Low LDL cholesterol, PCSK9 and HMGCR genetic variation, and risk of Alzheimer’s disease and Parkinson’s disease: Mendelian randomisation study. BMJ 2017;357:j1648. DOI: 10.1136/bmj. j1648; PMID: 28438747 Ference BA, Robinson JG, Brook RD, et al. Variation in PCSK9 and HMGCR and risk of cardiovascular disease and diabetes. N Engl J Med 2016;375:2144–53. DOI: 10.1056/NEJMoa1604304; PMID: 27959767 Kazi DS, Moran AE, Coxson PG, et al. Cost-effectiveness of PCSK9 inhibitor therapy in patients with heterozygous familial hypercholesterolemia or atherosclerotic cardiovascular disease. JAMA 2016;316:743. DOI: 10.1001/jama.2016.11004; PMID: 27533159 Arrieta A, Page TF, Veledar E, Nasir K. Economic evaluation of PCSK9 inhibitors in reducing cardiovascular risk from health system and private payer perspectives. PLoS One 2017;12:e0169761. DOI: 10.1371/journal.pone.0169761 Cannon CP, Khan I, Klimchak AC, et al. Simulation of lipidlowering therapy intensification in a population with

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Risk Prevention 27633186 33. P feffer MA, Claggett B, Diaz R, et al. Lixisenatide in patients with type 2 diabetes and acute coronary syndrome. N Engl J Med 2015;373:2247–57. DOI: 10.1056/NEJMoa1509225; PMID: 26630143 34. Margulies KB, Hernandez AF, Redfield MM, et al. Effects of liraglutide on clinical stability among patients with advanced heart failure and reduced ejection fraction. JAMA 2016;316:500. DOI: 10.1001/jama.2016.10260; PMID: 27483064 35. DeFilippis EM, Desai AS. Treatment of hyperkalemia in heart failure. Curr Heart Fail Rep 2017;14:266–74. DOI: 10.1007/s11897017-0341-0; PMID: 28656517 36. Weir MR, Bakris GL, Bushinsky DA, et al. Patiromer in patients with kidney disease and hyperkalemia receiving RAAS inhibitors. N Engl J Med 2015;372:211–21. DOI: 10.1056/NEJMoa1410853; PMID: 25415805 37. Pitt B, Anker SD, Bushinsky DA, et al. Evaluation of the efficacy and safety of RLY5016, a polymeric potassium binder, in a double-blind, placebo-controlled study in patients with chronic heart failure (the PEARL-HF) trial. Eur Heart J 2011;32:820–8. DOI: 10.1093/eurheartj/ehq502; PMID: 21208974 38. Eikelboom J, Merli G. Bleeding with direct oral anticoagulants vs warfarin: clinical experience. Am J Med 2016;129:S33–40. DOI: 10.1016/j.amjmed.2016.06.003; PMID: 27586367 39. Villines TC, Peacock WF. Safety of direct oral anticoagulants: insights from postmarketing studies. Am J Med 2016;129:S41–6. DOI: 10.1016/j.amjmed.2016.06.004; PMID: 27569672 40. Ruff CT, Giugliano RP, Antman EM. Management of bleeding with non-vitamin K antagonist oral anticoagulants in the era of specific reversal agents. Circulation 2016;134:248–61. DOI: 10.1161/CIRCULATIONAHA.116.021831; PMID: 27436881 41. Schiele F, Van Ryn J, Canada K, et al. A specific antidote for dabigatran: functional and structural characterization. Blood 2013;121:3554–62. DOI: 10.1182/blood-2012-11-468207; PMID: 23476049 42. Pollack CV, Reilly PA, van Ryn J, et al. Idarucizumab for dabigatran reversal — full cohort analysis. N Engl J Med 2017;377:431–41. DOI: 10.1056/NEJMoa1707278; PMID: 28693366 43. FDA approves Praxbind, the first reversal agent for the anticoagulant Pradaxa. FDA News Release. 2015. Available at:

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23126252 53. L incoff AM, Nicholls SJ, Riesmeyer JS, et al. Evacetrapib and cardiovascular outcomes in high-risk vascular disease. N Engl J Med 2017;376:1933–42. DOI: 10.1056/NEJMoa1609581; PMID: 28514624 54. RTT News. Merck reports results of REVEAL outcomes study of Anacetrapib – quick facts. Business Insider. 2017. 55. Gibson CM, Mehran R, Bode C, et al. Prevention of bleeding in patients with atrial fibrillation undergoing PCI. N Engl J Med 2016;375:2423–34. DOI: 10.1056/NEJMoa1611594; PMID: 27959713 56. Cannon CP, Bhatt DL, Oldgren J, et al. Dual antithrombotic therapy with dabigatran after PCI in atrial fibrillation. N Engl J Med 2017; DOI: 10.1056/NEJMoa1708454; PMID: 28844193; epub ahead of print 57. Mega JL, Braunwald E, Wiviott SD, et al. Rivaroxaban in patients with a recent acute coronary syndrome. N Engl J Med 2012;366: 9–19. DOI: 10.1056/NEJMoa1112277; PMID: 22077192 58. Mega JL, Braunwald E, Mohanavelu S, et al. Rivaroxaban versus placebo in patients with acute coronary syndromes (ATLAS ACS-TIMI 46): a randomised, double-blind, phase II trial. Lancet 2009;374:29–38. DOI: 10.1016/S0140-6736(09) 60738-8 59. Eikelboom JW, Connolly SJ, Bosch J, et al. Rivaroxaban with or without aspirin in stable cardiovascular disease. N Engl J Med 2017; DOI: 10.1056/NEJMoa1709118; PMID: 28844192; epub ahead of print 60. Lu G, DeGuzman FR, Hollenbach SJ, et al. A specific antidote for reversal of anticoagulation by direct and indirect inhibitors of coagulation factor Xa. Nat Med 2013;19:446–51. DOI: 10.1038/ nm.3102; PMID: 23455714 61. Connolly SJ, Milling TJ, Eikelboom JW, et al. Andexanet alfa for acute major bleeding associated with factor Xa inhibitors. N Engl J Med 2016;375:1131–41. DOI: 10.1056/NEJMoa1607887; PMID: 27573206 62. Thalji NK, Ivanciu L, Davidson R, et al. A rapid pro-hemostatic approach to overcome direct oral anticoagulants. Nat Med 2016;22:924–32. DOI: 10.1038/nm.4149; PMID: 27455511 63. Milling TJ, Kaatz S. Preclinical and clinical data for factor Xa and ‘universal’ reversal agents. Am J Med 2016;129:S80–8. DOI: 10.1016/j.amjmed.2016.06.009; PMID: 27575436

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Risk Prevention

Proprotein Convertase Subtilisin/kexin Type 9 Inhibitors in Clinical Practice: A Focused Update Evan A Stein, MD, PhD Metabolic & Atherosclerosis Research Center, Cincinnati, OH

Abstract This article provides an updated review of the LDL-cholesterol efficacy, safety, and cardiovascular benefits of proprotein convertase subtilisin/ kexin type 9 (PCSK9) inhibitors. It focuses on evidence from numerous clinical trials and provides clinicians with a basis for understanding, assessing, and selecting these agents for clinical practice. It also provides some perspective on other potential agents in development that target PCSK9.

Keywords Proprotein convertase subtilisin/kexin type 9, low-density lipoprotein cholesterol, cardiovascular events, safety Disclosure: EAS has received consulting fees related to proprotein convertase subtilisin/kexin type 9 inhibitors and other lipid lowering drugs from Amgen, Regeneron, Sanofi, Genentech, Roche, The Medicines Co, ISIS, Catabasis, AstraZeneca, CymaBay, CVS/Caremark, Gemphire, and BMS. Acknowledgement: The author was solely responsible for the writing and submission of the manuscript. Received: 5 Sep 2017 Accepted: 9 Oct 2017 Citation: US Cardiology Review 2017;11(2):105–9. DOI: 10.15420/usc.2017:23:1 Correspondence: Evan A Stein, MD, PhD, Director Emeritus, Metabolic & Atherosclerosis Research Center, 5355 Medpace Way, Cincinnati, OH 45227, USA. E: esteinmrl@aol.com

Proprotein convertase subtilisin/kexin type 9 (PCSK9), discovered in 2003, is a circulating protein produced predominantly in the liver that plays a significant role in the recycling of LDL receptors (LDLRs).1,2 The LDLR, which normally recycles about 100 times in its lifetime, is the primary pathway for LDL-cholesterol (LDL-C) clearance from circulation. Plasma PCSK9 binds to LDLRs along with LDL-C, targeting the receptors for degradation, reducing their recycling and availability to clear LDL-C. Monoclonal antibodies (mAbs) bind to PCSK9 inhibiting the interaction of PCSK9 with LDLRs, preventing LDLR degradation and increasing the availability of LDLRs to enhance LDL-C clearance, resulting in reduction of LDL-C.1,2 In just 3 years following the publication of the first human studies with a PCSK9 mAb showing dramatic reductions in LDL-C, two agents (alirocumab and evolocumab) were approved by regulators and marketed worldwide for use as an adjunct to diet and maximally tolerated statin therapy in adult patients treated for clinical atherosclerotic cardiovascular disease (CVD) or heterozygous familial hypercholesterolemia (HeFH) who require additional LDL-C reduction.3–7 Evolocumab was also approved to treat patients ≥13 years with the rarer homozygous form of familial hypercholesterolemia (FH).5 In 18 months since approval results of a large and definitive outcome trial with evolocumab (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk; FOURIER trial) have demonstrated that the additional LDL-C reductions further reduce CVD events when added to statins.8 The initial concerns raised suggesting reductions in LDL-C below 50 mg/dl, or to low or very low LDL-C levels, would have little if any additional CVD benefit and may even be harmful by increasing the risk of hemorrhagic stroke, cognitive impairment, cataracts, or diabetes, have been proven to be misplaced on both efficacy and safety counts.9,10 These questions regarding benefit

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versus risk of greater LDL-C reductions and lower and lower LDL-C, which have plagued the use of all LDL-C reducing agents for decades, appear now to have finally been resolved, at least for drugs that enhance LDL clearance.8,11–13 Based on the extensive clinical trial evidence, PCSK9 inhibition with fully human mAbs clearly now has an important and routine role in CVD risk reduction. The major issues remaining for patients, physicians, and payers to enable widespread use and universal implementation of these very effective agents appears to be dosing frequency and cost.14,15 Hopefully, with agents currently in development requiring less frequent administration and more competitive pricing, if, and when, they come to the market in the next few years, these issues will be resolved.

Effect of PCSK9 Monoclonal Antibodies on LDLcholesterol Reduction and Other Lipoproteins It is important to understand the fundamental difference between PCSK9 inhibitors and statins. All statins are dose limited by toxicity and, thus their LDL-C efficacy is defined not by potency but by the highest safest dose, which varies considerably between agents. The most potent statin ever marketed, cerivastatin, was reasonably effective but toxic at doses <1 mg/day, while rosuvastatin, which is safe at 40 mg/day, is the most efficacious statin marketed, reducing LDL-C ~55 %. This contrasts with PCSK9 mAbs where it was apparent in Phase I that once they bound all free PCSK9 a maximal ~60 % reduction in LDL-C was achieved.3,16 Higher doses produced no further reduction, or toxicity, but did result in longer duration of stable maximal LDL-C decrease (see Table 1). For alirocumab and evolocumab the relationship between dose and stable maximal LDL-C reduction follows a rough rule-of-thumb: 70–75 mg will reduce

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Risk Prevention Table 1: Ten Key Points Regarding PCSK9, LDL-cholesterol, and Cardiovascular Disease 1. Plasma PCSK9 has a unique and singular function; binding to hepatic LDL receptors, reducing their recycling and clearance of LDL-C 2. mAbs bind PCSK9 preventing them interacting with LDL receptors, enhancing LDL receptor recycling, and accelerating LDL-C removal from the circulation 3. Once all free PCSK9 is bound to mAb a maximal ~60 % reduction is achieved and no further reduction occurs with higher doses 4. Increased doses do result in longer duration of PCSK9 suppression and LDL-C reduction; rough ‘rule-of-thumb’ is 70–75 mg of mAb will reduce LDL-C maximally (~60 %) for 1 week, 2 × the 1-week dose (140–150 mg) for 2 weeks, and 3 × the 2-week dose (420–450 mg) for 4 weeks 5. The maximum dose of a mAb in 1 ml is 150 mg, thus doses >150 mg require multiple injections or an infusion device 6. Reduction in CVD events per mg/dl reduction in LDL-C is consistent with that found with statins (~24 % decrease for every 40 mg/dl) 7. The CVD benefit extends to very low LDL-C even <10 mg/dl with no plateau 8. No off-target adverse effects from inhibiting PCSK9 have been found; no safety monitoring is required for the approved mAbs 9. Large CVD outcome trials have found no adverse effects from very low LDL-C of <25 mg/dl or even <10 mg/dl 10. Based on current efficacy and safety data from outcome trials and cost of drug, the most appropriate dosing (dose and dosing interval) should be selected to achieve the lowest, and maximal, stable reduction in LDL-C CVD = cardiovascular disease; LDL-C = low density lipoprotein cholesterol; mAbs = monoclonal antibodies; PCSK9 = proprotein convertase subtilisin/kexin type 9

LDL-C 60 % for 1 week; twice the dose (140–150 mg) for 2 weeks; and three times the 2-week dose (420–450 mg) for 4 weeks.17,18 These doses administered less frequently will appear to produce less LDL-C reduction when LDL-C is measured just prior to the next dose (‘trough’ level) and results in what is referred to as a ‘saw-tooth’ effect where the LDL-C reductions vary over time.3,18–21 Another important difference between PCSK9 mAbs and other LDL-C lowering drugs is they have to be given by injection. A comfortable volume for an auto-injector is 1 ml, which holds a maximal of 150 mg of mAb, thus doses required for maximal stable LDL-C reductions for >2 weeks require multiple auto-injectors or a slow infusion device.22 PCSK9 inhibitors given in appropriate doses and dosing intervals uniformly reduce LDL-C ~60 % across patients on diet alone, low and maximal dose statin, or statin plus ezetimibe.23 They provide the same LDL-C response in patients with HeFH and non-FH and the response in HeFH is independent of underlying the LDL receptor mutation.23–25 In the rare patient with homozygous FH the LDL-C reduction with the approved dose of evolocumab, 420 mg monthly, is ~30 %, half that of HeFH and non-FH patients, and the response is heavily dependent on the underlying genetic mutations.26 A number of studies have shown that statin-adverse patients tolerate PCSK9 mAbs well.27,28 In addition to LDL-C reductions PCSK9 mAbs produce expected parallel reductions in non-HDL-C and apolipoprotein B, and small increases in HDL-C. Unlike statins and ezetimibe PCSK9 inhibition results in a robust 25–30 % decrease in lipoprotein(a) but does not reduce high-sensitivity C-reactive protein (hsCRP).29,30

PCSK9 Monoclonal Antibodies and Cardiovascular Disease Risk Reduction Despite robust reductions in LDL-C with statins, which were first approved for use in 1988, it took another 7 years until the results of the Scandinavian Simvastatin Survival Study (4S) trial to provide evidence of CVD benefit.31,32 This contrasts with PCSK9 mAbs where data from Phase III with evolocumab and alirocumab strongly suggested CVD benefit.24,33 The encouraging results were fully validated by FOURIER, the largest and shortest duration CVD outcome trial for a LDL-C lowering agent, which achieved a 15 % reduction (hazard ratio [HR] 0.85; 95 % CI [0.79–0.92]; p<0.001) in the primary endpoint, a composite of cardiovascular death, MI, stroke, hospitalization for unstable angina, or coronary revascularization.8 The secondary ‘hard endpoints’ of CVD

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death, definitive MI, and stroke were reduced 20 % (HR 0.80; 95 % CI [0.73–0.88]; p<0.001). Some, especially those in the media and financial world, expressed “disappointment” in the magnitude of reduction, which was likely based on a lack of understanding of the trial’s stopping rules along with the raised expectations from the two small exploratory or post hoc studies.14,15,34 FOURIER was designed to terminate when at least 1,630 patients had experienced the key secondary endpoints, which was expected to provide 90 % power to detect a relative reduction of at least 15 %. Based on an assumption of a 2 % per year event rate in the placebo arm, it was anticipated that the 27,500 patients would be treated for a median of about 43 months.35 However, the key secondary endpoint rate was nearly double projections with the trial achieving 1,829 endpoints after a median of 26 months requiring termination, and the reduction in the primary endpoint exceeded the preset HR of 0.8 5 % (p<0.001).8 Concern has been expressed as there was no difference in CVD death, which may be related to the short duration of the trial; however, the two serious, debilitating and costly events of MI and stroke were reduced by 27 % and 21 % (p<0.001 and p<0.01), respectively.8 Furthermore, as emphasized by the FOURIER investigators, the reduction in CVD events increased progressively with duration of treatment and at 3 years were similar to that seen with statin therapy.8

Cardiovascular Disease Benefit and Very Low LDLcholesterol Preliminary evidence of continuing CVD benefit down to very low LDL-C of <25 mg/dl came from a post hoc analysis by Ray et al. of CVD events in 10 Phase III trials with alirocumab.36 They showed LDL-C reduction from a mean of 50 mg/dl to a mean of 25 mg/dl (i.e. half the patients had LDL-C <25 mg/dl) resulted in as much CVD reduction as reducing LDL-C from a mean of 75 mg/dl to a mean of 50 mg/dl.36 Ray et al. concluded that the relationship seen in statin trials between reductions in LDL-C and CVD of every 40 mg/dl decrease in LDL-C resulted in a 24 % reduction in CVD events, was consistent down to the lowest LDL-C achievable in these trials.36 Further evidence was provided from an exploratory post hoc analysis in patients with baseline LDL-C <70 mg/dl in the Global Assessment of Plaque Regression With a PCSK9 Antibody as Measured by Intravascular Ultrasound (GLAGOV) trial.37 Compared with the placebo group (mean LDL-C 70.6 mg/dl), those treated with evolocumab (mean LDL-C of 24 mg/dl) had significantly greater reduction in percent atherosclerosis volume (−1.97 % versus −0.35 %; p<0.001).37

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PCSK9 Inhibitors in Clinical Practice Using a Locally Weighted Polynomial Regression analysis, GLAGOV showed a linear relationship between on-trial achieved LDL-C level and atheroma regression down to a LDL-C of 20 mg/dl.37 Definitive evidence was provided in the recent FOURIER trial where the median LDL-C in the evolocumab group was only 30 mg/dl, 42 % of subjects had LDL-C <25 mg/dl and 25 % <20 mg/dl.8 In a subsequent prespecified secondary analysis from FOURIER, Giugliano et al. reported in greater detail the relationship between LDL-C and the primary and secondary CVD outcomes as well as 10 prespecified safety events.13 LDL-C, measured by the ‘gold standard’ ultracentrifugation technique due to inaccuracy of calculated LDL-C at low LDL-C levels, was <20 mg/dl in 2,669 patients, 20 mg/dl to <50 mg/dl in 8,003, 50 mg/dl to <70 mg/dl in 3,444, 70 mg/dl to <100 mg/dl in 7,471, and ≥100 mg/dl in the remaining 4,395 patients. The relationship between LDL-C and the primary and secondary CVD endpoints extended to a LDL-C of <10 mg/dl (the bottom 1st percentile), p=0.0012 for the primary endpoint, p=0.0001 for the secondary endpoint.13

PCSK9 Monoclonal Antibodies and Safety Despite the need for regular subcutaneous administration both fully human mAbs, alirocumab, and evolocumab have good tolerability and adherence. Based on the data from the clinical development programs in >10,000 patients treated with these two mAbs for 3+ years, no specific or serious clinical or laboratory adverse events were found. As a result regulatory authorities required no specific safety monitoring in the label for either agent, which is unusual for an entirely new class of lipid lowering agents.4–7 This has been supported by safety data from larger and longer trials such as FOURIER and Studies of PCSK9 Inhibition and the Reduction of Vascular Events (SPIRE).8,12 Mild injection site reactions and antidrug antibodies have been reported with the approved mAbs but no physical, psychological, endocrine, or reproductive abnormalities or ‘off-target’ effects have been observed. However, development of neutralizing antibodies that reduced or eliminated LDL-C lowering, along with increased rate and severity of injection site reactions with bococizumab, a not-fully human PCSK9 mAb, resulted in termination of its development.38 Some caution regarding longer-term use is necessary because, as with statins, it may take decades of therapy in many tens of thousands of patients to detect more subtle, or agent-specific, sideeffects not readily apparent from relatively short-term trials. Inhibition of plasma PCSK9 itself has not be associated with adverse effects but Mendelian randomization studies suggest PCSK9 loss-of-function variants are associated with roughly the same effect as loss-of-function variants in 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR) in terms of the risk of diabetes per unit decrease in the LDL-C.39,40 An analysis by Ference et al. found the increased risk of diabetes for HMGCR and PCSK9 loss-of-function variants were independent and additive, but was confined to people with impaired fasting glucose levels.39 As documented from extensive clinical trial data with statins, the risk of diabetes from Mendelian randomization studies was less than the protective effect against cardiovascular events, which account for the majority of mortality and morbidity in diabetics.

Do Very Low LDL-cholesterol Pose Safety Concerns? For more than 40 years, going back to clofibrate and bile acid sequestrants, reducing LDL-C and lower LDL-C levels have been postulated to be “harmful” with concerns ranging from cancer to suicide.41 Many of the associations have been based on faulty interpretation of epidemiological

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data or post hoc analysis of adverse events in clinical trials that were drug or mechanism specific. Actual relationship to LDL-C levels has never been validated and repeatedly dispelled by additional clinical trial evidence, and decades of routine use of more and more efficacious LDL-C lowering agents and lower and lower LDL-C levels.11,42 However, this has not prevented similar concerns to be raised with PCSK9 mAbs, which when added to statins are able to routinely reduce LDL-C to levels rarely achieved in the past.9,10,43 These latest concerns focused on hemorrhagic stroke, cognitive impairment, diabetes, and cataracts.11–13,43 As discussed, Mendelian genetic variant studies demonstrate a small increased risk of diabetes in a subgroup of people with already impaired glucose tolerance associated with both HMGCR and PCSK9 variants.39 However, the risk was not related to low or very low LDL-C but to the reduction of LDL-C from any level, which has been confirmed from clinical trial data with statins and is now included in their labeling. The concern of cataracts emanated from a post hoc analysis of the alirocumab pooled Phase II and III trials by Robinson et al., which reported an increase in self- or physicianreported cataracts with alirocumab in groups achieving LDL-C <25 mg/dl or <15 mg/dl.43 However, the analysis contained a number of substantial flaws that cannot be eliminated by statistical manipulation: at baseline these groups had 30–50 % more diabetics, worse diabetes control as judged by hBA1c levels, and were older than groups with LDL-C >25 mg/dl or placebo.43 The analysis also used calculated LDL-C, by Friedewald formula, to select the LDL-C cut points, which underestimates true LDL-C by approximately 30 % and misclassifies about one-third of subjects with levels <25 mg/dl.44 The cataract concerns were rapidly put to rest by the recent analysis by Giugliano et al. of very low LDL-C levels in FOURIER and further supported by those from the bococizumab SPIRE trial.12,13 In SPIRE, a prespecified safety analysis assessed new cataract development in 6,285 bococizumab-treated patients and LDL-C <25 mg/dl compared with 7,259 treated with bococizumab >25 mg/dl and 13,967 placebo-treated patients. Not only was the rate of 0.9 per 1,000 patient years of treatment in the very low LDL-C group not increased but was lower than the rates of 1.3 and 1.1 per 1,000 patients in the LDL-C >25 mg/dl and placebo groups, respectively.12 A lack of any relationship between hemorrhagic stroke and low LDL-C levels was initially reported by Wiviott et al. from the Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE-IT) trial where they found no hemorrhagic stroke in patients with LDL-C <40 mg/dl.42 Further evidence of no increased risk came from the nearly 1,000 patients in the Improved Reduction of Outcomes: Vytorin Efficacy International (IMPROVE-IT) trial treated with statin or statin plus ezetimibe for a median of 6 years who achieved LDL-C <30 mg/dl and had a lower rate of hemorrhagic stroke compared with the groups >30 mg/dl.11 The safety analysis from FOURIER and SPIRE trials also found no relationship between hemorrhagic stroke, cognitive function, or cataracts, and very low LDL-C levels.12,13 Cognitive impairment was assessed in a prospective substudy (Evaluating PCSK9 Binding Antibody Influence On Cognitive Health in High Cardiovascular Risk Subjects; EBBINGHAUS) as part of FOURIER, which found no difference compared with placebo.45 The analysis by Giugliano et al., which focused on very low LDL-C <20 mg/dl examined 10 prespecified safety endpoints, including cataract-related adverse events, hemorrhagic stroke, neurocognitive adverse events, and new-onset diabetes mellitus.13 They reported no significant association between achieved LDL-C and any of the safety concerns, and when taken together with the benefit of decreased CVD events concluded that the

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Risk Prevention data from FOURIER supported further LDL-C lowering in patients with CVD to well below current recommendations.13 The decision by regulators to not require safety monitoring for low LDL-C for either alirocumab or evolocumab is now further supported by the FOURIER and SPIRE trials. On the basis of all the evidence generated in regard to benefit/risk related to very low LDL-C over the last decade, it is long past the time for consensus guidelines by bodies such as American College of Cardiology and American Heart Association to eliminate the arbitrary, data deficient, suggested lower ‘safe’ LDL-C of 40 mg/dl, which appear in guidelines and laboratory reports and only serve to generate anxiety for patients and clinicians when LDL-C is now reduced below this level.9 The data generated from PCSK9 mAbs strongly supports that, just as for hsCRP, no lower limit for LDL-C should be specified based on the available evidence that lower is better.

or 200, 300, or 500 mg inclisiran, or two doses at 90-day intervals of placebo or 100, 200, or 300 mg of inclisiran. The investigators recently reported serum PCSK9 reductions of 70–80 %, and decreases in LDL-C of approximately 50 % at 90 days post-dosing with 300 mg.47 Inclisiran is now entering Phase III trials and is anticipated that dosing frequency will be two or three times a year.

Alternative Approaches to Monoclonal Antibodies for Inhibiting or Reducing PCSK9

Conclusion

The majority of PCSK9 is produced in hepatocytes, and reducing synthesis with small interfering RNA (siRNA) targeted to the liver provides a selective mechanism to silence the translation of PCSK9 messenger RNA.46 Inclisiran, a chemically-synthesized siRNA molecule, produces sustained hepatocyte specific PCSK9-specific RNA silencing. In a Phase II multicenter, double-blind, placebo-controlled trial patients were randomized to either a single subcutaneous dose of placebo

Abifadel M, Varret M, Rabès J, et al. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat Genet 2003;34:154–6. DOI: 10.1038/ng1161; PMID: 12730697 2. Seidah NG, Prat A. The biology and therapeutic targeting of the proprotein convertases. Nat Rev Drug Discov 2012;11:367–83. DOI: 10.1038/nrd3699; PMID: 22679642 3. Stein EA, Mellis S, Yancopoulos GD, et al. Effect of a monoclonal antibody to PCSK9 on LDL cholesterol. N Engl J Med 2012;366:1108–18. DOI: 10.1056/NEJMoa1105803; PMID: 22435370 4. FDA approves Praluent to treat certain patients with high cholesterol. 2015. Available at: www.fda.gov/NewsEvents/ Newsroom/PressAnnouncements/ucm455883.htm (accessed July 28, 2017) 5. FDA approves Repatha to treat certain patients with high cholesterol. 2015. Available at: www.fda.gov/NewsEvents/ Newsroom/PressAnnouncements/ucm460082.htm (accessed July 28, 2017) 6. European Medicines Agency/Committee for Medicinal Products for Human Use (CMHP). Summary of Opinion: Repatha/ evolocumab. 2015. Available at: www.ema.europa.eu/docs/ en_GB/document_library/Summary_of_opinion_-_Initial_ authorisation/human/003766/WC500187093.pdf (accessed July 28, 2017) 7. European Medicines Agency. Press release: Praluent recommended for approval to lower cholesterol. 2015. Available at: www.ema.europa.eu/docs/en_GB/document_library/Press_ release/2015/07/WC500190458.pdf (accessed July 28, 2017) 8. Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med 2017;376:1713–22. DOI: 10.1056/NEJMoa1615664; PMID: 28304224 9. Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 2014;129(suppl 2): S1–45. DOI: 10.1161/01.cir.0000437738.63853.7a; PMID: 24222016 10. Fazio S, Linton MF. Debate: “How low should LDL cholesterol be lowered?” Viewpoint: “It doesn’t need to be very low.” Curr Control Trials Cardiovasc Med 2001;2:8–11. DOI: 10.1186/CVM-2-1008; PMID: 11806766 11. Giugliano RP, Wiviott SD, Blazing MA, et al. Long-term safety and efficacy of achieving very low levels of low-density lipoprotein cholesterol: a prespecified analysis of the IMPROVE-IT trial. JAMA Cardiol 2017;2:547–55. DOI: 10.1001/jamacardio.2017.0083; PMID: 28291866 12. Ridker PM, Revkin J, Amarenco P, et al. Cardiovascular efficacy and safety of bococizumab in high-risk patients. N Engl J Med

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A second approach, much earlier in clinical development, is a vaccine that generates antibodies against PCSK9 to provide prolonged PCSK9 suppression and LDL-C reduction. A peptide (AT04A, AFFITOPE®, AFFiRiS AG) designed to mimic the N-terminal epitope of the mature human and mouse homolog PCSK9 protein (amino acids 153–692), and formulated into a vaccine, has been reported to be effective in a rodent model. The agent is currently in Phase I trials.48

PCSK9 inhibitors are the most well understood, targeted, specific, and effective LDL-C lowering agents yet developed and when added to statins in patients with CVD result in very low LDL-C and significant additional reduction in CVD events with good tolerability and safety (see Table 1). The ability of these agents to safely reduce LDL-C in patients who need further LDL-C reduction despite maximal tolerated statin therapy should result in their rapid incorporation into the prevention regimen for CVD patients to help minimize, if not eliminate, the component of atherosclerosis related to LDL. n

2017;376:1527–39. DOI: 10.1056/NEJMoa1701488; PMID: 28304242 13. G iugliano RP, Pedersen TR, Park JG, et al. Clinical efficacy and safety of achieving very low LDL-cholesterol concentrations with the PCSK9 inhibitor evolocumab: a prespecified secondary analysis of the FOURIER trial. Lancet 2017; DOI: 10.1016/S01406736(17)32290-0; DOI: 10.1016/S0140-6736(17)32290-0; epub ahead of print. 14. Taylor P. Repatha outcomes data “less than stellar”. 2017. Available at: www.pmlive.com/pharma_news/repatha_ outcomes_data_less_than_stellar_1189399 (accessed August 16, 2017) 15. Gray N. Why uptake of new PCSK9 cholesterol meds has been so slow. 2016. Available at: www.biopharmadive.com/news/ why-uptake-of-new-pcsk9-cholesterol-meds-has-been-soslow/414459/ (accessed August 15, 2017) 16. Dias CS, Shaywitz AJ, Wasserman SM, et al. Effects of AMG 145 on low-density lipoprotein cholesterol levels: results from 2 randomized, double-blind, placebo-controlled, ascending-dose phase 1 studies in healthy volunteers and hypercholesterolemic subjects on statins. J Am Coll Cardiol 2012;60:1888–98. DOI: 10.1016/j.jacc.2012.08.986; PMID: 23083772 17. Stein EA, Giugliano RP, Koren MJ, et al. Efficacy and safety of evolocumab (AMG 145), a fully human monoclonal antibody to PCSK9, in hyperlipidaemic patients on various background lipid therapies: pooled analysis of 1359 patients in four phase 2 trials. Eur Heart J 2014;35:2249–59. DOI: 10.1093/eurheartj/ ehu085; PMID: 24598985 18. Giugliano RP, Desai NR, Kohli P, et al. Efficacy, safety, and tolerability of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 in combination with a statin in patients with hypercholesterolaemia (LAPLACE-TIMI 57): a randomised, placebo-controlled, dose-ranging, phase 2 study. Lancet 2012;380:2007–17. DOI: 10.1016/S0140-6736(12)61770-X; PMID: 23141813 19. Stein EA, Gipe D, Bergeron J, et al. Effect of a monoclonal antibody to PCSK9, REGN727/SAR236553, to reduce low-density lipoprotein cholesterol in patients with heterozygous familial hypercholesterolaemia on stable statin dose with or without ezetimibe therapy: a phase 2 randomised controlled trial. Lancet 2012;380:29–36. DOI: 10.1016/S0140-6736(12)60771-5; PMID: 22633824 20. Roth EM, Moriarty PM, Bergeron J, et al. A phase III randomized trial evaluating alirocumab 300 mg every 4 weeks as monotherapy or add-on to statin: ODYSSEY CHOICE I. Atherosclerosis 2016;254:254–62. DOI: 10.1016/ j.atherosclerosis.2016.08.043; PMID: 27639753 21. Stroes E, Guyton JR, Lepor N, et al. Efficacy and safety of alirocumab 150 mg every 4 weeks in patients with

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PCSK9 Inhibitors in Clinical Practice 33. S abatine MS, Giugliano RP, Wiviott SD, et al. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N Engl J Med 2015;372:1500–9. DOI: 10.1056/NEJMoa1500858; PMID: 25773607 34. Amgen is getting whacked after disappointing study results for its $14,000 heart drug (AMGN). 2017. Available AT: http://markets.businessinsider.com/news/stocks/r-amgencholesterol-drug-cuts-heart-attack-stroke-risk-more-than-20percentstudy-2017-3-1001845997 (accessed August 23, 2017) 35. Sabatine MS, Giugliano RP, Keech A, et al. Rationale and design of the further cardiovascular outcomes research with PCSK9 inhibition in subjects with elevated risk (FOURIER) trial. Am Heart J 2016;173:94–101. DOI: 10.1016/j.ahj.2015.11.015; PMID: 26920601 36. Ray KK, Ginsberg HN, Davidson MH, et al. Reductions in atherogenic lipids and major cardiovascular events: a pooled analysis of 10 ODYSSEY trials comparing alirocumab to control. Circulation 2016;134:1931–43. DOI: 10.1161/ CIRCULATIONAHA.116.024604; PMID: 27777279 37. Nicholls SJ, Puri R, Anderson T, et al., Effect of evolocumab on progression of coronary disease in statin-treated patients: the GLAGOV randomized clinical trial. JAMA 2016;316:2373–84. DOI: 10.1001/jama.2016.16951; PMID: 27846344 38. Ridker PM, Tardif JC, Amarenco P, et al. Lipid-reduction variability and antidrug antibody formation with bococizumab. N Engl J

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preparative ultracentrifugation below 70 mg/dl leading to overestimation of the LDL cholesterol reduction for new drugs in development. J Am Coll Cardiol 2014;63(Suppl):A1457. DOI: 10.1016/S0735-1097(14)61457-1 Giugliano RP, Mach F, Zavitz K, et al. Cognitive function in a randomized trial of evolocumab. N Engl J Med 2017;377:633–43. DOI: 10.1056/NEJMoa1701131; PMID: 28813214 Fitzgerald K, Frank-Kamenetsky M, Shulga-Morskaya S, et al. Effect of an RNA interference drug on the synthesis of proprotein convertase subtilisin/kexin type 9 (PCSK9) and the concentration of serum LDL cholesterol in healthy volunteers: a randomised, single-blind, placebo-controlled, phase 1 trial. Lancet 2014;383:60–8. DOI: 10.1016/S01406736(13)61914-5; PMID: 24094767 Ray KK, Landmesser U, Leiter LA, et al. Inclisiran in patients at high cardiovascular risk with elevated LDL cholesterol. N Engl J Med 2017;376:1430–40. DOI: 10.1056/NEJMoa1615758; PMID: 28306389 Landlinger C, Pouwer MG, Juno C, et al. The AT04A vaccine against proprotein convertase subtilisin/kexin type 9 reduces total cholesterol, vascular inflammation, and atherosclerosis in APOE*3Leiden.CETP mice. Eur Heart J 2017;38:2499–507. DOI: 10.1093/eurheartj/ehx260; PMID: 28637178

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Perspective

Early Retirement E l i z a b e t h Ro s s M D FA CC

Disclosure: I have no disclosures or conflicts of interest. Citation: US Cardiology Review 2017;11(2):110–11. DOI: 10.15420/usc.2017:11:2:GE1 Correspondence: Elizabeth Ross MD FACC, E: dreross@netacc.net

edical journals and business publications are filled

large hospital system several years before. The hospital group

with advice on retirement. Most of the articles address

employed us. I was reviewing my employment renewal contract,

financial planning and lifestyle adjustments to ensure

when my husband said, “I wish you would not keep working

a happy retirement. But what leads a physician to decide to

until I die.” It was an epiphany for me. We both had colleagues

retire? How does it feel to say goodbye to your life’s work? I can

who had died while they were still working. More than one had

tell you that it is not straightforward.

died in their offices. Many of our friends had retirement dreams that were never realized because of ill health or worse.

Retirement was never in my game plan. After college, I briefly worked in the computer industry. Compared to being at

So 1 year ago, at age 63, I retired. I declined any retirement

university, working was too restrictive. I hated the corporate

parties. They never conveyed the excitement of what being a

dress code and the 9 to 5 workday. So I revised my career plan

doctor truly was. After years of devoting myself to the care of

and decided to spend as many years as possible in school.

my patients and keeping up with the advances in medicine, my

Since medical training seemed to take forever, I applied. The

job was done. I shared tearful goodbyes with my staff and some

best part was that you could get paid for training after medical

of my patients. Many expressed appreciation for my care and

school. I hoped to train in multiple fellowships to extend my

expertise. The most touching conversation was with the son of a

time in training. I loved everything about being a doctor. From

patient who was dong well many years after bypass surgery. He

the moment that I pulled the shroud off my anatomy class

related his gratitude for his father’s presence at family milestones

cadaver, I was entranced by the practice of medicine. They call it

like his wedding and the birth of his son. He credited me with

practice for a reason. You get better at it every day. Sometimes,

bestowing so much family joy. In truth, I had only chosen a skilled

you help to save a life. Even on an ordinary day, you make

cardiothoracic surgeon. But I was grateful for his kind words.

people feel better. Practicing medicine is continuous learning.

On the other hand, some comments about my retirement were

Science has changed cardiology practice dramatically. In my

demoralizing. One woman was relieved that she could see a

practice, I embraced every new technology and treatment.

colleague in the suburbs so she would no longer need to drive

Despite the extra hours that electronic medical records added

into town. Her comments felt callous but now that I am retired, I

to my day, I was thrilled to have so much data at my fingertips.

am happy to no longer deal with rush hour traffic myself!

I was enthusiastic about going to work each day. My colleagues and patients expected me to work until I died. I shared that

In retirement, I have taken up several hobbies that I had put

expectation. So it came as a shock when my husband suggested

aside as medicine took up all of my time. The long workdays

that I retire early. My partner and I had sold our practice to a

and the extra work on the weekends to catch up had absorbed

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Early Retirement

all of my time and energy. I used to joke that I was addicted to

good at something other than being a doctor. My sense of self-

my job. I was worried that it was my only talent. I was wrong.

worth has been challenged since I retired. When I am asked what

It has been a year since I retired. I still miss my colleagues,

I do, I can no longer say, â&#x20AC;&#x153;I am a cardiologistâ&#x20AC;?. On the other hand,

patients and staff. I miss earning a paycheck, and I am reluctant

I am no longer exhausted. I exercise regularly and feel years

to make large purchases. In truth, I do not want more things. I

younger than I thought was possible. I am surprised to be having

threw away a lifetime of accumulated things when we moved.

so much fun. My advice to any physician is to think about what

Instead, I am acquiring new experiences. I have taken up long

your retirement will be like. Retirement is a lot like medicine. It

abandoned hobbies like painting and sailing. I am thrilled to be

gets better with practice. n

US CARDIOLOGY REVIEW

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