USC 10.2

US Cardiology Review

Volume 10 • Issue 2 • Fall 2016

www.USCjournal.com

Volume 10 • Issue 2 • Fall 2016

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

Pharmacologic Strategies for Management of Pulmonary Arterial Hypertension Rebecca L Attridge, PharmD, MSc, BCPS, Rebecca D Moote, PharmD, MSc, BCPS and Deborah J Levine, MD

ISSN: 1758-3896 • eISSN: 1758-390X

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Registries for acquired arrhythmia syndromes

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Volume 10 • Issue 2 • Fall 2016

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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

University of California, San Francisco, CA

Todd M Brown, MD, MSPH

University of Alabama at Birmingham, Birmingham, AL

Leway Chen, MD, MPH

University of Rochester, Rochester, NY

NA Mark Estes III, MD Tufts University, Boston, MA

Barry H Greenberg, MD

University of California, San Diego, CA

Thomas A Haffey, MD, DO

Western University of Health Sciences, Pomona, CA

Elizabeth S Kaufman, MD

Case Western Reserve University, Cleveland, OH

Carey Kimmelstiel, MD

Tufts Medical Centre, Boston MA

Roberto M Lang, MD

University of Chicago, Chicago, IL

Warren Manning, MD

Harvard Medical School, Boston MA

Duane Pinto, MD, MSc

Harvard Medical School, Boston MA

Sidney C Smith, MD

University of North Carolina, Chapel Hill, NC

W Douglas Weaver, MD

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 Business Development Director, USA Jim Atkins • Publishing Director Liam O’Neill Managing Director David Ramsey • Commercial Director Mark Watson •

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

Cover image

Doppler echocardiogram ©kalus | www.istockphoto.com

Radcliffe Cardiology

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 © 2016 All rights reserved ISSN: 1758-3896 • eISSN: 1758-390X

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

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.

Structure and Format • • • •

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

•

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 • • • •

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

Peer Review • •

•

On submission, all articles are assessed by the Editor-in-Chief to determine their suitability for inclusion.

The Commissioning Editor, following consultation with the Editor-in-Chief, and/or a member of the Editorial Board, sends the manuscript to members of the Peer Review Board, who are selected on the basis of their specialist knowledge in the relevant area. All peer review is conducted double-blind.

Following review, manuscripts are either accepted without modification, accepted pending modification, in which case the manuscripts are returned to the author(s) to incorporate required changes, or rejected outright. The Editor-in-Chief reserves the right to accept or reject any proposed amendments.

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

Copyright and Permission Radcliffe Cardiology is the sole owner of all articles and other materials that appear in US Cardiology Review unless otherwise stated.

Permission to reproduce an article, either in full or in part, should be sought from the publication’s Managing Editor, Lindsey Mathews commeditor@radcliffecardiology.com.

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

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Contents

5 3

Foreword Donald E Cutlip, MD

Risk and Prevention

54 What the Cardiologist Needs to Know About Medications for Type 2 Diabetes

Stephen Ku, MD and Steven V Edelman, MD

Electrophysiology | Arrhythmias

60

Identification of Patients at Risk of Stroke From Atrial Fibrillation

6 5

ridging the Knowledge Gaps in Arrhythmogenic Cardiovascular Conditions: B The Critical Role of Registries

Raymond B Fohtung, MD and Michael W Rich, MD

Melody Hermel, MD, MBS, Rebecca Duffy, BS, Alexander Orfanos, BAc, Isabelle Hack, BA,

Shayna McEnteggart, BS MS, Kayle Shapero, BA, Supria Batra, MD and NA Mark Estes III, MD

7 5

Subclinical Atrial Fibrillation in Patients with Hypertrophic Cardiomyopathy

Braghadheeswar Thyagarajan, MD, Ankur Kalra, MD, Alefiyah Rajabali, MD, Jill B Whelan, MD and Elad Anter, MD

Pulmonary Vascular Diseases

7 8

Pharmacologic Strategies for Management of Pulmonary Arterial Hypertension

Rebecca L Attridge, PharmD, MSc, BCPS, Rebecca D Moote, PharmD, MSc, BCPS and Deborah J Levine, MD

Heart Failure

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

Acute Coronary Syndromes

9 1

ST-segment Elevation Myocardial Infarction: Challenges in Diagnosis

Robert F Riley, MD, MS and James M McCabe, MD

© RADCLIFFE CARDIOLOGY 2016

51

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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 reviews cover important topics in each of five sections of the journal and have been selected based on relevance to daily practice of the general cardiologist and advanced internist.

The issue leads off with a review in the Risk Prevention section by Drs. Steven Edelman and Stephen Ku on medications used for glycemic management in patients with diabetes. The presence of diabetes in a large number of patients who are followed by cardiologists, and the potential impact of diabetes medications on cardiovascular outcomes make this a valuable paper for all cardiologists caring for these patients.

The Electrophysiology and Arrhythmia section comprises three reviews. Dr Michael Rich reviews the identification of risk for stroke in patients with atrial fibrillation. This article provides an in depth look at CHADS2 and CHA2DS2-VASc scores for estimating stroke risk and offers essential guidance for selection of anticoagulation strategies. Next, Dr Mark Estes and colleagues discuss the current status and role for observational registries of patients with inherited or acquired arrhythmia syndromes. The review highlights the potential importance of these registries for reducing knowledge gaps and improving outcomes in these complex patients. Dr Ankur Kalra and colleagues close this section with a review of the difficulties in diagnosis and management of atrial fibrillation that may be clinically silent among patients with hypertrophic cardiomyopathy.

In the Heart Failure section, Dr Jorge Silva Enciso and colleagues review left ventricular assist devices as destination therapy for advanced heart failure. The increasing prevalence of heart failure dictates a critical need for improved advanced therapies as the proportion of patients able to receive cardiac transplantation becomes ever lower. Destination left ventricular assist devices offer promise for these patients and a basic understanding of these devices will be necessary for the practicing cardiologist.

In the Pulmonary Vascular Disease section, Dr Deborah Levine and colleagues provide an update on pharmacologic strategies in the management of pulmonary hypertension, showing that recent advances in pharmacologic management hold some promise for these patients.

We conclude this issue with a review by Drs James McCabe and Robert Riley on the ECG challenges in the diagnosis of ST segment elevation myocardial infarction (STEMI). Early activation of the cardiac catheterization team is a critical determinant of quality care for patients suffering STEMI, but missed diagnoses and inaccurate diagnosis impact survival and waste valuable resources. Understanding these challenges may help improve the overall quality and systems of care.

As we turn our attention and look forward to the next issue, we trust you will find these current works informative for your practice. n

Š RADCLIFFE CARDIOLOGY 2016

53

Risk and Prevention

What the Cardiologist Needs to Know About Medications for Type 2 Diabetes Step h e n Ku , M D a n d S t e v e n V E d e l m a n , M D Division of Endocrinology and Metabolism, University of California San Diego, San Diego, CA

Abstract Diabetes mellitus is associated with an increase in cardiovascular disease and mortality. Unfortunately, landmark trials in intensive glycemic control in type 2 diabetes patients have failed to reveal a consistent cardiovascular benefit, and focus has subsequently shifted to evaluating individual medications, primarily for potential harm. Several dedicated cardiovascular outcome studies have been reported in the last few years, largely supporting the cardiovascular safety of new diabetes therapies. In fact, empagliflozin, an inhibitor of sodium-glucose cotransporter 2, and liraglutide, an agonist of glucagon-like peptide 1 receptor, recently demonstrated a significant benefit in cardiovascular and all-cause mortality in adults with type 2 diabetes at high cardiovascular risk. These exciting results may signal a new chapter for the prevention of cardiovascular disease in type 2 diabetes using anti-hyperglycemic therapies.

Keywords Type 2 diabetes mellitus, cardiovascular disease, glycemic control, insulin, metformin, sulfonylureas, thiazolidinediones, dipeptidyl peptidase 4 inhibitors, glucagon-like peptide 1 receptor agonists, sodium-glucose cotransporter 2 inhibitors Disclosure: SVE is a consultant for Merck, AstraZeneca, Sanofi, Eli Lilly, Novo Nordisk, and Boehringer Ingelheim. SK has no conflicts of interest to declare.

Received: January 26, 2016 Accepted: May 10, 2016 Citation: US Cardiology Review, 2016;10(2):54–9 DOI: 10.15420/usc. 2016:4:2 Correspondence: Stephen Ku, VA San Diego Healthcare Center, Department of Endocrinology and Metabolism, 3350 La Jolla Village Drive (111G), San Diego, CA 92161, USA. E: stku@ucsd.edu

Cardiovascular disease is an important cause of morbidity and mortality in patients with type 1 and especially type 2 diabetes mellitus.1,2 Data from prospective studies suggest that diabetes is associated with a two to fourfold excess risk of coronary heart disease and coronary death.3–5 It was therefore hoped that controlling hyperglycemia would reduce cardiovascular disease incidence and mortality, but unfortunately, landmark trials in type 2 diabetes have shown mixed results. In fact, the pendulum has swung in the opposite direction with concerns about the cardiac risks of rosiglitazone, culminating in the US Food and Drug Administration (FDA) 2008 guidelines requiring cardiovascular safety data in novel therapies for type 2 diabetes. In this article, we will review landmark trials in glycemic control, the rosiglitazone story, and post-2008 cardiovascular outcome studies of new type 2 diabetes medications.

Landmark Trials The list of landmark studies in type 2 diabetes includes: the University Group Diabetes Program (UGDP), the United Kingdom Prospective Diabetes Study (UKPDS), Action to Control Cardiovascular Risk in Diabetes (ACCORD), Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE), and the Veterans Affairs Diabetes Trial (VADT) (see Table 1). Following the UGDP and the UKPDS, there was little question that improved glycemic control would prevent the onset and delay the progression of microvascular disease. The main purpose of the ACCORD, the ADVANCE, and the VADT studies was to look at the effect of tight glycemic control on macrovascular outcomes in patients with type 2 diabetes.

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Edelman_FINAL.indd 54

Initiated in 1961, the UGDP was the first large, prospective, randomized trial designed to answer the question of whether control of blood glucose levels helps to prevent vascular disease in patients with non-insulin dependent diabetes. Up until that point, support for or against this hypothesis generally came in the form of expert opinion or from studies that suffered from being non-randomized and retrospective.6 The UGDP randomized 1,027 patients with recently diagnosed type 2 diabetes to one of five treatment groups: • • • • •

placebo; phenformin, a biguanide; tolbutamide, a sulfonylurea; fixed dose insulin; and variable dose insulin, with insulin dose adjusted to achieve a fasting blood glucose <110 mg/dl and a blood glucose <210 mg/dl one hour after ingestion of 50 grams of glucose.7–14

Median follow-up was more than 5 years. While all treatment groups achieved an initial reduction in fasting glucose, only the variable dose insulin group maintained this reduction in subsequent follow-up visits. Compared to placebo, none of the treatment groups demonstrated benefit in all-cause or cardiovascular mortality, and unexpectedly, tolbutamide and phenformin caused an increase in cardiovascular mortality. These findings led to early discontinuation of the tolbutamide and phenformin treatments.

The UGDP reports provoked a great deal of controversy and criticism, largely because of the increased cardiovascular mortality with

© RADCLIFFE CARDIOLOGY 2016

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Type 2 Diabetes Table 1: A Summary of the Landmark Trials in Type 2 Diabetes Care Trial

Patients

Intervention

Glycemic Outcomes

Cardiovascular and Mortality Outcomes

UGDP

• 1,027 patients

• Placebo

• All treatment groups achieved

• Compared to placebo, no group reduced

• Recently-diagnosed type 2 diabetes

• Tolbutamide

initial reduction in fasting

all-cause or cardiovascular mortality

• Recruitment from 1961 to 1966

• Phenformin

glucose, but only the variable

Tolbutamide and phenformin increased

• Median follow-up >5 years

• Fixed dose insulin

dose insulin group maintained

cardiovascular mortality

• Variable dose insulin

this reduction in follow up

UKPDS

• 4,209 patients • Newly diagnosed type 2 diabetes • Recruitment from 1977 to 1991

• Conventional treatment with diet • Intensive treatment,

• Median follow-up 10 years

randomized to:

• Baseline A1c 7.1 %

– insulin

• Intensive treatment (excluding

demonstrated trend toward reduction in

compared with conventional

myocardial infarction, but without significant

treatment (7.0 versus 7.9 %) • In overweight patients,

– chlorpropamide

metformin lowered A1c

– glibenclamide

compared with conventional

– glipizide (if non-

treatment (7.4 versus 8.0 %)

• Standard therapy

• Type 2 diabetes (median duration

• Intensive therapy

and all-cause mortality • In secondary randomization, addition of

increased all-cause mortality • Intensive therapy lowered A1c compared with standard therapy (6.4 versus 7.5 %).

10 years) with established

significantly reduced myocardial infarction

on myocardial infarction, but significantly

overweight) • 10,251 patients

difference in all-cause mortality • In overweight patients, metformin

metformin to sulfonylurea had no effect

overweight) – metformin (if ACCORD

• Intensive treatment (excluding metformin)

metformin) lowered A1c

• No significant difference in composite of nonfatal myocardial infarction, nonfatal stroke, cardiovascular death • Intensive therapy seemed to increase all-

cardiovascular disease or

cause and cardiovascular mortality

cardiovascular risk factors • Recruitment in 2001 and 2003–2005 • Median follow-up 3.4 years • Baseline A1c 8.1 % ADVANCE

• 11,140 patients

• Standard control

• Type 2 diabetes (mean duration

• Intensive control with

7.9–8.0 years) with history of risk

regimen including

factor for vascular disease or history

gliclazide

• Intensive control lowered

• No significant difference in major

A1c compared with standard

macrovascular events, all-cause or

control (6.3 versus 7.0 %).

cardiovascular mortality

of macrovascular or microvascular disease • Recruitment from 2001 to 2003 • Median follow-up 5 years • Baseline A1c 7.2 % VADT

• 1,791 patients • Poorly controlled type 2 diabetes (mean duration 11.5 years) • Recruitment from 2000 to 2003

• Standard therapy with

• Intensive therapy lowered

half dose of two oral

A1c compared with standard

medications +/- insulin

therapy (6.9 versus 8.4 %)

• No significant difference in cardiovascular events, all-cause or cardiovascular mortality

• Intensive therapy with

• Median follow-up 5.6 years

full dose of two oral

• Baseline A1c 9.4 %

medications +/- insulin

ACCORD = Action to Control Cardiovascular Risk in Diabetes; ADVANCE = Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation; UGDP = University Group Diabetes Program; UKPDS = United Kingdom Prospective Diabetes Study; VADT = Veterans Affairs Diabetes Trial.

tolbutamide, and partly in response, the UKPDS was organized, again studying the morbidity and mortality impacts of insulin, sulfonylureas, and a biguanide, in this case metformin.15 In this study, 4,209 patients with newly diagnosed type 2 diabetes were recruited from 1977 to 1991.16,17 Average baseline hemoglobin A1c was 7.1 %. Non-overweight patients were randomized to conventional treatment with diet, or intensive treatment with insulin or a sulfonylurea (chlorpropamide, glibenclamide, or glipizide). Overweight patients were randomized to conventional treatment with diet, or intensive treatment with insulin or metformin or a sulfonylurea (chlorpropamide or glibenclamide). The goal of the conventional arm was to maintain fasting plasma glucose <270 mg/dl without hyperglycemia symptoms, while the goal of the intensive arm was fasting plasma glucose <108 mg/dl. Over 10 years of follow-

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Edelman_FINAL.indd 55

up, the median A1c values were lower in the intensive group (excluding metformin) compared with the conventional group (7.0 versus 7.9 %).

In a separate analysis of overweight patients, median A1c for the metformin group was 7.4 versus 8.0 % for conventional treatment.

Excluding metformin, there was a trend toward reduction in myocardial infarction with intensive therapy (14.7 versus 17.4 events per 1,000 patient-years, p=0.052), but no significant difference in all-cause mortality. In overweight patients, metformin significantly reduced myocardial infarction (11.0 versus 18.0 events per 1,000 patient-years, p=0.01) and all-cause mortality (13.5 versus 20.6 events per 1,000 patient-years, p=0.011). Interestingly, a secondary randomization was performed in the UKPDS in which patients with inadequate glycemic control on sulfonylurea therapy were randomized to addition or

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Risk and Prevention no addition of metformin. A1c over 4 years of follow-up decreased with addition of metformin (7.7 versus 8.2 %), but there was no significant difference in myocardial infarction and actually an increase in all-cause mortality (30.3 versus 19.1 events per 1,000 patient-years, p=0.041). It is important to point out that these latter results did not affect clinical practice in terms of adding metformin to a sulfonylurea, and that statistical flukes are possible even with large multicenter trials.

The UGDP and the UKPDS came to different conclusions regarding sulfonylureas, and to this date, it is still unclear what effect this class of medications has on mortality. A recent 2013 review of 72 randomized controlled trials concluded that there was insufficient evidence to determine whether sulfonylureas increase all-cause or cardiovascular mortality.18 In some ways, however, the concern regarding cardiovascular harm with sulfonylurea therapy overshadowed the fact that neither the UGDP nor the UKPDS showed significant cardiovascular benefit with intensive insulin therapy.19 In addition, the primary metformin randomization in the UKPDS led to a very different result compared with the secondary metformin randomization.

In the wake of these conflicting results, three large trials, the ACCORD, the ADVANCE, and the VADT, set out to answer the still-unresolved question of whether intensive glucose control in type 2 diabetes reduces cardiovascular complications.19–21 In the ACCORD trial, 10,251 patients with existing type 2 diabetes (median duration 10 years) and either established cardiovascular disease or additional cardiovascular risk factors were recruited in two phases, in 2001 and also from 2003 to 2005.22 Median baseline A1c was 8.1 %. Patients were randomized to standard therapy targeting an A1c of 7.0–7.9 %, or intensive therapy targeting an A1c <6.0 %. The primary outcome was a composite of nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes. Median A1c was lower in the intensive group (6.4 versus 7.5 %). No significant difference was seen in the primary outcome, but intensive therapy seemed to increase all-cause mortality (5.0 versus 4.0 %, p=0.04) and cardiovascular mortality (2.6 versus 1.8 %, p=0.02). These results led the study’s external data safety monitoring board to end the trial early, and prompted a worldwide discussion on what the glycemic goals should be in type 2 diabetes, especially for older patients with a history of coronary heart disease.

In the ADVANCE study, 11,140 patients with existing type 2 diabetes (mean duration 7.9–8.0 years) and a history of macrovascular disease or microvascular disease or risk factor for vascular disease were recruited from 2001 to 2003.23 Median baseline A1c was 7.2 %, and median follow-up was 5 years. Patients were randomized to intensive control, targeting an A1c of 6.5 % or less with therapy including gliclazide modified release, or standard control based on local guidelines. The primary outcomes were composites of macrovascular events (nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death) and microvascular events (new or worsening nephropathy or retinopathy).

At the end of follow-up, the intensive group achieved a lower median A1c (6.3 versus 7.0 %). Intensive control also reduced the incidence of combined major macrovascular and microvascular events (18.1 versus 20.0 %, p=0.01), primarily due to a reduction in nephropathy. There was no significant difference in major macrovascular events, cardiovascular mortality, or all-cause mortality.

56

Edelman_FINAL.indd 56

In the VADT, 1,791 patients with poorly controlled type 2 diabetes (mean duration 11.5 years) were recruited from 2000 to 2003.24 Mean baseline A1c was 9.4 %, and median follow-up was 5.6 years. Patients were randomized to standard therapy (half-maximal dose of two oral medications with insulin added if A1c was not <9 %) or intensive therapy (maximal dose of two oral medications with insulin added if A1c was not <6 %). The two oral medications were chosen based on baseline body mass index (BMI): patients with BMI 27 kg/m2 or more were started on metformin plus rosiglitazone, while patients with BMI <27 kg/m2 received glimepiride plus rosiglitazone. The primary composite outcome was time to first occurrence of any cardiovascular event (myocardial infarction, stroke, cardiovascular death, new or worsening congestive heart failure, amputation for ischemic gangrene, inoperable coronary artery disease, or surgical intervention for cardiac, cerebrovascular, or peripheral vascular disease). The intensive group achieved a lower A1c (6.9 versus 8.4 %). There was no significant difference in the primary composite outcome, or in all-cause or cardiovascular mortality.

Two different groups of patients were studied in these landmark trials, with the UGDP and the UKPDS studying recently diagnosed patients (although many of these subjects most likely had undiagnosed diabetes for many years), and the ACCORD, the ADVANCE, and the VADT studying patients with long-standing diabetes of 8–12 years duration and with documented cardiovascular disease or risk factors for cardiovascular disease. The glycemic control achieved in the UGDP is difficult to compare to that of the UKDPS as no A1c values were reported in the former, primarily because the utility of glycated hemoglobin had not been demonstrated prior to the development of the UGDP protocol. However, in many ways, the UKPDS served as a rebuttal to the UGDP findings of increased cardiovascular mortality with tolbutamide and phenformin. The UKPDS reported a trend toward reduced myocardial infarction and no mortality difference with intensive therapy with insulin or sulfonylurea.

It also reported a statistically significant benefit in myocardial infarction and all-cause mortality with metformin in overweight newly-diagnosed type 2 diabetic patients. It is important to acknowledge that this positive result is based on a relatively small number of patients, 342 in the metformin arm. In addition, the secondary randomization protocol produced the confusing result of increased all-cause mortality and a lack of benefit in myocardial infarction when metformin was added to sulfonylurea therapy.

Both the ACCORD and the ADVANCE trials studied large numbers of patients with long-standing type 2 diabetes, but produced different results in terms of cardiovascular and all-cause mortality. One difference between the two studies was baseline A1c, with the ACCORD trial patients having a higher baseline A1c, indicating worse control leading up to study enrollment. Also, the A1c difference between the intensive and standard groups was wider in the ACCORD study, possibly allowing a mortality difference to be detected between the two treatment groups. On the other hand, patients in the VADT had even worse baseline glycemic control prior to enrollment, and an even wider gap in A1c between the treatment groups, but their results did not echo the ACCORD study results.

In summary, despite several large trials over the years, intensive glycemic control of type 2 diabetes has not convincingly improved

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Type 2 Diabetes macrovascular outcomes. The general consensus at this time is that the effect of glucose control on cardiovascular disease in type 2 diabetes, if it exists, is minimal.

The Rosiglitazone Story In the setting of uncertainty about the cardiovascular benefit of glycemic control, controversy developed over the potential cardiovascular harms of rosiglitazone, over and above the well-accepted effect of thiazolidinediones on heart failure. In 2003, the World Health Organization reported a signal for cardiac disease and thiazolidinediones from a database of adverse reaction reports. Following this, GlaxoSmithKline began analyzing phase II and III randomized controlled trials of rosiglitazone for excess cardiovascular risk. This meta-analysis was presented to the FDA in August 2006, with the conclusion that there was an increase in cardiac ischemic events with rosiglitazone (hazard ratio 1.31, 95 % confidence interval 1.01–1.70).25 In May 2007, Nissen and Wolski published a separate meta-analysis that found a significant increase in myocardial infarction with rosiglitazone (odds ratio 1.43, p=0.03) and a trend toward increased cardiovascular mortality with rosiglitazone (odds ratio 1.64, p=0.06).26 The latter study garnered a great deal of press and even Congressional attention, although it also received criticism that highlighted the difficulty in pooling data from disparate trials to draw conclusions about relatively rare adverse events.

For example, it was noted that many of the included trials were of short duration and not designed to evaluate cardiovascular outcomes, there was heterogeneity in patient populations and drug dosing regimens studied, and trials were excluded if they reported no myocardial infarction or cardiovascular death events.27 In 2009, results of the Rosiglitazone Evaluated for Cardiovascular Outcomes in Oral Agent Combination Therapy for Type 2 Diabetes (RECORD) trial were reported.28 This was a large randomized prospective trial of 4,447 patients looking at cardiovascular outcomes after addition of rosiglitazone to either metformin or sulfonylurea, compared to the combination of metformin and sulfonylurea. After a mean follow-up of 5.5 years, there was no significant difference in the primary composite outcome of cardiovascular hospitalization or cardiovascular death. Due to allegations of data mishandling, the FDA required an independent re-adjudication of these results. This was performed by the Duke Clinical Research Institute and presented to the FDA in June 2013, confirming the results of the original RECORD publication in showing no difference in cardiovascular outcomes. The FDA subsequently removed its prescribing and dispensing restrictions for rosiglitazone in November 2013, and fully eliminated its rosiglitazone Risk Evaluation and Mitigation Strategy in December 2015.

It is worth noting that pioglitazone, another thiazolidinedione, was the subject of the Prospective Pioglitazone Clinical Trial in Macrovascular Events (PROactive), a randomized trial of 5,238 patients.29 This study reported no significant difference in its primary composite endpoint (all-cause mortality, nonfatal myocardial infarction, stroke, acute coronary syndrome, surgical intervention in the coronary or leg arteries, or amputation above the ankle) but did report significant benefit with pioglitazone in the main secondary composite endpoint of all-cause mortality, nonfatal myocardial infarction, and stroke.

New Therapies In part due to the rosiglitazone controversy, the FDA issued guidelines in December 2008 on the evaluation of cardiovascular risk in the

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development of new therapies for type 2 diabetes. In essence, unless a phase III study demonstrates cardiovascular superiority (upper bound of the 95 % confidence interval of the risk ratio <1.0) or non-inferiority (upper bound of the 95 % confidence interval of the risk ratio <1.3) of a new therapy compared with placebo, a postmarketing safety trial will generally be necessary.30 Thus far, six trials have been published, looking at saxagliptin, alogliptin, sitagliptin, lixisenatide, liraglutide, and empagliflozin, respectively, with many more to come (see Table 2).

Saxagliptin, alogliptin, and sitagliptin are inhibitors of dipeptidyl peptidase 4 (DPP-4), decreasing the degradation of endogenous glucagon-like peptide 1 (GLP-1) by DPP-4 and thereby enhancing pancreatic insulin secretion and inhibiting glucagon release. Saxagliptin was studied in the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus – Thrombolysis in Myocardial Infarction (SAVOR-TIMI 53) trial, which randomized 16,492 patients with type 2 diabetes and cardiovascular risk factors or history of cardiovascular events to receive saxagliptin or placebo.31 There was no significant difference in the primary composite endpoint of cardiovascular death, nonfatal myocardial infarction, or nonfatal ischemic stroke (hazard ratio 1.00, p<0.001 for non-inferiority).

However, there was an increased risk of hospitalization for heart failure with saxagliptin (hazard ratio 1.27, p=0.007). Alogliptin was studied in the Examination of Cardiovascular Outcomes with Alogliptin Versus Standard of Care (EXAMINE) trial, which randomized 5,380 patients with type 2 diabetes and recent myocardial infarction or hospitalization for unstable angina to receive alogliptin or placebo.32 There was no significant difference in the primary composite endpoint of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke (hazard ratio 0.96, p<0.001 for non-inferiority). Given the saxagliptin result concerning heart failure, an exploratory analysis of the EXAMINE trial was undertaken, which did not show any increased risk of heart failure with alogliptin.33 Finally, sitagliptin was studied in the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) trial, which randomized 14,671 patients with type 2 diabetes and established cardiovascular disease to receive sitagliptin or placebo.34 There was no significant difference in the primary composite endpoint of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for unstable angina (hazard ratio 0.98, P<0.001 for non-inferiority), and no significant difference in the rate of hospitalization for heart failure (hazard ratio 1.00, p=0.98).

Lixisenatide and liraglutide are in the class of diabetes medications that directly activate the receptor for endogenous GLP-1. Lixisenatide was studied in the Evaluation of Lixisenatide in Acute Coronary Syndrome (ELIXA) trial, which randomized 6,068 patients with type 2 diabetes and recent acute coronary event to receive lixisenatide or placebo.35 There was no significant difference in the primary composite endpoint of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for unstable angina (hazard ratio 1.02, p<0.001 for non-inferiority), and no significant difference in hospitalization for heart failure (hazard ratio 0.96, p=0.75). The results of liraglutide's cardiovascular safety trial were recently presented at the 2016 meeting of the American Diabetes Association and simultaneously published online in the New England Journal of Medicine.36 In the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome

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Risk and Prevention Table 2: Cardiovascular Outcome Trials of New Type 2 Diabetes Medications Trial

Medication

Patients

Results

SAVOR-TIMI 53

Saxagliptin

16,492

No significant difference in primary composite cardiovascular endpoint, but hospitalization for heart failure was significantly increased with saxagliptin

EXAMINE

Alogliptin

5,380

No significant difference in primary composite cardiovascular endpoint

TECOS

Sitagliptin

14,671

No significant difference in primary composite cardiovascular endpoint

CARMELINA

Linagliptin

8,000 (estimated enrollment)

Estimated completion date: January 2018

CAROLINA

Linagliptin

6,000 (estimated enrollment)

Estimated completion date: September 2018

ELIXA

Lixisenatide

6,068

No significant difference in primary composite cardiovascular endpoint

LEADER

Liraglutide

9,340

Significant benefit in primary composite cardiovascular endpoint

SUSTAIN 6

Semaglutide

3,297

Estimated completion date: January 2016 (results not yet published)

EXSCEL

Exenatide

14,000 (estimated enrollment)

Estimated completion date: April 2018

REWIND

Dulaglutide

9,622 (estimated enrollment)

Estimated completion date: April 2019

EMPA-REG OUTCOME

Empagliflozin

7,020

Significant benefit in primary composite cardiovascular endpoint

CANVAS

Canagliflozin

4,418

Estimated completion date: June 2017

DECLARE-TIMI 58

Dapagliflozin

17,276 (estimated enrollment)

Estimated completion date: April 2019

CREDENCE

Canagliflozin

3,700 (estimated enrollment)

Estimated completion date: January 2020

CANVAS = Canagliflozin Cardiovascular Assessment Study; CARMELINA = Cardiovascular and Renal Microvascular Outcome Study with Linagliptin in Patients with Type 2 Diabetes Mellitus; CAROLINA = Cardiovascular Outcome Study of Linagliptin Versus Glimepiride in Patients with Type 2 Diabetes; CREDENCE = Evaluation of the Effects of Canagliflozin on Renal and Cardiovascular Outcomes in Participants with Diabetic Nephropathy; DECLARE-TIMI 58 = Multicenter Trial to Evaluate the Effect of Dapagliflozin on the Incidence of Cardiovascular Events; ELIXA = Evaluation of Lixisenatide in Acute Coronary Syndrome; EMPA-REG OUTCOME = Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients; EXAMINE = Examination of Cardiovascular Outcomes with Alogliptin Versus Standard of Care; EXSCEL = Exenatide Study of Cardiovascular Event Lowering; LEADER = Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results - A Long Term Evaluation; REWIND = Researching Cardiovascular Events with a Weekly Incretin in Diabetes; SAVOR-TIMI 53 = Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus – Thrombolysis in Myocardial Infarction; SUSTAIN 6 = Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes; TECOS = Trial Evaluating Cardiovascular Outcomes with Sitagliptin.

Results (LEADER) trial, 9,340 patients with type 2 diabetes at high risk for cardiovascular disease were randomized to receive liraglutide or placebo. The primary composite outcome (death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke) occurred in fewer patients in the liraglutide group than in the placebo group (hazard ratio 0.87, p=0.01 for superiority). In addition, there was a significant benefit with liraglutide in the exploratory outcomes of cardiovascular mortality (hazard ratio 0.78, p=0.007) and all-cause mortality (hazard ratio 0.85, p=0.02). ELIXA and LEADER trials led to different results; however, it is not clear if these were due to differences in the study design, demographics of the subjects, or inherent differences between lixisenatide and liraglutide.

Empagliflozin is an inhibitor of sodium-glucose cotransporter 2 (SGLT-2), leading to decreased renal glucose reabsorption and increased urinary glucose excretion. In the Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME), 7,020 patients with type 2 diabetes at high risk for cardiovascular events were randomized to empagliflozin or placebo.37 Empagliflozin demonstrated a significant benefit in the primary composite endpoint of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke (hazard ratio 0.86, p=0.04 for superiority). In terms of secondary outcomes, there was less cardiovascular mortality (hazard ratio 0.62, p<0.001), all-cause mortality (hazard ratio 0.68, p<0.001), and hospitalization for heart failure (hazard ratio 0.65, p=0.002) with empagliflozin; although there was a non-significant increase in silent myocardial infarction and stroke. The mechanisms behind these cardiovascular benefits, which seemed to appear early in the study, remain speculative, and may include effects on blood pressure, weight, the renin-angiotensin system, and volume status. Additionally, further research is needed to determine

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if this is a class effect shared by all SGLT-2 inhibitors, and if benefit is limited to secondary cardiovascular prevention or extends to primary prevention as well.

Clinical Care Metformin is considered first-line therapy for type 2 diabetes,38,39 and particularly in resource-limited practice settings, sulfonylureas are often still used when dual therapy is needed. Increasingly, however, practitioners have been turning to newer medications as second-line agents, including the DPP-4 inhibitors, GLP-1 receptor agonists, and SGLT-2 inhibitors, which have advantages in reducing hypoglycemia risk and weight gain. On top of these advantages, cardiovascular benefit has now been demonstrated with empagliflozin and liraglutide, which may lead to prioritization of these medications within type 2 diabetes treatment algorithms for patients at high cardiovascular risk.

Conclusion While intensive glycemic control in type 2 diabetes has reduced microvascular complications, the expected improvement in cardiovascular outcomes has not clearly materialized in large randomized studies. In fact, intensive control may worsen all-cause and cardiovascular mortality in patients with a long history of poorly controlled type 2 diabetes at high risk for cardiovascular disease.

Disturbingly, concerns about rosiglitazone’s safety from GlaxoSmithKline’s presentation to the FDA and Nissen and Wolski’s 2007 publication led to the requirement that all new diabetes medications have to be evaluated in long-term cardiovascular outcome trials. However, to date, none of the subsequent cardiovascular studies of new diabetes therapies have demonstrated harm, except for an increase in heart

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Type 2 Diabetes failure hospitalizations with saxagliptin that has not been seen with other drugs in the same class. Given the long duration and high cost of these studies, typically measured in the hundreds of millions of dollars, many leaders in the field feel strongly that this requirement should be abolished as it is hampering diabetes drug development.

1.

2.

3.

4.

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Diabetes Care 2016;39 Suppl 1:S60–71. doi: 10.2337/dc16-S011; PMID: 26696684 Gregg EW, Gu Q, Cheng YJ, et al. Mortality trends in men and women with diabetes, 1971 to 2000. Ann Intern Med 2007;147 :149–55. PMID: 17576993 Sarwar N, Gao P, Seshasai SR, et al. Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies. Lancet 2010;375 :2215–22. doi: 10.1016/S0140-6736(10)60484-9; PMID: 20609967 Brunner EJ, Shipley MJ, Witte DR, et al. Relation between blood glucose and coronary mortality over 33 years in the Whitehall Study. Diabetes Care 2006;29 :26–31. PMID: 16373891 Huxley R, Barzi F, Woodward M. Excess risk of fatal coronary heart disease associated with diabetes in men and women: meta-analysis of 37 prospective cohort studies. BMJ 2006;332 :73–8. PMID: 16371403 Knowles HC Jr. The problem of the relation of the control of diabetes to the development of vascular disease. Trans Am Clin Climatol Assoc 1965;76 :142–7. PMCID: PMC2279482 Klimt CR, Knatterud GL, Meinert CL, et al. A study of the effects of hypoglycemic agents on vascular complications in patients with adult-onset diabetes. I. Design, methods and baseline results. Diabetes 1970;19 Suppl:747–83.

Meinert CL, Knatterud GL, Prout TE, Klimt CR. A study of the effects of hypoglycemic agents on vascular complications in patients with adult-onset diabetes. II. Mortality results. Diabetes 1970;19 Suppl:789–830. PMID: 4926376 Goldner MG, Knatterud GL, Prout TE. Effects of hypoglycemic agents on vascular complications in patients with adultonset diabetes. III. Clinical implications of UGDP results. JAMA 1971;218 :1400–10. PMID: 4941698 Knatterud GL, Meinert CL, Klimt CR, et al. Effects of hypoglycemic agents on vascular complications in patients with adult-onset diabetes. IV. A preliminary report on phenformin results. JAMA 1971;217 :777–84. PMID: 4935344 The University Group Diabetes Program. A study of the effects of hypoglycemic agents on vascular complications in patients with adult-onset diabetes. V. Evaluation of phenformin therapy.

Diabetes 1975;24 Suppl 1:65–184. PMID: 1090475 A study of the effects of hypoglycemic agents on vascular complications in patients with adult-onset diabetes. VI. Supplementary report on nonfatal events in patients treated with tolbutamide. Diabetes 1976;25 :1129–53. PMID: 992232 Knatterud GL, Klimt CR, Levin ME, et al. Effects of hypoglycemic agents on vascular complications in patients with adult-onset diabetes. VII. Mortality and selected nonfatal events with insulin treatment. JAMA 1978;240 :37–42. PMID: 351218 Effects of hypoglycemic agents on vascular complications in

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Finally, the SGLT-2 inhibitor empagliflozin and GLP-1 receptor agonist liraglutide have produced a great deal of excitement in the diabetes community after showing a significant cardiovascular benefit in patients with established cardiovascular disease. It remains to be seen where this excitement will lead and what future studies will reveal. n

patients with adult-onset diabetes. VIII. Evaluation of insulin therapy: final report. Diabetes 1982;31 Suppl 5:1–81.

UK prospective study of therapies of maturity-onset diabetes.

I. Effect of diet, sulphonylurea, insulin or biguanide therapy on fasting plasma glucose and body weight over one year.

Diabetologia 1983;24 :404–11. PMID: 6350078 Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998;352 :837–53.

Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group.

Lancet 1998;352 :854–65. PMID: 9742977 Hemmingsen B, Schroll JB, Lund SS, et al. Sulphonylurea monotherapy for patients with type 2 diabetes mellitus.

Cochrane Database Syst Rev 2013;4 :CD009008. doi: 10.1002/14651858.CD009008.pub2; PMID: 23633364 Duckworth WC, McCarren M, Abraira C. Glucose control and cardiovascular complications: the VA Diabetes Trial. Diabetes Care 2001;24 :942–5. PMID: 11347758 ADVANCE Management Committee. Study rationale and design of ADVANCE: action in diabetes and vascular diseasepreterax and diamicron MR controlled evaluation. Diabetologia 2001;44 :1118–20. PMID: 11596665 Goff DC Jr, Gerstein HC, Ginsberg HN, et al. Prevention of cardiovascular disease in persons with type 2 diabetes mellitus: current knowledge and rationale for the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. Am J Cardiol 2007;99 :4i–20i. PMID: 17599424 Gerstein HC, Miller ME, Byington RP, et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008;358 :2545–59. doi: 10.1056/NEJMoa0802743; PMID: 18539917 Patel A, MacMahon S, Chalmers J, et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes.

N Engl J Med 2008;358 :2560–72. doi: 10.1056/NEJMoa0802987; PMID: 18539916 Duckworth W, Abraira C, Moritz T, et al. Glucose control and vascular complications in veterans with type 2 diabetes.

N Engl J Med 2009;360 :129–39. doi: 10.1056/NEJMoa0808431; PMID: 19092145 Mulrow CD, Cornell J, Localio AR. Rosiglitazone: a thunderstorm from scarce and fragile data. Ann Intern Med 2007;147 :585–7.

PMID: 17938398 Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes.

N Engl J Med 2007;356 :2457–71. doi: 10.1056/NEJMoa072761 Diamond GA, Bax L, Kaul S. Uncertain effects of rosiglitazone on the risk for myocardial infarction and cardiovascular death. Ann Intern Med 2007;147 :578–81. PMID: 17679700

28. Home PD, Pocock SJ, Beck-Nielsen H, et al. Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes (RECORD): a multicentre, randomised, open-label trial. Lancet 2009;373 :2125–35. doi: 10.1016/S0140-6736(09)60953-3; PMID: 19501900 29. Dormandy JA, Charbonnel B, Eckland DJ, et al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet 2005;366 :1279–89. PMID: 16214598 30. Hirshberg B, Raz I. Impact of the U.S. Food and Drug Administration cardiovascular assessment requirements on the development of novel antidiabetes drugs. Diabetes Care 2011;34 Suppl 2:S101–6. doi: 10.2337/dc11-s202; PMID: 21525438 31. Scirica BM, Bhatt DL, Braunwald E, et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med 2013;369:1317–26. doi: 10.1056/ NEJMoa1307684; PMID: 23992601 32. White WB, Cannon CP, Heller SR, et al. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med 2013;369 :1327–35. doi: 10.1056/NEJMoa1305889; PMID: 23992602 33. Zannad F, Cannon CP, Cushman WC, et al. Heart failure and mortality outcomes in patients with type 2 diabetes taking alogliptin versus placebo in EXAMINE: a multicentre, randomised, double-blind trial. Lancet 2015;385 :2067–76. doi: http://dx.doi.org/10.1016/S0140-6736(14)62225-X 34. Green JB, Bethel MA, Armstrong PW, et al. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N Engl J Med 2015;373 :232–42. doi: 10.1056/NEJMoa1501352; PMID: 26052984 35. Pfeffer MA, Claggett B, Diaz R, et al. Lixisenatide in patients with type 2 diabetes and acute coronary syndrome.

N Engl J Med 2015;373 :2247–57. doi: 10.1056/NEJMoa1509225; PMID: 26630143 36. Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med 2016; DOI: 10.1056/NEJMoa1603827: epub ahead of press.

37. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015;373 :2117–28. doi: 10.1056/NEJMoa1504720; PMID: 26378978 38. American Diabetes Association. Standards of medical care in diabetes-2016. 7. Approaches to glycemic treatment. Diabetes Care 2016;39 Suppl 1:S52–9. doi: 10.2337/dc16-S010; PMID: 26696682 39. Garber AJ, Abrahamson MJ, Barzilay JI, et al. Consensus statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the comprehensive type 2 diabetes management algorithm - 2016 executive summary. Endocr Pract 2016;22 :84–113. doi: 10.4158/ EP151126.CS; PMID: 26731084

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Electrophysiology | Arrhythmias

LE ATION.

Identification of Patients at Risk of Stroke From Atrial Fibrillation R a y mo n d B F o h t u n g , M D a n d M i c h a e l W R i c h , M D Washington University School of Medicine, St Louis, MO

Abstract Atrial fibrillation (AF) is a highly prevalent arrhythmia associated with a fivefold increase in the risk of stroke. However, this risk is not homogeneous and varies considerably depending on the presence of several demographic and clinical factors. Independent risk factors for stroke in patients with AF include age ≥65 years, female sex, congestive heart failure, prior stroke or transient ischemic attack, hypertension, diabetes mellitus and vascular disease. Based on these indicators, risk stratification schemes to identify patients at low-, moderate-, and high-risk for stroke have been developed and validated. The CHADS2 and CHA2DS2-VASc schemes are widely used and have good predictive accuracy for stroke. Current guidelines recommend the CHA2DS2-VASc scheme, in part because it more accurately identifies patients at truly low risk for stroke who do not require antithrombotic therapy. This article provides an overview of risk factors for stroke in patients with AF, including discussion of the CHADS2 and CHA2DS2-VASc schemes.

Keywords Atrial fibrillation, CHADS2, CHA2DS2-VASc, risk factors, risk stratification, stroke, thromboembolism Disclosure: The authors have no conflicts of interest to declare.

Received: January 28, 2016 Accepted: April 6, 2016 Citation: US Cardiology Review, 2016;10(2):60–4 DOI: 10.15420/usc.2016:1:1 Correspondence: Michael W Rich, MD, Washington University School of Medicine, 660 S. Euclid Avenue, Campus Box 8086, St Louis, MO 63110, USA. E: mrich@wustl.edu

Atrial fibrillation (AF) is the most common clinically significant arrhythmia, with an overall prevalence of approximately 1 % in the general population.1 An estimated 2.3 million adults in the US have AF, and this number is projected to increase to 5.6 million by 2050.1 The most clinically important complication from AF lies in the risk for cardiac thrombus formation and systemic embolism. Accordingly, AF has been shown to be a potent independent risk factor for embolic strokes.2 Non-valvular AF increases the risk of stroke by nearly fivefold.2 However, the risk of stroke varies greatly, ranging from 1 % to 15 % per year,3 and is highly dependent on the presence of other coexisting risk factors.

Identifying AF patients at risk for stroke has important therapeutic and prognostic implications. Thromboprophylaxis with anticoagulants and anti-platelet agents can reduce the risk of stroke in appropriately selected patients with AF,4 but carries an increased risk of bleeding and may require lifestyle modifications such as dietary changes, and frequent monitoring if warfarin is used. To balance the risks and benefits of thromboprophylaxis, AF patients at very low risk for stroke usually do not require therapy. Those at low-to-moderate risk may be treated with anti-platelet therapy or anticoagulation, while those at moderate or high risk generally require prophylactic anticoagulation.

In addition to identifying risk factors for stroke in AF patients, several schemes have been developed to stratify patients into risk groups to facilitate clinical decision-making.

This article reviews the risk factors for stroke in patients with AF, and risk stratification schemes that can be used to identify patients at risk of stroke from AF.

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Access at: www.USCjournal.com

Clinical Risk Factors for Stroke The following sections discuss identified clinical factors associated with a significantly increased risk of stroke in patients with AF.

Age Increasing age is a strong independent risk factor for stroke in AF patients.5–8 In an analysis of patients with ‘lone AF’ (i.e. no other risk factors, including no previous stroke, transient ischemic attack, hypertension, congestive heart failure, diabetes, angina, or MI), the annual rate of stroke was 0 % in patients aged <60 years, 1.6 % in patients aged 60–69, 2.1 % in patients aged 70–79, and 3 % in patients aged >80 years.5 In a systematic review of 18 studies that examined risk factors for stroke in AF patients, eight of 13 studies that considered age found increasing age to be a significant risk factor for stroke.9 In a pooled analysis of trials examining independent risk factors for stroke, older age was a consistent independent risk factor for stroke, resulting in a 1.5-fold increase in risk per decade.7

Sex Female sex has been noted to be an independent risk factor for stroke in several studies of AF patients.6,7,10–12 In the systematic review of 18 studies described in the previous section, female sex was a significant risk factor in five of 10 trials that considered sex.9 Of note, one of the five trials showed that this significant association was maintained only in those with sustained AF, but not paroxysmal AF. Furthermore, one of the 10 studies that considered sex showed male sex to be a significant risk factor for stroke only in those with paroxysmal AF.

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AF and Stroke Risk Prior Stroke or Transient Ischemic Attack Having a prior stroke or transient ischemic attack (TIA) is arguably the strongest risk factor for stroke in AF patients.5–8,10 A pooled analysis of trials that evaluated prior stroke or TIA as a risk factor for stroke in AF found it to be the strongest independent risk factor for subsequent stroke, reporting that it increased stroke risk by 2.5-fold.7

Table 1: Adjusted Stroke Rates for CHADS 2 Scores and Risk Categories † CHADS2

Score

Adjusted stroke rate (strokes

0

1.9

per 100 patient-years)

1

2.8

Hypertension

2

4.0

Both a history of hypertension and systolic blood pressure >160 mmHg have been shown to be consistent independent risk factors for stroke,5–8,10 resulting in a twofold increase in stroke risk.7 A review of studies examining a history of hypertension as a risk factor for stroke showed that in nine of 13 studies it was an independent risk factor.9 Of note, two studies showed that a systolic blood pressure >160 mmHg was also an independent risk factor for stroke.9

3

5.9

4

8.5

5

12.5

6

18.2

Low

0

0.8

Moderate

1–2

2.7

High

3–6

5.3

Diabetes Mellitus Diabetes mellitus (DM) is also a significant independent risk factor for stroke,5,7,8 resulting in a 1.7-fold increase in risk in AF patients.7 However, among six studies that evaluated diabetes as a risk factor for stroke, only two found it to be an independent risk factor, whereas four did not.

Hence, the data on DM are less consistent than for some of the other risk factors.

Risk category

CHADS2 assigns 1 point for congestive heart failure, hypertension, age ≥75 years, and diabetes mellitus, and 2 points for prior stroke or transient ischemic attack. Source: Gage et al., 2001.20

†

Table 2: Adjusted Stroke and Thromboembolism Rates for CHA 2 DS 2 -VASc Scores and Risk Categories † CHA2DS2-VASc

Score

Adjusted 1-year stroke or other

0

0

1

0.7

2

1.9

3

4.7

4

2.3

5

3.9

6

4.5

7

10.1

8

14.2

9

100

Risk category Low

0

0

Moderate

1

0.6

High

2–9

3.0

thromboembolism rate (%)

Heart Failure Clinical heart failure (HF) is commonly considered a risk factor for stroke in AF patients, and although some analyses support this assertion,8,10 the overall evidence is less robust. In a review of trials that examined risk factors for stroke in AF, only one of four studies found HF to be an independent predictor of stroke.9 In another review, clinical HF was not found to not be a consistent independent risk factor for stroke in three cohorts.7

Vascular Disease Vascular disease (i.e. myocardial infarction, peripheral arterial disease) has been found to be an independent predictor of thromboembolism in non-valvular AF. 13 Several studies have shown prior myocardial infarction to be significantly associated with an increased risk of stroke in patients with AF, in both univariate5,14 and multivariate analyses. 15–17 The presence of complex atherosclerotic aortic plaques in the thoracic aorta demonstrated on transesophageal echocardiogram has also been shown to independently increase the risk of thromboembolic events in AF patients prescribed aspirin and low dose warfarin (international normalized ratio goal 1.2–1.5).18 Moreover, in a retrospective review of stroke patients with non-valvular AF, those with high-grade (≥50 %) carotid stenosis had more cortical infarcts suggesting that carotid artery disease may be associated with stroke in AF.19

Stratification Schemes to Identify Patients at Risk of Stroke from AF To identify patients at low, moderate or high risk of stroke from AF, several stratification schemes have been developed. A listing of approximately 15 different stratification schemes and the factors included in each risk category has been published previously.8 We will focus our discussion on the two most commonly used schemes.

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CHA2DS2-VASc assigns 1 point for congestive heart failure, hypertension, age 65–74 years, diabetes mellitus, vascular disease (coronary artery disease, peripheral arterial disease, aortic aneurysm), and female sex category, and 2 points for age ≥75 years and prior stroke or transient ischemic attack. Source: Lip et al., 2010.22

†

CHADS 2 In 2001, Gage et al.20 proposed the CHADS2 stroke risk stratification scheme, which was derived from prior schemes developed by the Atrial Fibrillation Investigators (AFI) and Stroke Prevention in Atrial Fibrillation (SPAF) investigators. CHADS2 serves as an acronym for these risk factors, and includes congestive heart failure (1 point), hypertension (1 point), age ≥75 years (1 point), DM (1 point) and history of stroke or TIA (2 points).

CHADS2 was validated using the National Registry of Atrial Fibrillation (NRAF), which included hospitalized Medicare beneficiaries with AF and thus represented a real-life cohort. Stroke rates were increased by a factor of approximately 1.5 for each 1-point increase in CHADS2 score.

The adjusted stroke rates for CHADS2 scores of 0, 1, 2, 3, 4, 5 and 6

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Electrophysiology | Arrhythmias were 1.9, 2.8, 4.0, 5.9, 8.5, 12.5 and 18.2 strokes per 100 patient-years, respectively (see Table 1).20 In a second analysis aimed at validating CHADS2, conducted in patients prescribed aspirin in multicenter trials, those at low risk (score of 0), moderate risk (score of 1–2) and high risk (score of 3–6) were found to have average rates of 0.8, 2.7 and 5.3 strokes per 100 patient-years, respectively.21 CHADS2 was also shown to have greater predictive accuracy for stroke compared with the AFI and SPAF schemes.21 The CHADS2 scheme continues to be widely used in clinical practice.

Advantages of the CHADS2 scheme include the fact that it has been validated in multiple populations4,20–22 and that it is easy to use because all five risk factors can be readily obtained from the patient’s history.

Important limitations are that the NRAF included only hospitalized older patients not receiving anticoagulation, and may therefore have selected individuals at higher risk for stroke. In addition, even patients with a CHADS2 score of 0 had an annual stroke rate of 1.9 %; thus, the scheme does not accurately identify patients at very low risk.

CHA 2 DS 2-VASc The CHA2DS2-VASc risk stratification scheme was developed by Lip et al.22 in 2009 in an attempt to improve the CHADS2 scheme. The authors pointed out that some risk factors associated with increased risk of stroke in AF, including female sex and vascular disease18,23–25 (i.e. myocardial infarction, peripheral vascular disease, and complex aortic plaque) are not included in the CHADS2 scheme. CHA2DS2-VASc incorporates these risk factors and also places increased emphasis on the importance of age. The CHA2DS2-VASc scheme comprises congestive heart failure (1 point), hypertension (1 point), age ≥75 (2 points), DM (1 point), stroke/TIA/thromboembolism (2 points), vascular disease (1 point), age 65–74 years (1 point), and sex category-female (1 point). CHA2DS2-VASc was validated in a large cohort of patients participating in the Euro Heart Survey for AF. The adjusted 1-year rates for stroke or other thromboembolism for CHA2DS2-VASc scores ranging from 0 to 9 are shown in Table 2.22 In addition, the stroke or thromboembolism rates for those at low (score of 0), moderate (score of 1) and high risk (score of ≥2) were 0 %, 0.6 % and 3.0 %, respectively.22 The CHA 2DS 2-VASc scheme has several advantages compared with CHADS2. It was validated in a more representative real-life cohort and was also shown to have better predictive accuracy than CHADS2.22 CHA2DS2-VASc identifies patients at very low risk for stroke (score of 0) who do not require anti-thrombotic therapy,8,26 and reduces the number of patients stratified to the moderate risk group (score of 1) for whom there is uncertainty about whether to treat with aspirin or an anticoagulant.22,27,28

Other Risk Factors for Stroke Several other clinical and non-clinical risk factors for stroke in AF patients have been reported. However, these factors are less commonly used in everyday clinical practice, in part because they require additional testing and the results are often not readily available at the time of presentation.

Echocardiographic risk factors for stroke in AF Several echocardiographic parameters have been associated with increased risk for stroke in AF, including left ventricular hypertrophy,14

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left ventricular systolic dysfunction, and left atrial enlargement. In a study performed by the SPAF investigators, left ventricular dysfunction on 2-dimensional echocardiography was a strong independent risk factor for thromboembolism.29 A later prospective analysis of 1066 patients with AF performed by the AFI investigators also showed that moderateto-severe left ventricular dysfunction on echocardiography was a strong independent predictor of stroke.30 Conversely, a subsequent study by the SPAF investigators failed to identify any echocardiographic parameters that were independently associated with thromboembolism.10 Left atrial size measured from the M-mode echocardiogram was shown to be a strong independent predictor of stroke in one study29 but not in a later study.30 Left atrial appendage length and width obtained via trans-esophageal echocardiogram was shown to be associated with risk of thromboembolism on univariate analysis but not multivariate analysis.31 In the same study, thrombus in the left atrium or left atrial appendage was associated with increased risk of thromboembolism on univariate but not multivariate analysis.31 Another trans-esophageal echocardiogram study showed that spontaneous echo contrast and complex atherosclerotic plaque in the thoracic aorta were independently predicative of thromboembolism.18 In summary, the incremental value of echocardiographic parameters for assessing stroke risk in patients with AF is unproven.

Chronic Kidney Disease Chronic kidney disease (CKD) is a strong independent risk factor for thromboembolism in patients with AF. In one analysis it was reported to be second only to prior stroke or TIA.32 In a retrospective analysis of a large cohort of patients with AF not receiving anticoagulation, both an estimated glomerular filtration rate (eGFR) <45 ml/min/1.73m2 and the presence of proteinuria were associated with significantly increased risk of thromboembolism.33 In AF patients enrolled in the SPAF III trial who were assigned to the aspirin or fixed low-dose warfarin group, eGFR as a continuous variable was independently predictive of thromboembolism.17 In another retrospective analysis of patients assigned to the aspirin arm of the Atrial Fibrillation Patients Who Have Failed or are Unsuitable for Vitamin K Antagonist Treatment (AVERROES) trial, stage III CKD was shown to be independently associated with increased risk of thromboembolism.34 Finally, in an analysis of patients enrolled in the Rivaroxaban Once-daily, direct factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation (ROCKET-AF) study, decreasing creatinine clearance (CrCl) was shown to independently predict thromboembolism.32 In addition, the authors proposed an improvement to the CHADS2 scheme by giving 2 extra points for CrCl <60 ml/l and represented the new scheme as R2CHADS2. This new scheme was validated in a separate large cohort of ambulatory AF patients and was shown to provide better stroke risk reclassification compared with CHADS2.32

Miscellaneous In an analysis of 78,844 AF patients in the UK General Practice Research Database, a C-reactive protein level >50 mg/l was significantly associated with stroke.8 In a pooled analysis of participants in the SPAF trials (SPAF I-III), estrogen hormone replacement therapy was associated with a higher risk of ischemic stroke.6 Serum high-density lipoprotein and total cholesterol have also been shown to be independent predictors of stroke

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AF and Stroke Risk in older patients with persistent or permanent AF.14 However, none of these markers are suitable for clinical use in estimating stroke risk.

AF, non-paroxysmal AF was associated with a 38 % greater risk of thromboembolism during long-term follow-up compared with paroxysmal AF.38

Valvular AF Most discussions about the risk of stroke in AF (including this review) pertain to non-valvular AF. Similarly, most trials examining the risk of stroke in AF have only enrolled patients with non-valvular AF. This is because certain valvular diseases (e.g. mitral stenosis) increase the risk of stroke even in the absence of AF, and markedly increase risk in the presence of AF. In particular, the risk of stroke is increased 17-fold in people with AF and rheumatic heart disease.35 There is also concern that the pathophysiology of stroke in valvular AF may be different from that in non-valvular AF.36 Furthermore, there is uncertainly about how to precisely define valvular AF. 36 From the clinical perspective, while rheumatic mitral stenosis markedly increases the risk of stroke in patients with AF, the impact of other valvular disorders is less clear. Some studies suggest that mild mitral regurgitation increases the risk for stroke, while moderate-to-severe mitral regurgitation may be associated with reduced risk.36 At present, there is no evidence that aortic or tricuspid valve disease increases risk of systemic thromboembolism in patients with AF.

AF Detected by Implanted or Wearable Cardiac Monitoring Devices As a result of the increased utilization of implanted cardiac devices – including pacemakers, defibrillators, and loop recorders, as well as wearable devices such as 30-day event monitors – clinically ‘silent’ or asymptomatic AF is being detected with increasing frequency.

However, although the prevalence, duration, and burden of AF detected by these devices have been shown to be independent risk factors for stroke and thromboembolism, the Randomized Trial of Anticoagulation Guided by Remote Rhythm Monitoring in Patients With Implanted Cardioverter-Defibrillator and Resynchronization Devices (IMPACT) study failed to show a beneficial effect of anticoagulation therapy on a composite outcome of ischemic stroke, embolic events, and major bleeding.39 Hence, additional studies are needed to determine the optimal management of patients with subclinical AF detected by cardiac monitoring devices.

Conclusion Stroke Risk in Paroxysmal Versus Non-paroxysmal AF Analyses of the risk of stroke in AF do not always make the distinction between paroxysmal and non-paroxysmal (i.e. persistent and permanent) AF. However, the risk of stroke by subtype of AF has been examined in several trials and has not emerged as an independent risk factor for stroke;7,9,37 i.e. the risk for stroke did not differ according to whether AF was paroxysmal, persistent, or permanent.

However, in a recent meta-analysis of nearly 100,000 patients with

1.

2.

3.

4.

5.

6.

7.

8.

9.

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DOI: 10.1001/jama.290.20.2685; PMID: 14645310 Atrial Fibrillation Investigators. Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation.

Analysis of pooled data from five randomized controlled trials. Arch Intern Med 1994;154:1449–57. DOI: 10.1001/ archinte.1994.00420130036007; PMID: 8018000 Hart RG, Pearce LA, McBride R, et al. Factors associated with ischemic stroke during aspirin therapy in atrial fibrillation: analysis of 2012 participants in the SPAF I-III clinical trials. The Stroke Prevention in Atrial Fibrillation (SPAF) Investigators. Stroke 1999;30:1223–9. DOI: 10.1161/01.STR.30.6.1223; PMID: 10356104 Stroke Risk in Atrial Fibrillation Working Group. Independent predictors of stroke in patients with atrial fibrillation: a systematic review. Neurology 2007;69:546–54. DOI: 10.1212/01. wnl.0000267275.68538.8d; PMID: 17679673 Van Staa TP, Setakis E, Di Tanna GL, et al. A comparison of risk stratification schemes for stroke in 79,884 atrial fibrillation patients in general practice. J Thromb Haemost 2011;9:39–48.

DOI: 10.1111/j.1538-7836.2010.04085.x; PMID: 21029359 Hughes M, Lip GYH. Stroke and thromboembolism in atrial fibrillation: a systematic review of stroke risk factors, risk stratification schema and cost effectiveness data. Thromb Haemost 2008;99:295–304. DOI: 10.1160/TH07-08-0508; PMID: 18278178

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Several clinical and non-clinical risk factors for stroke in patients with AF have been identified, and clinically useful classification schemes have been developed to facilitate risk stratification in patients with AF. Current European Society of Cardiology and the American College of Cardiology–American Heart Association–Heart Rhythm Society guidelines for the management of patients with AF both endorse using the CHA2DS2-VASc scheme for risk stratification and therapeutic decision-making in patients with AF.40,41 n

10. Stroke Prevention in Atrial Fibrillation Investigators. Risk factors for thromboembolism during aspirin therapy in patients with atrial fibrillation: The stroke prevention in atrial fibrillation study. J Stroke Cerebrovasc Dis 1995;5:147–57. DOI: 10.1016/ S1052-3057(10)80166-1; PMID: 26486811 11. Dagres N, Nieuwlaat R, Vardas PE, et al. Gender-related differences in presentation, treatment, and outcome of patients with atrial fibrillation in Europe: a report from the Euro Heart Survey on Atrial Fibrillation. J Am Coll Cardiol 2007;49:572–7. DOI: 10.1016/j.jacc.2006.10.047; PMID: 17276181 12. Fang MC, Singer DE, Chang Y, et al. Gender differences in the risk of ischemic stroke and peripheral embolism in atrial fibrillation: the AnTicoagulation and Risk factors In Atrial fibrillation (ATRIA) study. Circulation 2005;112:1687–91. DOI: 10.1161/CIRCULATIONAHA.105.553438; PMID: 16157766 13. Olesen JB, Lip GYH, Lane DA, et al. Vascular disease and stroke risk in atrial fibrillation: a nationwide cohort study. Am J Med 2012;125:826.e13–e23. DOI: 10.1016/j.amjmed.2011.11.024; PMID: 22579139 14. Aronow WS, Ahn C, Kronzon I, et al. Risk factors for new thromboembolic stroke in patients ≥62 years of age with chronic atrial fibrillation. Am J Cardiol 1998;82:119–21. DOI: 10.1016/S0002-9149(98)00247-1; PMID: 9671020 15. Aronow WS, Gutstein H, Hsieh FY. Risk factors for thromboembolic stroke in elderly patients with chronic atrial fibrillation. Am J Cardiol 1989;63:366–7. DOI: 10.1016/00029149(89)90349-4; PMID: 2783633 16. Petersen P, Kastrup J, Helweg-Larsen S, et al. Risk factors for thromboembolic complications in chronic atrial fibrillation. The Copenhagen AFASAK study. Arch Intern Med 1990;150:819–21.

DOI: 10.1001/archinte.1990.00390160077016; PMID: 2183733 17. Hart RG, Pearce LA, Asinger RW, et al. Warfarin in atrial fibrillation patients with moderate chronic kidney disease.

Clin J Am Soc Nephrol 2011;6:2599–604. DOI: 10.2215/ CJN.02400311; PMID: 21903982 18. The Stroke Prevention in Atrial Fibrillation Investigators Committee on Echocardiography. Transesophageal echocardiographic correlates of thromboembolism in highrisk patients with nonvalvular atrial fibrillation. Ann Intern Med 1998;128:639–47. DOI: 10.7326/0003-4819-128-8-199804150-

00005; PMID: 9537937 19. Chang Y-J, Ryu S-J, Lin S-K. Carotid artery stenosis in ischemic stroke patients with nonvalvular atrial fibrillation. Cerebrovasc Dis 2002;13:16–20; PMID: 11810005 20. Gage BF, Waterman AD, Shannon W, et al. Validation of clinical classification schemes for predicting stroke: results from the National Registry of Atrial Fibrillation. JAMA 2001;285:2864–70.

DOI: 10.1001/jama.285.22.2864; PMID: 11401607 21. Gage BF, van Walraven C, Pearce L, et al. Selecting patients with atrial fibrillation for anticoagulation: stroke risk stratification in patients taking aspirin. Circulation 2004;110:2287–92. DOI: 10.1161/01.CIR.0000145172.55640.93; PMID: 15477396 22. Lip GYH, Nieuwlaat R, Pisters R, et al. Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: the euro heart survey on atrial fibrillation. Chest 2010;137:263–72.

DOI: 10.1378/chest.09-1584; PMID: 19762550 23. Schmitt J, Duray G, Gersh BJ, et al. Atrial fibrillation in acute myocardial infarction: a systematic review of the incidence, clinical features and prognostic implications. Eur Heart J 2009;30:1038–45. DOI: 10.1093/eurheartj/ehn579; PMID: 19109347 24. Siu CW, Jim MH, Ho HH, et al. Transient atrial fibrillation complicating acute inferior myocardial infarction: implications for future risk of ischemic stroke. Chest 2007;132:44–9. DOI: 10.1378/chest.06-2733; PMID: 17400657 25. Lip GYH. Coronary artery disease and ischemic stroke in atrial fibrillation. Chest 2007;132:8–10. DOI: 10.1378/chest.07-0500; PMID: 17625079 26. Potpara TS, Polovina MM, Licina MM, et al. Reliable identification of “truly low” thromboembolic risk in patients initially diagnosed with “lone” atrial fibrillation: the Belgrade atrial fibrillation study. Circ Arrhythmia Electrophysiol 2012;5:319– 26. DOI: 10.1161/CIRCEP.111.966713; PMID: 22319004 27. Olesen JB, Lip GYH, Hansen ML, et al. Validation of risk stratification schemes for predicting stroke and thromboembolism in patients with atrial fibrillation: nationwide cohort study. BMJ 2011;342:d124. DOI: 10.1136/bmj.d124; PMID: 21282258

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Electrophysiology | Arrhythmias 28. Coppens M, Eikelboom JW, Hart RG, et al. The CHA2DS2VASc score identifies those patients with atrial fibrillation and a CHADS2 score of 1 who are unlikely to benefit from oral anticoagulant therapy. Eur Heart J 2013;34:170–6. DOI: 10.1093/ eurheartj/ehs314; PMID: 23018151 29. The Stroke Prevention in Atrial Fibrillation Investigators.

Predictors of thromboembolism in atrial fibrillation: II. Echocardiographic features of patients at risk. Ann Intern Med 1992;116:6–12. DOI: 10.7326/0003-4819-116-1-6; PMID: 1727097 30. Atrial Fibrillation Investigators. Echocardiographic predictors of stroke in patients with atrial fibrillation: a prospective study of 1066 patients from 3 clinical trials. Arch Intern Med 1998;158: 1316–20. DOI: 10.1001/archinte.158.12.1316; PMID: 9645825 31. Stöllberger C, Chnupa P, Kronik G, et al. Transesophageal echocardiography to assess embolic risk in patients with atrial fibrillation. ELAT Study Group. Embolism in Left Atrial Thrombi.

Ann Intern Med 1998;128:630–8. DOI: 10.7326/0003-4819-128-8199804150-00004; PMID: 9537936 32. Piccini JP, Stevens SR, Chang Y, et al. Renal dysfunction as a predictor of stroke and systemic embolism in patients with nonvalvular atrial fibrillation: validation of the R(2)CHADS(2) index in the ROCKET AF (Rivaroxaban Once-daily, oral,

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DOI: 10.1161/CIRCULATIONAHA.112.107128; PMID: 23212720 Go AS, Fang MC, Udaltsova N, et al. Impact of proteinuria and glomerular filtration rate on risk of thromboembolism in atrial fibrillation: the anticoagulation and risk factors in atrial fibrillation (ATRIA) study. Circulation 2009;119:1363–9.

DOI: 10.1161/CIRCULATIONAHA.108.816082; PMID: 19255343 Eikelboom JW, Connolly SJ, Gao P, et al. Stroke risk and efficacy of apixaban in atrial fibrillation patients with moderate chronic kidney disease. J Stroke Cerebrovasc Dis 2012;21:429–35.

DOI: 10.1016/j.jstrokecerebrovasdis.2012.05.007; PMID: 22818021 Wolf PA, Dawber TR, Thomas HE, et al. Epidemiologic assessment of chronic atrial fibrillation and risk of stroke: the Framingham study. Neurology 1978;28:973–7; PMID: 570666 De Caterina R, Camm AJ. What is “valvular” atrial fibrillation? A reappraisal. Eur Heart J 2014;35:3328–35. DOI: 10.1093/eurheartj/ ehu352; PMID: 25265975 Hart RG, Pearce LA, Rothbart RM, et al. Stroke with intermittent atrial fibrillation: incidence and predictors during aspirin therapy. Stroke Prevention in Atrial Fibrillation Investigators.

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39. DeCicco AE, Finkel JB, Greenspon AJ, Frisch DR. Clinical significance of atrial fibrillation detected by cardiac implantable electronic devices. Heart Rhythm 2014;11:719–24. DOI: 10.1016/j. hrthm.2014.01.001; PMID: 24394157 40. Camm AJ, Lip GYH, De Caterina R, et al. 2012 focused update of the ESC Guidelines for the management of atrial fibrillation. An update of the 2010 ESC Guidelines for the management of atrial fibrillation. Eur Heart J 2012;33:2719–47. DOI: 10.1093/eurheartj/ ehs253; PMID: 22922413 41. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the Heart Rhythm Society. Circulation 2014;130:2071–104. DOI: 10.1161/CIR.0000000000000040; PMID: 24682348

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Electrophysiology | Arrhythmias

Bridging the Knowledge Gaps in Arrhythmogenic Cardiovascular Conditions: The Critical Role of Registries Melody Hermel, MD, MBS, Rebecca Duffy, BS, Alexander Orfanos, BAc, Isabelle Hack, BA, Shayna McEnteggart, BS MS, Kayle Shapero, BA, Supria Batra, MD and NA Mark Estes III, MD Tufts Medical Center, Boston, MA

Abstract Cardiac registries have filled many gaps in knowledge related to arrhythmogenic cardiovascular conditions. Despite the less robust level of evidence available in registries when compared with clinical trials, registries have contributed a range of clinically useful information. In this review, the authors discuss the role that registries have played – related to diagnosis, natural history, risk stratification, treatment, and genetics of arrhythmogenic cardiovascular conditions – in closing knowledge gaps, and their role in the future.

Keywords Cardiac registries, arrhythmogenic cardiovascular conditions, registries, guidelines, genotype, genetic screening Disclosure: The authors have no conflicts of interest to declare Received: February 1, 2016 Accepted: May 12, 2016 Citation: US Cardiology Review, 2016;10(2):65–74 DOI: 10.15420/usc.2016:3:2 Correspondence: NA Mark Estes III, MD, Tufts Medical Center, 860 Washington Street, Boston, MA 01111, USA. E: nestes@tuftsmedicalcenter.org

One of the fundamental principles of evidence-based medicine is that clinical care should be based on data derived from appropriately designed trials, registries, and observational data from patients. The best available evidence is then used to develop guidelines for clinical care, assess quality, measure performance, and improve patient outcomes. The highest level of evidence in clinical medicine, also known as Level of Evidence A, is derived from multiple prospective randomized clinical trials (RCTs) or from meta-analysis.

Data derived from a single randomized prospective trial, nonrandomized studies, or populations evaluated in registries are considered to be Level of Evidence B. The least robust types of evidence in clinical medicine are consensus opinion of experts, case studies, and standard of care opinion, which are considered to be Level of Evidence C. These levels of evidence provide clinicians with an estimation of certainty regarding treatment effect. It is evident that Level of Evidence A has the highest and C has the lowest certainty. While the best available evidence is always used by professional societies to guide clinical care, this evidence meets the standards of Level A in only approximately 30 % of guideline recommendations.

While RCTs are regarded as the ‘gold standard’ of evidence-based medicine, they are not feasible for many conditions due to small patient populations, ethical considerations, lack of feasibility, or insufficient funding. Increasingly, registries have played a major role in bridging gaps in knowledge when data from RCTs are not available. By definition, registries collect data regarding diagnosis, treatment, and outcomes based on physician’s judgment without any mandated interventions.

While there are many limitations to registries, the collective data can be used to assess many dimensions of diagnosis, natural history, risk stratification, and treatment. More recently, registries have become an

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essential research tool in assessing genotype–phenotype relationships, with profound implications for family members of probands.

Contemporary disease registries in cardiovascular medicine have demonstrated the capacity to favorably impact clinical management of uncommon conditions, particularly arrhythmogenic cardiovascular conditions.1 The patient populations in disease registries represent unbiased samples that most resemble the true clinical population, rather than patients selected based on the restrictive inclusion and exclusion criteria of clinical trials.1 Registries, therefore, contribute valuable insight into large ‘real-world’ populations over time.

Among the conditions for which only registry data are available to guide clinical care are multiple cardiovascular conditions manifesting with cardiac arrhythmias. Despite the absence of RCTs for these arrhythmogenic disease entities, knowledge has been advanced sufficiently to result in meaningful improvements in patient outcomes based solely on registry observations.

The prototype registry was established for patients with the congenital long QT syndrome (LQTS).2,3 This syndrome is characterized by a long QT interval (corrected QT interval [QTc] >440 msec), stress-induced syncope, and the occurrence of life-threatening tachyarrhythmias.2,3 Over three and a half decades, this registry has served as the foundation for meaningful advances in diagnosis, risk stratification, treatment, and useful knowledge related to genotype–phenotype relationships for patients with this condition.

Other cardiovascular syndromes commonly manifesting with arrhythmias include arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C), Brugada syndrome, hypertrophic cardiomyopathy (HCM), and

Access at: www.USCjournal.com

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Electrophysiology | Arrhythmias Table 1: Arrhythmogenic Right Ventricular Dysplasia Paper Title

Year

Authors

Center

(Reference)

Diagnostic

Natural

Risk

Criteria

History

Stratification

Intervention GenotypePhenotype Correlation

Echocardiographic evaluation has a

2013

Platonov P.,

Nordic

et al8

low sensitivity for detection of patients with Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) using the guidelines criteria of 2010 The diagnostic performance of imaging methods 2014

Borgquist R.,

in ARVC using the 2010 Task Force Criteria

et al

Compound and Digenic Heterozygosity

2010

Nordic

9

Xu T.,

N. American

et al12

Contributes to Arrhythmogenic Right Ventricular Cardiomyopathy Prophylactic implantable defibrillator in

2010

Corrado D.,

AHA

et al10

patients with Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia and no prior ventricular fibrillation or sustained ventricular tachycardia Clinical presentation, long-term follow-up

2015

and outcomes of 1001 Arrhythmogenic Right

Groeneweg J., Hopkins/ et al13

Dutch combo

Platonov P.,

Nordic

Ventricular Cardiomyopathy patients and family members Heart transplantations in the Nordic

2013

et al15

Arrhythmogenic Right Ventricular Cardiomyopathy registry Association of competitive and recreational sport 2015

Ruwald A.,

participation with cardiac events in patients with

et al16

N. American

arrhythmogenic right ventricular cardiomyopathy: results from the North American multidisciplinary study of arrhythmogenic right ventricular cardiomyopathy Ventricular arrhythmias in the North American

2014

Usefulness of inducible ventricular tachycardia

Link M.,

N. American

et al14

Multidisciplinary Study of ARVC 2013

Saugner A.M., Zurich et al17

to predict long-term adverse outcomes in Arrhythmogenic Right Ventricular Cardiomyopathy Pathogenic desmosome mutations in index-

2011

Cox M., et al

patients predict outcome of family screening:

Dutch

18

Dutch Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy Genotype-Phenotype Follow-Up Study Desmosomal gene analysis in arrhythmogenic right ventricular dysplasia/cardiomyopathy:

2010

Fressart V.,

Swiss/French

et al19

spectrum of mutations and clinical impact in practice

cardiac sarcoidosis (CS). The focus of this review is advances in knowledge provided by contemporary registries related to these cardiovascular conditions commonly manifesting with cardiac arrhythmias. Currently, clinical diagnosis and evidence-based treatment of these conditions result in an excellent long-term prognosis. By contrast, failure to diagnose and appropriately treat patients with these conditions can result in fatal outcomes. In this respect, informed diagnosis and treatment are considered to be clinical imperatives.

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Based on the relatively small patient populations and the multiple considerations noted above, RCTs have not been conducted for these conditions. A systematic review of the literature, using PubMed, Ovid, and Google Scholar, was conducted related to ARVD/C, Brugada Syndrome, HCM, LQTS, and CS for multicenter, prospective registries. To provide the best available contemporary data, registries were included if they enrolled at least 50 patients, had published results after 2010, and had a follow-up of at least 2 years. After a systematic review of all

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Arrhythmogenic Cardiovascular Conditions Registries Table 2: Brugada Syndrome Paper Title

Date

Authors

Center

(Reference)

Diagnostic

Natural

Risk

Criteria

History

Stratification

Intervention Genotype/ Phenotype Correlation

Long-Term Prognosis of Patients Diagnosed

2010

Probst V, Veltmann C, FINGER Brugada Eckardt L, et al.23

with Brugada Syndrome: Results From the FINGER Brugada Syndrome Registry Low Prevalence of Risk Markers in Cases of

Registry 2011

Raju H, Papadakis M, Raju et al.

Govindan M, et al.26

Sudden Death Due to Brugada Syndrome Risk stratification in individuals with the

Syndrome

2011

Delise P, Allocca G,

Delise et al.

Marras E, et al.24

Brugada type 1 ECG pattern without previous cardiac arrest: usefulness of a combined clinical and electrophysiologic approach Risk Stratification in Brugada Syndrome:

2012

Results of the PRELUDE (PRogrammed

Priori S, Gasparini M, PRELUDE Napolitano C, et al.25 Registry

ELectrical stimUlation preDictive valuE) Registry Outcome after implantation of a cardioverter- 2013

Sacher F,

defibrillator in patients with Brugada

Probst V, Maury P,

syndrome: a multicenter study - part 2

et al.28

Prevalence, characteristics, and prognosis role 2013

Rollin A, Sacher F,

of type 1 ST elevation in the peripheral ECG

Gourraud JB, et al.27

Sacher et al.

Rollin et al.

leads in patients with Brugada syndrome

registries, the knowledge gained was classified into multiple dimensions including: defining diagnostic criteria, characterizing the natural history, risk stratifying, therapy, and genotypic–phenotypic relationships for the cardiovascular conditions.

Arrhythmogenic Right Ventricular Dysplasia/ Cardiomyopathy ARVD/C is a rare, inherited disorder characterized by patchy replacement of ventricular myocardium by fibrofatty tissue, commonly manifesting with ventricular arrhythmias and sudden death.4–19 After the original description in 1977, collective data from registries served as the foundation for the original diagnostic criteria for ARVD/C developed in 1994.4 Multiple registries were subsequently used to refine the diagnostic criteria in 2010.5,7 These new diagnostic criteria have a higher sensitivity and specificity for the condition compared with the 1994 criteria.

With the 2010 ARVD/C diagnostic criteria, national and international databases have provided insights into the advantages and limitations of endocardial voltage mapping cardiac imaging modalities, genetic testing, and family history that will be incorporated in future revisions of the diagnostic criteria.8–13 Table 1 summarizes the contributions of registries included in this systematic review to the current diagnostic criteria and knowledge related to the natural history, risk stratification, intervention, and genotype–phenotype relationship for ARVD/C. Beyond the refinement of diagnostic criteria, registries have also elucidated many aspects of the natural history of patients with ARVD/C.4–19 Among the most valuable insights gained from registries is that this condition is associated with a high frequency of lifethreatening ventricular arrhythmias. A considerable amount of the registry information related to ARVD/C addresses the clinical course of patients with implantable cardioverter defibrillators (ICDs) versus those

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without ICDs.12–14 Valuable insights have been gained into risk stratification for ventricular arrhythmias.12–17 In particular, registries have confirmed that patients who participate in competitive sport have earlier onset of symptoms and an increased risk of ventricular arrhythmia than those who participated in recreational sport or who were inactive.12–17 Spontaneous or induced ventricular arrhythmias and younger age at presentation have also been established as risk factors for future ventricular arrhythmiasbased analyses of multiple registries.14,17 Additionally, it has now been established that the presence of one plakophilin-2 (PKP2) variant or other desmosome-encoding gene variant results in earlier onset and more severe ARVD/C than those who are heterozygous.12 Management and therapeutic interventions for patients with ARVD/C have been developed based on observations provided by registries.

The consistent observation in registries that competitive athletics results in disease progression commonly manifesting with ventricular arrhythmias, has resulted in the recommendation for restriction of competitive athletics.11,16,17 A recent analysis of a North American registry suggests that recreational sports participation may be as safe as no athletic participation.16 The frequency with which patients have episodes of ventricular tachycardia requiring intervention by an ICD has been defined by registries.10,13,14,16,17 The many clinical similarities of isolated and familial ARVD/C has been elucidated from one observational registry.13 Finally, registries have consistently showed that the need for patients with ARVD/C to advance to heart transplant is rare.10,13–17 Another consistent finding among contemporary registries is that pathogenic desmosomal gene mutations, mainly truncating PKP2 mutations, correlate with the clinical manifestation of ARVD/C.11–13,18,19 This pathogenic gene is associated with a sixfold risk of ARVD/C diagnosis in mutation-carrying relatives when compared with relatives

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Electrophysiology | Arrhythmias Table 3: Hypertrophic Cardiomyopathy Paper Title

Year

Authors

Center

(Reference)

Diagnostic

Natural

Risk

Criteria

History

Stratification

Intervention GenotypePhenotype Correlation

Alcohol Septal Ablation for the Treatment of

2011

Nagueh S, Groves Nagueh

Hypertrophic Obstructive Cardiomyopathy:

B, Schwartz L,

A multicenter North American registry

et al.36

Ventricular tachycardia/fibrillation early after

2013

Alsheikh-Ali A,

et al.

Alsheikh-Ali

defibrillator implantation in patients with

Link M, Semsarian et al.

hypertrophic cardiomyopathy is explained by

C, et al.37

a high-risk subgroup of patients Vriesendorp

Vriesendorp

hypertrophic cardiomyopathy: patient

P, Schinkel A,

et al.

outcomes, rate of appropriate and inappropriate

Cleemput J,

Implantable cardioverter-defibrillators in

2013

et al.38

interventions, and complications Risk stratification and outcome of patients

2013

Maron B, Rowin E, Maron et al.

Casey S, et al.30

with hypertrophic cardiomyopathy ≥60 years of age Prevention of sudden cardiac death with

2013

Maron B, Spirito P, Maron et al.

implantable cardioverter-defibrillators in

Ackerman M,

children and adolescents with hypertrophic

et al.39

cardiomyopathy O’Mahoney C,

O’Mahoney

sudden cardiac death in hypertrophic

Jichi F, Pavlou M,

et al.

cardiomyopathy (HCM Risk-SCD)

et al.34

A novel clinical risk prediction model for

Significance of sarcomere gene mutations

2014

2014

Biagini E, Olivotto I, Biagini et al.

analysis in the end-stage phase of hypertrophic

Iascone M,

cardiomyopathy

et al.41

Prognostic value of quantitative contrast-

2014

Chan R, Maron B,

Chan et al.

Olivotto I, et al.35

enhanced cardiovascular magnetic resonance for the evaluation of sudden death risk in patients with hypertrophic cardiomyopathy Clinical phenotype and outcome of

2014

hypertrophic cardiomyopathy associated

Coppini R, Ho C,

Coppini

Ashley E, et al.32

et al.

Spirito P, Autore

Spirito et al.

with thin-filament gene mutations Risk of sudden death and outcome in patients

2014

with hypertrophic cardiomyopathy with benign

C, Formisano F,

presentation and without risk factors

et al.31

Independent Assessment of the European

2015

Maron B, Casey S, Maron et al.

Chan R, et al.40

Society of Cardiology Sudden Death Risk Model for Hypertrophic Cardiomyopathy Hypertrophic Cardiomyopathy in Adulthood Associated With Low Cardiovascular Mortality

2015

Maron B, Rowin E, Maron et al.

Casey S, et al.33

With Contemporary Management Strategies

of patients without mutations.18,19 However, the North American registry data suggest that harboring one PKP2 mutation may not be sufficient to determine overt clinical disease.7,11 Compound or digenic heterozygosity, acquired disruption of proteins, or environmental factors were required in 42 % of cases for overt clinical phenotype.11 A Swiss/French registry identified 41 disease-causing mutations in patients with ARVD/C, indicating that there is a large spectrum of mutations with multiple mechanisms including missense, splicing, frameshift, and deletions mutations.19 It is evident that the knowledge regarding the genotype– phenotype relationships for ARVD/C is incomplete. Currently, a large

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National Institutes of Health-funded registry is enrolling patients with the objective of elucidating these complex relationships.

Brugada Syndrome The Brugada syndrome is characterized by ST-segment elevation in the right precordial leads, episodes of ventricular fibrillation, and sudden cardiac death (SCD).20–28 Observations from registries allowed development of formal criteria in 2005.20 Since then, registries have independently reported on many aspects of the natural history of those identified with symptomatic and asymptomatic Brugada syndrome.20–28

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Arrhythmogenic Cardiovascular Conditions Registries Table 4: Long QT Syndrome Paper Title

Year

Authors

Center

(Reference)

Diagnostic

Natural

Risk

Criteria

History

Stratification

Intervention GenotypePhenotype Correlation

Beta-blocker efficacy in high-risk patients

2010

Goldenberg I,

with the congenital long-QT syndrome types

Bradley J, Moss A,

1 and 2: implications for patient management

et al43

Trigger-specific risk factors and response

2010

Kim JA, Lopes CM,

Multicenter

LQT Registry

to therapy in long QT syndrome type 2

Moss AJ, et al50

Long QT syndrome with compound mutations 2010

Itoh, H., Shimizu, W., Multicenter

is associated with a more severe phenotype:

Hayashi, K., et al56

A Japanese multicenter study Schwartz PJ,

International

Who Receive an Implantable Cardioverter-

Spazzolini C,

LQTS ICD

Defibrillator and What Happens to Them?

Priori SG, et al52

registry

Buber J, Mathew J,

Multicenter

Moss AJ, et al51

LQTS Registry

Who Are the Long-QT Syndrome Patients

Risk of recurrent cardiac events after onset

2010

2011

of menopause in women with congenital long-QT syndrome types 1 and 2 Mutation and Gender Specific Risk in

2011

Risk Factors for Recurrent Syncope and

Migdalovich D, Moss Multiple LQT AJ, et al49

Type-2 Long QT Syndrome 2011

Subsequent Fatal or Near-Fatal Events in

registries

Liu JF, Jons C, Moss International AJ, et al45

LQT registry

Children and Adolescents With Long QT Syndrome Barsheshet A,

International

rate and the risk of life-threatening cardiac

Peterson DR,

LQT registry

events in adolescents with congenital

Moss AJ, et al54

Genotype-specific QT correction for heart

2011

long-QT syndrome Not all Beta-Blockers are Equal in the

2012

Chockalingam P,

Management of Long QT Syndrome Types 1

Crotti L, Girardengo

and 2: Higher Recurrence of Events under

G,

Metoprolol

et al53 Barsheshet A,

Multiple LQT

KCNQ1 Channel and the Risk of Life-

Goldenberg I,

registries

Threatening Events

O-Uchi J, et al47

Mutations in Cytoplasmic Loops of the

Risk of life-threatening cardiac events

2012

Mutlicenter

2013

Mullally J,

Multicenter

among patients with long QT syndrome

Goldenberg I, Moss LQTS Registry

and multiple mutations

AJ, et al55

Efficacy of different beta-blockers in the

2014

treatment of long QT syndrome

Abu-Zeitone A,

Multicenter

Peterson DR, Polonsky B, et al46

Influence of Diabetes Mellitus on Outcome in Patients Over 40 Years of Age With the Long

2010

Ouellet G, Moss AJ, International Jons C, et al48

LQTS registry

QT Syndrome

One large contemporary registry has allowed elucidation of the annual cardiac event rates for patients with a previous episode of aborted SCD (7.7 %).23 By contrast, those presenting with syncope have a considerably lower annual incidence of life-threatening ventricular arrhythmia (1.9 %).23 Finally, asymptomatic patients have been noted to have a low annual rate of major arrhythmic events (0.5 %).23 Two other large prospective registries have confirmed these important findings regarding risk stratification in patients with Brugada syndrome.23–25 These consistent findings among multiple registries of the relatively low annual sudden death rate in those without prior cardiac arrest have

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helped clinicians make decisions regarding the risks and benefits of ICD placement in this patient population.23–25 Data from one registry suggest that the majority (72 %) of SCDs in patients with Brugada syndrome are in low-risk, asymptomatic patients.26 This observation highlights the challenge of predicting and preventing sudden death in low-risk patient populations. In addition to aborted SCD and syncope, a spontaneous type 1 ECG has been noted to be an independent predictor of arrhythmic events.23 In addition to the France, Italy, Netherlands, Germany FINGER registry predictors, the

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Electrophysiology | Arrhythmias Table 5: Cardiac Sarcoidosis Paper Title

Year

Authors

Center

(Reference)

Diagnostic

Natural

Risk

Criteria

History

Stratification

Intervention GenotypePhenotype Correlation

CMR imaging predicts death and other adverse

2013

Greulich64

2015

Takaya65

2013

Kron62

2012

Schuller58

2014

Blankstein59

2012

Suzuki67

2014

Crawford63

2014

Kandolin61

2012

Yousseff69

events in suspected cardiac sarcoidosis Outcomes in patients with high-degree atrioventricular block as the initial manifestation of cardiac sarcoidosis Efficacy and safety of implantable cardiac defibrillators for treatment of ventricular arrhythmias in patients with cardiac sarcoidosis Implantable cardioverter defibrillator therapy in patients with cardiac sarcoidosis Cardiac positron emission tomography enhances prognostic assessments of patients with suspected cardiac sarcoidosis Genetic Characterization and Susceptibility for Sarcoidosis in Japanese Patients: Risk Factors of BTNL2 Gene Polymorphisms and HLA Class II Alleles Magnetic resonance imaging for identifying patients with cardiac sarcoidosis and preserved or mildly reduced left ventricular function at risk of ventricular arrhythmias Cardiac Sarcoidosis: Epidemiology, Characteristics and Outcome over 25 Years in a Nationwide Study The Use of 18F-FDG PET in the Diagnosis of Cardiac Sarcoidosis: A Systematic Review and Metaanalysis Including the Ontario Experience

Programmed Electrical Stimulation Predictive Value (PRELUDE) registry identifies ventricular effective refractory period of <200 msec and QRS fragmentation as independent risk indicators able to identify patients at high risk for ICD implantation.25 In contrast to previous findings, the FINGER registry indicates that VT/VF inducibility during programmed electrical stimulation is found to have no predictive value in identifying high-risk patients.25 Other factors, including family history of SCD, gender, inducibility of ventricular tachyarrhythmias during electrophysiological study and the presence of an SCN5A gene mutation, have been noted to have limited predictive value.23 These findings directly impacted on therapeutic recommendations identified in the 2005 Brugada Syndrome: Report of the Second Consensus Conference.20 A consistent observation from Brugada syndrome registries is that ICD implantation is the only effective treatment for prevention of SCD.20 Appropriate shock rates during follow-up after ICD implantation are highest for patients implanted with ICDs due to a previous aborted sudden cardiac arrest and lower for those with syncope.28 The limited available data regarding ICD shocks in asymptomatic patients demonstrates a low frequency of appropriate shocks.28 The appropriate shock rates are greatest in symptomatic patients as compared with asymptomatic patients.28 While optimal ICD programming and follow-up increased appropriate shock rates, lead failure proved to be an issue throughout patient follow-up (29 % at 10 years).28

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One large registry demonstrated that the presence of a mutation in the SCN5A gene lacks predictive value for arrhythmic events.23 Analysis from risk stratification data from another indicates that type 1 ST elevation in peripheral ECG leads are significantly more likely to contain SCN5A mutations, and express a more severe Brugada syndrome phenotype with a higher risk of arrhythmic events.27 Overall, contemporary registries consistently report a low prevalence of SCN5A mutations among the studied cohorts, suggesting a lack of diagnostic contribution from genetic testing.20–28 Table 2 summarizes the contributions of registries to many dimensions of current knowledge related to the Brugada syndrome.

Hypertrophic Cardiomyopathy Hypertrophic cardiomyopathy (HCM) is a disease caused by a mutation in the sarcomeric genes, which can present with SCD, ventricular arrhythmias, or, more insidiously, with heart failure.29–40 With a high prevalence of this condition in the general population, estimated at 1 in 500 individuals, large databases have defined many dimensions of the condition.29–41 Publications based on data from these registries have been the foundation of defining diagnostic classification for the condition.29 In addition, all aspects of the natural history of HCM have been derived from registries. It is now known that 88 % of patients with HCM present at age ≥60 years, primarily with absent or mild HCM-related symptoms, and typically die from non-HCM related causes.29,32 Maron et al identified

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Arrhythmogenic Cardiovascular Conditions Registries 3.7 % of patients who suffered HCM-related mortality (progressive heart failure or transplant, embolic stroke, or arrhythmia-related death).30 Based on registry data it has become evident that asymptomatic patients or those with mild symptoms have a relatively favorable course with only 5.4 % of patients suffer HCM-related sudden death.30 SCD is found to be independently and inversely related to age, whereas heart failure and stroke are directly related to age.31 One large contemporary registry suggests that high-risk patients who survive life-threatening events (5.6 %) commonly survive in the setting of ICD intervention or heart transplant, thus implying that modern advances may improve mortality rates in this subgroup.33 Further registry data suggest that all-cause mortality rates are increased in patients with HCM aged ≥60 years when compared with an agematched population, predominantly as a result of non-HCM–related diseases.33 Spirito et al found SCD risk was not entirely negligible (event rate of 0.6 % per year) in patients without conventional risk factors and with absent to mild symptoms.31 A recent multicenter cohort study found that age, maximal left ventricular (LV) wall thickness, left atrial diameter, LV outflow tract gradient, family history of SCD/non-sustained ventricular tachycardia, and unexplained syncope are associated with appropriate ICD shock or SCD in patients with HCM.34 These predictors are used to model the possibility of SCD after 5 years, and it was concluded that most patient with HCM with SCD or appropriate ICD interventions are misclassified with low-risk scores.34 Of the 1629 patients examined, 35 experienced SCD, of which only four have a high predictive risk score that is consistent with a recommendation of ICD implantation.

These conclusions indicate the need for continued assessment of accurate risk stratification in this particular population. 33 A study examining cardiovascular MRI found that the extent of late gadolinium enhancement is associated with an increased risk of SCD.35 Clinical outcome following septal alcohol ablation demonstrates survival rate estimates at 1, 5, and 9 years being 97 %, 86 %, and 74 %, respectively.36 Predictors of mortality include low baseline LV ejection fraction, lower number of septal artery ethanol injection, higher number of ablation procedures per patient, high post-ablation septal wall thickness, and requirement of beta-blockade post-procedure.36 Other studies have examined the effectiveness of ICD implantation in patients with HCM. It has been noted that 22 % of patients with ICD implantation receive at least one subsequent ICD shock.37 The risk of discharge is highest in the first year post-transplant (10.8 % per person-year), and more frequent in patients who receive ICD implantation as a secondary prevention measure.37 Similarly, the frequency of appropriate ICD shock is higher in both patients receiving implantation for secondary prevention and in male patients. Inappropriate ICD interventions and device-related complications occur in 3.7 % and 3.6 % of patients, respectively.38 Registries also give important insights into outcomes of pediatric patients with ICD implantation.40 Appropriate interventions occur in 19 %, with mean time from implant to first appropriate shock being 2.9±2.7 years.40 Extreme LV hypertrophy is considered the most common risk factor for patients receiving primary prevention ICD therapy.40 A study comparing a cohort of patients with end-stage HCM (ES-HCM) with a reference cohort of HCM patients with normal LV ejection fraction concluded that ES-HCM is associated with various genetic

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substrates indistinguishable from patients in the reference cohort, with the exception of a larger number of complex genotypes of sarcomere genes.41 In addition data from this registry indicate that thin-filament mutations are associated with an increased likelihood of advanced LV dysfunction and heart failure when compared with thick-filament mutations. The risk of arrhythmia in these two subsets is comparable.32 Table 3 provides an overview of areas in which registries have expanded current knowledge related to the HCM.

Long QT Syndrome The LQTS is characterized by a long QT interval (QTc >440 msec), stressinduced syncope, and the occurrence of a unique form of ventricular tachycardia know as Torsades des Pointes.2,3 LQTS is estimated to have a prevalence of 1 in 3,000 to 1 in 5,000.42–56 The original International LQTS Registry and the many subsequent registries have filled many knowledge gaps related to diagnosis, risk stratification, treatment, and genotype–phenotype relationships for patients with this condition.42–56 On the basis of registry data, formal diagnostic criteria for the condition have been developed.42–56 For diagnostic ECG, the QT interval is measured manually from the beginning of the QRS complex to the end of the T wave. QTc is obtained using Bazett’s, Fridericia, or Framingham correction formula.2,3,42–44 LQT registries have provided many clinical insights related to risk stratification for syncope and sudden death that profoundly influence clinical decisions. Multiple studies identify prolonged QTc duration (≥500 msec) and 100-msec increments in the absolute QT interval as electrocardiographic markers of increased risk for syncopal episodes and life-threatening cardiac events.44,45,47 Other risk factors for syncope, prior SCD, or aborted cardiac attacks include ≥1 episodes of syncope and presence of LQTS genotypes.44,45 There is no observed risk increase of syncope or ventricular arrhythmias in patients with LQTS taking oral contraceptives.46 In addition, development of diabetes in adult patients with LQTS is not associated with an increased risk of first cardiac events dominated by syncope.48 These clinical and electrocardiographic criteria have been supplemented and refined by genetic confirmation of LQT gene mutations. Studies from the International LQTS registry indicate that a greater risk for cardiac events exists for male carriers of the LQT1 gene and female carriers of the LQT2 gene.43,44 For patients specifically diagnosed with type 2 LQTS (LQTS2), female gender has been demonstrated to be a powerful marker of increased risk of life-threatening cardiac events and the first occurrence of trigger cardiac events.49,50 The onset of menopause is associated with a significant increase in the risk of cardiac events in female carriers of LQT2, which suggests careful follow-up and long-term therapy are warranted in this population.51 Multiple registries have demonstrated that syncope and cardiac arrest could be reduced dramatically in patients with LQTS by use of beta-blockers.42–56 Accordingly, beta-blockers have emerged as the initial therapeutic option in patients with LQTS since the original observation of the therapeutic effect of these agents.43,50 Several contemporary studies validate their long-term efficacy in reducing the risk of cardiac events.43,50 Beta-blockers should be routinely administered to all patients at high risk of type 1 (LQT1) and LQT2 as they significantly reduce the risk of life-threatening events in both male

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Electrophysiology | Arrhythmias carriers of LQT1 and female carriers of LQT2.42 Differential efficacy of betablockers has been suggested for treating LQTS.46,54 Among patients with a prior cardiac event while taking beta-blockers, efficacy for recurrent events differ by drug, with propranolol being the least effective compared with other beta-blockers.46 It has also been consistently observed that patients with recurrent syncope while taking beta-blockers have an increased rate of subsequent cardiac events.44 On the basis of these observations it is currently recommended that ICD therapy be provided for this subset of patients with LQTS.44 In addtion, ICD therapy is recommended for all patients with LQTS who have survived a prior episode of cardiac arest.52 Genotype–phenotype correlations in the LQTS population have been facilitated by the commercial availabity of genetic testing. The robust clincal data available in multple registries have demonstrated that multiple mutations, compound mutations in either single or different genes, are associated with a more severe phenotype and a greater risk of lifethreatening cardiac events.54–56 Additional mutations, including mutation characteristics (transmembrane-missense versus nontransmembrane or nonmissense mutations), pore-loop mutations,49 and the presence of C-loop mutations in LQTS1, have been associated with greater risk of cardiac events.44,47,54 Table 4 summarizes the considerable contributions of registries related to the diagnosis, natural history, risk stratification, treatment, and genotype–phenotype relationships for LQTS.

Sarcoidosis CS affects a small minority of patients with pulmonary or systemic sarcoidosis, but when present is often associated with a spectrum of clinically significant conduction abnormalities and arrhythmias.57–68 Unlike other inherited arrhythmogenic cardiovascular conditions reviewed, sarcoidosis is not clearly identified as an inherited disorder. However, epidemiologic data suggest some genetic predisposition.57,60 It has become evident through registry data that the cardinal manifestations of CS are conduction disturbances and arrhythmias.57–68 Although sarcoidosis is typically a multisystem granulomatous disease with cardiac involvement in <10 % of patients with multisystem disease, isolated CS is a definite clinical entity.57–69 As CS commonly presents with life-threatening heart block, malignant arrhythmias, and congestive heart failure, detection and appropriate treatment are essential to ensure the best possible patient outcomes. Registries have played an essential role in filling the knowledge gaps in many domains related to CS.57–69 A recent consensus statement provides guidance for clinicians on the diagnosis and management of arrhythmias associated with CS including indications for ICDs.57 The current diagnostic criteria, natural history, and risk stratification process for CS are all based on data from multiple registries.57 In the therapeutic domain, pacemakers, ICD implantation, and early implementation of corticosteroid therapy have led to an improvement in the overall prognosis and clinical outcomes of CS based on observations from registries.57–69 Contemporary registries contributed to the recent establishment of CS diagnostic criteria in 2014.57,58 The 2014 criteria place greater emphasis on patients with proven systemic sarcoidosis, which is supported by the findings of Schuller et al.58 Blankstein et al. showed a correlation between 18F-fluorodeoxyglucose (18F-FDG) uptake on positron emission tomography (PET) scans and poor outcomes, thus allowing patients to now be officially diagnosed via PET scan evidence.59 The usefulness of MRI evidence has expanded with respect to CS diagnostic criteria refinement.59,60

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Recent registries contribute to the knowledge of risk stratification in CS patients. Two registries have specifically improved the usefulness of MRI and PET imaging. Crawford et al. demonstrated that delayed gadolinium enhancement in the right ventricle is associated with adverse events in patients who have a preserved ejection fraction and no prior history of ventricular tachycardia.63 Furthermore, delayed enhancement is associated with a high risk for recurrent ventricular tachycardia in patients with a history of ventricular tachycardia and enhancement.

MRIs with gadolinium also make good negative indicators, as a lack of delayed enhancement is associated with a low risk for ventricular tachycardia.63 Greulich et al. support these results and identify late gadolinium enhancement as the best independent predictor of both adverse and potentially lethal events.64 18F-FDG uptake on PET scans is an indicator of ventricular tachycardia risk and death.59 Takaya et al. concluded that patients with CS who present with high degree atrioventricular (AV) block, as opposed to ventricular tachycardia, are at high risk of fatal cardiac events.65 The primary intervention for CS in the reviewed registries is ICD implantation. Schuller et al. indicate that approximately one-third of patients with CS with implanted ICDs receive at least one appropriate therapy. Based on this finding, Schuller et al. hypothesize that this increased activity could cause scarring, which results in subsequent tachycardia.66 Kron et al. demonstrate that high-degree AV block is a good indicator of the need for a primary prevention ICD.62 Takaya et al. support these findings; patients initially presenting with AV block have similar outcomes to patients presenting with ventricular tachycardia.65 While corticosteroids remain the gold standard for treatment of CS, ICDs are necessary in higher-risk patients.57,60 Among the registries reviewed, there is a general lack of information on the genotype–phenotype correlation with CS, with the exception of the research conducted by Suzuki et al.67 This registry confirms that the HLA-DRB1 allele is a major contributing factor in the development of sarcoidosis. However, there is no specific phenotypic correlation with this allele or any other allele with respect to CS symptoms or outcomes.67 Table 5 summarizes the considerable contributions of registries to current knowledge related to CS.

Limitations There are limitations to the methods used in this review. Inclusion of registries published since 2010 is one limitation. Our focus was on new data contributed by contemporary registries rather than on a comprehensive historical review. With this approach, it is possible that unique information published prior to 2010 was not included.

Another limitation of the methodology we used is the lack of systematic assessment of registry data quality as part of the selection process for this review. As noted above, registries were included if they enrolled at least 50 patients, had published results after 2010, and had a follow-up of at least 2 years. A limitation of the published data and our review is the inability to assess for enrollment selection bias and generalizability. However, as noted above, the patient populations in disease registries typically represent unbiased samples that most resemble the true clinical population, rather than patients selected based on the restrictive inclusion and exclusion criteria of clinical trials.

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Arrhythmogenic Cardiovascular Conditions Registries Conclusion Cardiac registries have filled many gaps in knowledge related to arrhythmogenic cardiovascular conditions. When clinical trials are feasible, they demonstrate what can be done. Guidelines inform clinicians what should be done, registries inform clinicians regarding what is actually done. In the absence of clinical trials, registries represent the best available evidence to inform clinicians regarding what can be done. Registries are also used as the best available evidence for guidelines. Thereby informing clinicians what should be done. Despite the less robust level of evidence available in registries when compared

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with clinical trials, they have contributed clinically useful information related to arrhythmogenic cardiovascular conditions. The more mature registries, such as the LQTS registry, currently provide clinically useful genotype information that has a direct influence on therapy and genetic screening of relatives. It is evident that registries have had a major role in bridging current knowledge gaps related to diagnosis, natural history, risk stratification, treatment, and genetics of arrhythmogenic cardiovascular conditions. Registries also represent the best available evidence for future guidelines, quality metrics, performance measures, and improved patient outcomes. n

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Expert Opinion Subclinical Atrial Fibrillation in Patients with Hypertrophic Cardiomyopathy Br aghadhe eswa r T hy a g a ra ja n, MD, 1 Ank u r Ka l r a , M D , 2 ,3 A l e f i y a h Ra j a b a l i , M D , 4 J i l l B Wh e l a n , M D 4 a n d E lad An te r, MD 5 1. Department of Internal Medicine, Monmouth Medical Center, Long Branch, NJ; 2. Division of Interventional Cardiology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA; 3. Safety, Quality, Informatics and Leadership Program, 2016-17, Harvard Medical School, Boston, MA; 4. Cardiovascular Division, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA; 5. Harvard-Thorndike Electrophysiology Institute, Cardiovascular Division, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA

Abstract Atrial fibrillation is the most common arrhythmia in patients with hypertrophic cardiomyopathy. Patients with atrial fibrillation in hypertrophic cardiomyopathy are at an increased risk of stroke compared with patients without hypertrophic cardiomyopathy. While the burden of clinicallymanifest atrial fibrillation and its management with anticoagulation for stroke prevention in hypertrophic cardiomyopathy patients have been described, little is known about the prevalence, clinical outcomes and management of subclinical episodes of atrial fibrillation in patients with hypertrophic cardiomyopathy. This brief review sheds light on the concept of subclinical atrial fibrillation in hypertrophic cardiomyopathy patients, and discusses its diagnostic and management dilemmas in the era of burgeoning cardiac rhythm management devices utilization.

Keywords Atrial fibrillation, hypertrophic cardiomyopathy, thromboembolism, subclinical Disclosure: The authors have no conflicts of interest to declare.

Received: May 12, 2016 Accepted: July 08, 2016 Citation: US Cardiology Review 2016;10(2):75-7 DOI: 10.15420/usc.2016:7:2 Correspondence: Ankur Kalra, Division of Interventional Cardiology, Beth Israel Deaconess Medical Center, Harvard Medical School, 185 Pilgrim Road, Baker 4, Boston, MA 02215, USA. E: kalramd.ankur@gmail.com

Atrial fibrillation (AF) is the most common arrhythmia in patients with hypertrophic cardiomyopathy (HCM), with a reported prevalence of AF in HCM of about 25 %.1 Patients with AF in HCM tend to be more symptomatic and have an increased stroke risk compared with patients without HCM.2 While the occurrence and treatment of (symptomatic) AF in HCM have been extensively studied, there is little data on the significance, prevalence, and management of subclinical AF in HCM. Detection of subclinical AF in this population may be important for the prevention and treatment of thromboembolic complications with anticoagulation, thus improving quality of life.3

Subclinical Atrial Fibrillation The term subclinical or ’silent’ AF is defined as “the occurrence and detection of subclinical asymptomatic episodes of paroxysmal atrial fibrillation.”4 Greater than two million men and women have AF in the United States,5 albeit a recognized difficulty in assessment of true prevalence of subclinical AF. Symptomatic AF more often presents with hemodynamic compromise, while subclinical AF may manifest with more deleterious manifestations, i.e. acute ischemic stroke.

The Atrial Fibrillation Reduction Atrial Pacing Trial (ASSERT) reported that 10 % of patients, out of 2,850 subjects who were older than 65 years of

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age with pacemakers, had subclinical AF.6 In addition, the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) study reported that 12 % of the study population was asymptomatic at baseline.7 It was also noted in the AFFIRM study that asymptomatic AF was found more commonly in men compared with women. Patients with asymptomatic AF had a lower incidence of congestive heart failure and coronary artery disease, albeit a higher incidence of cerebrovascular events. These patients also had a longer duration of AF, lower heart rate, and better left ventricular function.7 The ASSERT also showed that patients with asymptomatic AF had a 2.5-fold higher risk of developing ischemic stroke or systemic embolism.6 Clinical risk factors that were predictors of subclinical AF were age >75 years, cryptogenic stroke, diabetes mellitus, hypertensive heart disease, implantable cardiac defibrillator or pacemaker, ischemic stroke, mitral valve disease, neurological disease, obesity, obstructive sleep apnea, and prior radiofrequency catheter ablation of AF.4

Atrial Fibrillation in Hypertrophic Cardiomyopathy In HCM patients, AF is four times more common than in the general population, and the age of onset is 10 years earlier.8 Factors predisposing to the development of AF in HCM include increase in age, decrease in left atrial function and increase in left atrial volume.9 Left atrial remodeling associated with HCM is a key pathophysiological mechanism

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Electrophysiology | Arrhythmias for development of AF in this population. These patients also tend to be more symptomatic compared with patients without HCM. A plausible explanation may be the loss of the atrial kick, which plays an important role in patients with diastolic dysfunction.1,2,10,11 However, left atrial size can be normal in HCM patients with AF, precluding evaluation for initiation of anticoagulation for prevention of thromboembolic complications based on left atrial size alone.10 In a cohort study by Kalra et al. that included 288 HCM patients with implantable cardiac defibrillators (ICDs), 27 patients (9 %) had subclinical AF. Of these, six patients went on to develop symptomatic AF over the course of 12 months, and two patients had embolic stroke.3 This study underscores the significance of early identification of subclinical AF in patients with HCM for prevention of thromboembolic complications by initiation of oral anticoagulation. Another retrospective study in HCM patients with cardiac rhythm management devices by Wilke et al. demonstrated that more than 50 % of patients developed de novo, predominantly subclinical, AF.12

Diagnosis of Subclinical Atrial Fibrillation Twelve-lead Electrocardiogram Diagnosis of subclinical AF is often challenging as patients are asymptomatic and do not seek medical attention. An electrocardiogram (ECG) may often fail to detect subclinical AF if it occurs outside the monitoring period. Prolonged cardiac monitoring detects more cases of subclinical AF in the cryptogenic stroke population compared with that of a 24-hour Holter monitor.13 Some of the other parameters that may be used in diagnosing subclinical AF in a resting ECG include ’P-maximum’, which represents prolonged atrial conduction time, and ’P-wave dispersion’, which represents non-uniform atrial conductivity, a surrogate for underlying remodeling occurring in the atria in patients with AF. A P-maximum of at least 110 ms has a sensitivity of 88 % and specificity of 75 %, and P-wave dispersion of at least 40 ms has a sensitivity of 83 % and specificity of 85 % for AF.14 A corrected QT interval (QTc) threshold ≥438 ms has a sensitivity of 59.4 % and specificity of 83.7 % as a predictor of AF in patients presenting with ischemic stroke.15 Presence of frequent atrial premature beats has also been suggested as a marker for predisposition to AF.16 None of these parameters, however, have been evaluated for predicting AF episodes in patients with HCM.

Biomarkers Molecular biomarkers may be used in identifying the presence of subclinical AF. Occasionally, troponin is increased in patients with AF.17 Inflammatory markers such as serum interleukin-18 and C-reactive protein have been found to be high in patients with asymptomatic AF.18,19 In addition, plasma von Willebrand factor, fibrinogen, and D-dimer are also elevated in patients with AF compared with their matched controls.20,21 However, the clinical utility of these biomarkers in evaluating HCM patients for the presence of subclinical AF in outpatient clinics is not known.

Echocardiography It is known that increase in left atrial size increases the risk of newonset AF.22 Echocardiographic findings in the AFFIRM trial showed that asymptomatic patients had slightly larger left atrial dimension (4.4 cm versus 4.3 cm; p=0.01), while the left ventricular function was normal in this subgroup.7 Transesophageal echocardiography studies have also

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demonstrated a reduced left atrial appendage peak velocity, and the presence of left atrial spontaneous echocardiographic contrast in this patient subset, reflecting left atrial stasis.23 Concomitant mitral valve disease is also associated with an increase in the incidence of AF.24

Management of Subclinical Atrial Fibrillation in Hypertrophic Cardiomyopathy Once a diagnosis of subclinical AF is made in patients with HCM, management options to prevent thromboembolic complications come into question. In patients with asymptomatic AF with rapid ventricular response, electrical or pharmacological cardioversion may be offered.

Low-dose amiodarone (class IIa) is considered the most effective regimen, its use remaining limited in the young adult population due to the side effect profile.25,26 Alternatively, disopyramide (class IIa), sotalol, dofetilide, and dronaderone (class IIb) can also be utilized.26 Due to the enlarged left atrium, the potential for clot formation is considerably increased in patients with HCM, thus leading to increased risk of thromboembolic stroke compared with the general population, about 0.8 % per year.2 Prophylactic anticoagulation with warfarin or non-vitamin K oral anticoagulants (i.e. dabigatran, rivaroxaban, apixaban, or edoxaban) in HCM patients with clinical or overt AF is a class I recommendation (level of evidence: C).26 However, whether this recommendation can be extrapolated to HCM patients with subclinical AF is currently unknown, and merits further study with prospective, long-term follow-up data on clinical outcomes. Also, the threshold of subclinical AF burden that favors a risk:benefit ratio toward long-term anticoagulation, and warrants initiation of long-term anticoagulation, requires more investigation. The CHADS-VASc score has not been validated for predicting thromboembolic risk from AF in HCM, and should not be used for risk stratification and decision-making with regard to initiation of anticoagulation.26 If a decision is made to initiate anticoagulation, the choice of the anticoagulant can be decided as per individual needs considering other comorbidities, and the overall bleeding risk.

Outcomes of Subclinical Atrial Fibrillation in Hypertrophic Cardiomyopathy Currently, only one study has measured the burden of subclinical AF in HCM patients.3 In this study, out of the 288 HCM patients implanted with ICDs, 27 patients (9 %) were diagnosed with subclinical AF and 51 patients (18 %) were known to have diagnosed AF. In the subclinical AF group, two patients (7.4 %) had embolic strokes who were not on any anticoagulation, and six patients (22.0 %) developed paroxysmal symptoms of AF over the course of 12.1 5.9 months. In the diagnosed AF group, five patients (9.8 %) had an embolic stroke over the same time period. There was no statistical difference in the incidence of embolic stroke between the subclinical AF group and the diagnosed AF group (1.00).3

Conclusion Subclinical AF in HCM is an underdiagnosed clinical entity with equal risk for thromboembolic complications compared with HCM patients with known AF.3 The true prevalence of subclinical AF in HCM is currently unknown, warranting further study. Patients with HCM should be screened or monitored for episodes of subclinical AF for early identification and appropriate treatment strategy. All patients with HCM diagnosed with AF should be initiated on anticoagulation, thus preventing thromboembolic events and improving quality of life in these patients. n

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10. Olivotto I, Cecchi F, Casey SA, et al. Impact of atrial fibrillation on the clinical course of hypertrophic cardiomyopathy.

Circulation 2001;104 :2517–24. PMID: 11714644 11. Di Donna P, Olivotto I, Delcrè SD, et al. Efficacy of catheter ablation for atrial fibrillation in hypertrophic cardiomyopathy: impact of age, atrial remodelling, and disease progression.

Europace 2010;12 :347–55. DOI: 10.1093/europace/euq013; PMID: 20173211 12. Wilke I, Witzel K, Münch J, et al. High incidence of de novo and subclinical atrial fibrillation in patients with hypertrophic cardiomyopathy and cardiac rhythm management device. J Cardiovasc Electrophysiol 2016. DOI:10.1111/jce.12982; PMID: 27060297: epub ahead of print.

13. Gladstone DJ, Spring M, Dorian P, et al. Atrial fibrillation in patients with cryptogenic stroke. N Engl J Med 2014;370 :2467–77.

DOI: 10.1056/NEJMoa1311376; PMID: 24963566 14. Dilaveris PE, Gialafos EJ, Sideris SK, et al. Simple electrocardiographic markers for the prediction of paroxysmal idiopathic atrial fibrillation. Am Heart J 1998;135 (5 Pt 1):733–8.

PMID: 9588401 15. Hoshino T, Nagao T, Shiga T, et al. Prolonged QTc interval predicts poststroke paroxysmal atrial fibrillation. Stroke 2015;46:71–6. DOI: 10.1161/STROKEAHA.114.006612; PMID: 25414174 16. Kolb C, Nürnberger S, Ndrepepa G, et al. Modes of initiation of paroxysmal atrial fibrillation from analysis of spontaneously occurring episodes using a 12-lead Holter monitoring system.

Am J Cardiol 2001;88 :853–7. PMID: 11676946 17. Beaulieu-Boire I, Leblanc N, Berger L, Boulanger JM. Troponin elevation predicts atrial fibrillation in patients with stroke or transient ischemic attack. J Stroke Cerebrovasc Dis 2013;22 : 978–83. DOI: 10.1016/j.jstrokecerebrovasdis.2012.01.008; PMID: 22341670 18. Luan Y, Guo Y, Li S, et al. Interleukin-18 among atrial fibrillation patients in the absence of structural heart disease. Europace

2010;12 :1713–8. DOI: 10.1093/europace/euq321; PMID: 20833691 19. Chung MK, Martin DO, Sprecher D, et al. C-reactive protein elevation in patients with atrial arrhythmias: inflammatory mechanisms and persistence of atrial fibrillation. Circulation 2001;104 :2886–91. PMID: 11739301 20. Li-Saw-Hee FL, Blann AD, Gurney D, Lip GY. Plasma von Willebrand factor, fibrinogen and soluble P-selectin levels in paroxysmal, persistent and permanent atrial fibrillation: effects of cardioversion and return of left atrial function. Eur Heart J 2001;22 :1741–7. PMID: 11511124 21. Lip GY, Lowe GD, Rumley A, Dunn FG. Fibrinogen and fibrin D-dimer levels in paroxysmal atrial fibrillation: evidence for intermediate elevated levels of intravascular thrombogenesis.

Am Heart J 1996;131 :724–30. PMID: 8721646 22. Vaziri SM, Larson MG, Benjamin EJ, Levy D. Echocardiographic predictors of nonrheumatic atrial fibrillation. The Framingham Heart Study. Circulation 1994;89 :724–30. PMID: 8313561 23. Taguchi Y, Takashima S, Hirai T, et al. Significant impairment of left atrial function in patients with cardioembolic stroke caused by paroxysmal atrial fibrillation. Intern Med 2010;49 :1727–32.

PMID: 20720349 24. Grigioni F, Avierinos JF, Ling LH, et al. Atrial fibrillation complicating the course of degenerative mitral regurgitation: determinants and long-term outcome. J Am Coll Cardiol 2002;40 :84–92. PMID: 12103260 25. Robinson K, Frenneaux MP, Stockins B, et al. Atrial fibrillation in hypertrophic cardiomyopathy: a longitudinal study. J Am Coll Cardiol 1990;15 :1279–85. PMID: 2329232 26. Gersh BJ, Maron BJ, Bonow RO, et al. 2011 ACCF/AHA guideline for the diagnosis and treatment of hypertrophic cardiomyopathy: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2011;58:2703–38.

DOI: 10.1016/j.jacc.2011.10.825; PMID: 22075468

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Pulmonary Vascular Diseases

Pharmacologic Strategies for Management of Pulmonary Arterial Hypertension Re bec c a L Attridg e, P ha rmD, MSc, B CPS, 1 R e b e c c a D M o o t e, P h a r m D, M S c, 2 B CPS a n d D e b o ra h J L e vin e, MD 3 1. Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of the Incarnate Word Feik School of Pharmacy, University of Texas Health Science Center at San Antonio, San Antonio, TX; 2. School of Pharmacy, Regis University, Denver, CO; 3. Pulmonary and Critical Care Medicine, Pulmonary Hypertension Center, The University of Texas Health Science Center at San Antonio, San Antonio, TX

Abstract Pulmonary arterial hypertension (PAH) is defined as a mean pulmonary artery pressure ≥25 mmHg at rest with a pulmonary wedge pressure 15 mmHg and a pulmonary vascular resistance >3 Wood units measured by right cardiac catheterization. Increased awareness of the progressive nature of the disease has led to earlier evaluation, identification, and therapy. Management of PAH includes non-pharmacologic therapy as well as background and targeted medical therapy. Background therapy may include diuretics, digoxin, oxygen, and anticoagulation for specific patients. Five classes of targeted medical therapy are currently available to manage PAH, including prostacyclin analogs, endothelin receptor antagonists, phosphodiesterase inhibitors, a soluble guanylate cyclase stimulator, and a prostacyclin IP receptor agonist.

Recent evidence shows that initial combination therapy with some of these agents reduces the time to clinical failure and the incidence of PAH-related hospitalizations.

Keywords Pulmonary arterial hypertension, prostacyclin analogs, endothelin receptor antagonists, phosphodiesterase inhibitors, soluble guanylate cyclase stimulator, prostacyclin IP receptor agonist Disclosure: The authors have no conflicts of interest to disclose.

Received: February 24, 2016 Accepted: June 17, 2016 Citation: US Cardiology Review, 2016;10(2):78–84 DOI: 10.15420/usc.2016:2:2 Correspondence: Deborah J Levine, MD, Division of Pulmonary Diseases and Critical Care Medicine, Department of Medicine, The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, MC 7885, San Antonio, TX 78229, USA. E: djlevine@uthscsa.edu

Pulmonary hypertension is classified into five groups by the World Health Organization (WHO). Group 1, pulmonary arterial hypertension (PAH), is a progressive disease characterized by an elevation in pulmonary arterial pressure and pulmonary vascular resistance that may progress to right heart dysfunction and failure.1 PAH is defined as a mean pulmonary artery pressure (mPAP) ≥25 mmHg at rest, with a pulmonary capillary wedge pressure ≤15 mmHg and a pulmonary vascular resistance (PVR) >3 Wood units measured by right-sided cardiac catheterization.2–4 PAH is associated with certain medical conditions or as an idiopathic disease (idiopathic PAH [IPAH]). The prevalence of IPAH is estimated to be 5.9 cases per million adults in North America and Europe, with a female predominance (male-to-female ratio, 1:1.7).1–4 Recent registry data reveal that PAH is now being diagnosed more commonly in older patients, with a mean age at diagnosis ranging from 50 to 65 years old. 1,2,4 Medical conditions associated with PAH include certain congenital heart diseases; rheumatologic diseases including but not limited to scleroderma, systemic lupus erythematosus, and rheumatoid arthritis; human immunodeficiency virus (HIV) infection, and portal hypertension. 3 The contributing cause of PAH can be important for both outcomes and management. For example, patients

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Access at: www.USCjournal.com

with scleroderma who develop PAH, estimated between 7 % and 12 % of patients, have markedly worse outcomes in comparison to other PAH subgroups. 3 Multiple drugs and toxins have been associated with PAH including anorexigens such as fenfluramine and dexfenfluramine, toxic rapeseed oil, and even illicit drugs such as cocaine and amphetamines.1,3,4 Selective serotonin reuptake inhibitors (SSRIs) increase the risk of persistent pulmonary hypertension in newborns of pregnant women receiving SSRIs.4 Heritable PAH (HPAH) includes both IPAH with germline mutations and familial cases without an identified mutations, however, about 75 % of patients with HPAH have a bone morphogenetic protein receptor 2 (BMPR2) mutation.2

Epidemiology and Pathophysiology The prevalence of PAH is estimated to be 15–26 patients per million individuals, with only 15,000–20,000 of these patients currently receiving treatment.5 The US-based REVEAL registry (Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management) includes over 3,500 patients and found that 46 % of PAH was idiopathic while 25 % was associated with connective tissue diseases and 10 % was associated with congenital heart diseases.6 Early diagnosis of PAH

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Pharmacologic Management of Pulmonary Arterial Hypertension is improving due to increased awareness and knowledge of the disease state. IPAH is associated with a poor prognosis (median survival 2.8 years) after diagnosis without targeted therapy.7 Prior to the availability of disease-specific therapy for IPAH, survival rates for 1, 3, and 5 years were 68 %, 48 %, and 34 %, respectively.8 A recent epidemiologic study demonstrated survival rates at 1 and 3 years were 85 % and 68 %, respectively, in patients with PAH, and 91 % and 74 %, respectively, in patients with IPAH.9 PAH is caused by progressive vasoconstriction of the small pulmonary arteries. All subgroups of PAH have similar clinical and pathologic physiology, including endothelial cell dysfunction, thrombotic lesions, platelet activation, gain of constricting factors, loss of relaxing factors, intimal proliferation, medial hypertrophy, fibrosis, and inflammation.10 Progressive vascular remodeling occurs, leading to increased pulmonary arterial pressures and pulmonary vascular resistance. The right ventricle is normally exposed to much lower pressures than the left ventricle.

In the setting of persistent elevations in pulmonary pressures, right ventricular hypertrophy and eventually right heart failure develop.11

Table 1: World Health Organization Functional Classification of Pulmonary Arterial Hypertension Class

Description

I

Patients with PAH where there is no limitation of usual physical activity, ordinary physical activity does not cause increased dyspnea, fatigue, chest pain, or presyncope

II

Patients with PAH who have mild limitation of physical activity.

There is no discomfort at rest, but normal physical activity causes increased dyspnea, fatigue, chest pain, or presyncope

III

Patients with PAH who have marked limitation of physical activity. There is no discomfort at rest, but less than normal physical activity causes increased dyspnea, fatigue, chest pain, or presyncope

IV

Patients with PAH who are unable to perform any physical activity at rest and who may have signs of right ventricular failure. Dyspnea and/or fatigue may be present at rest, and symptoms are increased by almost any physical activity

PAH = Pulmonary Arterial Hypertension. Data from Badesch DB, Abman SH, Simonneau G, Rubin LJ, McLaughlin VV. Medical therapy for pulmonary arterial hypertension: Updated ACCP evidence-based clinical practice guidelines.14

Molecular, cellular, and genetic mechanisms that contribute to PAH are affected by several compounds, including prostacyclin (PGI2), endothelin-1 (ET-1), and nitric oxide (NO). PAH is characterized by decreased NO synthase expression and levels of circulation PGI2, a vasodilatory and antiproliferative substance that is produced by the endothelial cells, and increased levels of potent vasoconstrictors, including thromboxane and ET-1.10,12,13 Plasma levels of ET-1 are correlated with severity of PAH and prognosis.14

Clinical Presentation and Assessment of PAH Signs and symptoms of PAH vary depending on disease severity and comorbidities. As right ventricular dysfunction progresses, patients may experience exertional dyspnea, fatigue, weakness, syncope, lower extremity edema, and abdominal bloating and distension.4 Assessment of functional class is used to determine the impact of signs and symptoms on the patient function and quality of life (QoL). Table 1 shows patients with an increased risk of mortality are more likely to have a higher WHO functional class, older age, male gender, higher brain natriuretic peptide (BNP), higher right atrial pressure, and lower cardiac output. In contrast, patients with a decreased risk of mortality are more likely to have a lower WHO functional class, higher 6-minute walk distance (6MWD), lower BNP, and higher cardiac output.15 Doppler echocardiography serves as a noninvasive screening test to detect increased pulmonary pressures, and, more importantly, the morphology of the right-sided heart chambers. It can also be used to identify any left-sided heart disease or congenital heart disease.16 However, right heart catheterization (RHC) is required to definitively diagnose PAH. Pulmonary vasoreactivity is assessed during the RHC in specific subgroups of PAH, including IPAH, HPAH, or drug-induced PAH.17 A positive vasoreactivity response is a reduction of mPAP by at least 10 mmHg to a value of 40 mmHg or less with a stable cardiac index.18 Patients with a positive acute response (approximately 13 % of patients on initial testing) are most likely to have a beneficial hemodynamic and clinical response. Unfortunately, about half of these patients have negative response when tested 1 year later.19

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PAH commonly occurs due to connective tissue disease so serologic markers should be obtained to confirm or exclude these diagnoses.3,20 In addition, liver function tests, HIV status, pulmonary function tests, ventilation-perfusion lung scans and/or pulmonary angiography, and arterial blood oxygenation should all be assessed when establishing a PAH diagnosis and cause.3 Functional class and exercise capacity, determined by the 6MWD, should be assessed at baseline and at regularly scheduled clinic visits. Assessment of these and other variables can help categorize patient risk (shown in Table 2).3,20 Table 3 provides additional information on initial assessment and timing and when each assessment is indicated.

Approach to Treatment The goal of treatment of PAH is to improve functional class, exercise capacity, and QoL while delaying disease progression. Patients with PAH should be referred to an expert, specialized PAH center for early assessment of hemodynamics on right heart catheterization and optimal management. Treatment of PAH may be categorized into nonpharmacologic, conventional therapy, disease-specific therapy, and surgical interventions. Surgical therapy includes atrial septostomy, pulmonary thromboendarterectomy for CTEPH, and lung or heart–lung transplantation for severe disease.

Nonpharmacologic Therapy Nonpharmacologic therapy may address comorbid conditions that often accompany PAH. Counseling of avoidance of pregnancy is key due to high morbidity and mortality in females with PAH during and after pregnancy.7 All patients should receive immunization against influenza and pneumococcal disease.3 Certain PAH patients may require supplemental oxygen to keep oxygen saturations to a goal of greater than 90 % and to decrease hypoxic vasoconstriction. It is important to remember when in high altitude or air travel that there is a reduction in ambient air concentration of oxygen.21 Patients should maintain a low-sodium diet to avoid fluid retention in right heart failure.22 Cardiopulmonary rehabilitation improves functional status, exercise capacity, and QoL in patients with PAH.1

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Pulmonary Vascular Diseases Table 2: Risk Assessment in Pulmonary Arterial Hypertension Determinants of Prognosis

Low Risk <5 %

a

Intermediate

High Risk <10 %

diuretics in management of right heart failure and in patients with atrial arrhythmias.1 The typical target concentration is between 0.5 and 0.8 ng/mL.

Risk 5–10 %

(Estimated

Calcium Channel Blockers

1-year

Calcium channel blockers (CCBs) are infrequently used in the management of PAH and can only be used in patients with a positive response to acute vasodilator testing. As noted above, there are very few patients who demonstrate this response (approximately 13 % of patients with IPAH and even less with other etiologies of PAH). The number responding to long-term therapy is even lower (7 %).19 Vigilant monitoring to ensure adequate and continued response is required when CCBs are used. CCBs should not be used in the absence of demonstrated acute vasoreactivity.1

Mortality) Clinical signs

Absent

Absent

Present

No

Slow

Rapid

No

Occasional

Repeated

syncopeb

syncopec

I, II

III

IV

6MWD

>440 m

165–440 m

<165 m

Cardiopulmonary

Peak VO2 >15

Peak VO2 11–15

Peak VO2 <11 ml/min/kg

of right heart failure Progression of symptoms Syncope WHO functional class

exercise testing

ml/min/kg

ml/min/kg

(>65 % pred.)

(35–65 % pred.)

(<35 % pred.)

Ve/VCO2

Ve/VCO2

Ve/VCO2

slope <36

slope 36-44.9

slope ≥45

NT-proBNP

BNP <50 ng/l

BNP 50–300 ng/l

BNP >300 ng/l

plasma levels

NT-proBNP

NT-proBNP

NT-proBNP

<300 ng/ml

300–1400 ng/ml

>1400 ng/ml

Imaging

RA area <18 cm2

RA area 18–26 cm2

RA area >26 cm2

(echocardiography,

No pericardial

No or minimal,

Pericardial

CMR imaging)

effusion

pericardial

effusion

Hemodynamics

RAP <8 mmHg

RAP 8–14 mmHg

RAP >14 mmHg

CI ≥2.5 l/min/m2

CI 2.0–2.4 l/min/m2

CI ≤2.0 l/min/m2

SvO2 >65 %

SvO2 60–65 %

SvO2 <60 %

effusion

Most of the proposed variables and cut-off values are based on expert opinion. They may provide prognostic information and may be used to guide therapeutic decisions, but applications to individual patients must be done carefully. One must also note that most of these variables have been validated mostly for IPAH and the cut-off values used above may not necessarily apply to other forms of PAH. Futhermore, the use of approved therapies and their influence on the variables should be considered in the evaluation of the risk; b Occasional syncope during brisk or heavy exercise, or occasional orthostatic syncope in the otherwise stable patient; cRepeated episodes of syncope, even with little or regular physical activity. CI = cardiac index; CMR = cardiac magnetic resonance imaging; IPAH = idiopathic pulmonary arterial hypertension; 6MWD = 6-minute walk distance; NT-proBNP = N-terminal prohormone of brain natriuretic peptide; RA = right atrium; RAP = right atrial pressure; WHO = World Health Organization. Data from N. Galie et al. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension.4 a

Pharmacologic Therapy Conventional Pharmacologic Treatment Conventional therapy includes oral anticoagulants, diuretics, and digoxin.20 Anticoagulation with warfarin (goal international normalized ratio [INR] 1.5–2.5) may be considered in patients with PAH, particularly if they have IPAH, HPAH, or PAH due to anorexigens, to prevent in situ thrombosis of pulmonary arteries and decrease the risk of venous thromboembolism.4 Small retrospective and prospective studies support a survival benefit with anticoagulation.23–26 Anticoagulation is not recommended for patients with PAH associated with portal hypertension or HIV due to increased risk of bleeding.4 Loop diuretics are indicated in patients with decompensated right heart failure and hypervolemia as indicated by increased central venous pressure, abdominal organ congestion, peripheral edema, and ascites.3 Digoxin may be useful in certain patients with PAH as adjunctive therapy to

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Disease-Specific Pharmacologic Therapy Therapeutic targets in the treatment of PAH focus on supplementing endogenous vasodilators, inhibiting endogenous vasoconstrictors, and reducing endothelial platelet interaction and limiting thrombosis.

Five classes of disease-specific agents for PAH are now available: prostacyclin analogs, endothelin receptor antagonists, phosphodiesterase inhibitors, a soluble guanylate cyclase stimulator, and a prostacyclin IP receptor agonist.

Synthetic Prostacyclin and Prostacyclin Analogs PGI2 is produced by endothelial cells and is a potent vasodilator of all vascular beds. In addition, it also inhibits platelet aggregation and has both cytoprotective and antiproliferative properties. However, in patients with PAH, PGI2 synthase expression is reduced in pulmonary arteries, leading to pulmonary vasoconstriction and increased platelet aggregation.27 Several prostacyclin analogs are now available for treatment of PAH, including epoprostenol (available as IV Flolan ® and Veletri®), treprostinil (IV/SC: Remodulin®, inhaled: Tyvaso®, oral: Orenitram®), and iloprost (Ventavis®).

Epoprostenol is a synthetic analog of PGI2 that was introduced in 1995 as the first disease-specific therapy for patients with PAH, indicated for patients with WHO functional class III or IV. A 12-week, openlabel, randomized trial comparing continuous infusion epoprostenol to conventional therapy in functional class III and IV IPAH patients demonstrated improved exercise capacity, QoL, hemodynamics, and functional class in patients treated with epoprostenol. Despite the short trial duration of 12 weeks, investigators also found an improvement in survival in patients treated with epoprostenol versus conventional therapy (0 versus 8 patients, respectively; p=0.003); this finding remained significant after adjustment for a numerical difference in 6MWD at baseline (p <0.002).28 In addition, observational studies also support improved survival in patients with IPAH on epoprostenol compared with either historical control or predicted survival based on the National Institutes of Health Registry equation.29–31 It has a very short half-life of 3–5 minutes, requiring administration by continuous IV infusion. Epoprostenol must be initiated in the hospital setting at a low dose (2–4 ng/kg/min) and titrated up based on tolerance of side effects such as flushing, headache, diarrhea, jaw pain, abdominal cramping, and hypotension. The target dose for

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Pharmacologic Management of Pulmonary Arterial Hypertension Table 3: Suggested Assessment and Timing for the Follow-up of Patients with Pulmonary Arterial Hypertension At Baseline

Every 3–6 Months

a

Every 6–12 Months

a

3–6 Months after Changes in Therapy

Medical assessment

In Case of Clinical a

Worsening

+

+

+

+

+

ECG

+

+

+

+

+

6MWT/Borg

+

+

+

+

+

and determination of functional class

dyspnea score CPET

+

Echo

+

Basic labb

+

Extended labc

+

+

Blood gas analysisd

+

+

+

+

Right heart

+

+f

+e

+e

+

+

+a

+

+

+

+

+ + +

catheterization Intervals to be adjusted according to patient needs; bBasic lab includes blood count, INR (in patients receiving vitamin K antagonists), serum Creatinine, sodium, potassium, AST/ALT (in patients receiving ERAs), bilirubin and BNP/NT-proBNP; cExtended lab includes TSH, troponin, uric acid, iron status (iron, ferritin, soluble transferrin receptor) and other variables according to individual patient need; dFrom arterial or arterialized capillary blood; may be replaced by peripheral oxygen saturation in stable patients or if BGA is not available; eShould be considered; fSome centers perform RHCs at regular intervals during follow-up. ALT = alanine aminotransferase; AST = aspartate aminotransferase; BGA = blood gas analysis; BNP = brain natriuretic peptide; CPET = cardiopulmonary exercise testing; Echo = echocardiography; ECG = electrocardiogram; ERAs = endothelin receptor antagonists; FC = functional class; INR = international normalized ratio; lab = laboratory assessment; NT-proBNP = N-terminal pro-brain natriuretic peptide; RHC = right heart catheterization; TSH = thyroid stimulating hormone; 6MWT = 6-minute walking test. 4 a

the first 2–4 weeks is around 10–15 ng/kg/min. Patients are then titrated up based on how well they respond and side effects.21,29 The two available products, Flolan® and Veletri®, are unique in terms of stability and reconstitution with Flolan® being unstable at room temperature and Veletri® being the thermostable formulation. Patients must always have a backup supply of the drug and infusion pump as interruption of epoprostenol may lead to life-threatening pulmonary vasoconstriction.32 Infection, catheter obstruction, and sepsis are potential complications due to the route of administration.33 Treprostinil (Remodulin ®) is a stable analog of PGI 2 given for subcutaneous (SC) or IV infusion for WHO functional class III and IV patients.29 Notable advantages of treprostinil over epoprostenol include ease of use given stability at room temperature and increased safety due to a longer half-life (about four hours), lowering the risk of rebound pulmonary vasoconstriction that may happen with drug interruption.12 Treprostinil improves 6MWD and hemodynamics with outcomes that are similar to epoprostenol.34,35 A 12-week double-blind, placebo-controlled trial of 470 patients with WHO functional class II, III or IV PAH demonstrated that patients receiving SC treprostinil versus placebo had significant improvement in exercise capacity, dyspnea, and hemodynamic parameters.

Exercise capacity improved most in patients with a lower baseline 6MWD and in patients who could tolerate doses greater than 13.8 ng/kg/min.34 The initial dose for treprostinil is 1.25 ng/kg/min SC. Infusion site pain is common with the SC route, occurring in up to 85 % of patients and leading to discontinuation in 8 % of patients.21 Intravenous treprostinil may be considered in patients unable to tolerate SC.27 Transitions between prostacyclin agents or routes should be performed in an inpatient setting. Bacteremia, primarily due to gram-negative pathogens, have been reported more commonly with IV treprostinil than with IV epoprostenol.36

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Two inhaled formulations were developed in an effort to prevent complications associated with parenteral prostacyclin administration.

Iloprost (Ventavis®) is indicated for WHO functional class III and IV patients based on a 12-week randomized, placebo-controlled trial of 203 patients. Significantly more patients receiving inhaled iloprost versus placebo met the combined primary endpoint of improvement by one functional class and improvement in 6MWD by 10 % (16.8 versus 4.9 %, respectively; p=0.007).37 In addition, the placebo group had more clinical deterioration over the study duration (13.7 with placebo versus 4.0 % with iloprost; p=0.024).37 It is given by inhalation using a dosing system provided by the manufacturer (ADD system) with the initial dose being 2.5 mcg 6–9 times per day up to every 2 hours during waking hours.

The dose should be titrated and maintained at 5 mcg/dose if tolerated.

While clinical trials with iloprost have demonstrated an improvement in exercise capacity and functional class, it can be cumbersome to use as each inhalation dose can take 4–10 minutes to administer and multiple inhalations are required for a full dose.37 A backup supply is also necessary with iloprost due to a short half-life, similar to epoprostenol.18 Adverse effects are similar to other PGI2 analogs, including headache, flushing, and jaw pain. Inhaled treprostinil may also cause throat irritation and cough.

Inhaled treprostinil (Tyvaso®) improves exercise capacity and functional class and may be used for WHO functional class III and IV patients. In a randomized, double-blind, 12-week trial, patients receiving inhaled treprostinil in addition to bosentan or sildenafil experienced a 20-meter improvement in 6MWD compared to placebo (p<0.0006).38 A 2-year extension of the trial found that inhaled treprostinil provided sustained benefit and remained safe and efficacious.39 The approved initial dosing of inhaled treprostinil is three breaths (6 mcg per breath) four times daily during waking hours, and this dose should be titrated based on patient tolerance at 1- to 2-week intervals to maximum dose of nine breaths (total of 54 mcg) four times daily. Inhaled treprostinil requires less time

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Pulmonary Vascular Diseases Table 4: Recommendations for Efficacy of Initial Drug Combination Therapy for Pulmonary Arterial Hypertension (Group 1) a

Measure/Treatment

Ambrisentan +

Class -Level

b

WHO-FC

WHO-FC

II

III

WHO-FC IV

I

B

I

B

IIb

C

Other ERA + PDE-5i

IIa

C

IIa

C

IIb

C

Bosentan + sildenafil +

-

-

IIa

C

IIa

C

-

-

IIa

C

IIa

C

IIb

C

IIb

C

IIb

C

IIb

C

tadalafild

IV epoprostenol Bosentan + IV epoprostenol Other ERA or PDE-5i + SC treprostinil Other ERA or PDE-5i + other iv prostacyclin analogues Recommendations according to World Health Organization Functional Class. Sequence is by Rating. aClass of recommendation; bLevel of evidence; cReference(s) supporting recommendations; dTime to clinical failure as primary endpoint in RCTs or drugs with demonstrated reduction in all-cause mortality (prospectively defined). ERA = endothelin receptor antagonist; IV = intravenous; PDE-5i = phosphodiesterase type 5 inhibitor; RCT = randomized controlled trial; SC = subcutaneous; WHO-FC = World Health Organization functional class.4

to administer than iloprost but may be more complicated for patients to prepare.18 Common adverse effects include throat irritation and cough (unique to the inhaled products), headache, nausea, dizziness, and flushing. Inhaled treprostinil may also cause systemic hypotension, requiring careful monitoring if patients are concurrently on diuretics, antihypertensives, or other vasodilators.

The first oral prostacyclin analog, sustained-release trepostinil (Orenitram®), was approved by in the US in 2013 for patients with functional class II and III PAH. Oral treprostinil monotherapy improved 6MWD, but not functional class or time to clinical worsening, in a 12-week study of 349 patients with PAH.40 Oral treprostinil has also been studied in combination with endothelin receptor antagonists and/ or phosphodiesterase-5 inhibitors, without improvement in 6MWD.41,42 However, patients receiving higher doses of treprostinil did show more improvement in exercise capacity as measured by 6MWD. Adverse events include headache, nausea, diarrhea, and jaw pain. Oral treprostinil, like all prostacyclin analogs, inhibits platelet aggregation and may increase bleeding risk, particularly in patients receiving oral anticoagulants.

Endothelin Receptor Antagonists Three Endothelin Receptor Antagonists (ERAs) are currently available for management of patients with WHO functional class II, III, or IV PAH: bosentan (Tracleer®), ambrisentan (Letairis®), and macitentan (Opsumit®).

Bosentan is an orally active dual ETA and ETB receptor antagonist. In a 16-week randomized, placebo-controlled, double-blind trial (BREATHE-1) enrolling 213 patients, those receiving bosentan 125 mg twice daily (BID) or 250 mg BID versus placebo had improved exercise capacity, functional class, hemodynamics, echocardiographic, and Doppler variables, and time to clinical worsening.43 The initial dose is 62.5 mg twice daily for 4 weeks followed by 125 twice daily.43 Increased hepatic transaminases

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may occur due to competition by bosentan and its metabolites with the biliary excretion of bile salts, resulting in retention of bile salts that are cytotoxic to hepatocytes. In clinical trials, bosentan 250 mg BID was associated with a dose-dependent increase in hepatic transaminases that occurred significantly more than with the 125 mg BID dose. For this reason, bosentan 125 mg oral BID is the US Food and Drug Administration (FDA)-approved dose and the drug is only available through a distribution program, the Tracleer Access Program.18 Vigilant monitoring of liver function tests (LFTs) is required at baseline and every month, and dose reduction or interruption may be necessary if LFTs increase. Complete blood cell count should be monitored every 3 months due monitor for anemia while on bosentan. For all three of the ERAs, monthly pregnancy testing is required in women (pregnancy category X).

Ambrisentan is a once-daily selective ETA receptor antagonist that improves exercise capacity and hemodynamics and delays clinical worsening in PAH.44 Two large, concurrent randomized, doubleblind, placebo-controlled trials: Ambrisentan in Pulmonary Arterial Hypertension, Randomized, Double-Blind, Placebo-Controlled, Multicenter, Efficacy Study 1 and 2 (ARIES-1 and ARIES-2) over 12 weeks demonstrated a significant improvement in exercise capacity with 2.5, 5, and 10 mg daily doses.45 Most patients had WHO functional class II or III PAH. A 2-year extension trial (ARIES-E) supports long-term efficacy of ambrisentan with results showing continued improvement in 6MWD and functional class.46 Similar to bosentan, ambrisentan is only available through a distribution program, Letairis Education and Access Program (LEAP).18 Unlike bosentan, liver toxicity occurs very rarely with ambrisentan (0.8 % in 12-week trials and 2.8 % for up to 1 year).45,46 Common side effects include peripheral edema, nasal congestion, flushing, anemia, and palpitations. Treatment should be initiated with 5 mg once daily and increased to 10 mg once daily if required.

Macitentan is a once-daily dual ERA recently approved in the US following the Study with an Endothelin Receptor Antagonist in Pulmonary Arterial Hypertension to Improve Clinical Outcome (SERAPHIN) trial.47 Over approximately 3 months, both doses (3 and 10 mg) demonstrated statistically significant decreases in the composite end point of events related to PAH or death compared to placebo. Worsening of PAH was the most common event (defined as a decrease in 6MWD, worsening symptoms, and need for additional treatment). Patients were continued on concomitant therapy, if at stable doses for 3 months, with oral or inhaled prostanoids, calcium channel blockers, or oral phosphodiesterase inhibitors. Increases in LFTs were similar to placebo.

The FDA approved dose of macitentan is 10 mg daily. The most common side effects include nasopharyngitis, headache, and anemia. Female patients must go through a Risk Evaluation and Mitigation Strategy (REMS) program to receive the drug.

Phosphodiesterase-5 Inhibitors Two phosphodiesterase-5 inhibitors available for the treatment of WHO functional class II and III PAH, sildenafil (Revatio®) and tadalafil (Adcirca®), work by increasing the intracellular concentration of cyclic guanosine monophosphate, leading to vasorelaxation and antiproliferative effects on vascular smooth muscle cells. Sildenafil is a potent and highly specific phosphodiesterase-5 inhibitor shown to reduce mPAP and improve 6MWD, hemodynamic parameters and functional class.48 In a double-

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Pharmacologic Management of Pulmonary Arterial Hypertension blind, placebo-controlled trial, Sildenafil Use in Pulmonary Arterial Hypertension (SUPER), of 278 primarily WHO functional class II and III patients, those receiving sildenafil showed a significant improvement in 6MWD and hemodynamics at 12 weeks versus placebo. A continued improvement in 6MWD was seen in a 1-year extension study.48 The FDA-approved dose is 20 mg by mouth three times per day, however much higher doses, up to 80 mg three times daily, have been used.

Adverse effects include headaches, flushing, epistaxis, dyspepsia, hypotension, and diarrhea. Changes in vision have been reported, including blue-tinted vision and sudden loss of vision, requiring drug discontinuation. Tadalafil was approved by the FDA in 2009 following a 16-week double-blind, placebo-controlled study of 405 patients; Pulmonary Arterial Hypertension and Response to Tadalafil (PHIRST).

Patients primarily had WHO functional class II and III PAH and 53 % were on background therapy of bosentan. Use of tadalafil 40 mg daily was shown to significantly improve exercise capacity, QoL measures, and time to clinical worsening.49 Tadalafil and sildenafil levels are decreased in patients on bosentan therapy due CYP450 3A4 induction, requiring higher doses of both phosphodiesterase-5 inhibitors in patients on concurrent bosentan therapy.18,48 The most commonly reported adverse events were headache, myalgia, and flushing.49 Concurrent use with nitrate therapy is contraindicated and must be avoided with both sildenafil and tadalafil due to additive hypotension.

Table 5: Recommendations for Efficacy of Sequential Drug Combination Therapy for Pulmonary Arterial Hypertension (Group 1) a

Measure/Treatment

Macitentan added

Class -Level WHO-FC

WHO-FC

II

III

b

WHO-FC IV

I

B

I

B

IIa

C

I

B

I

B

IIa

C

I

B

I

B

IIa

C

-

-

I

B

IIa

B

IIa

B

IIa

B

IIa

C

IIb

B

IIb

B

IIb

C

IIa

C

IIa

C

IIa

C

IIb

C

IIb

C

IIb

C

-

-

IIb

C

IIb

C

IIb

C

IIb

C

IIb

C

IIb

C

IIb

C

IIb

C

IIb

C

IIb

C

IIb

C

IIb

C

IIb

C

IIb

C

III

B

III

B

III

B

to sildenafild Riociguat added to bosentan Selexipage added to ERA and/or PDE-5id Sildenafil added to epoprostenol Treprostinil inhaled added to sildenafil or bosentan Iloprost inhaled added to bosentan Tadalafil added to bosentan Ambrisentan added to sildenafil Bosentan added to epoprostenol

Soluble Guanylate Cyclase Stimulator

Bosentan added

Riociguat (Adempas ®) is a soluble guanylate cyclase stimulator that works synergistically with nitric oxide to increase pulmonary vasolidation. Riociguat was approved in 2013 for patients with WHO functional class II, III, and IV PAH following the Pulmonary Arterial Hypertension Soluble Guanylate Cyclase-Stimulator Trial 1 (PATENT-1) trial, which demonstrated that riociguat 2.5 mg by mouth three times daily significantly improved 6MWD, hemodynamic parameters, and WHO functional class compared to placebo.50 Baseline therapy of endothelinreceptor antagonists or nonintravenous prostacyclin analogs were continued. Importantly, use of riociguat with phosphodiesterase-5 inhibitors and nitrates is contraindicated due to the additive risk of hypotension. The initial dose is 1 mg by mouth three times daily, titrated by 0.5 mg three times daily every 2 weeks to a maximum dose of 2.5 mg by mouth three times daily Like the ERAs, riociguat is teratogenic and female patients must go through a REMS program to receive the drug.

to sildenafil Sildenafil added to bosentan Other double combinations Other triple combinations Riociguat added to sildenafil or other PDE-5i Recommendations according to World Health Organization Functional class. Sequence is by rating and by alphabetical order. aClass of recommendation; bLevel of evidence; cReference(s) supporting recommendations; dTime to clinical failure as primary endpoint in RCTs or drugs with demonstrated reduction in all-cause mortality (prospectively defined); eThis drug was not approved by the EMA at the time of publication of these guidelines. EMA = European Medicines Agendy; ERA = endothelin receptor antagonist; PAH = pulmonary arterial hypertension; PDE-5i = phosphodiesterase type 5 inhibitor; RCT = randomized controlled trial; WHO-FC = World Health Organization functional class.4

Prostacyclin IP Receptor Agonist Selexipag (Uptravi®), a novel prostacyclin IP receptor agonist, has been shown to decrease disease progression, hospitalizations for PAH, and complications from PAH, including death.51 In a phase 3, double-blind, placebo-controlled trial: Selexipag for the Treatment of Pulmonary Arterial Hypertension (GRIPHON) of 1156 patients with WHO functional class II and III, selexipag was associated with a decrease in death from any cause or complications related to PAH versus placebo (27.0 versus 41.6 %, respectively; HR 0.60, 99 % CI [0.46–0.78]; p<0.001).

Patients were followed for up to 3 years on therapy. These outcomes were similar in patients on no background therapy and when added to background ERAs, phosphodiesterase-5 inhibitors, or both.51 The initial starting dose is 200 mcg PO twice daily; this dose can be increased by 200 mcg twice daily increments to a maximum dose of 1600 mcg twice

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daily. Common side effects are similar to those caused by prostacyclin analogs, including flushing, headache, diarrhea, nausea, jaw pain, and myalgias. Selexipag may also cause anemia so a complete blood cell count should be monitored periodically. Selexipag has also been associated with an increased incidence of hyperthyroidism.

Combination Therapy Combination therapy can target multiple pathophysiologic mechanisms in PAH, resulting in improvement in hemodynamics, symptoms, functional class, and exercise capacity.52–55 Combination therapy may be started sequentially as PAH progresses or as initial therapy. Recent evidence-based guidelines provide comprehensive tables detailing drug combinations that have been studied for both initial combination therapy

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Pulmonary Vascular Diseases (see Table 4) and sequential combination therapy (see Table 5). The Initial Use of Ambrisentan plus Tadalafil in Pulmonary Arterial Hypertension (AMBITION) trial comparing ambrisentan and tadalafil together versus either alone in WHO functional class II or III demonstrated that initial combination therapy was associated with a significant reduction in time to clinical failure and PAH hospitalizations. Adverse effects such as peripheral edema, headache, nasal congestion, and anemia were more common in the combination group than either monotherapy group, although discontinuation rates were similar.56

Evaluation of Therapeutic Outcomes Response to therapy should be followed closely. Monitoring involves objectively assessing functional status and exercise capacity with the 6MWD and hemodynamics and right ventricular function with

1.

2.

3.

4.

5.

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17.

18.

19.

20.

21.

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Chest 2014;146 :449–75. DOI:10.1378/chest.14-0793; PMID: 24937180; PMCID: PMC4137591 D’Alonzo GE. Survival in patients with primary pulmonary hypertension. Ann Intern Med 1991;115 :343. DOI:10.7326 /0003-4819-115-5-343; PMID: 1863023 Benza RL, Miller DP, Gomberg-Maitland M, et al. Predicting survival in pulmonary arterial hypertension: insights from the Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management (REVEAL). Circulation 2010;122 :164–72. DOI:10.1161/CIRCULATIONAHA.109.898122; PMID: 20585012 Olsson KM, Hoeper MM. Novel approaches to the pharmacotherapy of pulmonary arterial hypertension. Drug Discov Today 2009;14 :284–90. PMID: 19121410 Shah SJ. Pulmonary hypertension. JAMA 2012;308 :1366.

DOI:10.1001/jama.2012.12347; PMID: 23032553 Park MH. Advances in diagnosis and treatment in patients with pulmonary arterial hypertension. Catheter Cardiovasc Interv 2008;71 :205–13. DOI:10.1002/ccd.21389; PMID: 18327839 Giaid A, Saleh D. Reduced expression of endothelial nitric oxide synthase in the lungs of patients with pulmonary hypertension. N Engl J Med 1995;333 :214–21. DOI: 10.1056/ NEJM199507273330403; PMID: 7540722 Rubens C, Ewert R, Halank M, et al. Big endothelin-1 and endothelin-1 plasma levels are correlated with the severity of primary pulmonary hypertension. Chest 2001;120 :1562–9.

PMID: 11713135 McGoon MD, Benza RL, Escribano-Subias P, et al. Pulmonary arterial hypertension: epidemiology and registries. J Am Coll Cardiol 2013;62 :D51–9. PMID: 24355642 Janda S, Shahidi N, Gin K, Swiston J. Diagnostic accuracy of echocardiography for pulmonary hypertension: a systematic review and meta-analysis. Heart 2011;97 :612–22. DOI:10.1136/ hrt.2010.212084; PMID: 21357375 Humbert M. Update in pulmonary hypertension 2008. Am J Respir Crit Care Med 2009;179 :650–6. DOI:10.1164/rccm.

200901-0136UP; PMID: 19351872 Bishop BM, Mauro VF, Khouri SJ. Practical considerations for the pharmacotherapy of pulmonary arterial hypertension.

Pharmacotherapy 2012;32 :838–55. DOI:10.1002/j.1875-9114.

2012.01114.x; PMID: 22806762 Sitbon O. Long-term response to calcium channel blockers in idiopathic pulmonary arterial hypertension. Circulation 2005;111 :3105–11. DOI:10.1161/CIRCULATIONAHA.104.488486; PMID: 15939821 Agarwal R, Gomberg-Maitland M. Current therapeutics and practical management strategies for pulmonary arterial hypertension. Am Heart J 2011;162 :201–13. DOI:10.1016/ j.ahj.2011.05.012; PMID: 21835279 Galiè N, Torbicki A, Barst R, et al. Guidelines on diagnosis and treatment of pulmonary arterial hypertension. The task force on

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echocardiography and right heart catheterization. It is also very important to monitor subjective measures like WHO functional class and quality of life outcomes. Table 3 provides suggested recommendations for specific baseline and follow-up assessments and when each is indicated.

Conclusion Significant advances have been made in determining the pathogenesis of PAH as well as in the evaluation and treatment of these patients over the past three decades. With approved targeted therapies such as ERAs, phosphodiesterase-5 inhibitors, and PGI2 analogs, clinical improvement is possible in most patients, leading to a better QoL and delay of disease progression. Recent guidelines provide clinicians recommendations for the initiation of combination therapy as well as recommendations for monitoring and assessment of patient response. n

diagnosis and treatment of pulmonary arterial hypertension of the European Society of Cardiology. Eur Heart J 2004;25 :2243–78.

PMID: 15589643 McGoon M, Gutterman D, Steen V, et al. Screening, early detection, and diagnosis of pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines. Chest 2004;126 :14S–34S. PMID: 15249493; DOI: 10.1378/chest.

126.1_suppl.14S Frank H, Mlczoch J, Huber K, et al. The effect of anticoagulant therapy in primary and anorectic drug-induced pulmonary hypertension. Chest 1997;112 :714–21. DOI:10.1378/chest.

112.3.714; PMID: 9315805 Fuster V, Steele PM, Edwards WD, et al. Primary pulmonary hypertension: natural history and the importance of thrombosis.

Circulation 1984;70 :580–7. DOI:10.1161/01.CIR.70.4.580; PMID: 6148159 Olsson KM, Delcroix M, Ghofrani HA, et al. Anticoagulation and survival in pulmonary arterial hypertension: results from the comparative, prospective registry of newly initiated therapies for pulmonary hypertension (COMPERA). Circulation 2014;129 :57–65. DOI: 10.1161/CIRCULATIONAHA.113.004526; PMID: 24081973 Caldeira D, Loureiro MJ, Costa J, et al. Oral anticoagulation for pulmonary arterial hypertension: systematic review and meta-analysis. Can J Cardiol 2014;30 :879–87. DOI: 10.1016/ j.cjca.2014.04.016; PMID: 24986048 Galie N, Manes A, Branzi A. Prostanoids for pulmonary arterial hypertension. Am J Respir Med 2003;2 :123–37. PMID: 14720012 Barst RJ, Rubin LJ, Long WA, et al. A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. N Engl J Med 1996;334 :296–301. PMID: 8532025 McLaughlin VV, Archer SL, Badesch DB, et al. ACCF/AHA 2009 expert consensus document on pulmonary hypertension a report of the American College of Cardiology Foundation task force on expert consensus documents and the American Heart Association developed in collaboration with the American College of Cardiology. J Am Coll Cardiol 2009;53 :1573–619.

PMID: 19389575 Badesch DB, Tapson VF, McGoon MD, et al. Continuous intravenous epoprostenol for pulmonary hypertension due to the scleroderma spectrum of disease. A randomized, controlled trial. Ann Intern Med 2000;132 :425–34. PMID: 19389575 Sitbon O, Humbert M, Nunes H, et al. Long-term intravenous epoprostenol infusion in primary pulmonary hypertension: prognostic factors and survival. J Am Coll Cardiol 2002;40 :780–8.

PMID: 12204511 Coons JC, Clarke M, Wanek MR, et al. Safe and effective use of prostacyclins to treat pulmonary arterial hypertension. Am J Heal Pharm 2013;70 :1716–23. DOI: 10.2146/ajhp130005; PMID: 24048608 Kallen AJ, Lederman E, Balaji A, et al. Bloodstream infections in patients given treatment with intravenous prostanoids. Infect Control Hosp Epidemiol 2008;29 :342–9. DOI: 10.1086/529552; PMID: 18462147 Simonneau G, Barst RJ, Galie N, et al. Continuous subcutaneous infusion of treprostinil, a prostacyclin analogue, in patients with pulmonary arterial hypertension: a double-blind, randomized, placebo-controlled trial. Am J Respir Crit Care Med 2002;165 : 800–4. PMID: 11897647 Gomberg-Maitland M, Tapson VF, Benza RL, et al. Transition from intravenous epoprostenol to intravenous treprostinil in pulmonary hypertension. Am J Respir Crit Care Med 2005;172 :1586–9. DOI: 10.1164/rccm.200505-766OC; PMID: 16151039 Kitterman N, Poms A, Miller DP, et al. Bloodstream infections in patients with pulmonary arterial hypertension treated with intravenous prostanoids: insights from the REVEAL REGISTRY®. Mayo Clin Proc 2012;87 :825–34. DOI: 10.1016/j. mayocp.2012.05.014; PMID: 22883740; PMCID: PMC3498408 Olschewski H, Simonneau G, Galiè N, et al. Inhaled iloprost for severe pulmonary hypertension. N Engl J Med 2002;347 :322–9.

PMID: 12151469; DOI: 10.1056/NEJMoa020204 McLaughlin VV, Benza RL, Rubin LJ, et al. Addition of inhaled treprostinil to oral therapy for pulmonary arterial hypertension:

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DOI: 10.1378/chest.11-2212; PMID: 22628490 Tapson VF. Oral treprostinil for the treatment of pulmonary arterial hypertension in patients receiving background endothelin receptor antagonist and phosphodiesterase type 5 inhibitor therapy (The FREEDOM-C2 Study). CHEST J 2013;144 :952. DOI: 10.1378/chest.12-2875; PMID: 23669822 Rubin LJ, Badesch DB, Barst RJ, et al. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med 2002;346 :896–903.

PMID: 11907289 Galié N, Badesch D, Oudiz R, et al. Ambrisentan therapy for pulmonary arterial hypertension. J Am Coll Cardiol 2005;46 : 529–35. PMID: 16053970 Galiè N, Olschewski H, Oudiz RJ, et al. Ambrisentan for the treatment of pulmonary arterial hypertension: results of the ambrisentan in pulmonary arterial hypertension, randomized, double-blind, placebo-controlled, multicenter, efficacy (ARIES) study 1 and 2. Circulation 2008;117 :3010–19. PMID: 18506008 Oudiz RJ, Galiè N, Olschewski H, et al. Longterm ambrisentan therapy for the treatment of PAH. J Am Coll Cardiol 2009;54 : 1971–81. DOI: 10.1016/j.jacc.2009.07.033; PMID: 19909879 Pulido T, Adzerikho I, Channick RN, et al. Macitentan and morbidity and mortality in pulmonary arterial hypertension.

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Heart Failure

Current Status of the Left Ventricular Assist Device as a Destination Therapy Jorg e Silv a En c i s o, M D, E r i c A d l e r, M D a n d B a r r y G r e e n b e r g , M D Cardiology Division, Department of Medicine, University of California San Diego, San Diego, CA

Abstract The heart failure epidemic has led to an increase in the number of patients with advanced heart failure, which is associated with high morbidity and mortality. Current therapies for advanced heart failure are limited to heart transplantation and mechanical circulatory support, with palliative care reserved for those ineligible to receive advanced therapies. Clinical trials of ventricular assist devices for patients with advanced heart failure demonstrate an improvement in survival and quality of life akin to heart transplantation. The Achilles heal of this therapy is the adverse event burden. Patient selection and multidisciplinary care are two of the strategies being used to improve long-term outcomes.

Adjunct therapies in combination with left ventricular assist device therapy and advances in device technology in the near future may lessen the number of adverse events. This review summarizes the clinical outcomes, current challenges and future directions of left ventricular assist device therapy.

Keywords Advanced heart failure, destination therapy, mechanical circulatory support, left ventricular assist device Disclosure: The authors have no conflicts of interest to declare.

Received: March 3, 2016 Accepted: August 3, 2016 Citation: US Cardiology Review 2016;10(2):85–90 DOI: 10.15420/usc.2016:6:2 Correspondence: Jorge Silva Enciso, MD, Assistant Clinical Professor of Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla , CA 92093, USA. E: jsilvaenciso@ucsd.edu

Advanced heart failure (AHF) affects approximately 5–10 % of the current 6.6 million people living with heart failure, having a higher incidence in those above 65 years of age.1 The presence of the disease is associated with 50–80 % mortality at 1 year, indicating the need for innovative therapies to manage the burden of this disease. Heart transplantation is the gold standard for AHF, although limitations exist due to the availability of donor hearts; only ~4,500 orthotopic heart transplants are performed worldwide each year.2 Mechanical circulatory support offers the potential to restitute ventricular function, improve overall functional capacity and quality of life. This strategy, however, is not free from complications and device-related issues make this therapy a challenge to apply to a broader population.

The era of mechanical circulatory support began in the 1950s with the successful management of post-cardiotomy syndrome. The favorable outcomes led to new applications including their use as a bridge to heart transplantation (BTT) and, by 1994, the US Food and Drug Administration (FDA) gave approval for pneumatically-driven left ventricular assist devices (LVADs) as BTT.3 Soon after, electrically-driven LVADs where developed, and by 1999 Columbia University had reported its experience of 95 patients supported by HeartMate XVE for 108 days and eventually transplanted.4

the Treatment of Congestive Heart Failure (REMATCH) trial investigated LVADs as long-term myocardial replacement therapy or destination therapy (DT).5 This trial randomized New York Heart Association class IV patients with left ventricular ejection fraction ≤25 % to LVAD versus optimal medical therapy. Greater survival was shown in those receiving LVAD therapy at 1 year (52 versus 25 %), allowing the FDA to approve LVADs as a DT. Moreover, improvements in quality of life, depression and functional status were significant in the LVAD cohort.5 The first generation of LVADs featured pulsatile flow (PF), simulating the native pulsatile function of the heart, but the size of the device requiring implantation in the abdominal cavity limited its application to male patients in most cases. Furthermore, its multiple components tended to fail, it required replacement after 18 months, and frequent adverse events were noted including bleeding, stroke and device infection. Innovations in pump design with a smaller, single high-speed rotary impeller, providing continuous flow (CF) offered long-term durability. A randomized controlled trial in DT patients compared the outcomes of both flow profiles (PF versus CF).6 The CF group showed greater survival (58 versus 24 %) at 2-year follow up. Furthermore, freedom from disabling stroke and reoperation for device malfunction was higher in the CF-LVAD compared to the PF device (11 versus 46 %).6

The increasing prevalence of heart failure and the limitations of organ donor availability for heart transplantation led to LVADs being used as a permanent therapy in AHF patients who were not candidates for transplant. The Randomized Evaluation of Mechanical Assistance for

The favorable outcomes seen in these clinical trials of CF-LVAD made the therapy a feasible option for many AHF patients. The most recent Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) report shows that survival continues to improve, now being

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Heart Failure Figure 1: Implant Strategies According to the INTERMACS Registry 2008–2014 50 % 40 % BTT listed

30 %

BTT likely BTT moderate BTT unlikely

20 %

DT BT recovery

10 %

Rescue Other

20 08 12 –2 03 01 0 4:

24 23 20 14 :

20 08 47 –20 44 11 : 20 12 :2 22 1 20 13 :2 64 2

0%

BTR = bridge to recovery; BTT = bridge to heart transplantation; DT = destination therapy.

7 Source: adapted from Kirklin et al.

Table 1: HeartMate II Risk Score Calculations 12,§ Variable

Log Multiplier

Age

0.0274

Albumin (per g/dl)

0.723

Creatinine (per mg/dl)

0.74

INR (per unit)

1.136

Center volume <15*

0.807

Calculation formula: age − albumin + creatinine + INR + center volume §

Low risk (<1.58); medium risk (1.58≥ to ≤2.48); high risk (>2.48). *Enter value of 1 if total center left ventricular assist device volume is <15 and 0 if ≥15. INR = international normalization ratio.

80 % at 1 year and 70 % at 2 years.7 These results are consistent with post market approval data showing survival of 83 % and 75 % at 1 and 3 years, respectively.8 Not surprisingly, contemporary registry data report that CF pumps account for all DT implants since 2010 (see Figure 1).7

Matching Patients to Devices There are two current FDA-approved LVAD therapies: HeartMate II, which uses axial flow, and HeartWare, which uses centrifugal flow. The former has been approved as DT and BTT, while the latter is approved for BTT only. Selecting appropriate LVAD therapy for each patient is difficult, as the decision has to be considered against the complications and their impact on outcomes. The INTERMACS profile provides a guideline for risk-stratifying potential recipients of mechanical circulatory support.9 In a study by Boyle et al. using INTERMACS data, 101 patients on CF pumps were divided into three categories: cardiogenic shock (group 1), inotrope dependent (group 2) and ambulatory AHF (group 3).10 Survival at 36 months for group 1 versus 3 was lower (51.1 versus 95.8 %, p=0.011). it was found that patients with INTERMACS profiles 1–3 were associated with longer hospital stays compared to INERMACS profiles 4–7.10 Although recent registry data show that patients with profiles 1 and 2 remain the predominant population being implanted, there has been a trend since 2012 for more patients with INTERMACS profiles 3 and 4 to receive implants.7 This change is likely due to post FDA approval studies in DT patients demonstrating superior 2-year survival in those with profiles

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4–7 (who are not inotrope-dependent) compared to profiles 1–3 (67±6 % versus 59±4 %).11 Thus, the timing of implantation before further disease progression is important. Many AHF patients have clinical signs and symptoms that portend a further decline in health status, including medication intolerance, frequent heart failure-related hospitalizations and end-organ dysfunction (i.e. hepatic and renal). When these ominous signs develop, prompt referral to an AHF specialist should be considered, as patients with a higher risk of mortality may benefit from mechanical circulatory support therapy.

Predicting Risk Applying long-term device therapy to AHF patients can be associated with an increased risk of perioperative mortality and poor outcomes. Recent changes in implantation strategy reflect the increased understanding of patient selection, perioperative management and long-term care. Risk stratification prior to implantation is thus critical for good outcomes. The HeartMate II risk score has been developed using large multicenter clinical trial data assessing 90-day mortality, (see Table 1).12 The study included >50 % of patients receiving devices as DT in both derivation and validation groups. The HeartMate II risk score cutoffs were 1.58 for low risk, 1.58 to ≤2.48 for medium risk and ≥2.48 for high risk. The receiver operating characteristic curve in the total sample (derivation plus validation) was 0.71 (95 % CI [0.66–0.75]) and mortality in the validated cohort was 8 %, 11 %, and 25 %, for the low, medium and high-risk groups, respectively.12 Of the risk factors identified, age and center experience were determinants of long-term survival for patients implanted as DT (>12 months post implant).12 The model has limitations, however, as its has been shown to poorly discriminate 90-day mortality after LVAD implant when applied to other AHF cohorts and fails to discriminate between low-risk patients who can benefit from LVAD and patients with too high a risk, where LVAD therapy may be contraindicated or futile. Deciding which low-risk patient (ambulatory AHF that is not inotrope dependent) may benefit from this therapy can be a challenge. The Risk Assessment and Comparative Effectiveness of Left Ventricular Assist Device and Medical Management (ROADMAP) trial has shown that outcomes in those considered to have lower risk (INTERMACS profiles 4–7) are as favorable as earlier trials, with a survival at 1 year of 80 versus 64 % in those on optimal medical management.13 Furthermore, improvements in New York Heart Association class 6-minute walk distance, healthrelated quality of life, and depression were more significant in LVAD patients despite having increased adverse events (1.89 events/year) and frequent hospitalizations.13 The study was limited, however, by being a non-randomized observational study and by physicians allocating patients to LVAD therapy at their discretion, inherently introducing bias.

Nonetheless, risk prediction can help clinicians start a conversation with patients and caregivers to educate them about the risks and benefits of the therapy. Estimating mortality risk for continuing medical therapy versus LVAD therapy can also help patients understand whether the implantation of a device is in their best interest.

Adverse Events Despite the meaningful advances in device technology, LVAD continues to be associated with a high rate of adverse events. In the current era of CF-LVAD, only 30 % of patients are free from any major adverse event at 1 year, though this has improved from earlier DT trials.11,14 Device-related complications include stroke, infection, bleeding, pump thrombosis, and

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LVAD as Destination Therapy Table 2: Number of Adverse Events (Percentage) Following the Implantation of a Continuous Flow Left Ventricular Assist Device Event

HeartMate II BTT trial 2009

Bleeding requiring

38

HeartMate II DT trial 2009

6

HVAD BTT trial 2012

39

HVAD DT trial 2015

INTERMACS 16

2011–2013

148 (53)

108 (81)

42 (13)

176 (59.5)

3867 (59.8)

Thrombosis

4 (1)

5 (4)

14 (4.2)

--

588 (9.09)

Replacement

12 (4)

12 (9)

7 (2.1)

23 (7.8)

45 (9)

Infection

41 (14)

47 (35)

56 (17)

201 (67.9)

3933 (60.8)

Cerebrovascular

24 (8)

24 (18)

51 (15.3)

85 (28.7)

1086 (16.8)

53 (19)

32 (24)

98 (29.5)

110 (37.2)

1268 (19.6)

14

transfusion

(thrombosis/device malfunction)

accident (ischemic/ hemorrhagic) Right ventricular failure BTT = bridge to heart transplantation; DT = destination therapy.

ventricular arrhythmias. Non device-related complications include right heart failure. The impact of these complications on mortality is time dependent. In the early phase (<3 months) multiple organ failure is the major cause of death; after 3 months, neurological causes predominate.7 A description of the causes, mechanisms and treatment of each complication goes beyond the scope of this review and has been given by prior authors.15 Two recent clinical trials assessing the use of CF technology in DT patients have provided further insight into the burden of complications: ROADMAP13 and ENDURANCE™ (A Clinical Trial to Evaluate the HeartWare Ventricular Assist System).16 The ROADMAP trial was a prospective multicenter non-randomized observational study evaluating the outcomes of initial treatment with LVAD (n=94) versus optimal medical management (OMM, n=103) in ambulatory New York Heart Association IV patients not on inotrope. Individuals in the OMM group were able to transition to LVAD therapy if necessary.13 Within 1 year, adverse events were more frequent in the LVAD group: 47 % due to bleeding (31 % due to gastrointestinal causes), 6.4 % due to pump thrombosis, 8.5 % due to stroke (5.3 % ischemic and 4.3 % hemorrhagic), and 18.1 % due to ventricular arrhythmias; however, worsening heart failure symptoms occurred more often in the OMM group (35 versus 10.6 %). The composite event rate per patient year for the LVAD group was 1.89 versus 0.83 for the OMM group. Bleeding was the leading cause for rehospitalizations post implant in LVAD; worsening heart failure caused the majority of rehospitalizations in OMM patients.

Notably, major causes of death in the LVAD group were sepsis, multiple organ failure, right heart failure, ventricular tachycardia, thrombus and stroke. Despite this, quality of life was better for LVAD patients (55 versus 23 %, p<0.001). The ENDURANCE trial evaluated 2-year survival and freedom from disabling stroke in patients with HeartWare HVAD versus HeartMate II devices.16 The study demonstrated non-inferiority of the CF centrifugal design over the axial flow device. A higher rate of pump exchange occurred with the axial flow design (16.2 versus 8.8 %), while a higher stroke rate occurred with the centrifugal flow design (28.7 versus 12.1 %).16 Although, post approval LVAD DT studies have shown a favorable trend towards a reduction in adverse events and recent registry data support this, the issue of readmissions is a

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limiting step in the expansion of this technology to a broader heart failure population (see Table 2).

Readmissions In general, the annual rate of recurrent hospitalizations due to adverse events in CF-LVAD patients is 65 %. The majority of adverse events occur in the first 6 months post implant, with the most common being bleeding (gastrointestinal), cardiac causes (heart failure and arrhythmias), infections, and thrombosis (stroke or pump thrombosis).7,17 The Mayo Clinic findings from 224 admissions in 115 patients followed for 2.3 years supported these findings, with the major causes of hospitalization in the first 6 months being bleeding (30 %), cardiac (30 %), infections (22 %), and thrombosis (14 %).18 After 6 months readmissions decreased, but after 2 years bleeding admissions were more frequent. The factors associated with admissions after LVAD implant were preoperative anemia, higher levels of pro brain natriuretic peptide, lower glomerular filtration rate, and higher right atrial/pulmonary artery wedge pressure ratio (as a measure of impaired right ventricular function).18 A similar study by the Cleveland Clinic analyzed 118 HeartMate II LVAD patients and found that 52 % had 177 unplanned hospital readmissions: 87 were nondevice related, mainly from progression of underlying cardiac disease, and 90 were device related, largely due to device infection.19 More DT patients were readmitted, and overall 25 days were spent in hospital in the first 12 months.19 From a cost analysis perspective, patients with DT are estimated to live 4.4 years on average beyond the first year, but resource utilization by LVAD patients after rehospitalizations is large.20 A strategy to reduce hospitalizations is critical, as currently LVAD-DT does not meet the cost-effective benchmark.20,21 Unplanned hospitalizations are common, and increase with increasing time on mechanical support.

The avoidance of hospitalization requires a multidisciplinary team of specialists that can aid patients and caregivers in identifying a good support system and home environment. Close attention needs to be given to patients with significant comorbidities (i.e. diabetes, renal dysfunction, peripheral vascular disease) and longer hospital stay post implant.22 Different strategies to reduce rehospitalization may include: follow up in the post-operative period, with weekly visits determined by the proximity to the surgical procedure; assigning coordinators to followup on tests after the patient has been discharged; and partnering with

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Heart Failure Figure 2: Pulsatile Modes in Left Ventricular Assist Devices 34

LVAD flow [L/min], Pressures [mmHg]

90

Continous

Asynchronous

Synchronous Co-pulse Counter-pulse

80 70

The new Thoratec HeartMate 3 model is currently undergoing a clinical trial (MOMENTUM 3). The new pump design provides centrifugal flow and improves hemo-compatibility by having large gaps between the impeller and the housing that reduce red blood cell destruction. It employs a fully magnetic levitated rotor that can provide flows between 2.5 and 10 L/min and produces a near-physiological pulse pressure of 25 mmHg every 2 seconds.

60

Miniaturization

50

Another important aspect of device technology is reducing its size to allow shorter implant times, less invasive surgery and the potential expansion to other AHF populations. HeartWare MVAD is a pump with an axial impeller that uses hydrodynamic and magnetic force to move the rotor. The flow path exits the device perpendicular to the rotor’s orientation and uses modifiable pulsatility patterns, which may reduce arteriovenous malformation.

40 30 20 10 0

Source: modified from Soucy et al.

Partial Support and Myocardial Recovery 34

community hospitals or physicians who understand ventricular assist device technology and management. A recent occurrence of a devicerelated complication and the general status of the patient aids early recognition of potential complications and also provides an opportunity for further educating the patient and his or her family about device function and alarm recognition.

Emerging Applications Developments in technology, patient selection and other therapies used in conjunction with mechanical circulatory support are being used to reduce the risks associated with and improve the outcomes of LVAD therapy. There is a focus on improving the hemo-compatibility of devices to reduce thrombotic and bleeding events; developing software algorithms that allow pulsatility parallel to a patient’s functional needs; the creation of smaller devices for less invasive procedures and shorter recovery; and the development of totally implantable designs that use wireless energy transfer systems.

Pulsatility Recent research has produced insights into vascular responses to pulse pressure. It has been found that pulse amplitude is related to the endothelial production of nitric oxide and vasodilation, and that pulse pressure improves circulation in the capillary beds of end organs.23 Moreover, significant hemodynamic benefits of PF-LVADs can be seen in total cardiac output and lower pulmonary pressures and left atrial pressure, providing superior unloading compared to CF-LVADs. A return to pulsatility may reduce the number of adverse events, as studies have shown that patients with low pulsatility have increased non-surgical bleeding episodes.24 Observational studies have demonstrated that PF-LVADs may be better at inducing myocardial recovery than CF-LVADs, possibly by enhancing coronary flow, as noted by improvements in systolic and diastolic function, and a reduction in brain natriuretic peptide and extracellular markers.25 Based on these observations, there is now interest in developing algorithms to generate pulse pressure in an attempt to reduce adverse events associated with CF-LVADs.

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Reports of functional recovery following LVAD implantation have accelerated research in the field of myocardial regeneration. The rates of sustained cardiac recovery across the studies range from 1 to 36 %, with most patients who demonstrate substantial improvement in left ventricular ejection fraction having a non-ischemic dilated cardiomyopathy as the etiology of their heart failure, younger age and shorter disease duration.26 Initial reports from observational trials have noted that continued use of neurohormonal blockade might promote recovery. A prospective study of 20 LVAD patients receiving maximal doses of beta-blocker, angiotensin-converting-enzyme inhibitor, spironolactone and digoxin followed by high-dose clenbuterol reported complete normalization of left ventricular size and function in 12 patients who eventually underwent device explantation.27 Of these individuals, the estimated survival without recurrence of heart failure was 83 % at 1 and 3 years.27 Though these findings have yet to be reproduced in larger trials, national registries report 1–5 % explantation rates.7 These low rates may be explained by variations in medical therapy added to LVAD, variable unloading protocols and a mixture of populations by type and duration of heart failure.28 Mechanical unloading does change the myocardial structure and function as early as 30 days post implantation.29 Despite the structural changes seen after mechanical support, a gap still exists between the positive morphological changes seen and complete recovery in function. This may be due to the persistence of sarcomere contractile dysfunction after implantation.30 A more tangible approach for recovery may be to partially support the left ventricle by rotational speed modulation when synchronized with the cardiac cycle. Studies of patients who were partially unloaded (lower speeds) have shown improvement in myocardial performance, including increased peak oxygen consumption, resting myocardial blood flow, and lower myocardial oxygen consumption.31 This mode of operation on newer devices with the addition of pulsatility may create the right environment for cardiac remodeling and potential recovery. Indeed, synchronous unloading of the left ventricle by the assist device can be adjusted to deliver maximum flow either during systole (co-pulsation, which increases the speed during systole and decreases speed in diastole) or diastole (counter-pulsation, which increases the speed during diastole and decreases speed during

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LVAD as Destination Therapy systole). The former generates an arterial pulse, while the latter unloads more effectively while enhancing coronary flow and end-organ perfusion.32,33 Asynchronous mode, independent of the native heart rate, has the advantage of not requiring a trigger and combining intermittent co-pulsation and counter-pulsation support.34

Transcutaneous Energy Transmission System This type of system has been in development since the 1960s and has limited applications. The use of this technology can potentially reduce driveline infections, which is one of the main causes of rehospitalization.

The technology transfers power from an external coil to a subcutaneouslyplaced internal coil by using magnetic fields. One caveat is the misalignment during charge and risk of heat production.35 More recently, the freerange resonant electrical energy delivery (FREE-D) system has used coil mechanics. Its benefit over the older system is it is able to transfer power wirelessly across distances of a meter.36 The potential application of a total implantable system will allow patients to become more comfortable with their device, as being “wireless” may boost their mobility and autonomy, and positively impact their quality of life.36

End of Life after LVAD While ventricular assist devices help provide significant symptom relief for patients, patients continue to have many other symptoms that persist including physical pain, major depression, and organic mental syndromes.

As such, extensive discussion with patients and their caregivers is required prior to LVAD implantation so they have a realistic sense of what life is like with a LVAD as well as having the chance to express their wishes.

Recently the Center for Medicare Services has required that a palliative care physician be part of the core LVAD team. Ideally the palliative care

1.

Norton C, Georgiopoulou VV, Kalogeropoulos AP, et al.

Epidemiology and cost of advanced heart failure. Prog Cardiovasc Dis 2011;54 :78–85. DOI: 10.1016/j.pcad.2011.04.002; PMID: 21875507 2. Yusen RD, Edwards LB, Kucheryavaya AY, et al. The registry of the International Society for Heart and Lung Transplantation: thirty-first adult lung and heart-lung transplant report–2014; focus theme: retransplantation. J Heart Lung Transplant 2014;33 :1009–24. DOI: 10.1016/j.healun.2014.08.004; PMID: 25242125 3. Helman DN, Rose EA. History of mechanical circulatory support.

Prog Cardiovasc Dis 2000;43 :1–4. PMID: 10935552 4. Sun BC, Catanese KA, Spanier TB, et al. 100 long-term implantable left ventricular assist devices: the Columbia Presbyterian interim experience. Ann Thorac Surg 1999;68 : 688–94. PMID: 10475472 5. Rose EA, Gelijns AC, Moskowitz AJ, et al. Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure (REMATCH) Study Group. Long-term use of a left ventricular assist device for end-stage heart failure. N Engl J Med 2001;345 :1435–43. PMID: 11794191 6. Slaughter MS, Rogers JG, Milano CA, et al. Advanced heart failure treated with continuous-flow left ventricular assist device. N Engl J Med 2009;361 :2241–51. DOI: 10.1056/ NEJMoa0909938; PMID: 19920051 7. Kirklin JK, Naftel DC, Pagani FD, et al. Seventh INTERMACS annual report: 15,000 patients and counting. J Heart Lung Transplant 2015;34 :1495–504. DOI: 10.1016/j.healun.2015.10.003; PMID: 26520247 8. Takeda K, Takayama H, Kalesan B, et al. Long-term outcome of patients on continuous-flow left ventricular assist device support. J Thorac Cardiovasc Surg 2014;148 :1606–14. DOI: 10.1016/j.jtcvs.2014.04.009; PMID: 25260275 9. Alba AC, Rao V, Ivanov J, et al. Usefulness of the INTERMACS scale to predict outcomes after mechanical assist device implantation. J Heart Lung Transplant 2009;28 :827–33.

DOI: 10.1016/j.healun.2009.04.033; PMID: 19632580 10. Boyle AJ, Ascheim DD, Russo MJ, et al. Clinical outcomes for continuous-flow left ventricular assist device patients stratified by pre-operative INTERMACS classification. J Heart Lung

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11.

12.

13.

14.

15.

16.

17.

18.

19.

physician should meet with the potential patient prior to LVAD to clarify the goals of care. The palliative care team can assist with pain and symptom management postoperatively, and with transition to end-of-life care when appropriate.

Living with a LVAD requires extensive commitment from the primary caregiver. Persons defined as primary caregivers include spouses, children, or even close friends. A primary caregiver who is willing to commit to indefinite 24-hour support of the patient after LVAD implantation needs to be identified and educated regarding the extent and nature of the commitment before LVAD placement.

Further study is required to define the degree of caregiver burden among this patient population and effective strategies to reduce this burden.

Conclusion The heart failure population is expected to increase to >8 million people in the US by 2030, and heart failure is likely to become the number one cause of disability in the country.37 The total cost of management will increase exponentially, and thus strategies to mitigate the disabling nature of the disease are required. LVADs are one treatment strategy and have advanced significantly since their early applications to become a viable option to manage AHF in the long term. It is hoped that improvements in circulatory systems, the miniaturization of devices, re-introduction of PF and the availability of a fully implantable system will improve the beneficial effects of LVAD therapy while limiting the complications associated with mechanical support.

In the future, it is expected that strategies combining LVADs and pharmacological or cell-based therapy may ultimately lead to full myocardial recovery. n

Transplant 2011;30 :402–7. DOI: 10.1016/j.healun.2010.10.016; PMID: 21168346 Jorde UP, Kushwaha SS, Tatooles AJ, et al. HeartMate II Clinical Investigators. Results of the destination therapy post-food and drug administration approval study with a continuous flow left ventricular assist device: a prospective study using the INTERMACS registry (Interagency Registry for Mechanically Assisted Circulatory Support). J Am Coll Cardiol 2014;63 :1751–7.

DOI: 10.1016/j.jacc.2014.01.053; PMID: 24613333 Cowger J, Sundareswaran K, Rogers JG, et al. Predicting survival in patients receiving continuous flow left ventricular assist devices: the HeartMate II risk score. J Am Coll Cardiol 2013;61 :313–21. DOI: 10.1016/j.jacc.2012.09.055; PMID: 23265328 Estep JD, Starling RC, Horstmanshof DA, et al. ROADMAP Study Investigators. Risk Assessment and Comparative Effectiveness of Left Ventricular Assist Device and Medical Management in Ambulatory Heart Failure Patients: Results From the ROADMAP Study. J Am Coll Cardiol 2015;66 :1747–61. DOI: 10.1016/j. jacc.2015.07.075; PMID: 26483097 Kirklin JK, Naftel DC, Kormos RL, et al. Fifth INTERMACS annual report: risk factor analysis from more than 6,000 mechanical circulatory support patients. J Heart Lung Transplant 2013;32 : 141–56. DOI: 10.1016/j.healun.2012.12.004; PMID: 23352390 Birati EY, Jessup M. Left ventricular assist devices in the management of heart failure. Cardiac Failure Review 2015;1 :25 Pagani FD. Adverse event burden and mechanical circulatory support: Looking toward the future. J Thorac Cardiovasc Surg 2016;151 :10–2. DOI: 10.1016/j.jtcvs.2015.09.052; PMID: 26463654 Forest SJ, Bello R, Friedmann P, et al. Readmissions after ventricular assist device: etiologies, patterns, and days out of hospital. Ann Thorac Surg 2013;95 :1276–81. DOI: 10.1016/ j.athoracsur.2012.12.039; PMID: 23481701 Hasin T, Marmor Y, Kremers W, et al. Readmissions after implantation of axial flow left ventricular assist device. J Am Coll Cardiol 2013;61 :153–63. DOI: 10.1016/j.jacc.2012.09.041; PMID: 23219299 Smedira NG, Hoercher KJ, Lima B, et al. Unplanned hospital readmissions after HeartMate II implantation: frequency, risk

20.

21.

22.

23.

24.

25.

26.

27.

factors, and impact on resource use and survival. JACC Heart Fail 2013;1 :31–9. DOI: 10.1016/j.jchf.2012.11.001; PMID: 24621797 Long EF, Swain GW, Mangi AA. Comparative survival and cost-effectiveness of advanced therapies for end-stage heart failure. Circ Heart Fail 2014;7 :470–8. DOI: 10.1161/ CIRCHEARTFAILURE.113.000807; PMID: 24563450 Rogers JG, Bostic RR, Tong KB, et al. Cost-effectiveness analysis of continuous-flow left ventricular assist devices as destination therapy. Circ Heart Fail 2012;5 :10–6. DOI: 10.1161/ CIRCHEARTFAILURE.111.962951; PMID: 22052901 Dunlay SM, Haas LR, Herrin J, et al. Use of post-acute care services and readmissions after left ventricular assist device implantation in privately insured patients. J Card Fail 2015;21 :816–23. DOI: 10.1016/j.cardfail.2015.06.012; PMID: 26093335 Nakano T, Tominaga R, Morita S, et al. Impacts of pulsatile systemic circulation on endothelium-derived nitric oxide release in anesthetized dogs. Ann Thorac Surg 2001;72:156–62.

PMID: 11465171 Wever-Pinzon O, Selzman CH, Drakos SG, et al. Pulsatility and the risk of nonsurgical bleeding in patients supported with the continuous-flow left ventricular assist device HeartMate II. Circ Heart Fail 2013;6 :517–26. DOI: 10.1161/ CIRCHEARTFAILURE.112.000206; PMID: 23479562 Kato TS, Chokshi A, Singh P, et al. Effects of continuousflow versus pulsatile-flow left ventricular assist devices on myocardial unloading and remodeling. Circ Heart Fail 2011;4 :546–53. DOI: 10.1161/CIRCHEARTFAILURE.111.962142; PMID: 21765125 Drakos SG, Mehra MR. Clinical myocardial recovery during long-term mechanical support in advanced heart failure: Insights into moving the field forward. J Heart Lung Transplant 2016;35:413–20. DOI: 10.1016/j.healun.2016.01.001; PMID: 26922277 Birks EJ, George RS, Hedger M, et al. Reversal of severe heart failure with a continuous-flow left ventricular assist device and pharmacological therapy: a prospective study. Circulation 2011;123 :381–90. DOI: 10.1161/CIRCULATIONAHA.109.933960; PMID: 21242487

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Heart Failure 28. Pan S, Aksut B, Wever-Pinzon OE, et al. Incidence and predictors of myocardial recovery on long-term left ventricular assist device support: Results from the United Network for Organ Sharing database. J Heart Lung Transplant 2015;34 :1624–9. DOI: 10.1016/j.healun.2015.08.004; PMID: 26442678 29. Drakos SG, Wever-Pinzon O, Selzman CH, et al. Magnitude and time course of changes induced by continuous-flow left ventricular assist device unloading in chronic heart failure: insights into cardiac recovery. J Am Coll Cardiol 2013;61 :1985–94.

DOI: 10.1016/j.jacc.2013.01.072; PMID: 23500219 30. Ambardekar AV, Walker JS, Walker LA, et al. Incomplete recovery of myocyte contractile function despite improvement of myocardial architecture with left ventricular assist device support. Circ Heart Fail 2011;4:425–32. DOI: 10.1161/ CIRCHEARTFAILURE.111.961326; PMID: 21540356 31. Maybaum S, Epstein S, Beniaminovitz A, et al. Partial loading of the left ventricle during mechanical assist device support is associated with improved myocardial function, blood flow and metabolism and increased exercise capacity. J Heart Lung Transplant 2002;21 :446–54. PMID: 11927221

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32. Moazami N, Dembitsky WP, Adamson R, et al. Does pulsatility matter in the era of continuous-flow blood pumps? J Heart Lung Transplant 2015;34 :999–1004. DOI: 10.1016/j.healun.2014.09.012; PMID: 25447568 33. Arakawa M, Nishimura T, Takewa Y, et al. Alternation of left ventricular load by a continuous-flow left ventricular assist device with a native heart load control system in a chronic heart failure model. J Thorac Cardiovasc Surg 2014;148 :698–704.

DOI: 10.1016/j.jtcvs.2013.12.049; PMID: 24521976 34. Soucy KG, Giridharan GA, Choi Y, et al. Rotary pump speed modulation for generating pulsatile flow and phasic left ventricular volume unloading in a bovine model of chronic ischemic heart failure. J Heart Lung Transplant 2015;34 :122–31.

DOI: 10.1016/j.healun.2014.09.017; PMID: 25447573 35. Slaughter MS, Myers TJ. Transcutaneous energy transmission for mechanical circulatory support systems: history, current status, and future prospects. J Card Surg 2010;25 : 484–9. DOI: 10.1111/j.1540-8191.2010.01074.x; PMID: 20642765 36. Asgari SS, Bonde P. Implantable physiologic controller for left ventricular assist devices with telemetry capability.

J Thorac Cardiovasc Surg 2014;147 :192–202. DOI: 10.1016/ j.jtcvs.2013.09.012; PMID: 24176267 37. Heidenreich PA, Albert NM, Allen LA, et al.; American Heart Association Advocacy Coordinating Committee; Council on Arteriosclerosis, Thrombosis and Vascular Biology; Council on Cardiovascular Radiology and Intervention; Council on Clinical Cardiology; Council on Epidemiology and Prevention; Stroke Council. Forecasting the impact of heart failure in the United States: a policy statement from the American Heart Association. Circ Heart Fail 2013;6:606–19. DOI: 10.1161/ HHF.0b013e318291329a; PMID: 23616602 38. Pagani FD, Miller LW, Russell SD, et al; HeartMate II Investigators.

Extended mechanical circulatory support with a continuousflow rotary left ventricular assist device. J Am Coll Cardiol 2009;54:312–21. DOI: 10.1016/j.jacc.2009.03.055; PMID: 19608028 39. Aaronson KD, Slaughter MS, Miller LW, et al. Use of an intrapericardial, continuous-flow, centrifugal pump in patients awaiting heart transplantation. Circulation 2012; 125:3191–200. DOI: 10.1161/CIRCULATIONAHA.111.058412; PMID: 22619284

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Acute Coronary Syndromes

ST-segment Elevation Myocardial Infarction: Challenges in Diagnosis R obert F Ri l e y, M D, M S a n d Ja m e s M M c Ca b e, M D Division of Cardiology, University of Washington School of Medicine, Seattle, WA

Abstract ST-segment elevation myocardial infarction (STEMI) remains a leading cause of morbidity and mortality in the US. While there is a codified definition of STEMI, challenges in diagnosis remain due to variability in electrocardiogram (ECG) presentation, conditions with similar presentations, variability in the electrical manifestation of ST-segment elevation on ECG, and systems issues with access to rapid diagnosis that can make this diagnosis challenging. This article aims to review these challenges.

Keywords STEMI, diagnosis, challenge, ECG Disclosure: The authors have no conflicts of interest to declare.

Received: February 3, 2016 Accepted: May 10, 2016 Citation: US Cardiology Review, 2016;10(2):91–4 DOI: 10.15420/usc.2016:5:2 Correspondence: Robert F Riley, Division of Cardiology, University of Washington Medical Center, 1959 NE Pacific Street, Seattle, WA 98105, USA. E: rfriley@uw.edu

Heart disease remains the leading cause of death in the US, with ischemic heart disease comprising almost half of these deaths based on the most recent 2013 mortality data.1 While there have been reports of declining rates of acute myocardial infarction (AMI) from various registries and Medicare beneficiary reports, coronary heart disease remained the underlying cause of death in one out of seven deaths in the US.2–4 The acute coronary syndromes (ACS) are responsible for the largest share of mortality among the etiologies of coronary heart disease, with ST-segment elevation myocardial infarction (STEMI) comprising 30–33 % of all ACS and contributing to the highest mortality along this spectrum with a reported mortality rate of 5.0–8.0 % in 2006 based on data from the National Registry of Myocardial Infarction.5,6 Given the significant morbidity and mortality associated with STEMI, there has been a push from both local and national medical associations to improve the timely diagnosis of STEMI to decrease time to definitive therapy. However, there remain challenges in diagnosis from both clinical recognition and timing of diagnosis. This review article aims to evaluate some of these challenges in diagnosis.

Definition of ST-segment Elevation Myocardial Infarction AMI is defined as a clinical event involving myocardial ischemia in which there is evidence of myocardial injury. Typically, this involves a rise and fall of cardiac biomarkers, along with supportive evidence in the form of symptoms, suggestive electrocardiogram (ECG) changes, or imaging evidence of a new loss of viable myocardium.7 STEMI is a type of AMI with symptoms characteristic of myocardial ischemia associated with ST-segment elevation on the ECG. It is defined in the Third Universal Definition of Myocardial Infarction as new ST-segment elevation at the J point of at least two contiguous leads of ≥2 mm (≥0.2 mV) in men or ≥1.5 mm (0.1 mV) in women in leads V2 and V3 or ≥1 mm in any other contiguous precordial

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leads or the limb leads for either gender. New left bundle branch block (LBBB) was previously considered a STEMI equivalent; however, data have consistently shown that it is infrequently associated with true ACS and is no longer considered diagnostic of a STEMI. In addition, ST depression in ≥2 precordial leads (V1–V4) may indicate a posterior transmural injury pattern, which can happen concurrent with inferior ST elevation or in isolation (‘isolated posterior infarct’); this diagnosis can be confirmed by the presence of ≥1 mm ST elevation in the posterior (V7–V9) leads.8 It should be noted that there are criteria for diagnosing STEMI in those with known (‘old‘) LBBB referred to as the Sgarbossa criteria, though the imperfect sensitivity and specificity of these findings for STEMI often result in clinical ambiguity in making this diagnosis.9

Differential Diagnosis of ST-segment Elevation While ST-segment elevation on the ECG is a diagnostic cornerstone for STEMI, this finding is not specific to STEMI. There are a variety of other causes of ST-segment elevation on the ECG (see Table 1) and the distinction between these entities is a combination of pattern recognition on the ECG and the clinical scenario, which are the two diagnostic points emphasized in the universal definition of STEMI. For example, ventricular aneurysms can have persistent ST-segment elevation in the leads corresponding to the aneurysmal myocardium. However, these ST-segment elevations should be present on prior ECGs and symptoms associated with the aneurysm are less likely to be consistent with acute myocardial ischemia, though they can present with ventricular arrhythmias due to the aneurysm itself or scar from prior infarctions.

Myocarditis and pericarditis can also present with ST-segment elevation and chest pain, though the ST-segment elevation is usually more diffuse and the clinical symptoms often differ from those associated with acute ischemia.10 However, there can be so-called ‘localized’ myocarditis or pericarditis, which is often a diagnosis of exclusion

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Acute Coronary Syndromes Table 1: Differential Diagnosis of ST-segment Elevation on electrocardiogram •

ST-segment elevation myocardial infarction (STEMI)

•

Ventricular aneurysm

•

Myocarditis/pericarditis

•

Takotsubo (stress) cardiomyopathy

•

Spontaneous coronary artery dissection

•

Myocardial injury from trauma (blunt force)

•

Prinzmetal’s (variant) angina

•

Benign early repolarization pattern

•

Left and right bundle branch blocks with associated repolarization

Many of the clinical scenarios on the differential diagnosis for chest pain and ST-segment elevation on the ECG can lead to false-positive diagnoses of STEMI that can only be excluded by coronary angiography.

Some have been previously discussed, such as localized pericarditis/ myocarditis, Takotsubo cardiomyopathy, left ventricular aneurysm, and LBBB. Others include:

abnormalities •

Pulmonary embolism

•

Brugada syndrome

•

Hypothermia

•

Hyperkalemia, hypercalcemia

Figure 1: Time from Initial ECG to Follow-up Diagnostic ECG in Patients with ST-segment Elevation Myocardial Infarction with an Initial Non-diagnostic ECG 10

33.5 % (N=1,528) diagnosed by 30 minutes Median: 46.0 (24.0, 101.0) minutes

8

% diagnosed

60.0 % (N=2,740) diagnosed by 60 minutes

6

72.4% (N=3,305) diagnosed by 90 minutes 78.6 % (N=3,589) diagnosed by 120 minutes

4

2

0 0

5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 95 100105110115120

Time from initial ECG to diagnostic ECG (minutes) ECG = electrocardiogram. Source: Riley, et al.17 Reproduced with permission from Elsevier © 2013.

depending on the diagnostic modalities (cardiac MRI, etc.) available to the practitioner. Takotsubo (stress-induced) cardiomyopathy is another clinical presentation that can be confused with STEMI. These patients often present after a stressful event, which can also predispose to acute plaque ruptures. The clinical symptoms and ECG findings can be similar between the two entities, so these patients are often referred emergently to the cardiac catheterization lab and the diagnosis is one of exclusion.

Transient ST elevation and Wellens’ T waves also represent spectrums along the ACS spectrum, but do not definitively represent transmural myocardial infarctions and are not always managed with emergent reperfusion. These examples illustrate that, while the diagnosis of STEMI can appear objectively straightforward, there is a degree of clinical subjectivity in symptom assessment correlating with the ECG findings.

In fact, prior data have shown that the sensitivity and specificity of distinguishing a true transmural infarct by ECG in the absence of clinical data were 65 % and 79 %, respectively, with an inter-reader agreement (kappa) of 0.33, reflecting poor reader agreement.11 These data suggest

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that it is paramount to integrate the ECG data with the clinical scenario instead of solely focusing on the metrics such as door-to-balloon times, possibly compromising the ability to evaluate non-coronary etiologies of ST-segment elevation on the ECG.12,13

• pulmonary embolism, which can present with ST-segment elevation in the anterior leads with T wave inversion; • Prinzmetal’s (variant) angina, which can present similarly to STEMI but will have normal-to-mild disease in the major epicardial coronary arteries, with coronary spasm elucidated on provocative testing; • spontaneous coronary dissection, which presents similarly to STEMI but shows a dissection flap causing cessation of coronary flow instead of a thrombotic lesion and is commonly seen in young, pregnant women; • hypothermia (temperature of <34 °C), which causes elevation of the J point (as opposed to the ST-segment), producing a characteristic ’J or Osborn wave’ with elevation of the J point correlating to the degree of hypothermia; and finally • electrolyte disturbances or Brugada pattern/syndrome, all of which have associated ECG abnormalities along with the ST-segment changes that are classic to the particular diagnosis.

Initial Versus Subsequent ECG Diagnosis Electrocardiographic findings during AMI can vary substantially depending on the type, stage, and extent of infarction and timing of the ECG acquisition.14–16 A study published from the National Cardiovascular Data Registry (NCDR) Acute Coronary Treatment and Intervention Outcomes Network (ACTION)-Get With the Guidelines (GWTG) database17 that evaluated 41,560 subjects from 432 sites from across the US found that 11.0 % of subjects ultimately diagnosed with STEMI had an initial non-diagnostic ECG, with a diagnostic ECG being obtained within 90 minutes in 72.4 % of this group. Times from initial non-diagnostic ECG to ECG diagnostic of STEMI in this group can be seen in Figure 1.

When clinical characteristics of those patients with initial diagnostic ECG versus those with subsequent diagnostic ECGs were evaluated, it was found that there was no significant difference in time of the ECG acquisition to symptom onset or coronary artery disease risk factors.

The authors concluded that ECG surveillance during the evaluation of ACS is warranted. However, determining which patients with an initial non-diagnostic ECG need additional ECG surveillance could not be ascertained from patient comorbidities or presentation characteristics alone. In addition, although this study did not provide evidence for the optimal timing of follow-up ECGs in this patient group, it is noteworthy that 72.4 % of patients with STEMI with an initial non-diagnostic ECG had a diagnostic ECG within 90 minutes of their initial ECG, providing at least a framework of when to obtain follow-up ECGs. Similar studies have shown that changes on serial 12-lead ECG evaluation (ST-segment elevation and/or depression, T wave inversion, development of Q waves) are more sensitive and specific than a single initial ECG alone

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Challenges in ST-segment Elevation Myocardial Infarction Diagnosis for the detection of ACS.18–21 Additionally, several studies evaluating patients with suspected ACS have found that changes on continuous ST-segment monitoring during the first few hours of evaluation were independently associated with cardiac death or AMI at 30 days.22,23 Therefore, both the American College of Emergency Physicians (ACEP) and the American College of Cardiology (ACC)/American Heart Association (AHA) currently recommend serial ECG monitoring in patients being evaluated for ACS (class IB recommendation).24,25 However, given the increased diagnostic accuracy of novel troponin assays for ACS, it is no longer clear whether serial ECGs are a necessary component of the workup of ACS. The Are Serial Electrocardiograms Additive to Serial Second-generation Troponins in Predicting Acute Coronary Syndromes in Patients with Undifferentiated Chest Pain (ASAP CATH) study (ClinicalTrials.gov identifier NCT01953276) is a prospective cohort study designed to answer this question. This study finished enrollment in 2015 and should publish results in the coming year.26

Impediments to Rapid Diagnosis Despite the ambiguity surrounding certain components of the diagnosis of STEMI, clinical assessment and ECG evaluation together are very sensitive for the diagnosis, with a miss rate of less than 5 % in Emergency Departments (EDs) across the US, though admittedly, miss rates are tremendously difficult to determine as they only incorporate missed patients who do not stay ’missed’.27 However, outcomes for patients with STEMI are driven in large part by not only making a definitive diagnosis, but also by making it in a timely manner (i.e. ‘symptom-to-device time’). A 2011 observational study from the ACTION Registry-GWTG reported that emergency medical services (EMS) transport was used for only 60 % of patients with STEMI, despite the significant positive correlation between arrival to an ED by ambulance (versus other transportation method) and faster times to reperfusion therapy.28 The importance of EMS involvement

1.

2.

3.

4.

5.

6.

7.

8.

9.

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Mozaffarian D, Benjamin EJ, Go AS, et al. Heart disease and stroke statistics--2015 update: a report from the American Heart Association. Circulation 2015;131 :e29–322. DOI: 10.1161/ CIR.0000000000000152; PMID: 25520374 Yeh RW, Sidney S, Chandra M, et al. Population trends in the incidence and outcomes of acute myocardial infarction.

N Engl J Med 2010;362 :2155–65. DOI: 10.1056/NEJMoa0908610; PMID: 20558366 Riley RF, Don CW, Powell W, et al. Trends in coronary revascularization in the United States from 2001 to 2009: recent declines in percutaneous coronary intervention volumes.

Circ Cardiovasc Qual Outcomes 2011;4 :193–7. DOI: 10.1161/ CIRCOUTCOMES.110.958744; PMID: 21304092 Peterson ED, Shah BR, Parsons L, et al. Trends in quality of care for patients with acute myocardial infarction in the National Registry of Myocardial Infarction from 1990 to 2006.

Am Heart J 2008;156 :1045–55. DOI: 10.1016/j.ahj.2008.07.028; PMID: 19032998 Hasdai D, Behar S, Wallentin L, et al. A prospective survey of the characteristics, treatments and outcomes of patients with acute coronary syndromes in Europe and the Mediterranean basin; the Euro Heart Survey of Acute Coronary Syndromes (Euro Heart Survey ACS). Eur Heart J 2002;23 :1190–201.

PMID: 12127921 Thygesen K, Alpert JS, White HD; Joint ESC/ACCF/AHA/WHF Task Force for the Redefinition of Myocardial Infarction. Universal definition of myocardial infarction. Eur Heart J 2007;28 :2525–38.

PMID: 17951287 Thygesen K, Alpert JS, Jaffe AS, et al. Third universal definition of myocardial infarction. Circulation 2012;126 :2020–35.

DOI: 10.1161/CIR.0b013e31826e1058; PMID: 22923432 Tabas JA, Rodriguez RM, Seligman HK, Goldschlager NF. Electrocardiographic criteria for detecting acute myocardial infarction in patients with left bundle branch block: a metaanalysis. Ann Emerg Med 2008;52 :329–36.e1. DOI: 10.1016/j.

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in diagnosing STEMI was also illustrated by several studies that showed that the performance of pre-hospital ECGs by EMS was associated with shorter reperfusion time and lower mortality rates from STEMI. The use of pre-hospital ECGs, particularly when coupled with communication of STEMI diagnosis and preferential transport to a percutaneous coronary intervention (PCI)-capable hospital, has been shown to result in rapid reperfusion times and improved clinical outcomes.29 Unfortunately, pre-hospital diagnoses remain relatively infrequent, in part because roughly half of all STEMI patients self-present to the ED, thereby obviating the opportunity for a pre-hospital diagnosis.30 For patients without a confirmed pre-hospital diagnosis, data suggests that establishing a STEMI diagnosis within 20 minutes maintains a strong correlation with door-to-treatment times <90 minutes and that this diagnostic period is far more heterogeneous than the other aspects of primary PCI.31 Thus, many initiatives have been implemented on local and national levels to address the importance of early STEMI diagnosis such as the ‘Door-to-Balloon’ (D2B) Alliance and the AHA’s ‘Mission: Lifeline’ program, which have resulted in significant improvements in symptom-to-treatment times and increased use of pre-hospital ECG evaluation for STEMI.32 Centers for Medicare and Medicaid Services (CMS) has also started altering their reimbursement based on this metric. As part of the ‘door-to-treatment’ push, ‘door-to-ECG’ time has been increasingly emphasized.

Conclusion STEMI is an important diagnosis to make in a timely fashion due to its associated morbidity and mortality. Despite relatively codified definitions for the diagnosis, there remains some clinical subjectivity in the diagnostic components, including both the specific ECG findings and the timing of ECG testing. However, there have been large-scale improvements in symptom onset-to-diagnosis-to-treatment windows that have led to improvements in outcomes in this patient group. n

annemergmed.2007; PMID: 18342992 10. Costantini M, Tritto C, Licci E, et al. Myocarditis with ST-Elevation Myocardial Infarction presentation in young man. A case series of 11 patients. Int J Cardiol 2005;101:157–8. PMID: 15860403 11. McCabe JM, Armstrong EJ, Ku I, et al. Physician accuracy in interpreting potential ST-segment elevation myocardial infarction electrocardiograms. J Am Heart Assoc 2013;2 :e000268.

DOI: 10.1161/JAHA.113.000268; PMID: 24096575 12. McCabe JM, Armstrong EJ, Kulkarni A, et al. Prevalence and factors associated with false-positive ST-segment elevation myocardial infarction diagnoses at primary percutaneous coronary intervention–capable centers: a report from the activate-sf registry. Arch Intern Med 2012;172 :864–71.

DOI: 10.1001/archinternmed.2012.945; PMID: 22566489 13. Fanari Z, Abraham N, Kolm P, et al. Aggressive Measures to Decrease “Door to balloon” Time and Incidence of Unnecessary Cardiac Catheterization: Potential Risks and Role of Quality Improvement. Mayo Clin Proc 2015;90 :1614–22. DOI: 10.1016/j. mayocp.2015.08.021; PMID: 26549506 14. Karlson BW, Herlitz J, Wiklund O, et al. Early prediction of acute myocardial infarction from clinical history, examination and electrocardiogram in the emergency room. Am J Cardiol 1991;68 :171–5. PMID: 2063777 15. McQueen MJ, Holder D, El-Maraghi NR. Assessment of the accuracy of serial electrocardiograms in the diagnosis of myocardial infarction. Am Heart J 1983;105 :258–61. PMID: 6823807 16. Nowakowski JF. Use of cardiac enzymes in the evaluation of acute chest pain. Ann Emerg Med 1986;15 :354–60. PMID: 3511799 17. Riley RF, Newby LK, Don CW, et al. Diagnostic time course, treatment, and in-hospital outcomes for patients with ST-segment elevation myocardial infarction presenting with nondiagnostic initial electrocardiogram: a report from the American Heart Association Mission: Lifeline program. Am Heart J 2013;165 :50–6. DOI: 10.1016/j.ahj.2012.10.027; PMID: 23237133 18. Hedges JR, Young GP, Henkel GF, et al. Serial ECGs are less accurate than serial CK-MB results for emergency department diagnosis of myocardial infarction. Ann Emerg Med 1992;21 :1445– 50. PMID: 1443839

19. Fesmire FM, Percy RF, Bardoner JB, et al. Usefulness of automated serial 12-lead ECG monitoring during the initial emergency department evaluation of patients with chest pain.

Ann Emerg Med 1998;31 :3–11. PMID: 9437335 20. Carmo P, Ferreira J, Aguiar C, et al. Does continuous ST-segment monitoring add prognostic information to the TIMI, PURSUIT, and GRACE risk scores? Ann Noninvasive Electrocardiol 2011;16: 239– 49. DOI: 10.1111/j.1542-474X.2011.00438.x; PMID: 21762251 21. Yan AT, Yan RT, Tan M, et al. Long-term prognostic value and therapeutic implications of continuous ST-segment monitoring in acute coronary syndrome. Am Heart J 2007;153 :500–6.

PMID: 17383285 22. Jernberg T, Lindahl B, Wallentin L. The combination of a continuous 12-lead ECG and troponin T; a valuable tool for risk stratification during the first 6 hours in patients with chest pain and a non-diagnostic ECG. Eur Heart J 2000;21 :1464–72.

PMID: 10952839 23. Nørgaard BL, Andersen K, Dellborg M, et al. Admission risk assessment by cardiac troponin T in unstable coronary artery disease: additional prognostic information from continuous ST segment monitoring. TRIM study group. Thrombin Inhibition in Myocardial Ischemia. J Am Coll Cardiol 1999;33 :1519–27.

PMID: 10334417 24. Fesmire FM, Decker WW, Diercks DB, et al. Clinical policy: critical issues in the evaluation and management of adult patients with non-ST-segment elevation acute coronary syndromes. Ann Emerg Med 2006;48 :270–301. PMID: 16934648 25. Anderson JL, Adams CD, Antman EM, et al. 2011 ACCF/AHA Focused Update Incorporated into the ACC/AHA 2007 Guidelines for the Management of Patients With Unstable Angina/Non-STElevation Myocardial Infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 2011;123 :e426–579. DOI: 10.1161/CIR.0b013e318212bb8b; PMID: 21444888 26. Riley RF MC, Russell GB, Soliman EZ, et al. Are serial electrocardiograms additive to serial second-generations troponins in predicting acutecoronary syndromes in patients with undifferentiated chest pain (ASAP CATH) study. In:

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Acute Coronary Syndromes ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000-2016/02/01. Available at: www.clinicaltrials. gov/ct2/show/NCT01953276 (May 12, 2016).

27. Pope JH, Aufderheide TP, Ruthazer R, et al. Missed diagnoses of acute cardiac ischemia in the emergency department.

N Engl J Med 2000;342 :1163–70. PMID: 10770981 28. Mathews R, Peterson ED, Li S, et al. Use of emergency medical service transport among patients with ST-segmentelevation myocardial infarction: Findings from the National Cardiovascular Data Registry Acute Coronary Treatment Intervention Outcomes Network Registry-Get With The Guidelines. Circulation 2011;124 :154–63. DOI: 10.1161/

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CIRCULATIONAHA.110.002345; PMID: 21690494 29. Ting HH, Krumholz HM, Bradley EH, et al. Implementation and integration of prehospital ECGs into systems of care for acute coronary syndrome: a scientific statement from the American Heart Association Interdisciplinary Council on Quality of Care and Outcomes Research, Emergency Cardiovascular Care Committee, Council on Cardiovascular Nursing, and Council on Clinical Cardiology. Circulation 2008;118 :1066–79. DOI: 10.1161/ CIRCULATIONAHA.108.190402; PMID: 18703464 30. Bagai A, Jollis JG, Dauerman HL, et al. Emergency department bypass for ST-segment-elevation myocardial infarction patients identified with a prehospital electrocardiogram:

a report from the American Heart Association Mission: Lifeline program. Circulation 2013;128 :352–9. DOI: 10.1161/ CIRCULATIONAHA.113.002339; PMID: 23788525 31. McCabe JM, Armstrong EJ, Hoffmayer KS, et al. Impact of door-to-activation time on door-to-balloon time in primary percutaneous coronary intervention for st-segment elevation myocardial infarctions: a report from the Activate-SF registry.

Circ Cardiovasc Qual Outcomes 2012;5 :672–9. PMID: 22949494 32. Willson AB, Mountain D, Jeffers JM, et al. Door-to-balloon times are reduced in st-elevation myocardial infarction by emergency physician activation of the cardiac catheterisation laboratory and immediate patient transfer. Med J Aust 2010;193 :207–12.

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