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Volume 11 • Issue 1 • Spring 2017

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Do We Need a Different Approach to Assess Cardiovascular Risk in Women? Ijeoma Isiadinso, MD, MPH and Nanette K Wenger, MD

Cardiac Toxicity of Cancer Chemotherapy Aarti Asnani, MD and Randall T Peterson, PhD

Proprotein Convertase Subtilisin/Kexin 9 (PCSK9) Inhibition in Patients With or at High Risk of Coronary Heart Disease Shane Prejean, MD and Todd M Brown, MD, MSPH

When to Use Bioresorbable Vascular Scaffolds Xiaoyu Yang, MD, Mohamed Ahmed, MD and Donald E Cutlip, MD

Optical coherence tomography

Angiograph of left circumflex artery

Cardiac toxicity of cancer chemotherapy

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US Cardiology Review seeks Deputy Editors Unique opportunity to develop your understanding of medical publishing

US Cardiology Review journal is a peer-reviewed bi-annual journal comprising review articles and expert opinion articles. It features balanced and comprehensive articles written by leading authorities, addressing the most important and salient developments in the field of cardiology. The journal editorial team are now seeking to recruit suitably qualified applicants for a small board of Deputy Editors, to work in concert with the journal’s Editor-in-Chief, Professor Donald E Cutlip. The successful candidates will be general cardiologists or advanced internists. No previous experience in medical publishing is required; the Deputy Editors will be enthusiastic to learn through the process of assisting the Editor-in-Chief. The Deputy Editors will be involved in assessing submissions, facilitating the peer-review process, commissioning contributions and contribute to the evolution of the journal. Deputy Editors will be supported by the journal’s Managing Editor, and journal work is designed to be conducted primarily online with biannual teleconferences. If you think you have an interest in the role, please send your CV and a very brief covering letter to the Managing Editor, Lindsey Mathews at commeditor@radcliffecardiology.com

Editorial Board Editor in Chief Donald E Cutlip MD – Director, Cardiac Catheterization Laboratory in The Cardiovascular Institute, Beth Israel Deaconess Medical Center; Professor of Medicine, Harvard Medical School, Boston, MA

Ralph G Brindis, MD, MPH University of California, San Francisco, CA

Thomas A Haffey, MD, DO Western University of Health Sciences, Pomona, CA

Duane Pinto, MD, MSc Harvard Medical School, Boston MA

Todd M Brown, MD, MSPH University of Alabama at Birmingham, Birmingham, AL

Elizabeth S Kaufman, MD Case Western Reserve University, Cleveland, OH

Rajalakshmi Santhanakrishnan Wright State University, Dayton, OH

Carey Kimmelstiel, MD Tufts Medical Centre, Boston MA

Sidney C Smith, MD University of North Carolina, Chapel Hill, NC

Roberto M Lang, MD University of Chicago, Chicago, IL

W Douglas Weaver, MD Henry Ford Hospital, Detroit, MI

NA Mark Estes III, MD Tufts University, Boston, MA Barry H Greenberg, MD University of California, San Diego, CA

Warren Manning, MD Harvard Medical School, Boston MA

Recent US Cardiology Review journal articles of note … What the Cardiologist Needs to Know About Medications for Type 2 Diabetes Stephen Ku, MD and Steven V Edelman, MD

Identification of Patients at Risk of Stroke From Atrial Fibrillation Raymond B Fohtung, MD and Michael W Rich, MD

Current Status of the Left Ventricular Assist Device as a Destination Therapy Jorge Silva Enciso, MD, Eric Adler, MD and Barry Greenberg, MD

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Volume 11 • Issue 1 • Spring 2017

www.USCjournal.com

Editorial Board Donald E Cutlip MD Editor in Chief Director, Cardiac Catheterization Laboratory in The Cardiovascular Institute, Beth Israel Deaconess Medical Center; Professor of Medicine, Harvard Medical School, Boston, MA

Ralph G Brindis, MD, MPH

Carey Kimmelstiel, MD

University of California, San Francisco, CA

Tufts Medical Centre, Boston MA

Todd M Brown, MD, MSPH

Roberto M Lang, MD

University of Alabama at Birmingham, Birmingham, AL

University of Chicago, Chicago, IL

Leway Chen, MD, MPH

Warren Manning, MD

University of Rochester, Rochester, NY

Harvard Medical School, Boston MA

NA Mark Estes III, MD

Duane Pinto, MD, MSc

Tufts University, Boston, MA

Harvard Medical School, Boston MA

Barry H Greenberg, MD

Rajalakshmi Santhanakrishnan, MD

University of California, San Diego, CA

Wright State University, Dayton, OH

Thomas A Haffey, MD, DO

Sidney C Smith, MD

Western University of Health Sciences, Pomona, CA

University of North Carolina, Chapel Hill, NC

Elizabeth S Kaufman, MD

W Douglas Weaver, MD

Case Western Reserve University, Cleveland, OH

Henry Ford Hospital, Detroit, MI

Managing Editor Lindsey Mathews • Production Jennifer Lucy • Design Tatiana Losinska Digital Commercial Manager Ben Sullivan • New Business & Partnership Director Rob Barclay Publishing Director Liam O’Neill • Managing Director David Ramsey • Commercial Director David Bradbury •

Editorial Contact Lindsey Mathews commeditor@radcliffecardiology.com Circulation & Commercial Contact David Ramsey david.ramsey@radcliffecardiology.com •

Cover image

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

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Lifelong Learning for Cardiovascular Professionals

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: Spring 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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© R A D C L I F F E C AR DI OLOGY 2017


Contents

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Foreword Donald E Cutlip, MD

Risk and Prevention

 We Need a Different Approach to Assess Cardiovascular Risk in Women? 5 Do Ijeoma Isiadinso, MD, MPH and Nanette K Wenger, MD

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Dyslipidemia: Current Therapies and Guidelines for Treatment

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 roprotein Convertase Subtilisin/Kexin 9 (PCSK9) Inhibition in Patients With or at P High Risk of Coronary Heart Disease

Edward T Carreras, MD and Donna M Polk, MD, MPH

Shane Prejean, MD and Todd M Brown, MD, MSPH

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Guest Editorial: Commentary on the Findings of the GLAGOV Randomized Clinical Trial Jakub Podolec, MD, PhD and Lukasz Niewiara, MD

Heart Failure Toxicity of Cancer Chemotherapy  20 Cardiac Aarti Asnani, MD and Randall T Peterson, PhD

Interventional Cardiology to Use Bioresorbable Vascular Scaffolds  25 When

Xiaoyu Yang, MD, Mohamed Ahmed, MD and Donald E Cutlip, MD

 Anti-platelet Therapy after Coronary Stenting: Rationale for Personalized 31 Dual Duration of Therapy Donald E Cutlip, MD

Editorial: A Brave New World for Non-vitamin K Antagonist Oral Anticoagulants:  37 Guest Have We seen the Last of Warfarin? Michela Faggioni, MD, Michael C Gibson, MS, MD and Roxana Mehran, MD, FAHA

Electrophysiology Aspects of Rotor Mapping in Catheter Ablation of Atrial Fibrillation  39 Practical John M Miller, MD

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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.

T

he editorial board and staff are pleased to present the latest issue of US Cardiology Review. The submissions include reviews, editorials, and perspectives based on recently published clinical trials. They have been selected based on relevance to daily practice of the general cardiologist and advanced internist.

The issue leads off with an important and timely review in the Risk Prevention section by Isiadinso and Wenger on assessment of cardiovascular risk in women. The paper highlights the burden of cardiovascular disease and discusses several unique factors related to risk assessment in women. Better understanding of these issues and current limitations is critical for improving outcomes in these patients. Next are three papers in the Risk Prevention section on lipid management. Carreras and Polk present a general overview of current therapies for dyslipidemia and guideline-based approaches followed by a focused review from Prejean and Brown on the current status of PCSK-9 inhibitors. These papers are of special importance as we aim to optimize primary and secondary risk prevention based on the best available evidence. Podolec and Niewiara finish this section with a new feature in the Journal, providing the key learning points from a recent clinical trial, the GLAGOV trial of the PCSK9 inhibitor, evolocumab. This is followed by a much needed review on cardiac toxicity of cancer chemotherapy by Asnani and Peterson. The aging of our population and increased survival rates for a number of cancers makes awareness of these sometimes late cardiac complications essential for the practicing general cardiologist and internist. In the Interventional Cardiology section, Yang, Ahmed, and I review the data and current recommendations for optimal use of the recently approved absorb bioresorbable vascular scaffold. There are next two articles centered on current controversies in dual anti-platelet therapy (DAPT) after coronary stenting. These include an editorial on the rationale for personalized therapy based on individual ischemic and bleeding risks followed by a perspective from Mehran and Faggioni on the key learning points from the recently published PIONEER-AF PCI clinical trial. The need to develop new approaches to the DAPT dilemma for optimizing the balance of bleeding and ischemia is especially critical in this substantial group of patients with atrial fibrillation and coronary artery disease. Finally, in the Electrophysiology section Miller reviews the role of ablation techniques beyond pulmonary vein isolation for improving long-term success of atrial fibrillation management. This issue is a busy one and has been the result of much effort. I thank the editorial staff, our reviewers, and the authors for their hard work in these contributions. We trust you will find the results informative for your practice. n

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Š RADCLIFFE CARDIOLOGY 2017


Risk and Prevention

Do We Need a Different Approach to Assess Cardiovascular Risk in Women? Ijeoma Isia dinso, M D, M P H a n d N a n e t t e K We n g e r, M D Department of Medicine, Division of Cardiology, Emory University School of Medicine, Emory Women’s Heart Center, Atlanta, GA

Abstract For many years, heart disease was considered by many to be a ‘man’s disease’. This opinion was held for several decades, despite statistics showing that more women died from heart disease annually than men. Women are not simply smaller biologic versions of men, nor are they a homogeneous group. The complexity of the effect of hormonal, biologic and physiologic factors on a woman’s cardiovascular risk cannot be understood by extrapolating our knowledge of heart disease in men. Several factors influence a woman’s risk for cardiovascular disease (CVD). While traditional risk factors have long been known, several risk factors unique to or predominant in women also confer an increased risk for CVD. In this review we highlight the burden of CVD in women, and describe risk factors that are female-specific or female-predominant. We also review current risk assessment models and their efficacy in estimating a woman’s risk for CVD.

Keywords Cardiovascular disease, women, gender differences, risk factors, risk assessment Disclosure: The authors have no conflicts of interest to declare. Received: July 29, 2016 Accepted: October 27, 2016 Citation: US Cardiology Review 2017;11(1):5–9; DOI: 10.15420/usc.2016:8:2 Correspondence: Ijeoma Isiadinso, MD, MPH, 1365 Clifton Road NE, Atlanta, GA 30322, USA. E: Ijeoma.isiadinso@emory.edu

Prevalence of Cardiovascular Disease CVD is the leading cause of death in Europe and the United States. CVD mortality is on the decline in many countries, and in several European countries, cancer has now surpassed CVD as the leading cause of death.1 However, CVD remains the leading cause of death for both men and women in the United States and results in more female deaths than cancer, lung disease and diabetes combined. Until recently, the annual mortality rate for CVD in the United States was higher among women compared with men. However, the latest statistics show a dramatic change. In 2013, for the first time since 1984, more men died of cardiovascular disease than women.2 As a result of this historical gender disparity, significant efforts have been focused on increasing public awareness of the burden of CVD in women. A national survey conducted in 2012 showed that 51 % of women were aware that CVD was the leading cause of death in women, compared with 30 % in 1997.3

Symptoms of Coronary Heart Disease Women present with coronary heart disease (CHD) on average 10 years later than men. Men are more likely to present with a myocardial infarction (MI) as their initial manifestation of CHD, while women are more likely to present with angina. The most common symptom of CHD in both women and men is chest pain. Other typical anginal equivalents include dyspnea and diaphoresis. Although chest pain is the most common symptom, women are more likely to have atypical symptoms of CHD including jaw, back or arm pain, nausea and fatigue.4,5 It is important that clinicians and the general public are aware of these atypical symptoms to ensure prompt evaluation and treatment in

© RADCLIFFE CARDIOLOGY 2017

symptomatic women. Clinical misdiagnoses and delays in delivery of evidence-based, lifesaving cardiovascular care can occur as a result of this lack of awareness.

Risk Factors for CHD Traditional risk factors for CVD are well known, and include diabetes mellitus, age, family history of premature coronary artery disease (CAD), tobacco use, hypertension, obesity and physical inactivity (Table 1). Some of these factors impact a woman’s risk of CVD to a greater degree than they do in men. Women with diabetes are 3–7 times more likely to develop CAD. Men with diabetes, on the other hand, have a 2–3-fold increased risk for CAD.6 Among young and middle-aged women – a group that generally has lower rates of CAD than their male counterparts – the presence of diabetes is associated with a 4–5-fold higher rate of CAD.7 Tobacco use is associated with a higher risk of MI in women compared with men.8 Hypertension is one of the most common modifiable risk factors for CVD. It is more prevalent in men than women until age 45. After age 55, women have a higher prevalence than men.2,9 Some have attributed this to women living longer than men and as a result, the elderly population of women is larger than their male counterparts. Regardless of this, women with hypertension are less likely to be treated to goal.10 Several hormone-related factors can result in hypertension in women. Oral contraceptives (OC) will increase blood pressure slightly in most women, but rarely result in malignant hypertension. Different OCs have variable effects on blood pressure. For example, in the Nurses’

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Risk and Prevention Table 1: Summary of Risk Factors for Cardiovascular Disease, Including Female-Specific or Female-Predominant Risk Factors Non-modifiable

Modifiable

Female-specific or

risk factors

risk factors

predominant risk factors

• Age

• Hypertension

• Pregnancy induced

• Sex

• Diabetes mellitus

• Family history

• Obesity

preeclampsia,

of premature

•  Cigarette smoking

eclampsia

cardiovascular

disease

hypertension,

•  Physical inactivity

•  Gestational diabetes

• Dyslipidemia

• Polycystic ovarian

syndrome

• Menopause

•  Systemic inflammatory

rheumatologic diseases •  Mental stress/depression

Health Study, oral contraceptives with low doses of estrogen increased the risk of hypertension. 11 Prospective studies have shown that discontinuation of OC results in blood pressure returning to baseline within a few months.12 Despite studies demonstrating equal lipid-lowering benefit in men and women, women are less likely to be treated with statins after an MI.13,14 Furthermore, menopause has specific effects on lipoproteins levels. After menopause, triglyceride and low-density lipoprotein cholesterol levels rise and high-density lipoprotein cholesterol levels decline, resulting in an unfavorable lipid profile. It is uncertain whether these changes occur as a result of hormonal or lifestyle changes.

Female-specific or Female-predominant Risk Factors There are also additional female-specific or female-predominant risk factors that clinicians and patients must be aware of and include in the assessment of CVD in women. The association between systemic autoimmune inflammatory disease and increased cardiovascular risk is well known. Although the mechanism is not well understood, there is extensive literature demonstrating that systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) confer an increased risk of CAD independent of traditional risk factors alone.15–18 Accelerated atherosclerosis is a well-recognized finding in both groups.15,19,20 Both SLE and RA occur at higher rates among women than in men. Premature cardiovascular mortality has been seen in patients with SLE with a mean age of MI at age 52 in one cohort.21 CVD is the leading cause of morbidity and mortality in patients with SLE. Patients with RA have an increased risk of CHD, and there is a 2-fold greater risk of developing heart failure and a 1.5–2-fold increased risk of CAD compared with the general population. They are also less likely to have angina as the presenting symptom for CHD. Gestational diabetes mellitus (GDM) is associated with increased future risk of type 2 diabetes mellitus and CVD compared with women without GDM.22–24 Pregnancy-induced hypertension is a spectrum of disorders that includes preeclampsia-eclampsia, chronic hypertension, chronic hypertension with superimposed preeclampsia and gestational hypertension.25 New-onset gestational hypertension, preeclampsia and eclampsia have been shown to be associated with increased

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future cardiovascular risk and cardiovascular risk factors.26–28 A metaanalysis reported the relative risk of CHD in women with a history of preeclampsia to be more than double that of women who have not had preeclampsia.29 Women who deliver preterm or a small for gestational age baby are also at increased future risk for CHD,30–32 and women who suffer from spontaneous pregnancy loss are at increased future risk for coronary heart disease and MI. A history of stillbirth was associated with a >3.5 times higher risk of MI (age-adjusted hazard ratio [HR] 3.70; (95 % CI [1.69–8.11]). Recurrent miscarriage (more than three occurrences) was associated with an approximately 9 times higher risk of MI (ageadjusted HR 8.90; 95 % CI [3.18–24.90]).33 In a meta-analysis of 10 studies, miscarriage was associated with a higher likelihood of developing future CHD with an odds ratio (OR) of 1.45 (95 % CI [1.18–1.78]).34 The risk for CAD in women increases beginning 10 years from the onset of menopause. Women who undergo premature menopause, as a result of radiation, chemotherapy or surgery, are at increased risk for CAD compared with those who transition into natural menopause 10 years later. However, the findings of the Women’s Health Initiative and the Heart and Estrogen/Progestin Replacement Study provided conclusive evidence that menopausal hormone therapy is not beneficial in preventing heart disease.35,36 As a result, it is not recommended for the primary or secondary prevention of CVD Psychosocial factors have also been associated with CHD.37 According to 2014 statistics, 15.7 million (6.7  %) adults in the United States had at least one depressive episode within the prior year.38 More women have depression compared with men in every age group, with rates of depression among women nearly twice those of men.39,40 The prevalence of depression is much higher in the cardiac population at nearly 15 %, which is three times that seen in the general population.41 Long-term prospective studies have found depression to be associated with the development of CHD, independent of other risk factors for CHD.42–44 Data support a correlation between severity of depression and the risk of cardiovascular events.45 In a prospective study among women without known CVD, symptoms of depression were directly associated with risk of CHD events in age-adjusted and multivariate models.46 In up to two-thirds of patients with MI, mild depressive symptoms occur post-MI,47 and major depressive disorder has been reported to develop in almost 20 % of patients after an MI.48,49 Anxiety has also been associated with increased risk of fatal CHD in women.50 Unlike traditional risk factors for CAD, there are no current cardiology guidelines for the treatment of psychosocial risk factors. However, given the robust literature demonstrating an association between depression and cardiovascular events and poor outcome post-MI, it is imperative that patients with CAD or recent MI are screened and treated for depression. The 2011 American Heart Association/American College of Cardiology Foundation recommends healthcare providers consider the treatment of depression for its other clinical benefits, as treatment has not been shown to improve cardiovascular outcomes.51 Polycystic ovarian syndrome (PCOS) is the most common endocrine disorder in women of reproductive age. Women with PCOS are at increased risk for insulin resistance, type 2 diabetes mellitus, dyslipidemia and the development of metabolic syndrome.52–54 A study by Christian et

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CVD Risk Assessment in Women al showed coronary artery calcification to be more prevalent in women with PCOS compared with controls (39 % vs. 21  %; OR 2.4; p=0.05).55 Given the increased prevalence of cardiovascular risk factors among women with PCOS, aggressive risk factor screening, modification, and treatment should be pursued in this group.

Table 2: Classification of CVD Risk in Women Ideal cardiovascular

At risk (≥1 major

High risk (≥1 high

health

risk factors)

risk states)

Total cholesterol

Cigarette smoking

Clinically manifest CVD

<200 mg/dl (untreated)

Risk Assessment Models

BP <120/<80 mmHg

SBP ≥120 mmHg, DBP

Clinically manifest

Several risk assessment calculators have been developed for the estimation of CHD risk. The Framingham Risk Score (FRS) was first published in 1998 and provides a 10-year estimate of CHD risk.56 The 2008 revised FRS was modified to include additional cardiovascular clinical endpoints including heart failure, transient ischemic attack and symptomatic peripheral arterial disease. While this risk model provided an improved estimate of CVD, it still suffers from some challenges, and underestimates risk in women.

(untreated)

≥80 mmHg or treated

cerebrovascular

hypertension disease

Fasting blood glucose

Total cholesterol

Clinically manifest

<100 mg/dl (untreated)

>200 mg/dl, HDL-C

peripheral arterial

≤50 mg/dl or on treatment disease

One of the limitations of the FRS is that it does not account for the increased cardiovascular risk in patients with systemic inflammatory diseases. Furthermore, more women are affected by SLE and RA, and therefore their risk of CVD may be underestimated using this risk model. The FRS provides a short-term (10-year) risk estimate of CHD in women. Women traditionally tend to have lower short-term cardiovascular risk, but a higher lifetime cardiovascular risk. Finally, it does not include family history, pregnancy-related risk attributes, or evidence of subclinical CVD in cardiovascular risk estimation. Other risk prediction models for women include the Reynolds Risk Score). Key differences between the Reynolds Risk Score and other cardiovascular prediction models are the inclusion of high-sensitivity C-reactive protein, and family history of MI.57 The use of this scoring system may be more accurate at predicting risk for CVD in women with chronic inflammatory diseases. The 2011 Effectiveness-Based Guidelines for the Prevention of CAD in Women outlines an algorithm for risk stratifying women.58 It provides an algorithm for the classification of women as ideal cardiovascular health, at-risk, or high-risk for CVD, based on several criteria (Table 2). Those classified as at risk or high risk are appropriate candidates for aggressive cardiovascular risk-factor modification and secondary preventive efforts to reduce recurrent atherosclerotic cardiovascular events. For women who are considered to have ideal cardiovascular health, initiatives focused on lifestyle modification to prevent the development of clinical risk factors for CVD or clinical atherosclerotic CVD are imperative. Given the high lifetime risk for CVD in women, these preventive strategies are of utmost importance for women who do not have clinical atherosclerotic CVD. However, this document predates the 2013 American College of Cardiology and American Heart Association (ACC/AHA) prevention guidelines. The ACC and AHA developed a new calculator in 2013 for the estimation of cardiovascular events.59 The pooled cohort equation is gender-specific provides both a 10-year atherosclerotic cardiovascular disease risk, and a lifetime risk for CVD (http://tools.acc.org/ASCVDRisk-Estimator). This is significant given the higher lifetime risk for CVD in women and allows providers to recommend aggressive lifestyle changes and medications to reduce cardiovascular risk and events.

US CARDIOLOGY REVIEW

for dyslipidemia

Body mass index <25 kg/m2

Obesity

Abdominal aortic

aneurysm

Abstinence from smoking

End-stage or chronic

Poor diet

renal disease

Physical activity at goal

Physical inactivity

Diabetes mellitus

Healthy diet

Family history of

10-year predicted CVD

premature CAD in

risk ≥10 %

first-degree relative

Metabolic syndrome

Evidence of advanced

subclinical atherosclerosis

Poor exercise capacity

on treadmill testing

and/or abnormal heart

rate recovery

Systemic autoimmune

collagen-vascular disease

(i.e. SLE or RA)

History of gestational

diabetes preeclampsia

or pregnancy induced

(≥150 min/week of moderate intensity or ≥75 min/week of vigorous activity or a combination)

hypertension BP = blood pressure; CAD = coronary artery disease; CVD = cardiovascular disease; DBP = diastolic blood pressure; HDL-C = high-density lipoprotein cholesterol; LDL-C = lowdensity lipoprotein cholesterol; RA = rheumatoid arthritis; SBP = systolic blood pressure; SLE = systemic lupus erythematosus. Source: Mosca et al, 201158 Copyright©, American Heart Association, Inc.

Despite the advantages and disadvantages of each of the multivariate risk models, no single risk model is the most accurate at estimating cardiovascular risk. The best method of estimating cardiovascular risk in asymptomatic individuals involves using one of the multivariate risk models combined with laboratory results, taking into account of family history of premature CAD and the presence of non-traditional risk factors.

Evaluation of Symptomatic Women for CHD The exercise treadmill test (ETT) is the oldest and most commonly used test for evaluating CAD in symptomatic women. In women who have a normal baseline electrocardiogram (ECG) and good functional capacity, the ETT is the appropriate test in the initial evaluation of women with suspected CHD. It is recommended by the ACC/AHA as the initial

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Risk and Prevention diagnostic test of choice in symptomatic women with intermediate pretest likelihood of CAD.60 For clinicians who are unsure of a woman’s functional capacity, the Duke Activity Status Index is helpful. It is a 12-item questionnaire that can be used to estimate metabolic equivalents of task (METs) associated with activities of daily living. The information provided identifies those who are unable to achieve 5 METs and should be considered for pharmacologic stress testing.61 The sensitivity and specificity of detecting obstructive CAD in women using the ETT is lower than in men.62 This is because of the lower exercise capacity and prevalence of obstructive CAD, as well as the high prevalence of ST segment depression during exercise in women compared with men. However, the ETT is not a futile test. It can also identify myocardial ischemia, which may be unrelated to obstructive coronary disease such as in coronary microvascular dysfunction. The Duke Treadmill Score and functional capacity provide valuable prognostic information in the risk stratification of symptomatic women.63–65 A low Duke Treadmill Score is associated with <1 % annual mortality rate compared with an annual mortality rate of nearly 5  % in those with a high Duke Treadmill Score .63 Those who have lower functional capacity have higher cardiovascular event rates than those who are able to achieve at least 5 METs on exercise testing. A negative stress ECG also has a high negative predictive value. Stress echocardiogram is performed with the combination of echocardiogram and either exercise or the use of a pharmacologic agent. This modality is appropriate for intermediate-risk symptomatic women who have poor functional capacity, an abnormal baseline ECG that precludes interpretation of the ST segment during exercise, or an intermediate Duke Treadmill Score. The addition of imaging to an ETT improves the diagnostic accuracy of detecting obstructive CAD above the ETT alone. The sensitivity and specificity of the ETT for detecting obstructive CAD increases from 31–71 % and 66–86 %, respectively, to 80–88 % and 81–86 %, respectively, with the addition of echocardiography.66–69 In addition to wall motion abnormalities, the stress echocardiogram can identify other causes of chest pain or dyspnea in women including hypertrophic cardiomyopathy, valvular heart disease, or pulmonary hypertension. Stress single photon emission computed tomography myocardial perfusion imaging (SPECT) can be used in the diagnostic evaluation

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Nichols M, Townsend N, Scarborough P, et al. Cardiovascular disease in Europe 2014: epidemiological update. Eur Heart J 2014;35 :2950–9. DOI: 10.1093/eurheartj/ehu299; PMID: 25139896 Mozaffarian D, Benjamin E, Go A, et al. Heart disease and stroke statistics – 2016 Update. A report from the American Heart Association. Circulation 2016;133 :e38–360. DOI: 0.1161/ CIR.0000000000000350; PMID: 26673558 Mosca L, Hammond G, Mochari-Greenberger H, et al. Fifteenyear trends in awareness of heart disease in women: results of a 2012 American Heart Association national survey. Circulation 2013;127 :1254–63. DOI: 10.1161/CIR.0b013e318287cf2f; PMID: 23429926 Canto JG, Rogers WJ, Goldberg RJ, et al. Association of Age and Sex With Myocardial Infarction Symptom Presentation and In-Hospital Mortality. JAMA 2012;307 :813–22. DOI: 10.1001/ jama.2012.199; PMID: 22357832 Khan NA, Daskalopoulou SS, Karp I, et al; GENESIS PRAXY Team. Sex differences in acute coronary syndrome symptom presentation in young patients. JAMA Intern Med 2013;173 :1863–71. DOI: 10.1001/jamainternmed.2013.10149; PMID: 24043208 Huxley R, Barzi F, Woodward M. Excess Risk of fatal coronary

of intermediate-risk symptomatic women who have limited functional capacity or an abnormal baseline ECG. Pharmacologic stress SPECT has a diagnostic sensitivity of 91 % and specificity of 86  % in women. Stress SPECT myocardial perfusion imaging provides valuable prognostic information based on the size and extent of ischemic perfusion defects, as well as ejection fraction. Cardiovascular events are lower in women with small reversible defects, confined to single coronary artery territory or with preserved left ventricular ejection fraction compared with those who have multiple or large perfusion defects or left ventricular ejection fraction <35 %. Stress photon emission tomography (PET) has been useful in improving the diagnostic accuracy of detecting obstructive CAD in women who have breast attenuation artifact on stress SPECT imaging or poor windows on stress echocardiography. Unlike stress echocardiography or stress SPECT imaging, exercise cannot be performed during stress PET testing because of the short half-life of rubidium. It is an appropriate diagnostic test for detecting obstructive CAD in women who are of intermediate pretest probability for CAD, but are unable to exercise or have attenuation artifacts on SPECT imaging. Stress cardiac magnetic resonance imaging (CMR) has become more attractive in the assessment of symptomatic women. It has the advantage of avoiding the use of radiation during stress testing compared with stress PET or SPECT. This is an issue that deserves consideration when determining which stress test to perform in a young, premenopausal woman who cannot exercise. In addition, CMR provides additional information pertaining to cardiac morphology, coronary anatomy and evaluation of the thoracic aorta in women presenting with chest pain.

Conclusion Cardiovascular risk assessment in women involves a thorough history, physical examination, and laboratory testing for the identification of risk factors for CVD. Risk assessment calculators can be used to stratify an asymptomatic woman into specific risk categories and further direct preventive strategies to reduce the future risk of CVD. Asymptomatic women who have risk factors for CVD should undergo aggressive modification of cardiovascular risk factors. Symptomatic women should undergo appropriate testing to evaluate for obstructive and nonobstructive CAD. n

heart disease associated with diabetes in men and women: meta-analysis of 37 prospective cohort studies. BMJ 2006;332:73–8. DOI: 10.1136/bmj.38678.389583.7C; PMID: 16371403 7. Kalyani RR, Lazo M, Ouyang P, et al. Sex differences in diabetes and risk of incident coronary artery disease in healthy young and middle-aged adults. Diabetes Care 2014;37 :830–8. DOI: 10.2337/dc13-1755; PMID: 24178997 8. Willett WC, Green A, Stampfer MJ, et al. Relative and absolute excess risks of coronary heart disease among women who smoke cigarettes. N Engl J Med 1987;317 :1303–9. DOI: 10.1056/ NEJM198711193172102; PMID: 3683458 9. August, P. Hypertension in women. Adv Chronic Kidney Dis . 2013;20 :396–401. DOI: 10.1053/j.ackd.2013.07.002; PMID: 23978544 10. Keyhani S, Scobie J, Hebert PL, McLaughlin MA. Gender disparities in blood pressure control and cardiovascular care in a national sample of ambulatory care visits. Hypertension 2008;51 :1149–55. DOI: 10.1161/HYPERTENSIONAHA.107.107342; PMID: 18259013 11. Chasan-Taber L, Willett WC, Manson JE, et al. Prospective study of oral contraceptives and hypertension among women in the United States. Circulation 1996;94 :483–9. DOI: 10.1161/01.

CIR.94.3.483; PMID: 8759093 12. Pemu P, Ofili E. Hypertension. J Clin Hypertens 2008;10 : 406–10. 13. Wenger NK, Lewis SJ, Welty FK, et al. Beneficial effects of aggressive low-density lipoprotein cholesterol lowering in women with stable coronary heart disease in the Treating to New Targets (TNT) study. Heart 2008;94 :434–9. DOI: 10.1136/ hrt.2007.122325; PMID: 18070940 14. Daly C, Clemens F, Lopez Sendon JL, et al. Gender differences in the management and clinical outcome of stable angina. Circulation 2006;113 :490–8. DOI: 10.1161/ CIRCULATIONAHA.105.561647; PMID: 16449728 15. Roman M, Shanker B, Davis A, et al. Prevalence and correlates of accelerated atherosclerosis in systemic lupus erythematosus. N Engl J Med 2003;349 :2399–406. DOI: 10.1056/ NEJMoa035471; PMID: 14681505 16. del Rincón ID, Williams K, Stern MP, et al. High incidence of cardiovascular events in a rheumatoid arthritis cohort not explained by traditional cardiac risk factors. Arthritis Rheum 2001;44 :2737–45. PMID: 11762933 17. Solomon DH, Karlson EW, Rimm EB, et al. Cardiovascular morbidity and mortality in women diagnosed with rheumatoid arthritis. Circulation 2003;107 :1303–7. DOI: 10.1161/01.

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CIR.0000054612.26458.B2; PMID: 12628952 18. Aviña-Zubieta JA, Choi HK, Sadatsafavi M, et al. Risk of cardiovascular mortality in patients with rheumatoid arthritis: a meta-analysis of observational studies. Arthritis Rheum 2008;59 :1690–7. DOI: 10.1002/art.24092; PMID: 19035419 19. Asanuma Y, Oeser A, Shintani AK, et al. Premature coronaryartery atherosclerosis in systemic lupus erythematosus. N Engl J Med 2003;349 :2407–15. DOI: 10.1056/NEJMoa035611; PMID: 14681506 20. Kahlenberg JM, Kaplan MJ. Mechanisms of premature atherosclerosis in rheumatoid arthritis and lupus. Annu Rev Med 2013;64 :249–63. DOI: 10.1146/annurevmed-060911-090007; PMID: 23020882 21. Urowitz MB, Gladman DD, Anderson NM, et al. Cardiovascular events prior to or early after diagnosis of systemic lupus erythematosus in the systemic lupus international collaborating clinics cohort. Lupus Sci Med 2016;3 :e000143. DOI: 10.1136/ lupus-2015-000143; PMID: 27099765 22. Bellamy L, Casas JP, Hingorani A, Williams D. Type 2 diabetes mellitus after gestational diabetes: a systematic review and meta-analysis. Lancet 2009;373 :1773–9. DOI: 10.1016/S01406736(09)60731-5; PMID: 19465232 23. Carr D, Utzschneider K, Hull R, et al. Gestational diabetes mellitus increases the risk of cardiovascular disease in women with a family history of type 2 diabetes. Diabetes Care 2006;29 :2078–83. DOI: 10.2337/dc05-2482; PMID: 16936156 24. Bentley-Lewis R. Late cardiovascular consequences of gestational diabetes mellitus. Semin Reprod Med 2009;27 :322–9. DOI: 10.1055/s-0029-1225260; PMID: 19530066 25. American College of Obstetricians and Gynecologists; Task Force on Hypertension in Pregnancy. Hypertension in Pregnancy. Report of the American College of Obstetricians and Gynecologists’ Task Force on Hypertension in Pregnancy. Obstet Gynecol 2013;122 :1122–31. DOI: 10.1097/01. AOG.0000437382.03963.88; PMID: 24150027 26. Männistö T, Mendola P, Vääräsmäki M, et al. Elevated blood pressure in pregnancy and subsequent chronic disease risk. Circulation 2013;127 :681–90. DOI: 10.1161/ CIRCULATIONAHA.112.128751; PMID: 23401113 27. Lykke JA, Langhoff-Roos J, Sibai BM, et al. Hypertensive pregnancy disorders and subsequent cardiovascular morbidity and type 2 diabetes mellitus in the mother. Hypertension 2009;53 :944–51. DOI: 10.1161/HYPERTENSIONAHA.109.130765; PMID: 19433776 28. Marín R, Gorostidi M, Portal CG, et al. Long-term prognosis of hypertension in pregnancy. Hypertens Pregnancy 2000;19 : 199–209. PMID: 10877988 29. Bellamy L, Casas JP, Hingorani A, Williams D, et al. Pre-eclampsia and risk of cardiovascular disease and cancer in later life: systematic review and meta-analysis. BMJ 2007;335 :974. DOI:10.1136/bmj.39335.385301.BE; PMID: 17975258 30. Nardi O, Zureik M, Courbon D, et al. Preterm delivery of a first child and subsequent mothers’ risk of ischaemic heart disease: a nested case-control study. Eur J Cardiovasc Prev Rehabil 2006;13 :281–3. DOI: 10.1097/01.hjr.0000183917.35978.a6; PMID: 16575285 31. Catov JM, Wu CS, Olsen J, et al. Early or recurrent preterm birth and maternal cardiovascular disease risk. Ann Epidemiol 2010;20 :604–9. DOI: 10.1016/j.annepidem.2010.05.007; PMID: 20609340 32. Bukowski R, Davis KE, Wilson PW. Delivery of a small for gestational age infant and greater maternal risk of ischemic heart disease. PLoS One 2012;7 :e33047. DOI: 10.1371/journal. pone.0033047; PMID: 22431995 33. Kharazmi E, Dossus L, Rohrmann S, Kaaks R. Pregnancy loss and risk of cardiovascular disease: a prospective populationbased cohort study (EPIC-Heidelberg). Heart 2011;97 :49–54. DOI: 10.1136/hrt.2010.202226; PMID: 21123827 34. Oliver-Williams CT, Heydon EE, Smith GC, Wood AM. Miscarriage and future maternal cardiovascular disease: a systematic review and meta-analysis. Heart 2013;99 :1636–44. DOI: 10.1136/ heartjnl-2012-303237; PMID: 23539554 35. Hulley S, Grady D, Bush T, et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen Replacement Study (HERS) research group. JAMA 1998;280 :

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605–13. DOI:10.1001/jama.280.7.605; PMID: 9718051 36. Rossouw JE, Anderson GL, Prentice RL, et al; Writing Group For the Women’s Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principle results from the Women’s Health Initiative randomized controlled trial. JAMA 2002; 288 :321–33. DOI:10.1001/jama. 288.3.321; PMID: 12117397 37. Varghese T, Hayek SS, Shekiladze N, et al. Psychosocial risk factors related to ischemic heart disease in women. Curr Pharm Des 2016;22 :3853–70. DOI: 10.2174/138161282266616051 9113605; PMID: 27194439 38. Center for Behavioral Health Statistics and Quality (2015). Behavioral health trends in the United States: Results from the 2014 National Survey on Drug Use and Health (HHS Publication No. SMA 15-4927, NSDUH Series H-50). Available at: http://www. samhsa.gov/data/sites/default/files/NSDUH-FRR1-2014/NSDUHFRR1-2014.htm (accessed November 27, 2016) 39. Kessler RC, Berglund P, Demler O, et al. The epidemiology of major depressive disorder: Results from the National Comorbidity Survey Replication (NCS-R). JAMA 2003;289 : 3095–105. DOI: 10.1001/jama.289.23.3095; PMID: 12813115 40. Kessler RC. Epidemiology of women and depression. J Affect Disord 2003;74 :5–13. DOI: 10.1016/S0165-0327(02)00426-3; PMID: 12646294 41. Colquhoun DM, Bunker SJ, Clarke DM, et al. Screening, referral and treatment for depression in patients with coronary heart disease. Med J Aust 2013;198 :482–4. DOI: 10.5694/mja13.10153; PMID: 23682890 42. Wulsin LR, Singal BM. Do depressive symptoms increase the risk for the onset of coronary disease? A systematic quantitative review. Psychosom Med 2003;65 :201–10. PMID: 12651987 43. Anda R, Williamson D, Jones D, et al. Depressed affect, hopelessness, and the risk of ischemic heart disease in a cohort of U.S. adults. Epidemiology 1993;4 :285–94. PMID: 8347738 44. Ariyo AA, Haan M, Tangen CM, et al. Depressive symptoms and risks of coronary heart disease and mortality in elderly Americans. Cardiovascular Health Study Collaborative Research Group. Circulation 2000;102 :1773–9. DOI: 10.1161/01. CIR.102.15.1773; PMID: 11023931 45. Lesperance F, Frasure-Smith N, Talajic M, Bourassa MG. Fiveyear risk of cardiac mortality in relation to intial severity and one-year changes in depression symptoms after myocardial infarction. Circulation 2002;105 :1049–53. DOI: 10.1161/ hc0902.104707; PMID: 11877353 46. Whang W, Kubzansky LD, Kawachi I, et al. Depression and risk of sudden cardiac death and coronary heart disease in women: Results from the Nurses’ Health Study. J Am Coll Cardiol 2009;53 :950–8. DOI: 10.1016/j.jacc.2008.10.060; PMID: 19281925 47. Cay EL, Vetter N, Philip AE, Dugard P. Psychological status during recovery from an acute heart attack. J Psychosom Res 1972;16 :425–35. DOI: 10.1016/0022-3999(72)90068-2; PMID: 4666660 48. Thombs BD, Bass EB, Ford DE, et al. Prevalence of depression in survivors of acute myocardial infarction. J Gen Intern Med 2006;21 :30–8. DOI: 10.1111/j.1525-1497.2005.00269.x; PMID: 16423120 49. Carney RM, Freedland KE. Depression, mortality, and medical morbidity in patients with coronary heart disease. Biol Psychiatry 2003;54 :241–7. DOI: 10.1016/S0006-3223(03)00111-2; PMID: 12893100 50. Albert CM, Chae CU, Rexrode KM, et al. Phobic anxiety and risk of coronary heart disease and sudden cardiac death among women. Circulation 2005;111 :480–7. DOI: 10.1161/01. CIR.0000153813.64165.5D; PMID: 15687137 51. Smith SC Jr, Benjamin EJ, Bonow RO, et al. AHA/ACCF secondary prevention and risk reduction therapy for patients with coronary and other atherosclerotic vascular disease: 2011 update: a guideline from the American Heart Association and American College of Cardiology Foundation. Circulation 2011;124 :2458–73. DOI: 10.1161/CIR.0b013e318235eb4d; PMID: 22052934 52. Dokras A, Bochner M, Hollinrake E, et al. Screening women with polycystic ovary syndrome for metabolic syndrome. Obstet Gynecol 2005;106 :131–7. DOI: 10.1097/01.

AOG.0000167408.30893.6b; PMID: 15994628 53. Dokras A. Cardiovascular disease risk factors in polycystic ovary syndrome. Semin Reprod Med 2008;26 :39–44. DOI: 10.1055/ s-2007-992923; PMID: 18181081 54. Ehrmann DA, Liljenquist DR, Kasza K, et al; PCOS/Troglitazone Study Group. Prevalence and predictors of the metabolic syndrome in women with polycystic ovarian syndrome. J Clin Endocrinol Metab 2006;91 :48–53. DOI: 10.1210/jc.2005-1329; PMID: 16249284 55. Christian RC, Daniel DA, Thomas B, et al. Prevalence and predictors of coronary artery calcification in women with polycystic ovary syndrome. J Clin Endocrinol Metab 2003;88 : 2562–8. DOI: 10.1210/jc.2003-030334; PMID: 12788855 56. Wilson P, D’Agostino R, Levy D, et al. Prediction of coronary heart disease using risk factor categories. Circulation 1997; 97:1837–47. DOI: 10.1161/01.CIR.97.18.1837; PMID: 9603539 57. Ridker P, Buring J, Rifai N, et al. Development and validation of improved algorithms for the assessment of global cardiovascular risk in women: The Reynolds Risk Score. JAMA 2007;297 :611–9. DOI: 10.1001/jama.297.6.611; PMID: 17299196 58. Mosca L, Benjamin EJ, Berra K, et al. Effectiveness-based guidelines for the prevention of cardiovascular disease in women—2011 update: a guideline from the American Heart Association. Circulation 2011;123 :1243–62. DOI: 10.1161/ CIR.0b013e31820faaf8; PMID: 21325087 59. Goff DC Jr, Lloyd-Jones DM, Bennett G, et al. 2013 ACC/AHA guideline on the assessment of cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 2014;129 (suppl 2):S49–S73. DOI: 10.1161/01.cir.0000437741.48606.98; PMID: 24222018 60. Mieres JH, Gulati M, Bairey Merz NB, et al; American Heart Association Cardiac Imaging Committee of the Council on Clinical Cardiology; Cardiovascular Imaging and Intervention Committee of the Council on Cardiovascular Radiology and Intervention. Role of noninvasive testing in the clinical evaluation of women with suspected ischemic heart disease: a consensus statement from the American Heart Association. Circulation 2014;130 :350–79. DOI: 10.1161/ CIR.0000000000000061; PMID: 25047587 61. Hlatky M, Boineau RE, Higginbotham MB et al. A brief selfadministered questionnaire to determine functional capacity (the Duke Activity Status Index). Am J Cardiol 1989;64 :651–4. DOI: 10.1016/0002-9149(89)90496-7; PMID: 2782256 62. Kwok Y, Kim C, Grady D, et al. Meta-analysis of exercise testing to detect coronary artery disease in women. Am J Cardiol 1999;83 :660–66. DOI: 10.1016/S0002-9149(98)00963-1; PMID: 10080415 63. Mark DB, Shaw L, Harrell FE, et al. Prognostic value of a treadmill exercise score in outpatients with suspected coronary artery disease. N Engl J Med 1991;325 :849–53. DOI: 10.1056/ NEJM199109193251204; PMID: 1875969 64. Mark DB, Hlatky MA, Harrell FE, et al. Exercise treadmill score for predicting prognosis in coronary artery disease. Ann Intern Med 1987;106 :793–800. DOI: 10.7326/0003-4819-106-6-793; PMID: 3579066 65. Alexander KP, Shaw LJ, Shaw LK, et al. Value of exercise treadmill testing in women. J Am Coll Cardiol 1998;32 :1657–664. DOI: 10.1016/S0735-1097(98)00451-3; PMID: 9822093 66. Sanfilippo AJ, Abdollah H, Knott TC, et al. Stress echocardiography in the evaluation of women presenting with chest pain syndrome: a randomized, prospective comparison with electrocardiographic stress testing. Can J Cardiol 2005;21 :405–12. PMID: 15861257 67. Marwick TH, Anderson T, Williams MJ, et al. Exercise echocardiography is an accurate and cost-efficient technique for detection of coronary artery disease in women. J Am Coll Cardiol 1995;26 :335–41. DOI: 10.1016/0735-1097(95)80004-Z; PMID: 7608432 68. Sawada SG, Ryan T, Fineberg NS, et al. Exercise echocardiographic detection of coronary artery disease in women. J Am Coll Cardiol 1989;14 :1440–7. DOI: 10.1016/07351097(89)90378-1; PMID: 2809000 69. Williams MJ, Marwick TH, O’Gorman D, et al. Comparison of exercise echocardiography with an exercise score to diagnose of coronary artery disease in women. J Am Coll Cardiol 1994;74 :435–8. PMID: 8059721

9


Risk and Prevention

Dyslipidemia: Current Therapies and Guidelines for Treatment Edward T Carreras, MD and Donna M Polk, MD, MPH Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women’s Hospital, Boston, MA

Abstract Despite significant advances in prevention and treatment, cardiovascular disease continues to be the leading cause of morbidity and mortality in the United States and worldwide. Nevertheless, the mortality from cardiovascular disease has decreased dramatically over the past few decades. Among the modifiable risk factors, dyslipidemia is a leading contributor to the development of coronary heart disease, and cholesterol-lowering treatment, primarily with statins, has been considered responsible for improvements in cardiovascular outcomes over the past 20 years. As such, physicians and researchers are frequently reevaluating the optimal approach and recommendations for cholesterollowering therapy for the primary prevention of cardiovascular disease. The objectives of this article are to review the evidence and efficacy of cholesterol-lowering therapies and to examine the current major societal guidelines for the management of dyslipidemia and appropriate patient selection.

Keywords Dyslipidemia, cholesterol-lowering treatment, statin, primary prevention, cardiovascular disease Disclosure: The authors have no conflicts of interest to declare Received: October 4, 2016 Accepted: January 18, 2017 Citation: US Cardiology Review 2017;11(1):10–5;. DOI: 10.15420/usc.2016:9:2 Correspondence: Edward T Carreras, MD, Brigham and Women’s Hospital, 75 Francis Street, Boston, MA 02115, USA. E: ecarreras@partners.org

Cardiovascular disease affects more than one-third of American adults and is the leading cause of mortality in the United States and worldwide.1 Only 4.5 % of those over the age of 20 meet the ideal levels of the seven metrics of cardiovascular health including cholesterol levels.1 Of modifiable risk factors, including smoking, hypertension, diabetes, and obesity, dyslipidemia has been shown to be the most strongly associated with myocardial infarction (MI). 1,2 Numerous epidemiological studies have demonstrated that cardiovascular risk increases significantly as low-density lipoprotein cholesterol (LDL-C) increases.3,4 Cholesterol-lowering therapies are thought to be primarily responsible for the reduction in deaths due to coronary heart disease in the United States over the past few decades, and there is a clear association between LDL-C-lowering therapies and improved global outcomes from cardiovascular disease.5–8 The management of dyslipidemia continues to be the cornerstone of primary and secondary prevention of cardiovascular diseases and is a major focus of recent and ongoing study. In this article, we will review the evidence for lifestyle and pharmacological therapies for dyslipidemia and will summarize and compare the current major societal guidelines for cholesterol-lowering therapies for the primary and secondary prevention of cardiovascular disease, with particular focus on recommendations for appropriate patient selection for LDL-C-lowering therapies for primary prevention. This review is based on a literature search performed in PubMed for articles published between 1980 and 2016, using combinations of the following terms: cholesterol, hyperlipidemia, dyslipidemia, cardiovascular

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Access at: www.USCjournal.com

disease, atherosclerosis, coronary artery disease, treatment. References within the obtained publications were also reviewed.

Treatment Strategies Lifestyle Modifications Lifestyle modifications have been shown to lower serum cholesterol levels, with the most notable benefits coming from diet and weight loss. Dietary strategies to improve cholesterol include reducing cholesterol intake to <200 mg daily and reducing total fat intake to <20 % of total caloric intake. Additionally, the inclusion of dietary soluble fiber, phytosterol esters, soy isoflavones, and nuts have all been shown to reduce LDL-C, in most cases by 5–10 mg/dL.8 Physical activity does not reduce LDL-C independent of weight loss, but has been shown to improve cardiovascular health through other mechanisms, and is a cornerstone of weight loss. Overall, through weight loss, reducing dietary cholesterol and fat intake, LDL-C can be lowered by approximately 10–15 %.9

Statins Statins are the cornerstone of treatment for elevated LDL-C levels and are the most commonly prescribed pharmacological agent used to lower LDL-C. Statin medications inhibit hydroxymethylglutaryl CoA reductase, the rate-limiting enzyme in the production of cholesterol, leading to a reduction in intrahepatic cholesterol, up-regulation of hepatic LDL receptors, and enhanced hepatic LDL uptake, thereby lowering serum LDL. Many studies have evaluated the efficacy of statins in the primary and secondary prevention of cardiovascular disease (Table 1).10–21 One meta-analysis of statin trials for primary prevention in low-risk patients

© RADCLIFFE CARDIOLOGY 2017


Therapies and Guidelines for Dyslipidemia Table 1: Major Clinical Trials Evaluating the Efficacy of Statin Therapy Study

Population

WOSCOPS

Drug and

Primary

Mean Follow-up

Baseline Mean

LDL-C

Relative CV Risk

Dose (mg)

Endpoint

(years)

LDL (mg/dL)

Reduction

Reduction (p-value)

6,595 men aged Pravastatin 40 Nonfatal MI, 4.9 192 26 % 45–64 years with CHD death high cholesterol and no history of MI in the west of Scotland

31 % (<0.001)

AFCAPS/ 6,605 patients Lovastatin MI, UA, sudden 5.2 150 25 % without CHD and 20–40 cardiac death average LDL-C TexCAPS

37 % (<0.001)

PROSPER

5,804 patients aged Pravastatin 40 70–82 years with preexisting vascular disease or risk factors

15 % (0.014)

ALLHAT-LLT

10,355 patients Pravastatin 40 Nonfatal MI, 4.8 146 17 % aged ≥55 years with CHD death high cholesterol, HTN, and ≥1 other CHD risk factors

9 % (<0.16)

ASCOT-LLA

10,305 patients with

36 % (0.0005)

HTN, ≥3 risk factors, CHD death and lower than average cholesterol

CARDS

2,838 patients with Atorvastatin 10 type 2 diabetes and without CV disease or high LDL-C

MI, UA with 3.9 117 40 % 37 % (0.001) hospitalization, coronary revascularization, stroke, cardiac arrest, CHD death

ASPEN

2,410 patients with Atorvastatin 10 type 2 diabetes and LDL-C below guideline targets

Nonfatal MI, UA with 4.0 113 29 % hospitalization, CABG, nonfatal stroke, cardiac arrest, CV death

10 % (0.34)

MEGA

7,832 patients with Pravastatin high cholesterol 10–20 and without CV disease in Japan

MI, angina, 5.3 157 15 % coronary revascularization, cardiac death

33 % (0.01)

JUPITER

17,802 patients Rosuvastatin 20 without CV disease, LDL-C, 130 mg/dL and hsCRP 0.2 mg/L

MI, UA with 1.9 108 50 % hospitalization, revascularization, stroke, CV death

44 % (<0.00001)

4S

4,444 patients Simvastatin 20–40 with CHD

MI, cardiac arrest, 5.4 187 38 % 34 % (<0.00001) cardiac death

CARE

4,159 patients with Pravastatin 40 Nonfatal MI, 5.0 139 32 % average LDL-C CHD death and history of MI

24 % (0.003)

LIPID

9,014 patients with Fluvastatin 80 CHD death 6.1 150 25 % recent history of MI or hospitalization for UA

24 % (<0.001)

LIPS

1,677 patients after Fluvastatin 80 first PCI with stable angina, UA, or silent ischemia

Nonfatal MI, 3.9 131 27 % coronary re-intervention, cardiac death

22 % (0.01)

HPS

20,536 patients Simvastatin 40 with CV disease, diabetes, or HTN in the UK

Nonfatal MI, 5.0 131 30 % revascularization, stroke, CHD death

24 % (<0.001)

Nonfatal MI, 4.3 147 11 % UA, cardiac revascularization, resuscitated cardiac arrest, cardiac death

17 % (0.02)

Atorvastatin 10

ALLIANCE 2,442 patients Atorvastatin with CHD and 10–80 hyperlipidemia

Nonfatal MI, 3.2 146 34 % stroke, coronary death

Nonfatal MI,

3.3

133

35 %

ACS = acute coronary syndrome; CABG = coronary artery bypass graft; CHD = coronary heart disease; CV = cardiovascular; hsCRP = high-sensitivity C-reactive protein; HTN = hypertension; LDL-C = low-density lipoprotein cholesterol; MI = myocardial infarction; PCI = percutaneous coronary intervention; UA = unstable angina. Adapted from Wadhera et al. 2016.8

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Risk and Prevention with baseline LDL-C levels of 100–160 mg/dL found that with the use of statins, a 39 mg/dL reduction in LDL-C was associated with a 38 % relative risk reduction in nonfatal MI, coronary revascularization, stroke, or coronary death, as well as a 10 % relative risk reduction in all-cause mortality.21 Furthermore, high-intensity statin therapies, defined as those associated with a ≥50 % LDL-C reduction, were shown to be associated with further reductions in LDL-C and an increase in the relative risk reduction of nonfatal MI, coronary revascularization, stroke, or coronary death of approximately 15 %.21

Ezetimibe reduces dietary and biliary cholesterol absorption by inhibiting the intestinal and hepatic Niemann-Pick C1-Like 1 protein, thereby lowering total cholesterol and LDL-C levels. Early studies comparing ezetimibe with placebo in the absence of statins found that ezetimibe reduces LDL-C by approximately 15–20 %.36,37 A recent large clinical trial evaluating the addition of ezetimibe to statins in patients with prior acute coronary syndrome found an approximately 24  % reduction in LDL-C levels and a 6.4 % reduction in the relative risk of cardiovascular death, major coronary events, or nonfatal stroke at 7 years.38

Patients with diabetes mellitus are at increased risk for cardiovascular disease compared to patients without diabetes mellitus; specifically, diabetes mellitus in the absence of prior MI portends a similar risk for coronary heart disease as prior MI without diabetes mellitus.22–24 Furthermore, patients with diabetes mellitus experience a reduction in cardiovascular events with statin therapy similar to that in patients with known coronary heart disease without diabetes.10,12 For these reasons, diabetes mellitus is considered equivalent to coronary heart disease with respect to cardiovascular risk and guidelines for statin therapy, as discussed below.

PCSK9 Inhibitors

Despite the well-documented benefits from statins, patient adherence to therapy is frequently challenged by adverse effects. The most commonly reported adverse effect with statins is myalgia; however, the incidence of myalgia attributed to statins is often overestimated based on prior observational data, and placebo-controlled studies have shown nearly identical rates of myalgia in statin and placebo groups.25–28 More serious effects, such as rhabdomyolysis, occur far less commonly, with an incidence of approximately 0.04 %.29 Reversible transaminitis occurs in approximately 0.4  % of patients.29 Importantly, there is also a small and dose-dependent increase in the risk of new-onset diabetes associated with statins.30 The risk appears to be approximately 9  % and increases with higher doses.31

Non-statin Therapies In addition to statins, there are several other pharmacological therapies that have been studied for the management of dyslipidemia. Cholestyramine, a bile acid sequestrant, was the first medication studied that demonstrated the ability to significantly reduce LDL-C levels, with an approximately 12 % LDL-C reduction and 19  % relative risk reduction in MI or cardiovascular death when compared with placebo.32 Due to the adverse effects of constipation and gastrointestinal upset, cholestyramine is reserved for those with statin intolerance or with inadequate response to stain therapy. The potential additive benefit of reducing LDL-C and cardiovascular events with the concomitant use of statins and cholestyramine has not been prospectively evaluated. Niacin (nicotinic acid) reduces LDL-C levels by inhibiting the hepatic production of very-low-density lipoprotein cholesterol (VLDL-C) and raises high-density lipoprotein cholesterol (HDL-C) levels by reducing the clearance and transfer of lipids to VLDL-C. Prior to the use of statins, niacin was evaluated against placebo and was found to be effective at lowering total cholesterol and reducing the incidence of nonfatal MI and possibly mortality.33 Despite this, clinical trials evaluating the addition of niacin to statin therapy in patients with cardiovascular disease found no additional clinical benefit, but an increase in adverse events.34,35

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Proprotein convertase subtilisin/kexin type 9 (PCSK9) has been the focus of recent research into the reduction of LDL-C. PCSK9 acts by degrading LDL receptors, thereby reducing the hepatic uptake of LDL.39 Inhibition of PCSK9 leads to decreased LDL receptor breakdown, increased hepatic uptake of LDL, and lower serum LDL levels.40 Studies have shown that loss-of-function mutations of PCSK9 are associated with lower LDL-C levels and a reduction in cardiovascular risk.39 In addition, PCSK9 appears to promote inflammation and endothelial dysfunction, leading to accelerated atherosclerosis, suggesting that PCSK9 inhibition may improve cardiovascular outcomes through mechanisms other than LDL-C reduction alone.41 The findings from trials of two PCSK9 inhibitors have recently been published. A placebo-controlled trial utilizing alirocumab in high-risk patients on statin therapy was found to significantly reduce LDL-C levels by 62 %, with a 48 % reduction in major cardiovascular events.42,43 Evolocumab was also studied against placebo and showed similar results; there was a 61  % reduction in LDL-C and 53  % reduction in major cardiovascular events.44,45 Further large, multicenter clinical trials evaluating both alirocumab and evolocumab are ongoing.42,46 Both PCSK9 inhibitors have been associated with a similar overall rate of adverse events compared to placebo.47 The US Food and Drug Administration has approved both PCSK9 inhibitors as an adjunct to diet and maximally-tolerated statin therapy in adults with atherosclerotic cardiovascular disease or familial hypercholesterolemia who require additional LDL-C lowering.

Novel Agents In addition to PSCK9 inhibitors, there are several other novel therapies for LDL reduction currently being investigated. One pharmacological therapy targets cholesterylester transfer protein (CETP), which normally works to facilitate the transfer of cholesteryl esters and triglycerides from HDL to lipoproteins. CETP inhibition has been shown to lead to increases in HDL and decreases in LDL-C and lipoprotein(a) levels.8 Early studies of CETP inhibitors have failed to show any clinical benefit, while one study of the CETP inhibitor anacetrapib is currently ongoing.48

Major Guidelines Guidelines for the management of dyslipidemia have been published by multiple different national and international medical societies, including joint guidelines from the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS), and from the American College of Cardiology (ACC) and the American Heart Association (AHA) (Figure 1).49 The European guidelines divide patients into four categories based on risk factors and utilize systemic coronary risk estimation

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Therapies and Guidelines for Dyslipidemia Figure 1: Comparison of the American Heart Association/American College of Cardiology (ACC/AHA, left) and European Society of Cardiology/European Atherosclerosis Society (ESC/EAS, right) Guidelines for the Management of Dyslipidemia

Age 21−75

High-intensity statin

Age >75

Moderate-intensity statin

SCORE <1 %

LDL-C <100

No intervention

LDL-C 100–190

Lifestyle intervention

LDL-C >190

Consider drug treatment

LDL-C <100

Lifestyle intervention

LDL-C >100

Consider drug treatment

LDL-C <100

Consider drug treatment

LDL-C >100

Immediate drug treatment

LDL-C <70

Consider drug treatment

LDL-C >70

Immediate drug treatment

Clinical ASCVD

High-intensity statin

LDL-C >190

DM LDL-C 70−189 Age 40−75 y

LDL-C 70−189 Age 40−75 y

10 y ASCVD Risk ≥7.5 %

10 y ASCVD Risk <7.5 %

10 y ASCVD Risk ≥7.5 %

SCORE 1−5 %

High-intensity statin

Moderate-intensity statin

SCORE 5−10 % or high risk

Moderate-intensity statin SCORE ≥10 % or very high risk

ACC/AHA

ESC/EAS

Low-density lipoprotein cholesterol (LDL-C) values are listed in mg/dL. All ages are listed in years. In both guidelines, lifestyle intervention is recommended for all patients in whom drug therapy is also recommended. High-risk patients in the ESC/EAS guidelines include those with severe hypertension or familial hypercholesterolemia. Very-high-risk patients in the ESC/EAS guidelines include those with cardiovascular disease, type 2 diabetes mellitus, type 1 diabetes mellitus with end organ damage, or moderate-to-severe chronic kidney disease. ASCVD = atherosclerotic cardiovascular disease; DM = diabetes mellitus; SCORE = systemic coronary risk estimation.

(SCORE) at 10 years in order to establish LDL-C goals for the initiation of pharmacological therapy. In low-risk patients with a SCORE <1 %, the recommended LDL-C goal is <100 mg/dL, but pharmacological therapy is only recommended if LDL-C remains >190 mg/dL despite lifestyle interventions. Moderate-risk patients are defined as those with a SCORE of 1–5 %, and in these patients pharmacological therapy should be considered if LDL-C is >100 mg/dL despite lifestyle modification. High-risk patients are those with a SCORE of 5–10  %, or those with certain significant risk factors, such as familial hypercholesterolemia or severe hypertension. In these patients, the guidelines recommend pharmacological therapy be added to lifestyle modifications for all patients with LDL-C >100 mg/dL, and consideration of pharmacological therapy in patients with LDL-C <100 mg/dL. Very-high-risk patients are defined as those with documented cardiovascular disease, type 2 diabetes mellitus, type 1 diabetes mellitus with end organ damage, moderate to severe chronic kidney disease, or a SCORE >10 %. In these patients, in addition to lifestyle modification, pharmacological therapy is recommended for all patients with LDL-C >70 mg/dL, and should be considered even for those with LDL-C below this level. The ACC/AHA guidelines were last updated in 2013, with several notable differences when compared to their prior iteration and to the 2011 ESC/ EAS guidelines.50 These guidelines focus on a fixed-dose approach to cholesterol-lowering treatment, in which statin therapy is no longer

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titrated to achieve LDL goals. This update also introduced a new Pooled Cohort Equation, which incorporates age, sex, smoking, blood pressure, total cholesterol, renal function, and the presence or absence of diabetes, left ventricular hypertrophy, and prior MI or stroke, in calculating an estimated risk of developing atherosclerotic cardiovascular disease (ASCVD) at 10 years. The guidelines recommend fixed-dose, high-intensity statin therapy that results in a >50 % reduction in LDL-C for three broad groups of patients: 1) documented ASCVD between the ages of 21 and 75 years; 2) LDL-C >190 mg/dL and age ≥21 years; and 3) LDL-C 70–189 mg/dL, age 40–75 years, diabetes mellitus, and 10-year ASCVD risk ≥7.5 %. Moderate-intensity statin therapy with a 30–50 % reduction in LDL-C is recommended for the following groups of patients: 1) documented ASCVD and age >75 years; 2) LDL-C 70–189 mg/dL, age 40–75 years, diabetes mellitus, and 10-year ASCVD risk <7.5  %; and 3) LDL-C 70–189 mg/dL, age 40–75 years, and 10-year ASCVD risk ≥7.5 %. Similar to the ESC/EAS guidelines, the ACC/AHA recommends lifestyle modification strategies for all patients and selective use of non-statin pharmacological therapies as adjuncts to statin therapy. The updated 2013 ACC/AHA guidelines contained two major changes from the previous iterations. The first is the abandonment of the previously recommended strategy to titrate statin dosing to achieve LDL-C goals. Dyslipidemia therapy, based on patients’ risk profiles, with fixed, high- or moderate-intensity statins is more consistent with the

13


Risk and Prevention Figure 2: Comparison of Predicted Versus Observed Event Rates in the European Prospective Investigation of CancerNorfolk Study Using the 2013 American Heart Association/ American College of Cardiology 10-year Cardiovascular Disease Risk Calculator and the European Systemic Coronary Risk Estimation (SCORE) Calculator ACC/AHA Risk Categories 0.25

CVD Event Rates

0.2

0.1

0.05

<5.0 %

5.0–7.5 %

7.5–10.0 %

>10.0 %

Predicted 10-year total CVD by ACC/AHA

Predicted 10-year fatal CVD by SCORE

Observed 10-year total CVD

Observed 10-year fatal CVD

CVD = cardiovascular disease. Adapted from Ray et al. 2011.53

majority of clinical trials, which tested the efficacy of statin therapy by using fixed doses. One potential major advantage to this strategy is the avoidance of statin underdosing and undertreatment of LDL-C, which may be more likely to occur when clinicians are encouraged to reduce statin dosing if and when a target LDL-C is reached.51 The ACC/AHA guidelines also now recommend less frequent routine LDL-C monitoring, however, which may create more difficulty in identifying adherence success, and leaves a greater degree of uncertainty regarding if and when to add non-statin therapies to improve LDL-C reduction.52 The second notable change is the introduction of the new Pooled Cohort Equation for the estimation of 10-year ASCVD risk. This risk estimator provides a lower threshold for initiating therapy for primary prevention when compared to the prior guidelines. The 7.5 % 10-year threshold for therapy, which carries a recommendation for a fixed-dose moderate-intensity statin in patients aged 40–75 years with LDL-C of 70–189 mg/dL, corresponds to a European SCORE of 2.5 %, at which drug therapy can be considered at LDL-C >100 mg/dL, but is not strictly recommend.53 This paradigm change in the approach to primary prevention and the recommendation to treat a significantly greater number of patients has garnered a considerable amount of publicity and criticism. Some recent studies have suggested that this strategy is a cost-effective method to improve population health.53–56 One study evaluated the European Prospective Investigation of Cancer (EPIC)-Norfolk population in order to assess the impact of the ACC/AHA guidelines on population health.53 The authors found that the new ACC/AHA guidelines would result in up to 65  % more individuals being treated with statins for primary prevention and would mildly overestimate the incidence of ASCVD over 10 years (Figure 2). The authors found no significant benefit

14

Overall, the ACC/AHA guidelines recommend treating an increased number of individuals for primary prevention and recommend treating all patients with higher statin doses, while the ESC/EAS guidelines take a less conservative approach to primary prevention, and recommend generally lower statin doses, titrated to LDL-C levels. The ACC/AHA risk calculator has not been prospectively evaluated and appears to overestimate cardiovascular risk, particularly in some ethnic populations.

Our Approach to Patient Selection

0.15

0

of the ACC/AHA Pooled Cohort Equation over SCORE in the EPICNorfolk population.

Given the major differences between the AHA/ACC and ESC/EAS guidelines, clinicians today are faced with challenges regarding choosing appropriate individuals to treat with statins for the primary prevention of cardiovascular disease. Adopting the AHA/ACC guidelines will result in a significant increase in the number of individuals treated and will significantly reduce average LDL-C levels. However, the long-term cost of this approach is not currently known. Given the burden of cardiovascular disease and enormous success at reducing cardiovascular morbidity and mortality over the past few decades with LDL-lowering therapies, we favor considering a risk-based assessment of patients including the fundamental basis of the 2013 AHA/ACC guidelines, and an individualized patient-based discussion regarding therapy. We view these guidelines as a framework for when to consider therapy, identify patients in whom earlier initiation of statin therapy may be beneficial, and identify those who may benefit from higher doses of statins, such as high-risk diabetics. In patients without known diabetes mellitus or ASCVD who have borderline 10-year risk scores that would warrant therapy, however, we favor an extensive risk and benefit discussion in order to make a joint decision about long-term therapy, taking into account patients’ preferences and values in order to ensure compliance and potential benefit from lipid-lowering therapy.

Conclusion Cardiovascular disease continues to be the number one cause of morbidity and mortality in the United States and worldwide, with treatment of dyslipidemia being the most effective modifiable target for improving cardiovascular outcomes. Statins are the cornerstone of LDLC-lowering therapy, while PCSK-9 inhibitors are now available for addition to maximally-tolerated statin therapy in the treatment of adults with heterozygous familial hypercholesterolemia or clinical atherosclerotic cardiovascular disease, who require additional lowering of LDL-C. The most recent update to the ACC/AHA guidelines recommends treating a greater number of patients for primary prevention and aiming to achieve percentage-based LDL reduction rather than specific LDL levels. The accuracy of the new ACC/AHA risk calculator and the long-term costs of this approach are not currently known. Moving forward, it will be helpful to prospectively validate the Pooled Cohort Equation’s accuracy at predicting cardiovascular risk and to test the results across various ethnic and geographic populations. For now, these new guidelines serve as a framework within which patients can be evaluated, while individual treatment decisions should always involve an individualized patientcentered approach, with consideration of individual risks, benefits, and values in choosing the most appropriate treatment strategy. n

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38. Cannon CP, Blazing MA, Giugliano RP, et al. IMPROVE-IT Investigators. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med 2015;372:2387–97. DOI: 10.1056/NEJMoa1410489; PMID: 26039521 39. Urban D, Poss J, Bohm M, et al. Targeting the proprotein convertase subtilisin/kexin type 9 for the treatment of dyslipidemia and atherosclerosis. J Am Coll Cardiol 2013;62: 1401–8. DOI: 10.1016/j.jacc.2013.07.056; PMID: 23973703 40. Everett BM, Smith RJ, Hiatt WR. Reducing LDL with PCSK9 inhibitors – the clinical benefit of lipid drugs. N Engl J Med 2015;373:1588–91. DOI: 10.1056/NEJMp1508120; PMID: 26444323 41. Walley KR, Thain KR, Russell JA, et al. PCSK9 is a critical regulator of the innate immune response and septic shock outcome. Sci Transl Med 2014;6:258ra143. DOI: 10.1126/ scitranslmed.3008782; PMID: 25320235 42. Robinson JG, Farnier M, Krempf M, et al. ODYSSEY LONG TERM Investigators. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med 2015;372:1489–99. DOI: 10.1056/NEJMoa1501031; PMID: 25773378 43. Joseph L, Robinson JG. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition and the future of lipid lowering therapy. Prog Cardiovasc Dis 2015;58:19–31. DOI: 10.1016/j. pcad.2015.04.004; PMID: 25936907 44. Sabatine MS, Giugliano RP, Wiviott SD, et al. Open-Label Study of Long-Term Evaluation against LDL Cholesterol (OSLER) Investigators. 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 45. Desai NR, Sabatine MS. PCSK9 inhibition in patients with hypercholesterolemia. Trends Cardiovasc Med 2015;25:567–74. DOI: 10.1016/j.tcm.2015.01.009; PMID: 25771732 46. Schwartz GG, Bessac L, Berdan LG, et al. Effect of alirocumab, a monoclonal antibody to PCSK9, on long-term cardiovascular outcomes following acute coronary syndromes: rationale and design of the ODYSSEY outcomes trial. Am Heart J 2014;168: 682–9. DOI: 10.1016/j.ahj.2014.07.028; PMID: 25440796 47. Navarese EP, Kolodziejczak M, Schulze V, et al. Effects of proprotein convertase subtilisin/kexin type 9 antibodies in adults with hypercholesterolemia: a systematic review and meta-analysis. Ann Intern Med 2015;163:40–51. DOI: 10.7326/ M14-2957; PMID: 25915661 48. Cannon CP, Shah S, Dansky HM, et al. Determining the Efficacy and Tolerability Investigators. Safety of anacetrapib in patients with or at high risk for coronary heart disease. N Engl J Med 2010;363:2406–15. DOI: 10.1056/NEJMoa1009744; PMID: 21082868 49. Catapano AL, Reiner Z, De Backer G, et al. European Society of Cardiology and European Atherosclerosis Society. ESC/EAS Guidelines for the management of dyslipidaemias The Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Atherosclerosis 2011;217:3–46. DOI: 10.1016/ j.atherosclerosis.2011.06.012; PMID: 21723445 50. Stone NJ, Robinson JG, Lichtenstein AH, et al. American College of Cardiology/American Heart Association Task Force on Practice Guidelines. 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. J Am Coll Cardiol 2014;63:2889–934. DOI: 10.1016/j.jacc.2013. 11.002; PMID: 24239923 51. Arnold SV, Kosiborod M, Tang F, et al. Patterns of statin initiation, intensification, and maximization among patients hospitalized with an acute myocardial infarction. Circulation 2014;129:1303–9. DOI: 10.1161/CIRCULATIONAHA.113.003589; PMID: 24496318 52. McGinnis B, Olson KL, Magid D, et al. Factors related to adherence to statin therapy. Ann Pharmacother 2007;41:1805–11. DOI: 10.1345/aph.1K209; PMID: 17925498 53. Ray KK, Kastelein JJ, Boekholdt SM, et al. The ACC/AHA 2013 guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular disease risk in adults: the good the bad and the uncertain: a comparison with ESC/EAS guidelines for the management of dyslipidaemias 2011. Eur Heart J 2014;35:960–8. DOI: 10.1093/eurheartj/ehu107; PMID: 24639424 54. Martin SS, Abd TT, Jones SR, et al. 2013 ACC/AHA cholesterol treatment guideline: what was done well and what could be done better. J Am Coll Cardiol 2014;63:2674–8. DOI: 10.1016/ j.jacc.2014.02.578; PMID: 24681146 55. Pencina MJ, Navar-Boggan AM, D’Agostino RB, et al. Application of new cholesterol guidelines to a population-based sample. N Engl J Med 2014;370:1422–31. DOI: 10.1056/NEJMoa1315665; PMID: 24645848 56. Pandya A, Sy S, Cho S, et al. Cost-effectiveness of 10-Year risk thresholds for initiation of statin therapy for primary prevention of cardiovascular disease. JAMA 2015;314:142–50. DOI: 10.1001/ jama.2015.6822; PMID: 26172894

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Risk and Prevention

Proprotein Convertase Subtilisin/Kexin 9 (PCSK9) Inhibition in Patients With or at High Risk of Coronary Heart Disease Shane Prejean, MD and Todd M Brown, MD, MSPH Division of Cardiovascular Disease, University of Alabama at Birmingham, Birmingham, AL

Abstract Proprotein convertase subtilisin/kexin 9 (PCSK9) is an enzyme that binds and inactivates the low-density lipoprotein (LDL) receptor onhepatocytes, leading to higher levels of serum LDL cholesterol (LDL-C). Individuals with ‘loss of function’ mutations in the PCSK9 gene havelower LDL-C levels and are at decreased risk of coronary heart disease. In light of this, inhibition of PCSK9 activity has become a target forreducing LDL-C levels, with approaches including monoclonal antibodies, antisense oligonucleotides, and RNA interference technology. Twomonoclonal antibodies to PCSK9, alirocumab and evolocumab, have recently been FDA approved. Although large-scale clinical trials to assesscardiovascular outcomes are awaited, reductions in LDL-C levels have been demonstrated, with no increase in muscle-related adverse effects.In addition to these monoclonal antibody approaches, inclisiran – a molecule that inhibits PCSK9 synthesis by RNA interference – is currentlyunder development. Phase 1 and 2 studies indicate an LDL-C-lowering effect comparable to that of monoclonal antibodies, with effectspersisting to as long as 180 days. Phase 3 studies are planned investigating dose administration two to three times per year. The aim of this report is to summarize the role of PCSK9 inhibition in the lowering of LDL-C. Approaches to PCSK9 inhibition are discussed, and an up-todate insight into current developments in the field is provided.

Keywords Hypercholesterolemia, low-density lipoprotein cholesterol, monoclonal antibodies, PCSK9, RNA interference Disclosure: SP has no conflicts of interest to declare. TMB receives research funding from Amgen Inc. and is the site principal investigator for a clinical trial funded by Omthera Pharmaceuticals and AstraZeneca. Received: February 20, 2017 Accepted: March 2, 2017 Citation: US Cardiology Review 2017;11(1):16–7. DOI: 10.15420/usc.2017:5:2 Correspondence: Todd M Brown, MD, MSPH, UAB Division of Cardiovascular Disease, LHRB 313, 1720 Second Avenue South, Birmingham, AL, 35294, USA. E: tmbrown@uab.edu

Proprotein convertases are proteolytic enzymes that activate proteins by post-translational alterations in protein structure. Proprotein convertase subtilisin/kexin 9 (PCSK9) is a proprotein convertase that binds and inactivates the low-density lipoprotein (LDL) receptor on the surface of hepatocytes resulting in higher levels of serum LDL cholesterol (LDL-C).1 Over-expression of PCSK9 leads to a decrease in LDL receptor-mediated LDL-C endocytosis and, therefore, increases circulating levels of LDL-C.1 Under-expression of PCSK9 leads to an increase in LDL receptormediated LDL-C uptake and clearance in hepatocytes, lowing serum LDL-C.1 Mendelian studies have provided evidence of the effect of PCSK9 activity on LDL-C levels and ultimately cardiovascular disease. Individuals with ‘gain-of-function’ mutations in PCSK9 have higher LDL-C levels, representing an autosomal dominant form of hypercholesterolemia.2,3 Conversely, individuals with ‘loss-of-function’ mutations in PCSK9 have lower LDL-C levels and lower coronary heart disease (CHD) risk.4 Developments in the understanding of PCSK9 function and its affect on LDL-C have led to the rapid development of therapies targeted at reducing PCSK9 activity. Interference with the activity of PCSK9 by multiple post-translational mechanisms including monoclonal antibodies, antisense oligonucleotides, or RNA interference technology has become a promising target for LDL-C reduction. In 2015, alirocumab and

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evolocumab, two subcutaneously administered monoclonal antibodies to PCSK9, were approved for use by the US Food and Drug Administration.5,6 These agents have been associated with a 40–70 % reduction in LDL-C in individuals with familial hypercholesterolemia and/or atherosclerotic disease when used as monotherapy in individuals intolerant to statins or in addition to statins and/or ezetimibe.7–17 Importantly, there has not been an increase in muscle-related adverse effects, and medication adherence has been as good as with other lipid-lowering agents.7–17 In addition to reductions in LDL-C, one agent, evolocumab, has been associated with coronary plaque regression. In the Global Assessment of Plaque Regression with a PCSK9 Antibody as Measured by Intravascular Ultrasound (GLAGOV) randomized clinical trial, evolocumab 420 mg administered monthly in addition to statin therapy was associated with a greater reduction in percent atheroma volume (PAV) as measured by intravascular ultrasonography as compared to those on statins alone (PAV difference -1.0 %; 95 % CI [-1.8 % to -0.64 %].18 Although large scale clinical trials powered to assess cardiovascular outcomes have yet to be published, one meta-analysis of 10,159 individuals who participated in 24 phase 2 or 3 clinical trials has demonstrated reductions in major adverse cardiovascular events with the use of alirocumab and evolocumab.19 Statistically significant reductions

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PCSK9 Inhibition in all-cause mortality (OR 0.45; 95 % CI [0.23–0.86]) and myocardial infarction (OR 0.49; 95  % CI [0.26–0.93]) were seen with a trend toward a significant reduction in cardiovascular mortality (OR 0.50; 95  % CI [0.23–1.10]).19 Serum creatinine kinase levels were lower in the PCSK9 group, and serious adverse events did not increase with administration of PCSK9 antibodies.19 In addition to monoclonal antibodies directed against PCSK9, agents using RNA interference technology to lower PCSK9 are currently being studied. Small interfering RNA (siRNA) molecules are taken up by hepatocytes and directly bind to the RNA-induced silencing complex (RISC), part of the cells natural machinery.20 Once the siRNA is loaded onto the RISC, the RISC cleaves messenger RNA encoding PCSK9 thereby preventing its translation into protein. Inclisiran is a long-acting, subcutaneously administered synthetic siRNA currently under development. 20 In a phase 1 clinical trial, inclisiran was associated with a similar degree of LDL-C reduction to that observed with PCSK9 antibodies; however, the duration of effect persisted for at least 180 days, demonstrating the potential for administration only once every 3–6 months.21 Importantly, there were no treatment discontinuations because of adverse events or serious adverse events noted.21 Phase 2 clinical trials are currently ongoing, and pre-specified interim analyses of these data have revealed >50 % reductions in LDL-C at 6 months with a 300 mg dose of inclisiran. Subsequent phase 3 trials are planned using the 300 mg dose of inclisiran administered two to three times per year.22 Although the majority of clinical data surrounding the potential cardiovascular benefits of PCSK9 inhibition have been acquired in individuals with familial hypercholesterolemia and/or high risk CHD who were stable, there is increasing interest in the role of PCSK9 inhibition in plaque stabilization in the acute coronary syndrome (ACS) setting.

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Artenstein AW, Opal SM. Proprotein convertases in health and disease. N Engl J Med 2011;365:2507–18. DOI: 10.1056/ NEJMra1106700; PMID: 22204726 Soutar AK, Naoumova RP. Mechanisms of disease: genetic causes of familial hypercholesterolemia. Nat Clin Pract Cardiovasc Med 2007;4:214–25. DOI: 10.1038/ncpcardio0836; PMID: 17380167 Abifadel M, Varret M, Rabès JP, et al. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat Genet 2003;34:154–6. DOI: 10.1038/ng1161; PMID: 12730697 Cohen JC, Boerwinkle E, Mosley TH Jr, Hobbs HH. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med 2006;354:1264–72. DOI: 10.1056/ NEJMoa054013; PMID: 16554528 FDA approves Praluent to treat certain patients with high cholesterol. 2015. Available at: www.fda.gov/NewsEvents/ Newsroom/PressAnnouncements/ucm455883.htm (accessed February 22, 2017). FDA approves Repatha to treat certain patients with high cholesterol. 2015. Available at: www.fda.gov/NewsEvents/ Newsroom/PressAnnouncements/ucm460082.htm (accessed February 22, 2017). McKenney JM, Koren MJ, Kereiakes DJ, et al. Safety and efficacy of a monoclonal antibody to proprotein convertase subtilisin/ kexin type 9 serine protease, SAR236553/REGN727, in patients with primary hypercholesterolemia receiving ongoing stable atorvastatin therapy. J Am Coll Cardiol 2012;59:2344–53. DOI: 10.1016/j.jacc.2012.03.007; PMID: 22463922 Roth EM, McKenney JM, Hanotin C, et al. Atorvastatin with or without an antibody to PCSK9 in primary hypercholesterolemia. N Engl J Med 2012;367:1891–900. DOI: 10.1056/NEJMoa1201832; PMID: 23113833 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

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PCSK9 levels are increased in individuals following ACS, and higher levels of PCSK9 are associated with higher rates of recurrent ACS and death. Potential beneficial effects of PCSK9 inhibition in ACS include reductions in oxidized LDL, inflammatory cells and platelets, and lipoprotein(a) levels.23 Data from large scale clinical trials powered to assess the effect of monoclonal antibodies to PCSK9 on cardiovascular risk are expected to be presented at the 2017 American College of Cardiology (ACC) Annual Scientific Sessions. The results of these studies should provide more definitive data on the role of these agents in individuals with or at high risk of CHD. Until then, clinicians must rely on the limited clinical data currently available when selecting the appropriate patients for this therapy. Some guidance has been provided by the ACC in a recent expert consensus statement on the use of non-statin cholesterol lowering medications.24 Based on this statement, high-risk patients who fail to achieve at least a 50 % reduction in LDL-C or an absolute LDL-C level of <70–100 mg/dL could be considered for PCSK9 inhibition.24 PCSK9 inhibition is a new and exciting mechanism for LDL-C lowering in patients with or at high risk of CHD. Although definitive data on cardiovascular outcomes is thus far lacking, there are good data that the monoclonal antibodies to PCSK9 substantially lower LDL-C and result in regression of coronary atherosclerosis. Preliminary data suggest that they may also significantly reduce cardiovascular events. These agents seem to be well tolerated and not associated with significant adverse events. At present, it remains unclear what the magnitude of cardiovascular risk reduction will be with these agents and what, if any, long term consequences there are to very low LDL-C levels. However, should these agents prove to be safe and effective therapies, they will have a substantial role in the treatment of patients with and at high risk of CHD. n

10. R  aal 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: the Reduction of LDL-C with PCSK9 Inhibition in Heterozygous Familial Hypercholesterolemia Disorder (RUTHERFORD) randomized trial. Circulation 2012;126:2408–17. DOI: 10.1161/ CIRCULATIONAHA.112.144055; PMID: 23129602 11. Sullivan D, Olsson AG, Scott R, et al. Effect of a monoclonal antibody to PCSK9 on low-density lipoprotein cholesterol levels in statin-intolerant patients: the GAUSS randomized trial. JAMA 2012;308:2497–506. DOI: 10.1001/jama.2012.25790; PMID: 23128163 12. 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 13. Koren MJ, Scott R, Kim JB, et al. Efficacy, safety, and tolerability of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 as monotherapy in patients with hypercholesterolaemia (MENDEL): a randomised, double-blind, placebo-controlled, phase 2 study. Lancet 2012;380:1995–2006. DOI: 10.1016/S0140-6736(12)61771-1; PMID: 23141812 14. Stroes E, Colquhoun D, Sullivan D, et al. Anti-PCSK9 antibody effectively lowers cholesterol in patients with statin intolerance: the GAUSS-2 randomized, placebo-controlled phase 3 clinical trial of evolocumab. J Am Coll Cardiol 2014;63:2541–8. DOI: 10.1016/j.jacc.2014.03.019; PMID: 24694531 15. Koren MJ, Lundqvist P, Bolognese M, et al. Anti-PCSK9 monotherapy for hypercholesterolemia: the MENDEL-2 randomized, controlled phase III clinical trial of evolocumab. J Am Coll Cardiol 2014;63:2531–40. DOI: 10.1016/j.jacc.2014.03.018; PMID: 24691094 16. Robinson JG, Nedergaard BS, Rogers WJ, et al. Effect of evolocumab or ezetimibe added to moderate- or highintensity statin therapy on LDL-C lowering in patients with

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hypercholesterolemia: the LAPLACE-2 randomized clinical trial. JAMA 2014;311:1870–82. DOI: 10.1001/jama.2014.4030; PMID: 24825642 Raal FJ, Stein EA, Dufour R, et al. PCSK9 inhibition with evolocumab (AMG 145) in heterozygous familial hypercholesterolaemia (RUTHERFORD-2): a randomised, double-blind, placebo-controlled trial. Lancet 2015;385:331–40. DOI: 10.1016/S0140-6736(14)61399-4; PMID: 25282519 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 Navarese EP, Kolodziejczak M, Schulze V, et al. Effects of proprotein convertase subtilisin/kexin Type 9 antibodies in adults with hypercholesterolemia: A systematic review and meta-analysis. Ann Intern Med 2015;163:40–51. DOI: 10.7326/M142957; PMID: 25915661 Khvorova A. Oligonucleotide therapeutics - A new class of cholesterol-lowering drugs. N Engl J Med 2017;376:4–7. DOI: 10.1056/NEJMp1614154; PMID: 28052224 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 Ray, KK. Inhibition of PCSK9 synthesis via RNA interference: 90 day data from Orion-1-a multi-centre phase-2 randomized controlled trial. Circulation 2016;134:e702–e720. Navarese EP, Kolodziejczak M, Kereiakes DJ, et al. Proprotein convertase subtilisin/kexin type 9 monoclonal antibodies for acute coronary syndrome: A narrative review. Ann Intern Med 2016;164:600–7. DOI: 10.7326/M15-2994; PMID: 26999484 Lloyd-Jones DM, Morris PB, Ballantyne CM, et al. 2016 ACC expert consensus decision pathway on the role of non-statin therapies for LDL-cholesterol lowering in the management of atherosclerotic cardiovascular disease risk: a report of the American College of Cardiology Task Force on Clinical Expert Consensus Documents. J Am Coll Cardiol 2016;68:92–125. DOI: 10.1016/j.jacc.2016.03.519; PMID: 27046161

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Risk and Prevention

Guest Editorial Commentary on the Findings of the GLAGOV Randomized Clinical Trial Jakub Podolec, MD, PhD and Lukasz Niewiara, MD Department of Interventional Cardiology, Jagiellonian University College of Medicine and the John Paul II Hospital, Krakow, Poland

Abstract Evolocumab – a human monoclonal antibody that inhibits proprotein convertase subtilisin/kexin type 9 (PCSK9) – significantly reduces low-density lipoprotein cholesterol levels. This agent has been tested in a series of clinical trials, one of which is discussed here: the GLAGOV study. Statintreated patients with coronary disease were treated with evolocumab or placebo with the result that patients in the evolocumab group low-density lipoprotein cholesterol (LDL-C) levels were significantly lower than the placebo group. Athersclerotic plaque regression was noticed in greater number of patients treated with evolocumab compared with placebo (64.3% versus 47.3%). While we await results from large outcome trials on PCSK9 inhibitors, the GLAGOV trial provides interesting findings of clinical advantages that may extend to LDL-C levels as low as 20 mg/dl.

Keywords PCSK9, evolocumab, lipid lowering therapy, IVUS Citation: US Cardiology Review 2017;11(1):18–9; DOI: 10.15420/usc.11.1.GE Correspondence: Jakub Podolec MD, PhDDepartment of Interventional Cardiology Jagiellonian University College of Medicine and the John Paul II Hospital, Pradnicka 80 Str., 31-202 Krakow, Poland. E: jjpodolec@gmail.com

Atherosclerosis is the primary cause of coronary artery disease morbidity and mortality worldwide.1 Low-density lipoprotein cholesterol (LDL-C)lowering therapies have already become one of the most important in the prevention of atherosclerosis complications.2 Evolocumab is a human monoclonal antibody that inhibits proprotein convertase subtilisin/kexin type 9 (PCSK9) and thus significantly reduces levels of LDL-C, and has been tested in a series of clinical trials on a wide range of lipid disorders.3,4 The Global Assessment of Plaque Regression With a PCSK9 Antibody as Measured by Intravascular Ultrasound (GLAGOV) study was a multicenter, randomized, double-blind, placebo-controlled clinical trial, which assessed the efficacy of the PCSK9 inhibitor evolocumab (Repatha®), measured by invasive intravascular ultrasound (IVUS).5 Patients aged ≥18 years with at least one non-significant coronary artery lesion with diameter stenosis >20 % were enrolled into the trial. All patients had to fulfill the following criteria: • P  atients on stable dose of atorvastatin (20–80 mg daily) (NB: If the dose of atorvastatin was not stable at the time of screening, the patient was introduced in a 4-week lipid stabilization period, after which control lipidogram was performed). • LDL-C levels >80 mg/dl or 60–80 mg/dl in the presence of at least one of the major risk factors (myocardial infarction or hospitalization for unstable in recent 2 years, type 2 diabetes mellitus, extra-coronary atherosclerosis) or minor risk factors including age (men aged ≥50 years; women aged ≥55 years), hypertension (blood pressure ≥140/90 mmHg or current use of antihypertensive medications), low

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high-density lipoprotein (HDL) cholesterol (men: <40 mg/dl; women: <50 mg/dl), family history of premature coronary heart disease (first-degree male relative aged <55 years or female relative aged <65 years), high-sensitivity C-reactive protein ≥2 mg/l, or current cigarette smoking. On screening, coronary angiography and IVUS imaging of coronary artery with non-significant lesion were performed. IVUS results were sent for further analysis to core laboratory (C5 Research, Cleveland Clinic). Evolocumab 420 mg was given subcutaneously, using a disposable autoinjector, each month for 18 months. The control group received placebo in a blinded manner. Patients were controlled every 12 weeks for the presence of significant laboratory deviations. The primary study endpoint was a nominal change in percent atheroma value (PAV) from baseline to week 78 of treatment determined by IVUS. Secondary endpoints included the assessment of nominal change in total atheroma volume (TAV) and the proportion of patients demonstrating any reduction of PAV or TAV from baseline. During the exploratory post-hoc analysis, comparison of the change in PAV and the percentage of patients undergoing regression of PAV in those with an LDL-C <70 mg/dl at baseline and locally weighted polynomial regression curve fitting was performed to examine the association between achieved LDL-C levels and disease progression. From May 3, 2012 to January 12, 2015, a total of 2,628 patients were screened; 1,246 of these were enrolled. From this group, 276 were

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Guest Editorial: The GLACOV Trial excluded based on protocol-specified criteria after lipid stabilization period or withdrawal of consent.

Outcomes Overall, 968 patients were randomized (1:1) either to the intervention group receiving monthly evolocumab (n=484) or the control group receiving subcutaneous injections of placebo (n=484). At 76 weeks’ follow-up, 846 patients (87 %) had evaluable IVUS imaging. Both groups were well balanced according to age, sex, and coronary artery disease risk factors. In addition, baseline PAV and TAV did not differ significantly between groups. Over 18 months, subcutaneous evolocumab 420 mg, used as an additional lipid-lowering therapy, achieved LDL-C levels averaging 36.6  mg/dl compared with 93 mg/dl in the statin-only group; led to significant regression in the mean change in PAV compared with the statin-only group; induced regression in a greater percentage of patients; and showed greater reduction in TAV with significant but not critical coronary artery narrowing. A post-hoc analysis showed an incremental benefit for combination therapy at LDL-C levels as low as 20 mg/dl. After 76 weeks, mean LDL-C levels were significantly lower with evolocumab treatment, showing a 56.3 mg/dl decrease compared with a 0.2 mg/dl increase in the control group. The mean difference between groups was –56.5 mg/dl (95  % CI [–59.7 to –53.4]; p<0.001). The evolocumab-treated group had also decreased levels of apolipoprotein B, triglycerides, and lipoprotein(a). A higher increase in HDL-C levels was observed in the intervention group (3.3 mg/dl versus 0.8 mg/dl in placebo group; p<0.001). Patients treated with evolocumab had a 0.95 % decrease in PAV, whereas patients treated with placebo had a 0.05  % increase in PAV, showing a difference of -1.0 % (95 % CI [-1.8 to -0.65) favoring evolocumab. In addition, decrease in TAV was greater among patients treated with evolocumab (-5.8 mm3 versus -0.9 mm3 in the control group); difference in TAV decrease was -4.9 mm3 (95 % CI [-7.3 to -2.5]; p<0.001) in favor of evolocumab. Plaque regression was induced in a greater percentage of patients receiving evolocumab than placebo (64.3  % versus 47.3  %; difference of 17.0  % [95 % CI [10.4–23.6]; p<0.001 for PAV and 61.5 % versus 48.9 %; difference of 12.5 % [95 % CI [5.9–19.2]; p<0.001 for TAV).

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Barquera S, Pedroza-Tobías A, Medina C, et al. Global overview of the epidemiology of atherosclerotic cardiovascular disease. Arch Med Res 2015;46:328–38. DOI: 10.1016/j.arcmed.2015.06.006; PMID: 26135634. Tsai I-T, Wang C-P, Lu Y-C, et al. The burden of major adverse cardiac events in patients with coronary artery disease. BMC Cardiovasc Disord 2017;17:1. DOI: 10.1186/s12872-016-0436-7; PMID: 28052754. Koren MJ, Giugliano RP, Raal FJ, et al. Efficacy and safety of

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In 144 patients with baseline LDL-C levels of less than 70 mg/dL, evolocumab treatment, compared with placebo, was associated with greater change in PAV at week 78 of IVUS follow-up (-1.97 % versus -0.35 %; between-group difference, -1.62 % [95 % CI [-2.50 % to -0.74 %]; p<0.001). In this subgroup, the percentage of patients with regression of PAV for evolocumab compared with placebo was 81.2 % versus 48.0 % (between-group difference, 33.2 % [95 % CI [18.6 %–47.7 %]; p<0.001). A LOESS plot showed a linear relationship between achieved LDL-C level and PAV progression for LDL-C levels ranging from 110 mg/dL to as low as 20 mg/dl.5

Discussion and Conclusions The GLAGOV trial revealed benefits of combination therapy in patients with baseline LDL-C below the lowest levels recommended by global guidelines (<70 mg/dl). No safety issues, such as excess in new-onset diabetes, myalgia, or neurocognitive adverse effects, were identified at the mean LDL-C levels of 36.6 mg/dl achieved in the trial. However, it should be mentioned that the sample size of the trial was modest, providing limited power for safety assessments. Over the years, LDL-C level has become one of the major factors in atherosclerosis progression. However, the question of how low lipid levels should be reduced to remains unknown. Evidence has grown suggesting that optimal LDL-C levels for patients with coronary disease may be much lower than recommended. While we await results from large outcome trials on PCSK9 inhibitors, the GLAGOV trial provides interesting findings of clinical advantages that may extend to LDL-C levels as low as 20 mg/dl. Further results from wide-scale randomized clinical trials, including the Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER) trial on long-term efficiency of evolocumab in secondary prevention of cardiovascular events,6 will hopefully address the most important questions that still remain unanswered. n

longer-term administration of evolocumab (AMG 145) in patients with hypercholesterolemia: 52-week results from the Open-Label Study of Long-Term Evaluation Against LDL-C (OSLER) randomized trial. Circulation 2014;129:234–43. DOI: 10.1161/CIRCULATIONAHA.1.13.007012; PMID: 24255061 Sabatine 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.

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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. 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 trial. Am Heart J 2016;173:94–101. DOI: 10.1016/j.ahj.2015.11.015; PMID: 26920601.

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Heart Failure

Cardiac Toxicity of Cancer Chemotherapy Aarti Asnani, MD 1 and Randall T Peterson, PhD 2 1. Corrigan Minehan Heart Center, Massachusetts General Hospital, Boston, MA; 2. College of Pharmacy, University of Utah, Salt Lake City, UT

Abstract With the aging of the population, the number of patients diagnosed with cancer has grown significantly over the past few decades. In parallel, survival rates have improved due to the increased efficacy and tolerability of cancer treatments. As such, the acute and long-term toxicities of cancer therapies have become increasingly prominent as contributors to morbidity and mortality in cancer survivors. Cardiac toxicity can occur with a broad range of cancer treatments, from conventional cytotoxic agents to newer targeted and immune-based therapies. Common manifestations of chemotherapy-associated cardiotoxicity include asymptomatic left ventricular dysfunction, congestive heart failure, myocardial ischemia, myocarditis, QT prolongation, and arrhythmia. In this review, we will describe antitumor agents that have commonly been associated with an increased risk of cardiac toxicity, with an emphasis on clinical manifestations, underlying mechanisms, and cardioprotective strategies that can be implemented in this setting.

Keywords Chemotherapy, cardiotoxicity, anthracyclines, trastuzumab, targeted therapies, immune checkpoint blockade Disclosure: The authors have no conflicts of interest to declare. Received: January 31, 2017 Accepted: February 16, 2017 Citation: US Cardiology Review 2017;11(1):20–4. DOI: 10.15420/usc.2017:2:2 Correspondence: Aarti Asnani, MD, Cardio-Oncology Program and Cardiovascular Research Center, Massachusetts General Hospital, 149 13th Street, Room 4.302, Boston, MA 02129, USA. E: aasnani@mgh.harvard.edu

Survival rates among patients diagnosed with cancer have improved dramatically over the past few decades. In 2016, there were an estimated 16 million cancer survivors in the United States, a number expected to increase to 20 million over the subsequent decade.1 One-third of these patients will survive at least 5 years after their initial cancer diagnosis, largely due to cancer therapies that are more efficacious and better tolerated. However, many of these treatments have the potential to contribute to cardiac toxicities that can affect quality of life, and in many cases, overall survival (see Table 1). Moreover, the development of cardiac toxicities can prevent clinicians from achieving effective doses of chemotherapy or prompt them to choose suboptimal cancer treatment regimens. At present, data to guide management of chemotherapyinduced cardiac toxicities stem from observational studies and small randomized trials, and the majority of recommendations are driven by clinical expertise (see Table 2). Here we will review a number of antitumor agents that have been associated with significant cardiac toxicity, from traditional cytotoxic chemotherapies that have been in use for decades to the newer targeted therapies and immune checkpoint inhibitors.

Cytotoxic Chemotherapy Anthracyclines The anthracyclines were the first major class of chemotherapies to be associated with cardiac toxicity. Anthracyclines are derivatives of Streptomyces that were originally discovered to have antitumor properties in the 1960s2 and first linked to cardiac toxicity in the early 1970s.3 Given the extensive data supporting their efficacy, anthracyclines are commonly used for the treatment of breast cancer, leukemia,

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lymphoma, and sarcoma, despite the advent of newer targeted therapies. The anthracycline doxorubicin (Adriamycin®) is well recognized for increasing the risk of cardiomyopathy, with the risk of congestive heart failure (CHF) increasing in proportion to the lifetime cumulative dose administered.4 Although the highest rates of cardiac toxicity have been described with cumulative doses exceeding 400 mg/m2, CHF has been reported in patients exposed to much lower doses.5 A recent study suggested that 9 % of patients treated with anthracyclines experienced cardiotoxicity, defined as a decline in left ventricular ejection fraction by >10 percentage points to an absolute value of <50 % within the first year following completion of anthracycline-based chemotherapy.6 Importantly, the risk of anthracycline-associated cardiotoxicity increases substantially when combined with other common cancer treatments such as chest radiation and trastuzumab.7 Despite decades of investigation, the precise mechanisms of anthracycline-induced cardiotoxicity have not been well defined. Prior work has focused primarily on the role of oxidative stress.8 Doxorubicin forms a semiquinone radical that reacts rapidly with oxygen to form a superoxide anion, leading to the production of hydroxyl radicals in the presence of heavy metals such as iron.9 In addition, doxorubicin binds directly to iron to generate free radicals.10 Doxorubicin-induced oxidative stress has been proposed to be mediated by mitochondrial iron accumulation,11 doxorubicin’s interaction with the beta isoform of topoisomerase II (Top2beta),12 and autophagy.13 However, despite evidence implicating oxidative stress as a common downstream feature of doxorubicin-induced cardiomyopathy, antioxidants are ineffective in

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Cardiac Toxicity of Chemotherapy Table 1: Mechanisms of Cardiotoxicity Associated with Cancer Treatments Type of Cancer

Specific Agents

Treatment

FDA-Approved

Proposed

Indications Mechanisms of

Cardiotoxicity

Is Risk of Cardiac

Is Risk of Cardiac

Toxicity Modified

Toxicity Dose-

by Pre-Existing

Dependent?

Cardiovascular

Disease/ Risk

Factors?

Anthracyclines Doxorubicin Daunorubicin Epirubicin Idarubicin Mitoxantrone

Yes Yes

Multiple myeloma Hodgkin disease Lymphoma Leukemia SCC of the head/ neck Tumors of the breast, ovary, prostate, stomach, thyroid, lung

Oxidative stress73,74 Mitochondrial dysfunction75,76 Mitochondrial iron accumulation11 Interaction with Top2beta12 Autophagy13

Fluoropyrimidines 5-Fluorouracil Capecitabine

Tumors of the colon, liver, pancreas, rectum, stomach, breast, ovary

Anti-HER2 Trastuzumab Pertuzumab Lapatinib

HER2-overexpressing breast cancer and metastatic gastric cancer

VEGF pathway inhibitors Sunitinib Sorafenib Wide range of hematologic Imatinib Dasatinib malignancies and solid Nilotinib tumors BTK inhibitor Ibrutinib

Protein kinase Unknown C-mediated vasoconstriction37 Impaired ROS handling38 Direct endothelial toxicity39

Not clearly established

Antagonism of HER2 pathway41,42

No

Yes

Sunitinib: Depletion of Likely coronary microvascular pericytes77 Sorafenib: Inhibition of Raf-1/B-raf78

Waldenström Under investigation Unknown macroglobulinemia Refractory CLL Refractory mantle cell lymphoma

Immune checkpoint Nivolumab Pembrolizumab Melanoma NSCLC Under investigation Unknown inhibitors Atezolizumab Ipilimumab RCC Head and neck cancer Hodgkin’s lymphoma Bladder cancer

Varies by agent; not clearly established

Not clearly established

Not clearly established; risk is likely increased with combination immune checkpoint inhibition

BTK = Bruton’s tyrosine kinase; CLL = chronic lymphocytic leukemia; FDA = U.S. Food and Drug Administration; HER2 = human epidermal growth factor receptor 2; NSCLC = non-small cell lung cancer; RCC = renal cell carcinoma; ROS = reactive oxygen species; SCC = squamous cell carcinoma; Top2beta = beta isoform of topoisomerase 2; VEGF = vascular endothelial growth factor.

preventing cardiotoxicity in patients.14,15 Similarly, iron chelators such as deferasirox have failed to protect against doxorubicin cardiotoxicity in preclinical models.16 Liposomal formulations can be used as alternatives to traditional anthracyclines with reduced rates of cardiotoxicity.17 These agents preferentially enter into the leaky microvasculature of tumors, but have limited extravasation into cardiomyocytes.18 Given the increased cost of liposomal formulations, as well as the increased risk of mucositis and hand–foot syndrome, they are used primarily in the setting of refractory or metastatic disease where high doses of anthracyclines are required. Based on extensive literature supporting the use of neurohormonal blockade in other types of cardiomyopathy, a few small, randomized clinical trials have been performed to examine the role of beta blockade and angiotensin-receptor blockade for the primary prevention of anthracycline-induced LV dysfunction.19–23 Currently, dexrazoxane is

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the only U.S. Food and Drug Administration (FDA)-approved drug used clinically to prevent doxorubicin-induced cardiomyopathy. It is believed to chelate intracellular iron, block iron-assisted oxidative radical production, and inhibit Top2beta.11,12,24,25 In practice, however, the use of dexrazoxane has been limited by concerns that it may interfere with doxorubicin’s ability to kill tumor cells26 and may also induce secondary malignancies.27 As such, the FDA has restricted its use to patients with metastatic breast cancer who have received a cumulative lifetime dose of at least 300 mg/m2 of doxorubicin or an equivalent dose of other anthracyclines. However, subsequent trials have not suggested any decrease in antitumor efficacy with the use of dexrazoxane, and similar oncologic response rates were reported in a large Cochrane meta-analysis.28 Similarly, two subsequent reports of childhood survivors of acute lymphoblastic leukemia who were treated with dexrazoxane did not suggest any increase in the rate of secondary malignancies.29,30 Thus, many clinicians continue to prescribe dexrazoxane in patients receiving a high cumulative dose of

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Heart Failure Table 2: Clinical Manifestations and Management of Cardiotoxicity Associated with Cancer Treatments Type of Cancer

Most Common Manifestations

Proposed Management

Clinical Trial Data to

Toxicity Permanent

Treatment

of Cardiotoxicity

Strategies

Guide Cardioprotective

or Reversible?

Therapy

Anthracyclines LV dysfunction CHF

Substitute liposomal formulation Neurohormonal blockade Dexrazoxane Discontinuation of therapy for CHF

Neurohormonal Often permanent blockade6,19,20,22,79,80 Statins81,82 Dexrazoxane28

Fluoropyrimidines Coronary vasospasm

Nitrates Calcium-channel blockers

None

Often reversible

Anti-HER2 LV dysfunction CHF

Interruption or discontinuation of therapy Neurohormonal blockade

Neurohormonal blockade22,83,84

Often reversible

VEGF pathway inhibitors Hypertension LV dysfunction CHF ACS QT prolongation

Hypertension: standard treatment; continue therapy. LV dysfunction, CHF, ACS: Interruption or discontinuation of therapy

None

Often reversible

BTK inhibitor

Standard therapies for AF

None

Often reversible

Discontinuation of therapy Steroids Infliximab Antithymocyte globulin

None

Unknown

AF

Immune checkpoint Myocarditis inhibitors

ACS = acute coronary syndrome; BTK = Bruton’s tyrosine kinase; CHF = congestive heart failure; LV = left ventricular; VEGF = vascular endothelial growth factor.

anthracyclines, particularly in those with pre-existing cardiovascular disease or other risk factors for the development of cardiotoxicity.

Fluoropyrimidines The fluoropyrimidines 5-fluorouracil and its oral prodrug capecitabine are commonly used in the treatment of gastrointestinal malignancies. Coronary vasospasm leading to myocardial ischemia has been widely described in association with fluoropyrimidine treatment, typically manifested by the development of angina.31 Notably, the presence of pre-existing ischemic heart disease may increase the risk of developing fluoropyrimidine-induced cardiotoxicity. 32 CHF, myocarditis, and ventricular arrhythmias have also been reported, suggesting a direct myocardial toxicity.33–35 Although cardiotoxicity is typically reversible on withdrawal of the offending agent, sudden death has been reported in the setting of fluoropyrimidine use.36 Proposed mechanisms of coronary vasospasm include protein kinase C-mediated vasoconstriction,37 impaired handling of reactive oxygen species,38 and direct endothelial toxicity.39 Calcium-channel blockers and nitrates are often prescribed for prophylaxis in patients suspected to have fluoropyrimidine-induced coronary vasospasm, although their efficacy in preventing subsequent episodes of vasospasm is debated.

include two humanized monoclonal antibodies, trastuzumab and pertuzumab, as well as the small-molecule inhibitor lapatinib. Cardiotoxicity arising from these therapies is most likely an on-target effect, as signaling through the HER2/neuregulin pathway is important in the cardiomyocyte response to injury during myocardial ischemia41 and anthracycline exposure.42 Initial studies demonstrated rates of LV dysfunction as high as 8 % for trastuzumab alone and 30  % for concomitant trastuzumab and anthracycline therapy,43 although estimates of cardiac toxicity have varied widely in subsequent clinical trials and community-based observational studies. Recent data suggest that combination therapy incorporating both trastuzumab and pertuzumab does not seem to increase the risk of cardiotoxicity.44 Of the three agents currently in use, lapatinib appears to be associated with the lowest risk of cardiotoxicity.45 Interruption or cessation of anti-HER2 therapy often results in recovery of LV function, although breast cancer outcomes may be affected as a result.46 If trastuzumab is interrupted due to cardiotoxicity, many patients experience recovery of LV function and can be safely re-challenged to complete a course of therapy. Late cardiotoxicity does not seem to occur after cessation of anti-HER2 therapy, unless patients are re-exposed to cardiotoxic chemotherapy.47

Targeted Therapies Anti-Human Epidermal Growth Factor Receptor 2 Therapy Recent developments in molecular profiling have led to a rapid increase in the number of cancer therapies targeting specific tyrosine kinases that are overexpressed in tumor tissue, particularly those involved in growth factor signaling. At present, the most commonly used targeted therapies are those that inhibit the human epidermal growth factor receptor 2 (HER2), which is overexpressed in approximately 25 % of all breast tumors,40 as well as some gastrointestinal and other tumors. Currently available therapies targeting the HER2 receptor

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Vascular Endothelial Growth Factor Pathway Inhibitors Inhibitors of the vascular endothelial growth factor signaling pathway are becoming increasingly used in the treatment of a number of malignancies, in particular renal cell carcinoma and gastrointestinal stromal tumor. Currently available agents range from monoclonal antibodies such as bevacizumab to small-molecule inhibitors such as sunitinib and sorafenib. Most of the small-molecule inhibitors in use today are multitargeted and thus affect the activity of a number of different tyrosine kinases, making it difficult to ascertain whether cardiotoxicity is related to on-target and/or off-target effects. In general, agents with a broad

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Cardiac Toxicity of Chemotherapy kinome-binding profile such as sunitinib have been associated with high rates of hypertension and LV dysfunction, although these effects are often reversible on discontinuation of the offending agent.48 It remains unclear whether the cardiomyopathy observed with these agents stems from direct toxicity to cardiomyocytes, or whether it is secondary to underlying vascular dysfunction and endothelial toxicity.49 Hypertension does appear to be an on-target effect, and in renal cell carcinoma, the development of hypertension correlates with increased efficacy of treatment and improved cancer outcomes.50 QT prolongation has also been observed with many of these agents51 and may be exacerbated by electrolyte abnormalities and other QT-prolonging medications such as antiemetics. In general, a prolongation of the corrected QT interval to >500 ms warrants a discussion of the risks and benefits of continuing therapy, although the underlying mechanisms and risk of developing torsades de pointes in this setting remain unclear.

Ibrutinib The irreversible Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib has been associated with high rates of AF. Ibrutinib is currently used for the treatment of relapsed or refractory chronic lymphocytic leukemia and mantle cell lymphoma as well as Waldenström macroglobulinemia. Initial clinical trials demonstrated rates of AF ranging 3–12 % in patients treated with ibrutinib.52,53 Notably, patients in these studies were older and had prior exposure to anthracyclines, factors that may have contributed to the high rates of AF observed. Preliminary work suggests that on-target effects may contribute to ibrutinib-mediated AF.54 However, newer BTK inhibitors have not been associated with increased rates of AF,55 suggesting an off-target mechanism. Although discontinuation of ibrutinib therapy is necessary in some patients, others respond well to standard treatments for AF and can continue ibrutinib at a full or reduced dose.56

Immune Checkpoint Inhibitors The use of immune checkpoint blockade has become widespread for the treatment of metastatic melanoma57–59 and increasingly for other indications such as non-small cell lung cancer60 and renal cell carcinoma.61 Currently available agents include pembrolizumab, nivolumab, and atezolizumab, which target the programmed cell death protein-1 (PD-1) pathway, and ipilimumab, which targets cytotoxic T-lymphocyteassociated protein 4 (CTLA-4). These monoclonal antibodies modulate the T-cell-inhibitory responses that allow for tumor evasion from host immunity. As a result, treatment with these agents results in T-cell

1. Bluethmann SM, Mariotto AB, Rowland JH. Anticipating the “Silver Tsunami”: prevalence trajectories and comorbidity burden among older cancer survivors in the United States. Cancer Epidemiol Biomarkers Prev 2016;25:1029–36. DOI: 10.1158/1055-9965.EPI-16-0133; PMID: 27371756. 2. Dubost M, Ganter P, Maral R, et al. A New antibiotic with cytostatic properties: rubidomycin. C R Hebd Seances Acad Sci 1963;257:1813–5. PMID: 14090569. 3. Lefrak EA, Pitha J, Rosenheim S, Gottlieb JA. A clinicopathologic analysis of adriamycin cardiotoxicity. Cancer 1973;32:302–14. PMID: 4353012. 4. Mulrooney DA, Yeazel MW, Kawashima T, et al. Cardiac outcomes in a cohort of adult survivors of childhood and adolescent cancer: retrospective analysis of the Childhood Cancer Survivor Study cohort. BMJ 2009;339:b4606. PMID: 19996459. 5. Von Hoff DD, Layard MW, Basa P, et al. Risk factors for doxorubicin-induced congestive heart failure. Ann Intern Med 1979;91:710–7. PMID: 496103.

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activation and proliferation, prompting a robust immune response against cancer cells.62 The cardiotoxicity of immune checkpoint inhibitors, while rare, has become increasingly important with the application of these therapies to expanding populations, especially when anti-PD-1 and anti-CTLA-4 agents are used in combination. Myocarditis is the predominant manifestation of cardiotoxicity, as described in initial clinical trials63,64 as well as case reports.65 A recent report highlighted two patients treated with combination immune checkpoint blockade and diagnosed with myositis as well as fulminant myocarditis; both patients died from cardiotoxicity.66 In these patients, endomyocardial biopsy demonstrated clonal T-cell infiltrates that were similar to those seen in tumor tissue. Preclinical models have suggested that modulation of the PD-1 pathway can lead to immune-mediated cardiovascular toxicity, primarily in the form of autoimmune myocarditis. Knockout of the PD-1 receptor in mice causes severe dilated cardiomyopathy characterized by high levels of immunoglobulin G autoantibodies that react specifically to cardiac troponin I.67,68 In mouse models of lupus and other experimentally induced inflammatory states, the PD-1 pathway has been recognized as an essential mediator of autoimmune myocarditis69–71 and has been similarly associated with high-titer autoantibodies against cardiac myosin.71 Proposed therapies include high-dose steroids, anti-tumor necrosis factor-alpha antibodies such as infliximab, and antithymocyte globulin, although there is currently no evidence to support an improvement in clinical outcomes with these measures.

Conclusion Over the past decade, efficient, target-based development of antitumor agents has facilitated the introduction of several new cancer therapies, many of which are being approved for new types of malignancy each year. In 2016 alone, the FDA approved the use of targeted therapies and immune checkpoint inhibitors for 19 new indications.72 Many targeted cancer therapies are relatively well tolerated compared with conventional cytotoxic chemotherapy, enabling long-term use in some patients. Cardiologists will thus be faced with the challenge of managing a range of cardiac toxicities that can significantly impact patient morbidity and mortality. Efforts to understand the underlying mechanisms and molecular predictors of cardiotoxicity will be essential to identify patients at high risk and to guide decisions regarding cardioprotection. Collaboration between cardiologists and oncologists in managing cardiotoxicity will be of the utmost importance to ensure the best outcomes in patients receiving these therapies. n

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11. Ichikawa Y, Ghanefar M, Bayeva M, et al. Cardiotoxicity of doxorubicin is mediated through mitochondrial iron accumulation. J Clin Invest 2014;124:617–30. DOI: 10.1172/ JCI72931; PMID: 24382354. 12. Zhang S, Liu X, Bawa-Khalfe T, et al. Identification of the molecular basis of doxorubicin-induced cardiotoxicity. Nat Med 2012;18:1639–42. DOI: 10.1038/nm.2919; PMID: 23104132. 13. Li DL, Wang ZV, Ding G, et al. Doxorubicin blocks cardiomyocyte autophagic flux by inhibiting lysosome acidification. Circulation 2016;133:1668–87. DOI: 10.1161/CIRCULATIONAHA.115.017443; PMID: 26984939. 14. Myers C, Bonow R, Palmeri S, et al. A randomized controlled trial assessing the prevention of doxorubicin cardiomyopathy by N-acetylcysteine. Semin Oncol 1983;10(1 Suppl 1):53–5. PMID: 6340204. 15. Legha SS, Wang YM, Mackay B, et al. Clinical and pharmacologic investigation of the effects of alpha-tocopherol on adriamycin cardiotoxicity. Ann N Y Acad Sci 1982;393:411–8. PMID: 6959564.

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Med 2015;373:1803–13. DOI: 10.1056/NEJMoa1510665; PMID: 26406148. 62. Sharma P, Allison JP. Immune checkpoint targeting in cancer therapy: toward combination strategies with curative potential. Cell 2015;161:205–14. DOI: 10.1016/j.cell.2015.03.030; PMID: 25860605. 63. Eggermont AM, Chiarion-Sileni V, Grob JJ, et al. Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): a randomised, double-blind, phase 3 trial. Lancet Oncol 2015;16:522–30. DOI: 10.1016/S14702045(15)70122-1; PMID: 25840693. 64. Brahmer JR, Tykodi SS, Chow LQ, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med 2012;366:2455–65. DOI: 10.1056/NEJMoa1200694; PMID: 22658128. 65. Laubli H, Balmelli C, Bossard M, et al. Acute heart failure due to autoimmune myocarditis under pembrolizumab treatment for metastatic melanoma. J Immunother Cancer 2015;3:11. DOI: 10.1186/s40425-015-0057-1; PMID: 25901283. 66. Johnson DB, Balko JM, Compton ML, et al. Fulminant myocarditis with combination immune checkpoint blockade. N Engl J Med 2016;375:1749–55. DOI: 10.1056/NEJMoa1609214; PMID: 27806233. 67. Nishimura H, Okazaki T, Tanaka Y, et al. Autoimmune dilated cardiomyopathy in PD-1 receptor-deficient mice. Science 2001;291:319–22. DOI: 10.1126/science.291.5502.319; PMID: 11209085. 68. Okazaki T, Tanaka Y, Nishio R, et al. Autoantibodies against cardiac troponin I are responsible for dilated cardiomyopathy in PD-1-deficient mice. Nat Med 2003;9:1477–83. DOI: 10.1038/ nm955; PMID: 14595408. 69. Lucas JA, Menke J, Rabacal WA, et al. Programmed death ligand 1 regulates a critical checkpoint for autoimmune myocarditis and pneumonitis in MRL mice. J Immunol 2008;181:2513–21. PMID: 18684942. 70. Tarrio ML, Grabie N, Bu DX, et al. PD-1 protects against inflammation and myocyte damage in T cell-mediated myocarditis. J Immunol 2012;188:4876–84. DOI: 10.4049/ jimmunol.1200389; PMID: 22491251. 71. Wang J, Okazaki IM, Yoshida T, et al. PD-1 deficiency results in the development of fatal myocarditis in MRL mice. Int Immunol 2010;22:443–52. DOI: 10.1093/intimm/dxq026; PMID: 20410257. 72. U.S. Food and Drug Administration. Hematology/Oncology (Cancer) Approvals & Safety Notifications. Available at: http://bit. ly/2lQn47e (accessed February 23, 2017) 73. Doroshow JH, Davies KJ. Redox cycling of anthracyclines by cardiac mitochondria. II. Formation of superoxide anion, hydrogen peroxide, and hydroxyl radical. J Biol Chem 1986;261:3068–74. PMID: 3005279. 74. Rajagopalan S, Politi PM, Sinha BK, Myers CE. Adriamycin-induced free radical formation in the perfused rat heart: implications for cardiotoxicity. Cancer Res 1988;48:4766–9. PMID: 2842038. 75. Zhou S, Starkov A, Froberg MK, et al. Cumulative and irreversible cardiac mitochondrial dysfunction induced by doxorubicin. Cancer Res 2001;61:771–7. PMID: 11212281. 76. Liu Y, Asnani A, Zou L, et al. Visnagin protects against doxorubicin- induced cardiomyopathy through modulation of mitochondrial malate dehydrogenase. Sci Transl Med 2014;6:266ra170. DOI: 10.1126/ scitranslmed.3010189; PMID: 25504881. 77. Chintalgattu V, Rees ML, Culver JC, et al. Coronary microvascular pericytes are the cellular target of sunitinib malate-induced cardiotoxicity. Sci Transl Med 2013;5:187ra69. DOI: 10.1126/ scitranslmed.3005066; PMID: 23720580. 78. Cheng H, Kari G, Dicker AP, et al. A novel preclinical strategy for identifying cardiotoxic kinase inhibitors and mechanisms of cardiotoxicity. Circ Res 2011;109:1401–9. DOI: 10.1161/ CIRCRESAHA.111.255695; PMID: 21998323. 79. Cardinale D, Colombo A, Sandri MT, et al. Prevention of high-dose chemotherapy-induced cardiotoxicity in high-risk patients by angiotensin-converting enzyme inhibition. Circulation 2006;114:2474–81. DOI: 10.1161/CIRCULATIONAHA.106.635144; PMID: 17101852. 80. Cardinale D, Colombo A, Lamantia G, et al. Anthracyclineinduced cardiomyopathy: clinical relevance and response to pharmacologic therapy. J Am Coll Cardiol 2010;55:213–20. DOI: 10.1016/j.jacc.2009.03.095; PMID: 20117401. 81. Acar Z, Kale A, Turgut M, et al. Efficiency of atorvastatin in the protection of anthracycline-induced cardiomyopathy. J Am Coll Cardiol 2011;58:988–9. DOI: 10.1016/j.jacc.2011.05.025; PMID: 21851890. 82. Seicean S, Seicean A, Plana JC, et al. Effect of statin therapy on the risk for incident heart failure in patients with breast cancer receiving anthracycline chemotherapy: an observational clinical cohort study. J Am Coll Cardiol 2012;60:2384–90. DOI: 10.1016/ j.jacc.2012.07.067; PMID: 23141499. 83. Seicean S, Seicean A, Alan N, et al. Cardioprotective effect of beta-adrenoceptor blockade in patients with breast cancer undergoing chemotherapy: follow-up study of heart failure. Circ Heart Fail 2013;6:420–6. DOI: 10.1161/ CIRCHEARTFAILURE.112.000055; PMID: 23425978. 84. Pituskin E, Mackey JR, Koshman S, et al. Multidisciplinary Approach to Novel Therapies in Cardio-Oncology Research (MANTICORE 101-Breast): a randomized trial for the prevention of trastuzumab-associated cardiotoxicity. J Clin Oncol 2016:JCO2016687830. PMID: 27893331.

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Interventional Cardiology

When to Use Bioresorbable Vascular Scaffolds Xiaoyu Yang, MD, Mohamed Ahmed, MD and Donald E Cutlip, MD Division of Cardiology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA

Abstract The development of the drug eluting stent (DES) was an important milestone in percutaneous treatment of coronary artery disease. The DES overcomes vessel recoil and restenosis to decrease the high rate of target lesion revascularization associated with balloon angioplasty and bare metal stents. Despite these benefits, the DES has an ongoing risk of stent-related complications because of permanent implantation of a foreign body and restriction of vascular vasomotion. Bioresorbable vascular scaffolds (BVS) are designed to provide mechanical support and drug delivery similar to the DES, followed by complete resorption over several years. Recent trials have demonstrated clinical non-inferiority of the BVS compared with contemporary DES, although certain clinical outcomes are concerning, particularly with regard to higher rates of scaffold thrombosis. The theoretical long-term benefits are promising, but remain unproven. Early adoption of this new technology in the United States should apply the lessons learned regarding rigorous strategies to decrease adverse events, including careful patient and lesion selection and meticulous implantation techniques.

Keywords Bioresorbable vascular scaffolds, coronary artery disease, percutaneous coronary intervention, stent thrombosis Disclosure: XY and MA have no relevant conflicts of interest to declare. DEC receives research support from Boston Scientific and CeloNova. Acknowledgement(s): XY and MA contributed equally to the content of this review Received: February 12, 2017 Accepted: February 24, 2017 Citation: US Cardiology Review 2017;11(1):25–30; DOI: 10.15420/usc.2017:3:2 Correspondence: Donald E Cutlip, MD, Division of Cardiovascular Medicine, Department of Medicine, Beth Israel Deaconess Medical Center, 185 Pilgrim Road, Baker 4, Boston, MA 02215, USA. E: dcutlip@bidmc.harvard.edu

Over the past 35 years, treatment of coronary artery disease and acute coronary syndrome has changed drastically. Balloon angioplasty offered an early mechanical solution but carried a high risk for acute complications and subsequent restenosis, mainly from recoil. The bare metal stent (BMS) improved restenosis because of recoil, but still carried a relatively high rate of restenosis because of excessive neointimal hyperplasia. The drug eluting stent (DES) further decreased restenosis by eluting anti-proliferative drugs over time and reducing neointima. However, the first generation of DES raised concerns of increased late and very late stent thrombosis, which were mitigated by prolonged duration of antiplatelet drugs. Newer generations of DES now have lower stent thrombosis risk (<1 % at 1 year),1 particularly when combined with dual antiplatelet therapy (DAPT), but the permanent metal structure in the coronary artery continues to create an ongoing risk of restenosis and stent thrombosis. Late events are related to persistent inflammation, neoatherosclerosis within the stented segment, and inability to restore normal vessel architecture and physiologic function in the presence of a metal structure. Recently, several new stent constructs have been studied and approved in the United States (US). The SYNERGY™ stent (Boston Scientific)2 is an everolimus-eluting stent (the same drug and platinum chromium alloy as the Promus Premier™ second-generation DES) with an abluminal polymer that absorbs in a few months, leaving behind a BMS. This device has demonstrated non-inferiority to a durable polymer everolimus-eluting

© RADCLIFFE CARDIOLOGY 2017

stent and is being evaluated for the safety of reducing the duration of antiplatelet therapy to 3 months. Bioresorbable vascular scaffolds (BVS) also use antirestenotic drugs identical to the second-generation DES, but the entire scaffold resorbs over several years. Absorb™ (Abbott) and DESolve™ (Elixir Medical Corporation) are poly-L-lactic acid based BVS that degrade by hydrolysis. DREAMS (Biotronik) is a magnesium-based BVS that degrades by oxidation–reduction reactions. The early experiences and large registry data from Europe led to the Conformité Européene (CE) Mark of Absorb in 2011 and DESolve in 2013. Subsequently, randomized trials in the US, Japan, and China led to the approval of Absorb in these countries. This review will focus on available data for the Absorb BVS and present a rational strategy for adoption of its use for clinical practice in the US. The goals for a BVS are to provide adequate radial support for a period long enough to avoid early recoil, release anti-proliferative drug for prevention of restenosis, and then resorb early enough to reap the clinical benefits of not leaving a metal device within the artery. Unlike most recent advances in coronary stent technology, the design of the BVS requires the use of thick struts to meet the goal of adequate radial support from a bioresorbable material. For example, the Absorb BVS strut thickness is 150 μm compared with strut thickness of 80–90 μm for contemporary metallic DES. The potential benefits of strut thickness <100 μm of metallic stents for reduced thrombogenicity and neointimal hyperplasia have been demonstrated3 and the potentially negative

Access at: www.USCjournal.com

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Interventional Cardiology impact on early and late outcomes of the thicker struts of BVS require consideration. The engineering of the current Absorb BVS allows for an early phase post-percutaneous coronary intervention (PCI; 0–6 months), during which the Absorb BVS provides enough radial strength for mechanical support to maintain vessel patency, while antirestenotic drugs are eluted to prevent restenosis. By 6–12 months, the BVS begins to lose radial strength and reduce mechanical restraints on the vessel to allow healing of the native vessel and restoration of vasoregulation. Once completely resorbed by 3 years, late adaptive remodeling will accommodate new intramural plaque. The restoration of vasomotion and pulsatility has been demonstrated by response to acetylcholine and nitrates.4,5 Optical coherence tomography (OCT) performed 5 years postBVS implantation demonstrates normal intima, media, and adventitia of the coronary artery, the so-called ‘golden tube.’6,7 Other potential practical benefits after the BVS is fully resorbed include the ability to perform coronary artery bypass, ‘unjailing’ of side branch vessels, better coronary computerized tomography imaging without artifacts from metallic stents, and treating restenosis without multiple layers of stents.

Historical Background and Early Data The first successful use of a fully degradable stent in human was the poly-L-lactic acid based non-drug-eluting Igaki-Tamai scaffold (Kyoto Medical Planning Co., Ltd.).8 Tamai et al. reported initial results from 15 patients in whom 25 scaffolds were successfully implanted in 2000. Long-term data with >10 years of follow-up for 50 patients treated with 84 Igaki-Tamai biodegradable stents showed cumulative target lesion revascularization (TLR) of 16 % after 1 year, 18 % after 5 years, and 28 % after 10 years.9 Despite these promising results, development of the Igaki-Tamai biodegradable stent was discontinued because of the need for a large 8-French guide catheter for delivery and potential vessel wall injury from this heat-treated, self-expandable device. Refinement of the resorbable scaffold led to development of the Absorb stent. Orniston et al. reported on an early version of the device noting a loss of scaffold area at 6 months likely because of early recoil.10 A subsequent design incorporated changes in manufacturing of the polymer backbone for slower resorption and increased early radial strength. This second-generation BVS was tested in 101 patients with simple atherosclerotic lesions in the ABSORB cohort B trial. Six months’ follow-up of 45 of the 101 patients included in the trial (cohort B1) demonstrated a modest reduction in lumen area as documented by intravascular ultrasound (IVUS) and OCT.11 These favorable results persisted at 12 months’ follow-up of the remaining 56 patients (cohort B2).12 IVUS and OCT examination at baseline and at 12 months’ follow-up showed that the scaffold area remained unchanged. The angiographic late lumen loss was 0.27 ± 0.32 mm with only a 1.94 % relative decrease in minimal lumen area (p=0.12) and without significant changes in mean lumen area as documented by IVUS. OCT examination at 12 months’ follow-up showed that 96.69  % of the struts were covered. Five-year OCT follow-up of 53 patients in ABSORB Cohort B without target lesion revascularization showed no visible struts.6 Major adverse cardiovascular events (MACE) occurred in 11  % with no stent thrombosis. ABSORB Cohort B angiographic and clinical results led to the CE mark of the Absorb BVS in 2011. After CE mark approval, the Gauging Coronary Healing With Bioresorbable Scaffolding Platforms In Europe (GHOST-EU) registry was one of the largest  early multicenter evaluations in routine

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practice, consisting of 10 centers and 1,189 patients.13 All patients with coronary disease suitable for stenting were eligible for the registry. Target lesion failure (TLF, defined as cardiac death, target vessel relatedmyocardial infarction [TV-MI], and target lesion revascularization [TLR]) was 4.4 % at 6 months with 1 % cardiac death and 2.5 % TLR. Diabetes was the only independent predictor of TLF. Paradoxically, TLF was lower (3.2 %) in the first 50 cases at each institution as compared with patients after 50 cases (5.2 %). The investigators hypothesized that this was likely because of more use of intravascular imaging and post-dilation in the earlier cases. Scaffold thrombosis (ScT) rates in the registry were higher than contemporary second-generation DES, with 1.5  % at 30 days and 2.1  % at 6 months. This may have been partly attributable to complex lesions with 27  % bifurcation lesions and 17  % requiring overlapping scaffolds. Alternatively, this may have been related to implantation techniques with only 49 % overall post-dilation.

Randomized Trials Five trials in the ABSORB series were randomized with Absorb BVS versus Xience (Abbott; metallic second-generation DES), both of which elute everolimus (see Table 1). All trials except TROFI II enrolled mostly stable coronary artery disease patients with some unstable angina patients, and excluded ST-elevation myocardial infarction (STEMI) and non-STEMI patients. ABSORB II immediately followed ABSORB Cohort B, and was powered to evaluate vasomotor function and late lumen loss at 3 years. ABSORB III was the largest randomized trial, designed for US approval and was powered for clinical endpoints. ABSORB TROFI II uniquely included only STEMI patients. ABSORB II randomized 501 patients. Initial post-PCI imaging showed lower acute lumen gain in the Absorb group based on quantitative coronary angiography (1.15 mm versus 1.46 mm, p<0.0001), and IVUS (2.85mm2 versus 3.6mm2, p<0.0001). MACE rates in the two groups were similar (5 % versus 3 % at 1 year and 7.6 % versus 4.3 % at 2 years).14,15 Likewise, TLF did not significantly differ between the two groups (7.0  % versus 3.0 %, p=0.07 at 2 years). In a substudy, more complex lesions had higher target vessel revascularization (TVR).16 Three-year results of ABSORB II were disappointing for the primary endpoints of vasomotion and late lumen loss.14 Vasomotion assessed by change in mean lumen diameter after intracoronary nitroglycerin was, unexpectedly, not superior in the Absorb group (0.047 mm versus 0.056 mm, psuperiority=0.49), and late lumen loss was actually larger in the Absorb group (0.37mm versus 0.25mm, pnoninferiority=0.78). Although not powered for clinical endpoints, some safety endpoints were concerning. TV-MI (7 % versus 1 %, p=0.01) and definite or probable device thrombosis (3  % versus 0  %, p=0.03) were higher in the Absorb group. In the Absorb group, there were two definite ScT within 1 year and six very late definite ScT (2  %) between 1 and 3 years. All very late ScT were in patients not taking DAPT, raising the question of the appropriate length of DAPT in these patients. Overall device-oriented events were 10 % in Absorb and 5 % in Xience (p=0.04), including TLR in 6 % versus 2 % (p=0.04).14 ABSORB CHINA was a randomized trial of 480 patients for approval in China based on non-inferiority of angiographic late lumen loss for Absorb BVS compared with Xience. The primary endpoint of in-segment late loss at 1 year was non-inferior (0.19 ± 0.38 mm versus 0.13 ± 0.38 mm; Pnoninferiority=0.01), and TLF at 1 year was similar (3.4  % versus 4.2  %).

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Bioresorbable Vascular Scaffolds Table 1: ABSORB Randomized Clinical Trials ABSORB

Patient

series

Population (n)

Patients

Randomization Years of Enrollment

Routine

Primary Outcome

Follow-up

Selective Secondary Outcomes

Angiography ABSORB II14,15 Stable (76 %) 501 2:1 November 3 years Vasomotion/change in and unstable 2011–June 2013 mean lumen diameter angina* after intracoronary nitroglycerin (0.047 mm year 0.056 mm, psuperiority=0.49). Late lumen loss (0.37 mm versus 0.25 mm, pnoninferiority=0.78)

MACE (5 % versus 3 % at 1 year and 7.6 % versus 4.3 % at 2 years). TLF (7.0 % versus 3.0 %, p=0.07 at 2 years). Target vessel MI (7.0 % versus 1.0 % at 3 years, p=0.01). Device thrombosis (3 % versus 0 % at 3 years, p=0.03)

ABSORB

TLF (3.4 % versus 4.2 %,

Stable and

480

2:1

July 2013–

1 year

In-segment late loss

unstable March 2014 (0.19±0.38 mm versus China17 CAD* 0.13±0.38 mm at 1 year, pnoninferiority=0.01)

p=0.62). Device thrombosis (0.4 % versus 0.0 %, p=NS)

ABSORB

Late lumen loss

Stable (88 %) 400

2:1

April 2013–

13 months

TLF (4.2 % versus 3.8 %,

Japan18 and unstable December 2013 pnoninferiority<0.0001) CAD (12 %)* ABSORB

STEMI

191

1:1

TROFI II21

January 2014–

6 months

September 2014

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(0.13±0.30 mm versus 0.12±0.32 mm, pnoninferiority<0.0001). Device thrombosis (1.5 % versus 1.5 %, p=1.00)

6-month OCT HS (1.74 (2.39) versus TLF (1.1 % versus 0 %, p=1.00) 2.80 (4.44); pnoninferiority<0.001)

2:1 March 2013– none TLF (7.8 % versus 6.1 %; ABSORB III Stable (58 %) 2008 and unstable April 2014 pnoninferiority=0.0070) CAD*

Ischemia-driven TVR (5.0 % versus 3.7 % at 1 year, p=NS). All-cause mortality (1.1 % versus 0.4 % at 1 year, p=NS). Device thrombosis (1.54 % versus 0.74 %, p=NS)

* (excluded STEMI and non-STEMI). CAD = coronary artery disease; HS = healing score (lower = better healing without uncovered or malapposed stents); MACE = major adverse cardiovascular events; NS = not significant; OCT= optical coherence tomography; STEMI = ST-elevation myocardial infarction; TLF = target lesion failure; TVR = target vessel revascularization.

Definite or probable device thrombosis was also not different (0.4 % versus 0.0 %).17 ABSORB JAPAN was a randomized trial of 400 patients to support approval in Japan based on clinical non-inferiority. The primary endpoint was TLF.18 At 1 year, TLF was similar for Absorb and Xience (4.2 % versus 3.8 %; Pnoninferiority< 0.0001, based on a prespecified 8.6 % non-inferiority margin). Definite or probable device thrombosis was slightly higher than other contemporary DES studies at 1.5  % in both groups. Intracoronary imaging was utilized in approximately 70 % of patients in each group and post-dilation was performed in approximately 80 % in each group. As with ABSORB II and ABSORB CHINA, ABSORB JAPAN showed higher in-device diameter stenosis and lower in-device acute gain in the Absorb group immediately post procedure. ABSORB III was the pivotal randomized trial with 2,008 patients that led to Food and Drug Administration (FDA) approval of Absorb in the US.19,20 The primary endpoint of TLF in the intention-to-treat analysis was 7.8 % in the Absorb group and 6.1 % in the DES group (pnoninferiority=0.007 based on a prespecified 4.5 % non-inferiority margin). For the per-treatment analysis, the TLF was 7.8 % in the Absorb group versus 5.7 % in the Xience group (Pnoninferiority=0.0183). The three powered secondary outcomes did not significantly differ between the two groups: 1-year angina (18.3 % versus 18.4  %), 1-year all revascularization (9.1  % versus 8.1  %), and 1-year

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ischemia-driven TVR (5.0 % versus 3.7  %). Several additional secondary outcomes at 1 year were numerically higher in the Absorb group, including all-cause mortality (1.1  % versus 0.4  %), cardiac death (0.6  % versus 0.1 %), all MI (6.9 % versus 5.6 %), and definite or probable device thrombosis (1.5 % versus 0.7 %). The doubling of device thrombosis was concerning. In post-hoc analyses, it was noted that the higher incidence of adverse events in Absorb occurred in smaller vessels. When lesions were separated by reference vessel diameter (RVD) into <2.25 mm (18.8 % of total lesions treated) versus ≥2.25 mm by quantitative coronary angiography (QCA), 1-year events were higher for <2.25 mm vessels treated with Absorb compared to those treated with Xience: TLF 12.9 % versus 8.3  %, device thrombosis 4.6  % versus 1.5  %, and TV-MI 10.0  % versus 4.5  %. In vessels ≥2.25 mm, these endpoints were similar for Absorb and Xience. TLF was 6.7 % versus 5.5 %, device thrombosis 0.9 % versus 0.6 %, and TV-MI 5.2 % versus 4.6 %.19 ABSORB TROFI II randomized 191 STEMI patients undergoing primary PCI.21 The primary endpoint was 6-month OCT healing score (HS) based on the presence of uncovered or malapposed stent struts and intraluminal filling defects (1.74 (2.39) versus 2.80 (4.44); Pnoninferiority=0.001). This was a small trial powered for non-inferiority of an imaging endpoint. Additionally, only 10 % of STEMI patients during enrollment period were randomized. Therefore, although STEMI lesions are an important target for BVS, we do not currently have enough data to support its use.

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Interventional Cardiology Figure 1: Angiography and OCT of BVS implanted in a subtotally occluded right coronary artery

Figure 2: Angiography and OCT of BVS implanted in serial lesions in the left circumflex artery

A 65-year-old woman with history of hypertension and asthma presented with chest pain and non-ST-elevation myocardial infarction. Diagnostic coronary angiography (A) via the right femoral artery revealed a 99 % subtotally occluded mid right coronary artery (arrow). OCT (B) showed a complex lesion with calcium (*), and lipid-rich (arrow) plaque and reference vessel diameter of 3.5 mm. A 3.5 x 23 mm Absorb was implanted and post-dilated with a 3.75 x 20 mm non-compliant balloon to high pressure. Final angiography (C) showed no residual stenosis and OCT (D) showed good scaffold apposition (arrow). BVS = bioresorbable vascular scaffolds; OCT = optical coherence tomography.

Several meta-analyses of randomized trials showed results similar to individual trials, which included higher numerical TLF and stent thrombosis for the Absorb BVS, though most were not statistically significant because of the small numbers of events. A meta-analysis of all the randomized trials, which comprised 3,738 patients, showed similar TLR (OR 0.97; 95 % CI [0.66–1.43]; p=0.87), TLF (OR 1.20; 95  % CI [0.90– 1.60]; p=0.21), and death (OR 0.95; 95 % CI [0.45–2.00]; p=0.89) between BVS and Xience. However, patients who received BVS had higher risk of definite or probable device thrombosis (OR 1.99; 95 % CI [1.00–3.98]; p=0.05).22 Another patient-level meta-analysis of four ABSORB trials (TROFI II was excluded because of the STEMI-only population) found MACE (RR 1.08; p=0.38) and TLF (RR 1.22; p=0.17) to be similar, but a trend for higher device thrombosis (RR 2.09; p=0.08). TVR MI was significantly higher in the BVS group (RR 1.45; p=0.04).23

US Applications Absorb is the only first-generation BVS approved in the US by the FDA (July 5, 2016) with the following labelling: “The Absorb BVS is a temporary scaffold that will fully resorb over time and is indicated for improving coronary luminal diameter in patients with ischemic heart disease due to de novo native coronary artery lesion (length ≤24 mm) with RVD of ≥2.5 mm and ≤3.75 mm.” Patient and lesion selection are important during the early adoption of this new technology.20 US operators are likely to start with simple lesions and select patients most likely to benefit from a fully resorbable device as Absorb is first introduced into general practice. Figures 1 and 2 are examples of lesions treated in clinical practice in the US. With increasing operator experience over time, BVS may be used to treat more complex

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A 66-year-old woamn with history of multiple sclerosis presented with exertional chest pressure for a few months. Diagnostic coronary angiography (A) via the right radial artery revealed serial 80 % (arrow) and 60 % (arrowhead) stenosis in the mid left circumflex artery. OCT (B) revealed a small dissection (*) with reference vessel diameter of 3.25 mm (C). A 3.0 x 28 mm Absorb BVS was implanted. Post-implantation OCT (D) showed mild scaffold malapposition (arrow). The Absorb BVS was post-dilated with 3.25 x 15mm non-compliant balloon. Final angiography (E) revealed minimal residual stenosis. BVS = bioresorbable vascular scaffold; OCT = optical coherence tomography.

lesions while more data are collected. As discussed, in subgroup analysis of ABSORB III, 1-year TLF, its components, and scaffold thrombosis were all higher in the Absorb group compared with the control group in vessels <2.25 mm. Given the potential mismatch between visual estimate and intracoronary imaging, the manufacturer strongly advises using QCA or intracoronary imaging for vessels visually ≤2.75 mm to confirm RVD ≥2.5 mm. The FDA panel also advocates quantitative measurements for vessels ≤3.0 mm to ensure appropriate sizing. Figure 3 shows an example of OCT vessel sizing of a 4.5 mm proximal RCA lesion that was too large for the Absorb BVS. The manufacturer labelling further recommends additional pre-dilation in all lesions with residual stenosis of 20–40 % prior to BVS implantation, and post-dilation with non-compliant balloon at >16 mmHg to ensure adequate scaffold apposition.

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Bioresorbable Vascular Scaffolds There is evidence that these strategies of careful lesion selection and deployment technique can improve outcomes. For example, one mechanism for very late ScT appears to be because of resorption of initially malapposed scaffold struts, causing thrombosis because of mechanical disruption.24,25 In a large registry study of 1,305 consecutive Absorb implants, ScT was 1.8 % at 30 days and 3.0  % at 1 year.26 Lower post-procedure minimum lumen and reference vessel diameters (RVD) were hallmarks of late ScT, and nine of 42 cases occurred after discontinuation of DAPT. Based on early results, a ‘BVS-specific protocol’ was designed to address incomplete BVS expansion with the following steps: 1) predilation with non-compliant balloon to the RVD, 2) BVS implantation only if the predilation balloon is fully expanded, 3) implantation of BVS to RVD, and 4) post-dilation with non-compliant balloon up to a maximum of 0.5 mm larger than RVD. The study showed that after the ‘BVS-specific protocol’ was adopted, ScT rates fell from 3.3  % to 1.0  % at 1 year, suggesting that ScT could be decreased by using careful, regimented implantation techniques. It is reasonable to speculate that such a strategy may have reduced event rates in ABSORB II​and ABSORB III and clearly should be an integral part of the procedure for early adoption

Figure 3: Angiography and OCT of a diseased right coronary artery too large for BVS implantation

An additional unanswered question for BVS implants is the duration of DAPT. All patients in the ABSORB studies were maintained on P2Y12 inhibitor for 12 months and aspirin indefinitely. The 2016 updated DAPT guidelines recommend at least 6 months of DAPT for DES in stable coronary artery disease and at least 12 months for DES in acute coronary syndrome.27 Longer duration is also reasonable based on results from the DAPT trial.28 There are no specific guidelines for DAPT duration after BVS implantation, although with concerns for higher very late ScT rate in clinical trials combined with the duration of scaffold resorption, prolonged DAPT should be strongly considered. It seems reasonable that initial experience in the US should be used in patients with relatively low bleeding risk and eligible for prolonged DAPT.

Lesion Complexity and Characteristics Lesion complexity is a major consideration for BVS implantation. Exclusion criteria in the ABSORB randomized trials were numerous, including, but not limited to, heavily calcified lesions, extreme angulation or tortuosity, left main or ostial lesions, bifurcation lesions, thrombotic lesions, and chronically occluded lesions. Although there are reports of real-practice experience and registry data on these more complex lesions from outside the US, these were usually reported by operators with substantial device experience and with meticulous technique.29–32 It seems advisable for the initial US experience to avoid more complex lesions such as heavily calcified lesions, bifurcation lesions, and chronic total occlusions. There should be a strategy to advance to higher complexity procedures after demonstrating favorable outcomes with simple lesions and with a commitment for systematic collection of outcomes data in the US.

Conclusion The BVS is a new category of device that has the potential for improving the treatment of coronary artery disease. The technology offers considerable promise, but as a first-generation device, BVS has been hampered with safety concerns. Additionally, the theoretical longterm benefits have yet to be proven. Adverse outcomes in early trials

US CARDIOLOGY REVIEW

A 70-year-old man with history of diabetes, hypertension, hyperlipidemia, prior stents in the left anterior descending, diagonal and right coronary arteries presented with progressive exertional chest pain and dyspnea for several months. Diagnostic coronary angiography (A) via right radial artery revealed 90 % stenosis of the proximal RCA (arrow) and 40 % in-stent restenosis in the distal RCA (arrowhead). Absorb BVS was considered, however, OCT of the lesion (B) revealed a lipid-rich plaque (*) with distal RVD of 4.0 mm (C) and proximal RVD of 4.5 mm (D). The lesion was stented with 4.0 x 12 mm Xience drug-eluting stent and post-dilated with 4.5 mm noncompliant balloon to high pressure. Final angiography (E) revealed no residual stenosis in the proximal RCA and stable moderate in-stent restenosis in the distal RCA. BVS = bioresorbable vascular scaffold; OCT = optical coherence tomography; RCA = right coronary artery; RVD = reference vessel diameter.

and practice appear to be related to implantation in smaller vessels or inadequate vessel preparation and lack of post-dilation. It seems reasonable that if the safety concerns can be mitigated by careful lesion sizing and selection in addition to improved implantation technique, the long-term benefit of a fully resorbed stent would become evident. During initial BVS adoption in the US, physicians should be conservative with careful patient and lesion selection and follow meticulous and regimented implantation techniques involving frequent intracoronary imaging for sizing, and pre- and post-dilation. This should include full adoption of the 4-step BVS specific implantation protocol as described above. Physicians should be cautious not to overextend treatment

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Interventional Cardiology to complex lesions until there has been substantial experience and demonstration of favorable safety. For now, treatment also should be limited to patients who can comply with at least 12 months of DAPT and longer therapy should be considered until the mechanisms of very late ScT are more completely understood. While we await the next generation

1.

 rube E, Chevalier B, Smits P, et al. The SPIRIT V study: a clinical G evaluation of the XIENCE V everolimus-eluting coronary stent system in the treatment of patients with de novo coronary artery lesions. JACC Cardiovascular Interventions 2011;4:168–75. DOI: 10.1016/j.jcin.2010.11.006; PMID: 21349455 2. Meredith IT, Verheye S, Dubois CL, et al. Primary endpoint results of the EVOLVE trial: a randomized evaluation of a novel bioabsorbable polymer-coated, everolimus-eluting coronary stent. J Am Coll Cardiol 2012;59:1362–70. DOI: 10.1016/j.jacc.2011.12.016; PMID: 22341736 3. Kolandaivelu K, Swaminathan R, Gibson WJ, et al. Stent thrombogenicity early in high-risk interventional settings is driven by stent design and deployment and protected by polymer-drug coatings. Circulation 2011;123:1400–9. DOI: 10.1161/CIRCULATIONAHA.110.003210; PMID: 21422389 4. Lane JP, Perkins LE, Sheehy AJ, et al. Lumen gain and restoration of pulsatility after implantation of a bioresorbable vascular scaffold in porcine coronary arteries. JACC Cardiovascular Interv 2014;7:688–95. DOI: 10.1016/j.jcin.2013.11.024; PMID: 24835327 5. Serruys PW, Onuma Y, Garcia-Garcia HM, et al. Dynamics of vessel wall changes following the implantation of the absorb everolimus-eluting bioresorbable vascular scaffold: a multi-imaging modality study at 6, 12, 24 and 36 months. EuroIntervention 2014;9:1271–84. DOI: 10.4244/EIJV9I11A217; PMID: 24291783 6. Serruys PW, Ormiston J, van Geuns RJ, et al. A polylactide bioresorbable scaffold eluting everolimus for treatment of coronary stenosis: 5-year follow-up. J Am Coll Cardiol 2016;67:766–76. DOI: 10.1016/j.jacc.2015.11.060; PMID: 26892411 7. Karanasos A, Simsek C, Gnanadesigan M, et al. OCT assessment of the long-term vascular healing response 5 years after everolimus-eluting bioresorbable vascular scaffold. J Am Coll Cardiol 2014;64:2343–56. DOI: 10.1016/j.jacc.2014.09.029; PMID: 25465421 8. Tamai H, Igaki K, Kyo E, et al. Initial and 6-month results of biodegradable poly-l-lactic acid coronary stents in humans. Circulation 2000;102:399–404. DOI: 10.1161/01.CIR.102.4.399; PMID: 10908211 9. Nishio S, Kosuga K, Igaki K, et al. Long-Term (>10 Years) clinical outcomes of first-in-human biodegradable poly-l-lactic acid coronary stents: Igaki-Tamai stents. Circulation 2012;125:2343–53. DOI: 10.1161/CIRCULATIONAHA.110.000901; PMID: 22508795 10. Ormiston JA, Serruys PW, Regar E, et al. A bioabsorbable everolimus-eluting coronary stent system for patients with single de-novo coronary artery lesions (ABSORB): a prospective open-label trial. Lancet 2008;371:899–907. DOI: 10.1016/S01406736(08)60415-8; PMID: 18342684 11. Serruys PW, Onuma Y, Ormiston JA, et al. Evaluation of the second generation of a bioresorbable everolimus drug-eluting vascular scaffold for treatment of de novo coronary artery stenosis: six-month clinical and imaging outcomes. Circulation 2010;122:2301–12. DOI: 10.1161/CIRCULATIONAHA.110.970772; PMID: 21098436

30

of BVS, which likely will have thinner struts, more consistent deployment results and faster resorption, we can thoughtfully proceed with using the current device as approved and recommended. The goal of ‘nothing left behind’ in a repaired and normally functioning coronary artery remains an important one. n

12. S  erruys PW, Onuma Y, Dudek D, et al. Evaluation of the second generation of a bioresorbable everolimus-eluting vascular scaffold for the treatment of de novo coronary artery stenosis: 12-month clinical and imaging outcomes. J Am Coll Cardiol 2011;58:1578–88. DOI: 10.1016/j.jacc.2011.05.050; PMID: 21958884 13. Capodanno D, Gori T, Nef H, et al. Percutaneous coronary intervention with everolimus-eluting bioresorbable vascular scaffolds in routine clinical practice: early and midterm outcomes from the European multicentre GHOST-EU registry. EuroIntervention 2015;10:1144–53. DOI: 10.4244/EIJY14M07_11; PMID: 25042421 14. Serruys PW, Chevalier B, Sotomi Y, et al. Comparison of an everolimus-eluting bioresorbable scaffold with an everolimuseluting metallic stent for the treatment of coronary artery stenosis (ABSORB II): a 3 year, randomised, controlled, singleblind, multicentre clinical trial. Lancet 2016;388:2479–91. DOI: 10.1016/S0140-6736(16)32050-5; PMID: 27806897 15. Serruys PW, Chevalier B, Dudek D, et al. A bioresorbable everolimus-eluting scaffold versus a metallic everolimuseluting stent for ischaemic heart disease caused by de-novo native coronary artery lesions (ABSORB II): an interim 1-year analysis of clinical and procedural secondary outcomes from a randomised controlled trial. Lancet 2015;385:43–54. DOI: 10.1016/S0140-6736(14)61455-0; PMID: 25230593 16. Kraak RP, Grundeken MJ, Hassell ME, et al. Two-year clinical outcomes of Absorb bioresorbable vascular scaffold implantation in complex coronary artery disease patients stratified by SYNTAX score and ABSORB II study enrolment criteria. EuroIntervention 2016;12:e557–65. DOI: 10.4244/ EIJV12I5A95; PMID: 27497355 17. Gao R, Yang Y, Han Y, et al. Bioresorbable vascular scaffolds versus metallic stents in patients with coronary artery disease: ABSORB China trial. J Am Coll Cardiol 2015;66:2298–309. DOI: 10.1016/j.jacc.2015.09.054; PMID: 26471805 18. Kimura T, Kozuma K, Tanabe K, et al. A randomized trial evaluating everolimus-eluting Absorb bioresorbable scaffolds vs. everolimus-eluting metallic stents in patients with coronary artery disease: ABSORB Japan. Eur Heart J 2015;36:3332–42. DOI: 10.1093/eurheartj/ehv435; PMID: 26330419 19. Ellis SG, Kereiakes DJ, Metzger DC, et al. Everolimus-eluting bioresorbable scaffolds for coronary artery disease. N Engl J Med 2015;373:1905–15. DOI: 10.1056/NEJMoa1509038; PMID: 26457558 20. Steinvil A, Rogers T, Torguson R, Waksman R. Overview of the 2016 U.S. Food and Drug Administration Circulatory System Devices Advisory Panel Meeting on the Absorb Bioresorbable Vascular Scaffold System. JACC Cardiovascular Interv 2016;9:1757– 64. DOI: 10.1016/j.jcin.2016.06.027; PMID: 27609249 21. Sabaté M, Windecker S, Iñiguez A, et al. Everolimus-eluting bioresorbable stent vs. durable polymer everolimus-eluting metallic stent in patients with ST-segment elevation myocardial infarction: results of the randomized ABSORB ST-segment elevation myocardial infarction-TROFI II trial. Eur Heart J 2016;37:229–40. DOI: 10.1093/eurheartj/ehv500; PMID: 26405232

22. C  assese S, Byrne RA, Ndrepepa G, et al. Everolimus-eluting bioresorbable vascular scaffolds versus everolimus-eluting metallic stents: a meta-analysis of randomised controlled trials. Lancet 2016;387:537–44. DOI: 10.1016/S0140-6736(15)00979-4; PMID: 26597771 23. Stone GW, Gao R, Kimura T, et al. 1-year outcomes with the Absorb bioresorbable scaffold in patients with coronary artery disease: a patient-level, pooled meta-analysis. Lancet 2016;387:1277–89. DOI: 10.1016/S0140-6736(15)01039-9; PMID: 26825231 24. Räber L, Brugaletta S, Yamaji K, et al. Very late scaffold thrombosis: intracoronary imaging and histopathological and spectroscopic findings. J Am Coll Cardiol 2015;66:1901–14. DOI: 10.1016/j.jacc.2015.08.853; PMID: 26493663 25. Meincke F, Spangenberg T, Heeger CH, et al. Very late scaffold thrombosis due to insufficient strut apposition. JACC Cardiovascular Interv 2015;8:1768–9. DOI: 10.1016/j. jcin.2015.06.026; PMID: 26476613 26. Puricel S, Cuculi F, Weissner M, et al. Bioresorbable Coronary Scaffold Thrombosis: Multicenter Comprehensive Analysis of Clinical Presentation, Mechanisms, and Predictors. J Am Coll Cardiol 2016;67:921–31. DOI: 10.1016/j.jacc.2015.12.019; PMID: 26916481 27. 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 Am Coll Cardiol 2016;68:1082–115. DOI: 10.1016/j.jacc.2016.03.513; PMID: 27036918 28. Mauri L, Kereiakes DJ, Yeh RW, et al. Twelve or 30 months of dual antiplatelet therapy after drug-eluting stents. N Engl J Med 2014;371:2155–66. DOI: 10.1056/NEJMoa1409312; PMID: 25399658 29. Ojeda S, Pan M, Romero M, et al. Outcomes and computed tomography scan follow-up of bioresorbable vascular scaffold for the percutaneous treatment of chronic total coronary artery occlusion. Am J Cardiol 2015;115:1487–93. DOI: 10.1016/j. amjcard.2015.02.048; PMID: 25851795 30. Wiebe J, Liebetrau C, Dorr O, et al. Feasibility of everolimuseluting bioresorbable vascular scaffolds in patients with chronic total occlusion. Int J Cardiol 2015;179:90–4. DOI: 10.1016/j. ijcard.2014.10.032; PMID: 25464422 31. La Manna A, Chisari A, Giacchi G, et al. Everolimus-eluting bioresorbable vascular scaffolds versus second generation drug-eluting stents for percutaneous treatment of chronic total coronary occlusions: Technical and procedural outcomes from the GHOST-CTO registry. Catheter Cardiovasc Interv 2016;88:E155-E163. DOI: 10.1002/ccd.26397; PMID: 26756959 32. Vaquerizo B, Barros A, Pujadas S, et al. One-year results of bioresorbable vascular scaffolds for coronary chronic total occlusions. Am J Cardiol 2016;117:906–17. DOI: 10.1016/j. amjcard.2015.12.025; PMID: 26874547

US CARDIOLOGY REVIEW


Interventional Cardiology

Dual Anti-platelet Therapy after Coronary Stenting: Rationale for Personalized Duration of Therapy Donald E Cutlip, MD Division of Cardiology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA

Abstract There is controversy regarding the appropriate duration of dual anti-platelet therapy after coronary stenting. Recent guidance has been updated to reflect improved outcomes after second-generation drug-eluting stenting, but a standard duration for all patients is not rational given the different risks for ischemic and bleeding complications. This paper reviews the data for short- and long-term dual anti-platelet therapy and considers approaches for developing a personalized strategy.

Keywords Stent, thrombosis, bleeding, myocardial infarction, anti-platelet therapy Disclosure: Research at the Beth Israel Deaconess Medical Center is supported by grants from CeloNova, Medtronic and Boston Scientific. Received: February 1, 2017 Accepted: February 15, 2017 Citation: US Cardiology Review 2017;11(1):31–6. DOI: 10.15420/usc.2017:7:2 Correspondence: Donald E Cutlip, MD, Division of Cardiology and Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 185 Pilgrim Road, Boston, MA; E: dcutlip@bidmc.harvard.edu

Stent thrombosis has been recognized as a serious complication of coronary stent placement since the procedure was first reported in the 1980s.1 Subsequent aggressive peri-procedural anti-thrombotic strategies with inpatient transition to warfarin reduced the risk to about 3.5 % for subacute (30-day) stent thrombosis,2,3 a rate that would be unacceptable by current standards and did not account for the yetunrecognized late and very late stent thrombosis events. The benefit of dual anti-platelet therapy (DAPT) with aspirin plus ticlopidine in association with optimal stent deployment techniques was shown to clearly reduce the risk for subacute stent thrombosis associated with bare metal stents (BMS) compared with aspirin alone or aspirin plus warfarin.4 Pooled analysis of BMS clinical trials incorporating 30 days of DAPT confirmed a subacute stent thrombosis rate <1  %, but noted a 20  % 6-month mortality for patients sustaining a stent thrombosis event.5 Eventually, clopidogrel replaced ticlopidine as a safer alternative for P2Y12 inhibition, but 30 days of DAPT remained the standard throughout the BMS era. The benefit of extending stent thrombosis beyond 30 days was first recognized following the placement of new coronary stents at the time of intracoronary brachytherapy,6 and resulted in the modification of DAPT duration from 30 days to 3 or 6 months, based on expert opinion from clinical trial Data and Safety Monitoring Committees. Late complications were anticipated in the design of first-generation drug-eluting stent (DES) clinical trials, which also incorporated longer DAPT durations. Interestingly, although stent thrombosis between 30 days and 1 year (late) and after 1 year (very late) did occur, there was no signal of increased risk with DES compared with BMS for up to 5 years in these clinical trials.7,8 Subsequent extension of these devices to broader patient and lesion subsets in routine practice highlighted the

© RADCLIFFE CARDIOLOGY 2017

significant problem of very late stent thrombosis,9,10 however, leading to a recommendation for further prolongation of DAPT to a minimum of 12 months.11 This recommendation was made with little evidence that 12 months was the optimal duration of DAPT. The lack of evidence along with the improved outcomes of newer-generation DES, ongoing concern about the dire consequences of stent thrombosis at any frequency, and increased recognition of the harmful impact of bleeding has resulted in the persistent question of how long (or short) a period of time DAPT should be continued for.

Reduced Risk of Late and Very Late Stent Thrombosis with Second-generation DES In the United States, there are two classes of second-generation DES that have been approved for use: the everolimus-eluting stent (EES), marketed as Promus™ by Boston Scientific and Xience® by Abbott Vascular; and the zotarolimus-eluting stent marketed as Resolute™ by Medtronic. Several studies have demonstrated the benefits of secondgeneration DES compared with first-generation DES, with benefits sustained or increasing from 1 to 5 years.12–15 In the Xience V Everolimus Eluting Coronary Stent System in the Treatment of Patients with de novo Native Coronary Artery Lesions (SPIRIT) III trial of the EES versus the first-generation paclitaxel-eluting stent, at 5 years there was a significant reduction in the composite endpoint of major adverse cardiac events (13.2 % versus 20.7  %, p=0.007), including non-significant reductions in very late stent thrombosis (0.5 % versus 1.0 %, p=0.38).15 The Resolute™ all-comers trial randomized 2,292 patients to either EES or Resolute™. The participants were representative of routine practice patients. At 5 years, the overall rates of definite stent thrombosis were similar (0.8 % versus 1.6 %, p=0.084), with nearly identical low rates of very late stent

Access at: www.USCjournal.com

31


Interventional Cardiology thrombosis (0.5 % versus 0.4  %, p=1.00). The annual hazard beyond 1 year of 0.1–0.2  % for very late stent thrombosis was markedly lower than the 0.7  % annual hazard previously noted for first-generation DES in a similar population.10 Perhaps even more remarkable are observational studies and a network meta-analysis that have indicated rates of stent thrombosis for second-generation DES that are even lower than BMS.16,17 Although these observational data must be interpreted in the context that the BMS included were older, thicker strut devices, the comparisons were not direct, and DAPT durations were shorter for BMS, they have provided further reassurance regarding the improved safety of secondgeneration DES.

Bleeding and Impact on Mortality after Coronary Stenting There is little doubt that bleeding has been underappreciated as a serious complication after coronary stenting and associated anti-thrombotic therapy. Earlier trials focused on rates of vascular complications and access site-related bleeding, but ongoing risks of non-access site bleeding were not reported. Part of the difficulty has been the absence of standardized criteria to define bleeding, with available definitions limited to those developed from early fibrinolytic clinical trials. The Bleeding Academic Research Consortium (BARC) has provided imperfect but standardized criteria for defining bleeding in the peri-procedural period and during follow-up.18 BARC classifies five categories of bleeding, including:18 1. Bleeding not requiring medical attention. 2. Bleeding requiring medical intervention but not meeting the criteria for categories 3, 4, or 5. 3.  Bleeding associated with a hemoglobin drop >3 g or requiring transfusion or related to cardiac tamponade, intracranial hemorrhage, or intraocular hemorrhage. 4. Bleeding related to cardiac surgery. 5. Fatal bleeding. Rates of bleeding after coronary stenting and during DAPT vary according to the baseline risk of the population, with older age, female gender, history of hypertension, renal insufficiency, concomitant oral anticoagulants, and acute coronary syndrome being indications predictive of higher bleeding risk in most studies.19–21 Bleeding related to the access site as well as non-access site bleeding has been associated with subsequent mortality, although the mortality risk appears to be highest for later, spontaneous bleeding.21–23 Multiple studies have now demonstrated that the risk of mortality associated with bleeding after coronary stenting is at least as great as that related to myocardial infarction (MI).21,24,25 Furthermore, the risk of bleeding associated with coronary stenting and DAPT is ongoing throughout the duration of DAPT, even among patients who remain free of bleeding events for the first 12 months.26,27

Evidence Supporting Shorter DAPT The proven safety advantage of second-generation DES and the increasing awareness of the consequences of bleeding related to prolonged DAPT have fueled interest in shorter durations of DAPT. Randomized clinical trials that have compared DAPT durations as short as 3 months with 12 months of DAPT are shown in Table 1.28–31 Generally, these trials were

32

designed to show non-inferiority in composite endpoints that included ischemic or bleeding events, and in some cases repeat revascularization events. Except for the Intracoronary Stenting and Antithrombotic Regiment: Safety and Efficacy of 6 Months Dual Antiplatelet Therapy after Drug-Eluting Stenting (ISAR-SAFE) study, the trials initiated randomization at the time of the index procedure, possibly limiting enrollment of higher-risk patients.31 ISAR-SAFE patients who remained free of events at 6 months were eligible for randomization. None of the studies comparing durations of DAPT were powered to assess differences in MI or stent thrombosis, and event rates were low in both the short and 12-month DAPT groups, consistent with the enrollment of lower-risk patients. ISARSAFE, which was powered to assess meaningful differences in ischemic endpoints, was terminated early due to low event rates and slow enrollment,31 suggesting that there may have been selection of low-risk patients for randomization in this trial as well. Other indirect evidence for the success of shorter DAPT duration for newer-generation DES comes from the Prospective Randomized Comparison of the BioFreedom Biolimus A9 Drug-Coated Stent versus the Gazelle Bare-Metal Stent in Patients at High Bleeding Risk (LEADERSFREE) trial.32 The BioFreedom™ device does not include a polymer for drug delivery and becomes a bare metal stent within 30 days. Patients at high risk of bleeding were randomized to the polymer-free DES or the identical BMS, and all patients were prescribed 30 days of DAPT. At 1 year, the DES cohort had a lower rate of cardiac death, MI or stent thrombosis (9.4 % versus 12.9 %, p=0.005), the primary endpoint, owing to reduced MI (6.1 % versus 8.9 %, p=0.01).32 The stent used in this study has much thicker struts (120 μm) than contemporary BMS or DES, which is a concern as it may have contributed to an increased risk of restenosis and stent thrombosis. This may also explain the high MI rate in the BMS group – nearly one-third of cases were directly related to restenosis – and also account for the much higher than expected rate of stent thrombosis in both groups (>2 % at 1 year).32 Taken together, these data support the safety of shorter DAPT duration in some patients, but are not conclusive for adopting DAPT <12 months as a routine strategy for all patients.

Evidence Supporting Longer DAPT Prior to current data showing low (0.1–0.2 %/year) rates of very late stent thrombosis with second-generation DES, most of the debate on DAPT duration was about whether it should be >12 months. Given the serious consequences of stent thrombosis and the increasing complexity of patients and lesions undergoing coronary stenting, with likely higher risk for very late stent thrombosis, the relative safety of longer-term therapy has remained a topic of interest. The question was addressed by three earlier randomized trials.33–35 Unfortunately, none of these trials was adequately powered to address meaningful differences in ischemic endpoints, in particular very late stent thrombosis. For example, in the Prolonging Dual Antiplatelet Treatment After Grading Stent-induced Intimal Hyperplasia (PRODIGY) study, very late definite or probable stent thrombosis occurred in 6/983 (0.6  %) patients assigned to 6 months of DAPT and 3/987 (0.3  %) patients assigned to 24 months of DAPT.35 With these observed rates and sample size, the study failed to exclude as much as an eightfold higher risk for very late stent thrombosis. The three randomized trials did, however,

US CARDIOLOGY REVIEW


Dual Anti-platelet Therapy Table 1: Randomized Trials of Short versus 12 Months Dual Anti-platelet Therapy (DAPT)

Results

§

Trial and

Patients

Stent

Primary

Myocardial

Stent

duration of

(n)

Type(s)

Endpoint

Infarction

Thrombosis

Bleeding

EXCELLENT 1,443 75 % EES 6 versus 25 % SES 12 months

TVF (4.8 versus 4.3 %, pNI=0.001)

1.8 versus 1.0 %, p=0.19

0.9 versus 0.1 %, p=0.10

0.3 versus 0.6 %, p=0.42

RESET 2,117 3 versus 12 months

TVF/ST/bleeding (4.7 versus 4.7 %, pNI<0.001)

0.2 versus 0.4 %, p=0.41

0.2 versus 0.3 %, p=0.65

0.2 versus 0.6 %, p=0.16

OPTIMIZE 3,119 E-ZES 3 versus 12 months

NACCE (6.0 versus 5.8 %, pNI=0.002)

0.8 versus 0.6 %, p=0.51*

0.3 versus 0.1 %, 1.0 versus 0.4 %, p=0.18* p=0.07

SECURITY 1,399 100 % SDES 6 versus 12 months

NACCE + ST 4.5 versus 3.7 %, pNI<0.05

2.3 versus 2.1 %, p=0.75

0.2 versus 0 %, p=0.30†

0.6 versus 1.1 %, p=0.28

ISAR-SAFE 4,000 11 % SES or PES 6 versus 89 % SDES 12 months

NACCE + ST (1.5 versus 1.6 %, p=0.70)

0.7 versus 0.7 %, p=0.85

0.3 versus 0.2 %, p=0.74

0.2 versus 0.3 %, p=0.74

DAPT

Short = 100 % EZES 12 months = 29 % SES; 71 % SDES

EES = everolimus-eluting stent; NACCE = net adverse cardiac and cerebral events defined as composite of death, myocardial infarction, stroke, or major bleeding; PES = first-generation paclitaxeleluting stent; pNI = p value for non-inferiority; SDES = second-generation drug-eluting stent; SES = first-generation sirolimus eluting stent; ST = stent thrombosis; TVF = target vessel failure, defined as cardiac death, myocardial infarction, or target vessel revascularization; ZES = Endeavor® zotarolimus-eluting stent; EXCELLENT = Efficacy of Xience/Promus Versus Cypher to Reduce Late Loss After Stenting study, Gwon et al, 2012;28 ISAR-SAFE = Intracoronary Stenting and Antithrombotic Regiment: Safety and Efficacy of 6 Months Dual Antiplatelet Therapy after Drug-Eluting Stenting, Schulz-Schupke et al, 2015;31 OPTIMIZE = Optimized Duration of Clopidogrel Therapy Following Treatment With the Endeavor, Feres et al, 2013;30 RESET = REal Safety and Efficacy of 3-month dual antiplatelet Therapy following Endeavor zotarolimus-eluting stent implantation. Kim et al, 2012;29 SECURITY = Second Generation Drug-Eluting Stent Implantation Followed by Six- Versus TwelveMonth Dual Antiplatelet Therapy, Colombo et al, 2014.47 §All results are frequency for short versus long, p value; *landmark analysis from 3 months; †from 6–24 months.

confirm consistently higher bleeding rates with longer-term DAPT.33–35 In PRODIGY, for example, major bleeding, defined as BARC 3 or 5, occurred in 3.4 % versus 1.9 % of patients (p=0.037).35 The safety and effectiveness of extending DAPT beyond 12 months was addressed more definitively in the Dual Anti-Platelet Therapy study.27 This study was conceived at the height of the concern over very late stent thrombosis with first-generation DES, but the rapid changes in practice and duration of enrollment required for this large, international trial resulted in nearly half of the population receiving second-generation DES. The study enrolled over 25,000 patients, including 22,866 who received a DES. After 12 months of prescribed DAPT plus aspirin, 9,961 of these patients who were compliant with DAPT and free from ischemic or bleeding events were randomized to aspirin plus placebo or to DAPT for an 18 additional months. Another group of 1,687 patients who had received only BMS were also randomized to continued thienopyridine or placebo. Unlike the previous long-term trials, the Dual Anti-Platelet Therapy study was powered to address meaningful differences in a composite ischemic endpoint of major adverse cardiac and cerebrovascular events, defined as death, stroke or MI, as well as a co-primary endpoint of definite or probable stent thrombosis. Bleeding classified as moderate or severe by Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Arteries (GUSTO) criteria was the major safety endpoint. The primary results for the DES cohort are shown in Table 2. The co-primary endpoints of major adverse cardiac and cerebrovascular events and stent thrombosis were each significantly lower for patients who continued DAPT for between 12 and 30 months.27 Notably, the absolute difference in risk for MI was greater than that for stent thrombosis, as approximately half of the reduction was for MI unrelated

US CARDIOLOGY REVIEW

Table 2: Dual Anti-Platelet Therapy Study Results (Drug-eluting Stent Cohort)* 38 Endpoint, n (%)

Thienopyridine

(n=5,020) (n=4,941)

Placebo

P Value

MACCE

211 (4.3)

285 (5.9)

<0.001

Stent Thrombosis

19 (0.4)

65 (1.4)

<0.001

All-cause Mortality

98 (2.0)

75 (1.5)

0.05

Cardiac Mortality

45 (0.9)

47 (1.0)

0.98

Myocardial Infarction

99 (2.1)

198 (4.1)

<0.001

Bleeding (GUSTO Moderate/ Severe)

119 (2.5)

73 (1.6)

<0.001

BARC 3 or 5 Bleeding

129 (2.7)

72 (1.6)

<0.001

BARC = Bleeding Academic Research Consortium; GUSTO = Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Arteries; MACCE = major adverse cardiac or cerebrovascular events, defined as death, myocardial infarction or stroke. *Results for 12–30 months after stent placement (randomization through treatment duration).

to a stent thrombosis event. The overall benefit of continued DAPT for reducing stent thrombosis was consistent across a number of subgroups, including patients receiving only BMS (0.5 % versus 1.1  %; hazard ratio 0.49; 95 % CI [0.15–1.64]; p=0.42) and those who received a second-generation EES (0.3  % versus 0.7  %; hazard ratio 0.38; 95  % CI [0.15–0.97]; p=0.76).27 The absolute differences in risk, however, were smaller in these subgroups, indicating a greater number needed to treat to avoid a single event. As in other studies, the Dual Anti-Platelet Therapy study demonstrated that benefits in ischemic endpoints must be balanced against the increased risk of bleeding. This risk was noted whether defined by GUSTO or BARC criteria, and despite the exclusion of patients on oral

33


Interventional Cardiology Table 3: Variables and Associated Integer Values Included in the Dual Anti-platelet Therapy Score. 38 Variable Points Age, years  ≥75   65 – <75  <65

-2 -1 0

Cigarette smoking

1

Diabetes 1 Myocardial infarction at presentation

1

Prior percutaneous coronary intervention or

1

prior myocardial infarction Stent diameter <3 mm

1

Congestive heart failure or left ventricular

2

ejection fraction <30 % Vein graft stent

2

anticoagulants and those who had a bleeding event during the 12 months prior to randomization.27 Another concern from the Dual Anti-Platelet Therapy study was the unexpected increase in overall mortality related to an increase in non-cardiac mortality without being offset by reduced cardiac mortality. Although detailed post-hoc analyses did not confirm a significant association between bleeding and non-cardiac mortality, there was a numerical increase in deaths due to either bleeding or trauma and cancer-related deaths. A later meta-analysis of clinical trials comparing shorter versus longer (>12 months) duration of DAPT among DES patients also reported higher non-cardiac mortality.36 The Dual Anti-Platelet Therapy study specified 30 months’ DAPT duration based on protocol design, but it is notable that in the 3 months after discontinuation of thienopyridine, there was an increase in the risk of MI and stent thrombosis, similar to that observed in the 12–15-month interval for the placebo group.27 It is uncertain whether this represents a need for even longer DAPT duration in some patients, or whether it is a possible effect of thienopyridine withdrawal.

bleeding (3.0 % versus 1.4 %, p<0.001) and an insignificant reduction in ischemia (1.7  % versus 2.3  %, p=0.07); whereas the difference in risk among patients with a high score (≥2) was highly significant for ischemia (2.7  % versus 5.7  %, p<0.001) but not for bleeding (1.8  % versus 1.4  %, p=0.26). This score is limited by the design of the Dual Anti-Platelet Therapy study, which excluded patients at the highest risk for bleeding and those with bleeding or ischemia in the first 12 months after stenting. The Patterns of Non-adherence to Anti-platelet Regimens in Stented Patients (PARIS) registry investigators also tabulated risk scores for ischemia or major bleeding based on baseline clinical characteristics.39 Older age, anemia, and requirement for oral anticoagulants were unique predictors for bleeding; while diabetes, acute coronary syndrome indication, and previous revascularization were unique predictors for ischemia. Renal insufficiency and current smoking increased the risk of both bleeding and ischemia. Of note, acute coronary syndrome presentation is a significant predictor of recurrent ischemia in both the DAPT and PARIS scores. Furthermore, in a recent meta-analysis, longer duration of DAPT (>6 months) was associated with reduced risk of MI or stent thrombosis among acute coronary syndrome patients but not stable coronary artery disease patients.40 Lesion and procedural complexity may also be important determinants of risk versus benefit for longer DAPT duration. In a patient-level meta-analysis of clinical trials comparing DAPT for 3 or 6 months with 12 months or longer, each component of complex percutaneous coronary intervention (three-vessel treatment, ≥3 stents implanted, ≥3 lesions treated, bifurcation treated with two stents, total stent length >60 mm, or chronic total occlusion) was associated with reduced major adverse cardiac events (defined as death, MI or stent thrombosis) for longer-term DAPT.41 The magnitude of the difference in risk increased with the number of complex percutaneous coronary intervention components present.

characteristics may help discriminate these risks for individual patients and allow for a personalized approach based on clinical and procedural risk rather than indiscriminate short or long durations.38–41

Patients requiring continued oral anticoagulants are at especially high risk for bleeding with prolonged DAPT. The optimal duration of DAPT and whether it should be abandoned in favor of single anti-platelet therapy with a P2Y12 inhibitor but no aspirin for a period of 1–12 months remain topics of debate and clinical study. There is evidence from the What is the Optimal antiplatElet and anticoagulant therapy in patients with oral anticoagulation and coronary StenTing (WOEST) trial that a regimen of continued oral anticoagulants with clopidogrel alone versus clopidogrel plus aspirin reduced major bleeding (GUSTO moderate or severe, 5.4 % versus 12.3  %, p=0.003) and all-cause mortality (2.5  % versus 6.3  %, p=0.027), without an increase in MI or stent thrombosis, but the study was not powered to assess for differences in ischemic outcomes.42

In the Dual Anti-Platelet Therapy study, a score was developed based on models that predicted risk of ischemia (MI or stent thrombosis) or GUSTO or moderate or severe bleeding (see Table 3).38 A sum of the factors generated a composite score with range from -2 to 10 that indicated net benefit or harm with continued thienopyridine. For example, for DAPT scores below the median (2), the continued use of thienopyridine compared with placebo after 12 months was associated with increased

More recently, the Study Exploring Two Strategies of Rivaroxaban and One or Oral Vitamin K Antagonist in Patients with Atrial Fibrillation who undergo Percutaneous Coronary Intervention (PIONEER AF-PCI) results were published. Investigators reported that among patients with atrial fibrillation undergoing coronary stenting a reduced dosage of rivaroxaban (15 mg daily) plus a P2Y12 inhibitor (95 % clopidogrel) for 12 months or very low dose rivaroxaban (2.5 mg twice daily) plus DAPT for 1, 6 or 12 months followed by rivaroxaban 15 mg daily plus aspirin

Balancing the Risks of Bleeding and Ischemia The optimal duration of DAPT must balance the risks of bleeding and ischemic events, each of which carry a substantial hazard for subsequent mortality. Although stent thrombosis carries the highest mortality risk in the subsequent 2 years after the event, especially if occurring within the first 30 days, it occurs much less frequently than overall MI or bleeding, such that the attributable risk is similar for combined ischemic and bleeding events.37 Several reports have indicated that baseline

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Dual Anti-platelet Therapy 75–100 mg daily for total of 12 months of therapy had reduced bleeding compared with warfarin plus DAPT for 1, 6, or 12 months followed by warfarin plus aspirin 75–100 mg daily.43 The three groups had similar rates of cardiovascular death, MI and stroke, but the study was not powered to exclude differences in these outcomes. These and other potential regimens including very short DAPT (1 month) or other novel oral anticoagulants with single anti-platelet agents provide numerous options for reducing bleeding events, but remain unproven for reducing stent thrombosis or MI. It is likely that even among patients who require continual oral anticoagulants, other clinical or procedural factors that increase the risk for stent thrombosis or MI may argue for longer or more aggressive anti-platelet strategies as part of a personalized strategy in some patients.

Current Society Guidelines and Options for Personalized Strategy The most recent guidelines from the European Society of Cardiology (ESC) and the American College of Cardiology and American Heart Association (ACC/AHA) incorporate options for shorter DAPT duration for patients deemed to be at higher bleeding risk, and longer duration (>12 months) for patients with low bleeding risk and high risk for ischemia.44–46 For patients with coronary stenting for stable CAD, the guidelines advise a minimum DAPT duration of 1 month for BMS and 6 months for DES if patients are not at a high risk of bleeding. If they have a high bleeding risk, the ACC/AHA guidelines allow for a shorter duration of 3 months after DES, while the ESC guidelines include options of 1 month of DAPT or initial dual therapy with clopidogrel plus an oral anticoagulant in DES patients with the highest bleeding risk and a requirement for oral

1.

 igwart U, Puel J, Mirkovitch V, et al. Intravascular stents S to prevent occlusion and restenosis after transluminal angioplasty. N Engl J Med 1987;316:701–6. DOI: 10.1056/ NEJM198703193161201; PMID: 2950322 2. Fischman DL, Leon MB, Baim DS, et al. A randomized comparison of coronary-stent placement and balloon angioplasty in the treatment of coronary artery disease. Stent restenosis study investigators. N Engl J Med 1994;331:496–501. DOI: 10.1056/NEJM199408253310802; PMID: 8041414 3. Serruys PW, de Jaegere P, Kiemeneij F, et al. A comparison of balloon-expandable-stent implantation with balloon angioplasty in patients with coronary artery disease. Benestent study group. N Engl J Med 1994;331:489–95. DOI: 10.1056/ NEJM199408253310801, PMID: 8041413 4. Leon MB, Baim DS, Popma JJ, et al. A clinical trial comparing three anti-thrombotic drug regimens after coronary artery stenting. New Engl J Med 1998;338:1665–71. DOI: 10.1056/ NEJM199812033392303; PMID: 9834303 5. Cutlip DE, Baim DS, Ho KK, et al. Stent thrombosis in the modern era: A pooled analysis of multicenter coronary stent clinical trials. Circulation 2001;103:1967–71. PMID: 11306525 6. Costa MA, Sabate M, van der Giessen WJ, et al. Late coronary occlusion after intracoronary brachytherapy. Circulation 1999;100:789–92. PMID: 10458712 7. Weisz G, Leon MB, Holmes DR, Jr., et al. Five-year followup after sirolimus-eluting stent implantation results of the SIRIUS (Sirolimus-Eluting Stent in De-Novo Native Coronary Lesions) trial. J Am Coll Cardiol 2009;53:1488–97. DOI: 10.1016/j. jacc.2009.01.050; PMID: 19389558 8. Ellis SG, Stone GW, Cox DA, et al; TAXUS IV Investigators. Long-term safety and efficacy with paclitaxel-eluting stents: 5-year final results of the TAXUS IV clinical trial (TAXUS IV-SR: Treatment of de novo coronary disease using a single paclitaxel-eluting stent). JACC Cardiovasc Interv 2009;2:1248–59. DOI: 10.1016/j.jcin.2009.10.003; PMID: 20129552 9. Wenaweser P, Daemen J, Zwahlen M, et al. Incidence and correlates of drug-eluting stent thrombosis in routine clinical practice. 4-year results from a large 2-institutional cohort study. J Am Coll Cardiol 2008;52:1134–40. DOI: 10.1016/j.jacc.2008.07.006; PMID: 18804739 10. Räber L, Wohlwend L, Wigger M, et al. Five-year clinical and angiographic outcomes of a randomised comparison of sirolimus-eluting and paclitaxel-eluting stents: results

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anticoagulants. Both sets of guidelines also consider it reasonable to extend therapy beyond 6 months if patients have a high risk of ischemia and low risk of bleeding. After stenting for acute coronary syndromes, the ACC/AHA guidelines advise 12 months of DAPT, with a consideration to shorten this to 6 months if a patient is at high bleeding risk or extend this beyond 12 months if a patient has tolerated DAPT without bleeding and remains at low risk for bleeding.45–46 The ESC guidelines are similar, except they advocate the consideration of shortening of DAPT duration to 3 months if a patient is at high bleeding risk.44

Conclusion DAPT after coronary stenting along with optimal stent deployment techniques has led to low rates of stent thrombosis. Concern about the ongoing risk of stent thrombosis beyond 1 year has been clearly reduced with the introduction of second-generation devices. Further reduction in both stent thrombosis and overall MI can be achieved with extended DAPT duration beyond 1 year. The unavoidable trade-off between risk of bleeding and possibly increased overall mortality with longer DAPT duration requires a careful consideration of the net benefit of continuing therapy beyond the minimum time necessary. A personalized strategy based on the balance of these risks rather than an indiscriminate approach adopting short- or long-term DAPT is required for optimal outcomes. Future studies should determine the necessary minimum durations for current and new devices and help to clarify algorithms for determining the absolute risk of ischemia versus bleeding, and thus the net clinical benefit of longer-term therapy. n

of the Sirolimus-Eluting Versus Paclitaxel-Eluting Stents for Coronary Revascularisation LATE trial. Circulation 2011;123:2819–28. DOI: 10.1161/CIRCULATIONAHA.110.004762; PMID: 21646500 Farb A, Boam AB. Stent thrombosis redux — the FDA perspective. New Engl J Med 2007;356:984–7. DOI: 10.1056/ NEJMp068304; PMID: 17296827 Stone GW, Midei M, Newman W, et al; SPIRIT III Investigators. Comparison of an everolimus-eluting stent and a paclitaxeleluting stent in patients with coronary artery disease: A randomized trial. JAMA 2008;299:1903–13. DOI: 10.1001/ jama.299.16.1903; PMID: 18430909 Stone GW, Rizvi A, Newman W, et al; SPIRIT IV Investigators. Everolimus-eluting versus paclitaxel-eluting stents in coronary artery disease. N Engl J Med 2010;362:1663–74. DOI: 10.1056/ NEJMoa0910496; PMID: 20445180 Smits PC, Vlachojannis GJ, McFadden EP, et al. Final 5-year follow-up of a randomized controlled trial of everolimus- and paclitaxel-eluting stents for coronary revascularization in daily practice: The COMPARE trial (a trial of everolimus-eluting stents and paclitaxel stents for coronary revascularization in daily practice). JACC Cardiovasc Interv 2015;8:1157–65. DOI:10.1016/j. jcin.2015.03.028; PMID: 26210806 Gada H, Kirtane AJ, Newman W, et al. 5-year results of a randomized comparison of Xience V everolimus-eluting and TAXUS paclitaxel-eluting stents: Final results from the SPIRIT III trial (clinical evaluation of the Xience V everolimus eluting coronary stent system in the treatment of patients with de novo native coronary artery lesions). JACC Cardiovasc Interv 2013;6:1263–6. DOI: 10.1016/j.jcin.2013.07.009; PMID: 24239202 Tada T, Byrne RA, Simunovic I, et al. Risk of stent thrombosis among bare-metal stents, first-generation drug-eluting stents, and second-generation drug-eluting stents: Results from a registry of 18,334 patients. JACC Cardiovasc Interv 2013;6:1267–74. DOI: 10.1016/j.jcin.2013.06.015; PMID: 24355117 Bangalore S, Kumar S, Fusaro M, et al. Short- and long-term outcomes with drug-eluting and bare-metal coronary stents: A mixed-treatment comparison analysis of 117 762 patient-years of follow-up from randomized trials. Circulation 2012;125:2873– 91. DOI: 10.1161/CIRCULATIONAHA.112.097014; PMID: 2258628 Mehran R, Rao SV, Bhatt DL, et al. Standardized bleeding definitions for cardiovascular clinical trials: A consensus report from the Bleeding Academic Research Consortium. Circulation

2011;123:2736–47. DOI: 10.1161/CIRCULATIONAHA.110.009449; PMID: 21670242 19. Ko DT, Yun L, Wijeysundera HC, et al. Incidence, predictors, and prognostic implications of hospitalization for late bleeding after percutaneous coronary intervention for patients older than 65 years. Circ Cardiovasc Interv 2010;3:140–7. DOI: 10.1161/ CIRCINTERVENTIONS.109.928721; PMID: 20332382 20. Fleming LM, Novack V, Novack L, et al. Frequency and impact of bleeding in elective coronary stent clinical trials – utility of three commonly used definitions. Catheter Cardiovasc Interv 2012;80:E23–9 21. Kazi DS, Leong TK, Chang TI, et al. Association of spontaneous bleeding and myocardial infarction with long-term mortality after percutaneous coronary intervention. J Am Coll Cardiol 2015;65:1411–20. DOI: 10.1016/j.jacc.2015.01.047; PMID: 25857906 22. Ndrepepa G, Neumann FJ, Richardt G, et al. Prognostic value of access and non-access sites bleeding after percutaneous coronary intervention. Circ Cardiovasc Interv. 2013;6:354–61. DOI: 10.1161/CIRCINTERVENTIONS.113.000433; PMID: 23881814 23. Vavalle JP, Clare R, Chiswell K, et al. Prognostic significance of bleeding location and severity among patients with acute coronary syndromes. JACC Cardiovasc Interv 2013;6:709–17. DOI: 10.1016/j.jcin.2013.03.010; PMID: 23866183 24. Lindsey JB, Marso SP, Pencina M, et al; EVENT Registry Investigators. Prognostic impact of periprocedural bleeding and myocardial infarction after percutaneous coronary intervention in unselected patients: Results from the EVENT (evaluation of drug-eluting stents and ischemic events) registry. JACC Cardiovasc Interv 2009;2:1074–82. DOI: 10.1016/j.jcin.2009.09.002; PMID: 19926047 25. Pocock SJ, Mehran R, Clayton TC, et al. Prognostic modeling of individual patient risk and mortality impact of ischemic and hemorrhagic complications: Assessment from the Acute Catheterization and Urgent Intervention Triage Strategy trial. Circulation 2010;121:43–51. DOI: 10.1161/ CIRCULATIONAHA.109.878017; PMID: 20026777 26. Tsai TT, Ho PM, Xu S, et al. Increased risk of bleeding in patients on clopidogrel therapy after drug-eluting stents implantation: Insights from the HMO Research Network-Stent Registry (HMORN-stent). Circ Cardiovasc Interv 2010;3:230–5. DOI: 10.1161/ CIRCINTERVENTIONS.109.919001; PMID: 20442361

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Interventional Cardiology 27. Mauri L, Kereiakes DJ, Yeh RW, et al; DAPT Study Investigators. Twelve or 30 months of dual antiplatelet therapy after drugeluting stents. N Engl J Med 2014;371:2155–66. DOI: 10.1056/ NEJMoa1409312; PMID: 25399658 28. Gwon HC, Hahn JY, 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;125:505–13. DOI: 10.1161/ CIRCULATIONAHA.111.059022; PMID: 22179532 29. Kim BK, Hong MK, Shin DH, et al; RESET Investigators. 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;60:1340–8. DOI: 10.1016/j.jacc.2012.06.043; PMID: 22999717 30. Feres F, Costa RA, Abizaid A, et al; OPTIMIZE Trial Investigators. Three vs twelve months of dual antiplatelet therapy after zotarolimus-eluting stents: The OPTIMIZE randomized trial. JAMA 2013;310:2510–22. DOI: 10.1001/jama.2013.282183; PMID: 24177257 31. Schulz-Schupke S, Byrne RA, Ten Berg JM, et al. ISAR-SAFE: A randomized, double-blind, placebo-controlled trial of 6 vs. 12 months of clopidogrel therapy after drug-eluting stenting. Eur Heart J 2015;36:1252–63. DOI: 10.1093/eurheartj/ehu523 32. Urban P, Meredith IT, Abizaid A, et al. Polymer-free drug-coated coronary stents in patients at high bleeding risk. N Engl J Med 2015;373:2038–47. DOI: 10.1007/s11886-017-0819-0; PMID: 28185168 33. Park SJ, Park DW, Kim YH, et al. Duration of dual antiplatelet therapy after implantation of drug-eluting stents. N Engl J Med 2010;362:1374–82. DOI: 10.1056/NEJMoa1001266; PMID: 20231231 34. Lee CW, Ahn JM, Park DW, et al. Optimal duration of dual antiplatelet therapy after drug-eluting stent implantation: A randomized, controlled trial. Circulation 2014;129:304–12. DOI: 10.1161/CIRCULATIONAHA.113.003303; PMID: 24097439 35. Valgimigli M, Campo G, Monti M, et al; the Prolonging Dual Antiplatelet Treatment After Grading Stent-Induced Intimal Hyperplasia Study Investigators. Short- versus long-term duration of dual-antiplatelet therapy after coronary stenting: A randomized multicenter trial. Circulation

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2012;125:2015–26. DOI: 10.1161/CIRCULATIONAHA.113.003303; PMID: 24097439 36. Palmerini T, Benedetto U, Bacchi-Reggiani L, et al. Mortality in patients treated with extended duration dual antiplatelet therapy after drug-eluting stent implantation: A pairwise and Bayesian network meta-analysis of randomised trials. Lancet 2015;385:2371–82. DOI: 10.1016/S0140-6736(15)60263-X; PMID: 25777667 37. Brener SJ, Kirtane AJ, Stuckey TD, et al. The impact of timing of ischemic and hemorrhagic events on mortality after percutaneous coronary intervention: The ADAPT-DES study. JACC Cardiovasc Interv 2016;9:1450–7. DOI: 10.1016/j.jcin.2016.04.037; PMID: 27372190 38. Yeh RW, Secemsky EA, Kereiakes DJ, et al; DAPT Study Investigators. Development and validation of a prediction rule for benefit and harm of dual antiplatelet therapy beyond 1 year after percutaneous coronary intervention. JAMA 2016;315:1735–49. DOI: 10.1001/jama.2016.3775; PMID: 27022822 39. Baber U, Mehran R, Giustino G, et al. Coronary thrombosis and major bleeding after PCI with drug-eluting stents: Risk scores from PARIS. J Am Coll Cardiol 2016;67:2224–34. DOI: 10.1016/j.jacc.2016.02.064; PMID: 27079334 40. Palmerini T, Della Riva D, Benedetto U, et al. Three, six, or twelve months of dual antiplatelet therapy after DES implantation in patients with or without acute coronary syndromes: An individual patient data pairwise and network meta-analysis of six randomized trials and 11 473 patients. Eur Heart J 2017: DOI: 10.1093/eurheartj/ehw627; PMID: 28110296; epub ahead of press 41. Giustino G, Chieffo A, Palmerini T, et al. Efficacy and safety of dual antiplatelet therapy after complex PCI. J Am Coll Cardiol 2016;68:1851–64. DOI: 10.1016/j.jacc.2016.07.760; PMID: 27595509 42. Dewilde WJ, Oirbans T, Verheugt FW, et al; WOEST Study Investigators. 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;381:1107–15. DOI: 10.1016/S0140-6736(12)62177-1; PMID: 23415013 43. 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 44. Windecker S, Kolh P, Alfonso F, et al. 2014 ESC/EACTS guidelines on myocardial revascularization: The task force on myocardial revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS) developed with the special contribution of the European Association of Percutaneous Cardiovascular Interventions (EAPCI). Eur Heart J 2014;35:2541–619. DOI: 10.1093/ eurheartj/ehu278; PMID: 25173339 45. Levine GN, Bates ER, Bittl JA, et al. 2016 ACC/AHA Guideline Focused Update on Duration of Dual Antiplatelet Therapy in Patients With Coronary Artery Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines: An Update of the 2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention, 2011 ACCF/AHA Guideline for Coronary Artery Bypass Graft Surgery, 2012 ACC/AHA/ACP/AATS/PCNA/ SCAI/STS Guideline for the Diagnosis and Management of Patients With Stable Ischemic Heart Disease, 2013 ACCF/AHA Guideline for the Management of ST-Elevation Myocardial Infarction, 2014 AHA/ACC Guideline for the Management of Patients With Non-ST-Elevation Acute Coronary Syndromes, and 2014 ACC/AHA Guideline on Perioperative Cardiovascular Evaluation and Management of Patients Undergoing Noncardiac Surgery. Circulation 2016;134:e123–55. DOI: 10.1161/ CIR.0000000000000404; PMID: 27026020 46. Roffi M, Patrono C, Collet JP, et al; Management of Acute Coronary Syndromes in Patients Presenting without Persistent ST-Segment Elevation of the European Society of Cardiology. 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 47. Colombo A, Chieffo A, Frasheri A et al. Second-generation drugeluting stent implantation followed by 6- versus 12-month dual antiplatelet therapy: the SECURITY randomized clinical trial. J Am Coll Cardiol 2014;64:2086–97. DOI: 10.1016/j.jacc.2014.09.008; PMID: 25236346

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Interventional Cardiology

Guest Editorial A Brave New World for Non-vitamin K Antagonist Oral Anticoagulants: Have We seen the Last of Warfarin? Michela Faggioni, MD, 1,2 Michael C Gibson, MS, MD 3 and Roxana Mehran, MD, FAHA 1 1. Interventional Cardiovascular Research and Clinical Trials, The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai,New York City, NY, USA; 2. Cardiac Thoracic and Vascular Department, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy; 3. Cardiovascular Division, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA

Abstract The use of non-vitamin K antagonist oral anticoagulants (NVKA) for antithrombotic treatment has freed patients with atrial fibrillation (AF) from the inconvenience and expense of international normalized ratio measurements. However, in the presence of coronary artery disease requiring percutaneous coronary intervention (PCI) the physician is challenged with decisions regarding which antiplatelet regimen to administer. The open-label, randomized, controlled, multicenter Study Exploring Two Treatment Strategies of Rivaroxaban and a Dose-Adjusted Oral Vitamin K Antagonist Treatment Strategy in Subjects With AF Who Undergo PCI (PIONEER AF-PCI) was the first randomized clinical trial to test safety and efficacy of a NVKA in patients with AF treated with PCI. At 1-year follow-up both dual and triple therapy with rivaroxaban were superior to triple therapy with warfarin in reducing the frequency of bleeding events. Findings from the PIONEER AF-PCI study indicate superiority of dual or triple therapy with rivaroxaban over warfarin.

Keywords Atrial fibrillation, non-vitamin K antagonist oral anticoagulants, antithrombotic treatment, percutaneous coronary intervention, rivaroxaban, warfarin Disclosures: MF and MCG have no disclosures.RM has received research grant support form Eli Lilly/DSI; BMS; AstraZeneca; The Medicines Company; OrbusNeich; Bayer; CSL Behring. She has worked as a consultant for Janssen Pharmaceuticals, Inc.; Osprey Medical Inc.; Watermark Research Partners; Medscape. She is on the advisory board of Abbott Laboratories. She has equity in Claret Medical Inc.; Elixir Medical Corporation; She has given industry sponsored lectures (without any marketing purpose) for PlatformQ; Sanofi-aventis; other activities comprise but are not limited to, committee participation, data safety monitoring board (DSMB) membership for Covidien and Forest Laboratories (no payment). Citation: US Cardiology Review 2017;11(1):37–8. DOI: 10.15420/usc.2017:6:1.GE Correspondence: Roxana Mehran, MD, FAHA, Mount Sinai Hospital, One Gustave L. Levy Place, Box 1030, New York, NY 10029, USA. E: roxana.mehran@mountsinai.org

The use of non-vitamin K antagonist oral anticoagulants (NVKA) has revolutionized the antithrombotic treatment of patients with atrial fibrillation (AF), finally freeing them of the inconvenience and expense of international normalized ratio measurements. However, add to the equation the presence of coronary artery disease requiring percutaneous coronary intervention (PCI) with stent placement and the physician is challenged with decisions regarding what antiplatelet regimen to administer. Although it is estimated that approximately 1–2 million people in the US and Europe have AF and coronary artery disease, there remains a paucity of randomized clinical trials in this population. The What is the Optimal Antiplatelet and Anticoagulant Therapy in Patients With Oral Anticoagulation and Coronary Stenting (WOEST) trial tested antithrombotic strategies in patients with AF after PCI was.1 This study proved that the use of dual therapy with warfarin and clopidogrel significantly decreased the risk of bleeding complications with no increase in the rate of thrombotic events. Despite the results of WOEST, there is still great heterogeneity in the choice of antithrombotic regimens in clinical practice. The role of NVKA in this setting is not well defined. Several studies on patients with AF have proved that NVKA reduce the risk of bleeding while

© RADCLIFFE CARDIOLOGY 2017

maintaining adequate antithrombotic efficacy. These results suggest a wider therapeutic window of NVKA than warfarin that might be particularly beneficial in stented patients with AF. Nevertheless, this hypothesis was not supported by any scientific evidence until the 1-year results of the Study Exploring Two Treatment Strategies of Rivaroxaban and a DoseAdjusted Oral Vitamin K Antagonist Treatment Strategy in Patients With Atrial Fibrillation Who Undergo Percutaneous Coronary Intervention (PIONEER AF-PCI) trial were finally published.2 The PIONEER AF-PCI study was the first randomized clinical trial to test safety and efficacy of a NVKA in patients with AF treated with PCI. In this study, 2124 patients were randomized to one of the following treatment strategies: 1) dual therapy with low-dose (15 mg daily) rivaroxaban plus a P2Y12 inhibitor for 12 months; 2) triple therapy with very low-dose rivaroxaban (2.5 mg, twice daily) plus dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 inhibitor for 1, 6 or 12 months; and 3) triple therapy with warfarin plus DAPT (WOEST-like arm) for 1, 6 or 12 months. The primary endpoint was clinically significant bleeding, a composite of major or minor bleeding according to thrombolysis in myocardial infarction (TIMI) criteria or bleeding requiring medical attention. At 1-year follow-up both dual and triple therapy with rivaroxaban were superior to triple therapy with warfarin in reducing

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Interventional Cardiology bleeding events. Although the PIONEER AF-PCI trial was underpowered to detect differences in ischemic complications, a recent post-hoc analysis showed a significant reduction in the rate of hospitalization for both cardiovascular and bleeding events in the rivaroxaban-based study arms, thus excluding a potential harm of rivaroxaban in combination with one or two antiplatelet drugs.3 Interestingly, the low and very low rivaroxabanbased strategies seemed equivalent in safety and efficacy. While definite conclusions cannot be drawn regarding the thromboembolic protection of these off-label dosages of rivaroxaban in combination with antiplatelet agents, findings from the PIONEER AF-PCI study provides crucial, muchawaited information on NVKA use in patients with AF after PCI that will certainly impact clinical practice. A potential role of NVKA in combination with antiplatelet drugs had already been investigated for the post-PCI treatment of patients in sinus rhythm. The Apixaban for Prevention of Acute Ischemic Events 2 (APPRAISE 2) trial tested full-dose apixaban in addition to DAPT in patients presenting with acute coronary syndrome (ACS).4 While conferring protection with regards to ischemic outcomes at 1 year, the full anticoagulating dose of apixaban resulted in an unacceptable increase in the frequency of intracranial hemorrhages and fatal bleeding events that caused the premature interruption of the trial. Conversely, the Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with Acute Coronary Syndrome–Thrombolysis in Myocardial Infarction 51 (ATLAS ACS 2-TIMI 51) trial tested non-fully anticoagulating doses of rivaroxaban 5 mg or 2.5 mg, twice daily (PIONEER-AF-PCI-like arm), in combination with DAPT in patients with ACS.5 In this study, the very low-dose (2.5 mg, twice daily) rivaroxaban added to DAPT significantly reduced the rates of mortality and recurrent myocardial infarction compared with placebo. Although a higher rate of major bleeding events was observed, there was no significant increase in the rate of fatal bleeding events with rivaroxaban treatment. The differences between clinical outcomes in this study and the APPRAISE

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 ewilde WJ, Oirbans T, Verheugt FW, et al. Use of clopidogrel D with or without aspirin in patients taking oral anticoagulant therapy and undergoing percutaneous coronary intervention: an open-label, randomised, controlled trial. Lancet 2013; 381:1107–15. 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

3.

2 trial might be explained in part by the lower dose of NVKA tested and in part by the fact that unlike the APPRAISE 2 study, the ATLAS ACS 2-TIMI 51 trial excluded patients who had a history of ischemic stroke or transient ischemic attack. In aggregate, looking back to the trials on NVKA or warfarin performed in the past few years it is apparent that the main objective is the reduction of bleeding events whereas an acceptable thromboembolic protection is usually reached by most treatment regimens. In other words, we can prevent ischemic strokes fairly well with all the drugs at our disposal, but preventing hemorrhagic strokes and other major bleeding events currently represents our main challenge. In this regard, the PIONEER AF-PCI study certainly marks the victory of dual or triple therapy with rivaroxaban over warfarin. Ongoing studies will provide information on the use of dabigatran, apixaban and edoxaban in patients with AF after PCI. Nevertheless, given the low incidence of thromboembolic events in this population it is unlikely that these studies will be powered to demonstrate the non-inferiority to warfarin of NVKA with respect to the prevention of ischemic complications. Are NVKA the key to finding a ‘one-size-fits-all’ regimen that will simplify treatment decision making after PCI in patients with AF? Possibly, but there is still a long road ahead. High-risk patients are usually excluded from clinical trials and that limits the generalizability of the results. For instance, in the PIONEER-AF-PCI study, the median CHADS2, CHA2DS2VASc, and HAS-BLED scores were only 2, 4, and 3, respectively. What is the best treatment for patients at high or very high thromboembolic and bleeding risk, or patients with complex coronary artery disease requiring the use of novel P2Y12 inhibitors, which have never been extensively studied in association with NVKA? With these questions in mind, we must admit that the safer risk profile so far shown by rivaroxaban may be the key to solving this conundrum and might entirely change our treatment approach for patients with AF undergoing PCI in the next few years. n

2016;375:2423–34. DOI: 10.1056/NEJMoa1611594; PMID: 27959713. Gibson CM, Pinto DS, Chi G, et al. Recurrent hospitalization among patients with atrial fibrillation undergoing intracoronary stenting treated with 2 treatment strategies of rivaroxaban or a dose-adjusted oral vitamin K antagonist treatment strategy. Circulation 2017;135:323–33. DOI: 10.1161/ CIRCULATIONAHA.116.025783; PMID: 27881555.

4.

5.

Alexander JH, Lopes RD, James S, et al. Apixaban with antiplatelet therapy after acute coronary syndrome. N Engl J Med 2011;365:699–708. DOI: 10.1056/NEJMoa1105819; PMID: 21780946. 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.

US CARDIOLOGY REVIEW


Electrophysiology

Practical Aspects of Rotor Mapping in Catheter Ablation of Atrial Fibrillation John M Miller, MD Indiana University School of Medicine, Indianapolis, IN

Abstract Historically, pulmonary veins have been the focus of atrial fibrillation (AF) ablation therapy, but it is increasingly being recognized that localized electric rotors and focal impulse sources have a role in maintaining AF. Targeting of these sources using focal impulse and rotor modulation (FIRM)-guided ablation has resulted in elimination of the source and improved long-term outcomes. FIRM uses wide-area mapping of both atria in AF, using commercially-available basket catheters (to provide contact electrograms). However, not all data support the use of FIRM. This paper provides a description of rotor mapping and ablation. In addition, practical strategies for optimizing the technique are discussed, including: catheter positioning; accurate diagnosis of the presence and locations of focal sources; and amount of ablation performed in regions with rotors or foci.

Keywords Atrial fibrillation, catheter ablation, rotor mapping Disclosure: The author has received honoraria from Medtronic, St. Jude Medical, Biotronik, Biosense-Webster and Boston Scientific, and has been a scientific advisor to Abbott (Topera®). Acknowledgements: The author is grateful for the technical editing support provided by Katrina Mountfort of Radcliffe Cardiology. Received: February 3, 2017 Accepted: February 26, 2017 Citation: US Cardiology Review 2017;11(1):39–41. DOI: 10.15420/usc.2017:4:2 Correspondence: John M Miller, MD, Professor of Medicine, Indiana University, 1800 N. Capitol Avenue, E-488, Indianapolis, IN, USA. E: jmiller6@iu.edu

A number of mechanisms underlie the different forms of atrial fibrillation (AF). Pulmonary vein (PV) ectopy may act as a driver maintaining AF or as a trigger in which spontaneous PV firing may initiate episodes of AF. Non-pulmonary triggers also exist. In addition, multiple wavelet re-entry and rotors may maintain AF.

targeted source ablation (focal impulse and rotor modulation [FIRM]). In 2012, the prospective Conventional Ablation for Atrial Fibrillation With or Without Focal Impulse and Rotor Modulation (CONFIRM) study showed that FIRM-guided ablation resulted in freedom from AF in 88 % of patients, compared with 44 % with non FIRM-guided ablation.2

While pulmonary vein isolation (PVI) is central to most AF ablation procedures, it is not a comprehensive solution. Despite complete isolation of the PVs, AF often continues. When persistent AF terminates during ablation, the PVs may not be isolated. In addition, an increasing number of repeat procedures involve patients with PVs that are already isolated. There is therefore a need for additional strategies in the catheter ablation of AF. These include: applying empiric lines on the left atrium (LA) roof, mitral or tricuspid isthmus; isolation of the vena cava or coronary sinus, ablation of complex fractionated electrograms, non-PV trigger ablation, posterior wall isolation, left atrial appendage isolation, scar ablation or homogenization; and rotor mapping and ablation. This article will focus on the use of rotor mapping.

FIRM ablation employs basket catheters (Constellation™, Boston Scientific; or FIRMap™, Topera®) to provide contact AF electrograms; the latter has evenly distributed electrodes on the outer aspect of the basket splines and is the most commonly used. The procedure involves recording 1 minute of AF with 64 unipolar signals at 1 kHz sampling frequency. In initial studies, FIRM was performed first followed by PVI, with ablation firstly in the right atrium (RA) then in the LA. As a result of increased experience, the procedure now begins with PVI, improving efficiency and yielding cleaner FIRM maps without contamination by PV potentials. Mapping now begins in the LA then the RA. Importantly, the endpoints have also changed. Initially termination of arrhythmia was the endpoint, since the turnaround on mapping (25 minutes) made it difficult to determine rotor elimination. Recently, on-site processing speed has shortened the time from the beginning of electrogram acquisition to reading the map to around 2 minutes, allowing the assessment of rotor elimination (the current desired endpoint of ablation). A typical workflow is shown in Figure 1.

Targeted Source Ablation Studies using multiple unipolar basket catheter recordings and analytical algorithms have demonstrated sites of complete rotation in each atrium that are spatially stable over multiple cycles.1 These rotors occur in small areas (1–3 cm2). Multiple rotors may operate concurrently, either in the same or the opposite atrium, occasionally playing off against each other, giving rise to complex activation patterns. Focal sources of spontaneous firing may also be observed. These findings led to the development of

© RADCLIFFE CARDIOLOGY 2017

The unipolar basket electrograms are recorded for 1 minute then exported into the RhythmView™ computational system. The algorithm selects the 4-second segment with the best data, as well as a second

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39


Electrophysiology Figure 1: Workflow for the Focal Impulse and Rotor Modulation Ablation of Rotors Part 1: Set-Up: Sheaths, Preliminaries Right femoral vein: 8.5 Fr Long × 2 – Transseptal to LA 8.5 Fr Short – RA map Left femoral vein: 8.5 Fr Short – RA basket/halo/ICE 7.5 Fr Short – CS 6 Fr Short – His

Anticoagulate

Transseptal to LA

FAM RA Tag Phrenic

FAM LA Tag Esophagus

Begin Mapping/Ablation

Part 2: Start with Pulmonary Vein Isolation wide antral circumferential ablation Initial Rhythm: Sinus

Initial Rhythm: AF

PV Isolation

PV Isolation

Part 3: FIRM-Guided Mapping and Ablation LA Map (RhythmViewTM)

Source Seen*

Plot Region on EAM

AF Terminates? Yes

No Source Seen

Move Basket

No Ablate Region

Attempt AF Initiation

AF Persists

AT/Flutter

None

Remap

FIRM Mapping* AT/Flutter

SR

Source Seen

AF Map/Ablate

Map/Ablate

RA FIRM Map

End Procedure

If initial rhythm is AT/flutter, either ablate these or carry out PVI first

No Source Seen

Attempt AF Initiation*

AT/Flutter

AF

None

End Procedure AF = atrial fibrillation; AT = atrial tachycardia?; CS = coronary sinus; EAM = electroanatomic mapping; FAM = fast anatomical mapping; FIRM = focal impulse and rotor modulation; Fr = French; ICE = intracardiac echocardiography; LA = left atrium; PVI = pulmonary vein isolation; RA = right atrium; SR = sinus rhythm

segment, and generates a diagnostic movie that is interpreted by the operator to identify rotors or focal sources, and assess their position and strength. Visual aids such as the rotational activity profile can then be applied to the highlight areas of rotation. The software and operator must be in agreement before proceeding with ablation; a second segment may be examined to confirm the findings. In order to perform the ablation, sources are displayed on an electroanatomic mapping system. Using coordinates from RhythmView™,

40

the core of rotation is identified, either by displaying four electrodes from two involved splines (preferred) or displaying all 64 electrodes. Two electroanatomic mapping system views are examined: one from above the splines, and one in profile. A dense ablation of the source area should be performed, including the core area and a slight margin, to allow for any area of core precession. The endpoint is to eliminate near-field recordings in the target area. The ablated area is generally 1–8 cm2 and requires between 1 minute and 8 minutes of ablation. Once fully treated, the area is remapped with FIRM. If the source remains

US CARDIOLOGY REVIEW


Catheter Ablation of Atrial Fibrillation (a rare occurrence), options include checking residual electrograms and/or slightly enlarging the area. When AF terminates, it is useful to attempt to reinitiate AF following ablation using one or two extrastimuli at one or two sites – as well as burst pacing to 2:1 capture without and with catecholamine facilitation – to determine whether it is able to sustain or not. The use of FIRM adds around an hour to the duration of the procedure. Rotors or focal sources are typically found in >98 % of cases (near PVs in 23 %, LA roof/anterior wall in 21 %, other LA sites in 20 %, and RA sites in >33 %) and ablation at these sites stops or slows AF in 83 % of cases (slows by >10 % in 27 %, terminates to atrial tachycardia in 17 %, terminates to sinus rhythm in 38 %), resulting in long-term freedom from AF in 82 % of individuals. Several data series have been reported in recent years.3–9 Not all reported data, however, support the use of FIRM-guided ablation.10–12 This is due partly to poor contact of the catheter with the atrial walls because of suboptimal basket positioning and coverage. For optimal results, all the splines must be fully deployed and evenly distributed. Twisting the shaft of the catheter aids separation of the splines. It is also important to have a good grounding electrode. Tips for reading maps include playing the movie two to three times without aids, and focussing on areas with consistent patterns, then turning on the rotational activity profile; if this suggests an area previously unseen, it should be inspected carefully to confirm. The use of the spotlight feature of the mapping system allows closer focus on the area of interest, reducing extraneous data. Additional segments should be reviewed for consistency. In addition, thresholds

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 arayan SM, Krummen DE, Rappel WJ. Clinical mapping N approach to diagnose electrical rotors and focal impulse sources for human atrial fibrillation. J Cardiovasc Electrophysiol 2012;23:447–54. DOI: 10.1111/j.1540-8167.2012.02332.x; PMID: 22537106 Narayan SM, Krummen DE, Shivkumar K, et al. Treatment of atrial fibrillation by the ablation of localized sources: CONFIRM (Conventional Ablation for Atrial Fibrillation With or Without Focal Impulse and Rotor Modulation) trial. J Am Coll Cardiol 2012;60:628–36. DOI: 10.1016/j.jacc.2012.05.022; PMID: 22818076 Miller JM, Mithilesh KD, Dandamudi G, et al. Single-center experience with rotor mapping and ablation for treatment of atrial fibrillation in 170 patients. Heart Rhythm Society 2016 Scientific Sessions; May 4, 2016; San Francisco, CA. Abstract PO01-50. Spitzer SG, Karolyi L, Römmler C, et al. Treatment of recurrent nonparoxysmal atrial fibrillation using focal impulse and rotor mapping (FIRM)-guided rotor ablation: Early recurrence and

US CARDIOLOGY REVIEW

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for identifying a rotor or focus vary among operators, and include a minimum of three rotations, rotation throughout a segment, and changing direction. Faster mapping allows us to see more sources, which can confound decision-making. Variability in the amount of ablation may also lead to inconsistent results; the author’s experience suggests that dense ablation is preferable. Reasons for not achieving more frequent AF terminations may include other unstable mechanisms, such as multi-wavelet re-entry. In addition, other rotors may be active but remain undetected. Some terminations are delayed following ablation. Another criticism of the technique is the fact that long-term recurrent AF does not correlate well with AF termination. Substrate elimination must be confirmed before such correlations are attempted. Furthermore, not all rotors may be pathogenic. Further study is warranted; in addition, refinements in software will improve sensitivity and specificity.

Conclusion While most agree that PVI is integral to AF ablation procedures, it is unclear which other strategies should be performed when AF persists. Rotors and foci are important in maintaining AF in many patients. Rotor/ focus mapping and ablation, with the endpoint of elimination of all rotors and foci, has been associated with improved outcomes. However, much of the data in support of FIRM-guided ablation has been obtained from single-centre case series; some small multicentre studies to date have yielded disappointing findings. There is a need for randomised multicentre studies to compare the technology with existing strategies. Future refinements in technology should further improve outcomes. n

long-term outcomes. J Cardiovasc Electrophysiol 2017;28:31–8. DOI: 10.1111/jce.13110; PMID: 27766704 Tomassoni G, Duggal S, Muir M, et al. Long-term follow-up of FIRM-guided ablation of atrial fibrillation: A single-center experience. Journal of Innovations in Cardiac Rhythm Management 2015;6:2145–51. Tilz RR, Lin T, Rillig A, et al. Nine months outcomes following focal impulse and rotor modulation for the treatment of atrial fibrillation using the novel 64-electrode basket catheter. European Heart Rhythm Association EUROPACE-CardioStim 2015; June 21, 2015; Milan, Italy. Presentation 192. Steinberg JS, Shah Y, Bhatt A, et al. Focal impulse and rotor modulation: Acute procedural observations and extended clinical follow-up. Heart Rhythm 2017;14:192–7. DOI: 10.1016/ j.hrthm.2016.11.008; PMID: 27826130 Rashid H, Sweeney A. Approaches for focal impulse and rotor mapping in complex patients: A US private practice experience. J Innov CRM 2015;6:2193–8. DOI:10.19102/ icrm.2015.061104

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 ommer P, Kircher S, Rolf S, et al. Successful repeat catheter S ablation of recurrent longstanding persistent atrial fibrillation with rotor elimination as the procedural endpoint: A case series. J Cardiovasc Electrophysiol 2016;27:274–80. DOI: 10.1111/jce.12874; PMID: 26527103 10. Buch E, Share M, Tung R, et al. Long-term clinical outcomes of focal impulse and rotor modulation for treatment of atrial fibrillation: A multicenter experience. Heart Rhythm 2016;13: 636–41. DOI: 10.1016/j.hrthm.2015.10.031; PMID: 26498260 11. Berntsen RF, Håland TF, Skårdal R, et al. Focal impulse and rotor modulation as a stand-alone procedure for the treatment of paroxysmal atrial fibrillation: A within-patient controlled study with implanted cardiac monitoring. Heart Rhythm 2016;13: 1768–74. DOI: 10.1016/j.hrthm.2016.04.016; PMID: 27132150 12. Gianni C, Mohanty S, Di Biase L, et al. Acute and early outcomes of focal impulse and rotor modulation (FIRM)-guided rotors-only ablation in patients with nonparoxysmal atrial fibrillation. Heart Rhythm 2016;13:830–5. DOI: 10.1016/j.hrthm.2015.12.028; PMID: 26706193

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A simply phenomenal course! My knowledge has improved tremendously… shedding a new light and bringing us out of the dark ages of the pure angiogram. Dr. Surendra Avula Christ Medical Centre, Illinois. Attendee of the Simple Education Essential Guide: Advances in Coronary Physiology March 2016

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