USC 10.1 by Radcliffe Cardiology

Volume 10 • Issue 1 • Spring 2016 • RELAUNCH ISSUE

www.USCjournal.com

Promising New Therapies in Heart Failure: Ivabradine and the Neprilysin Inhibitors Michelle Kittleson, MD, PhD

Ischemic Complications of Pregnancy: Who is at Risk? Sara C Martinez, MD, PhD and Sharonne N Hayes, MD

Optimizing Heart Rate and Controlling Symptoms in Atrial Fibrillation Pragnesh Parikh, MD and KL Venkatachalam, MD

Public Reporting of Cardiovascular Data: Benefits, Pitfalls, and Vision for the Future Gregory J Dehmer, MD, MACC, MSCAI, FAHA, FACP

SNS

Adrenaline Noradrenaline

,β1,β2 receptors

→ → →→

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RAAS Inhibitors

ACEI, ARB, MRA Neurohormal systems Left coronary artery Angiotensin II → right AT1 receptor in heartNeprilysin failure in the anterioroblique projection

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Vasodilatation Blood pressure Sympathetic tone Inactive Vasopressin fragments Aldosterone Hypertrophy Fibrosis Natriurersis/diuresis

Electrocardiogram rhythm strips

ARNIs Vasoconstriction Blood pressure Sympathetic tone Aldosterone Hypertrophy Fibrosis

→ → →→ →

→

→ → →→ → → →

}

Vasoconstriction Heart rate Contractility RAAS activity Vasopressin

NPS NP receptors

β blockers

Radcliffe Cardiology

Lifelong Learning for Cardiovascular Professionals

WHY YOU SHOULD CONNECT WITH THE EUROPEAN SOCIETY OF CARDIOLOGY

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Volume 10 • Issue 1 • Spring 2016

www.USCjournal.com

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

Ralph G Brindis, MD, MPH

University of California, San Francisco, CA

Todd M Brown, MD, MSPH

University of Alabama at Birmingham, Birmingham, AL

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 • Senior Designer Tatiana Losinska Digital Commercial Manager Ben Sullivan • New Business & Partnership Director Rob Barclay 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

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Published by Radcliffe Cardiology. All information obtained by Radcliffe Cardiology and each of the contributors from various sources is as current and accurate as possible. However, due to human or mechanical errors, Radcliffe Cardiology and the contributors cannot guarantee the accuracy, adequacy or completeness of any information, and cannot be held responsible for any errors or omissions, or for the results obtained from the use there of. Where opinion is expressed, it is that of the authors and does not necessarily coincide with the editorial views of Radcliffe Cardiology. Statistical and financial data in this publication have been compiled on the basis of factual information and do not constitute any investment advertisement or investment advice. Radcliffe Cardiology, Unit F, First Floor, Bourne End Business Park, Cores End Road, Bourne End, Buckinghamshire, SL8 5AS © 2016 All rights reserved ISSN: 1758-3896 • eISSN: 1758-390X

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Established: March 2016 Frequency: Bi-annual Current issue: Spring 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.

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

Submissions and Instructions to Authors

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

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

Editorial Expertise

Reprints

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

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

Structure and Format

Peer Review • On submission, all articles are assessed by the Editor-in-Chief to determine their suitability for inclusion. • The Commissioning Editor, following consultation with the Editor-in-Chief, and/or a member of the Editorial Board, sends the manuscript to members of the Peer Review Board, who are selected on the basis of their specialist knowledge in the relevant area. All peer review is conducted double-blind. • Following review, manuscripts are either accepted without modification, accepted pending modification, in which case the manuscripts are returned to the author(s) to incorporate required changes, or rejected outright. The Editor-in-Chief reserves the right to accept or reject any proposed amendments.

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

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

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

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Publisher’s Welcome Letter

Liam O’Neill Publishing Director, Radcliffe Cardiology

Dear Readers, On behalf of us all at Radcliffe Cardiology, it is with great pleasure that I introduce the relaunch issue of US Cardiology Review (USC), the first under our ownership. Despite being a UK-based publisher, Radcliffe Cardiology has enjoyed a great deal of support from the cardiology community throughout the United States with a high percentage of editorial board members, authors and peer-reviewers for our journals residing in the US. More than 50 % of our website traffic constitutes US physicians, resulting in nearly 30,000 cardiologists being part of our readership database. Therefore, it seemed logical with these high levels of engagement to publish a review journal focused purely on topical issues occurring within the cardiovascular ecosystem in America. We are both honoured and delighted that Professor Donald E Cutlip has accepted the role as Editor-inChief of the USC journal. To have a physician of his standing steering our editorial quality can only be of benefit to everyone involved with the journal, and we are very much looking forward to a long working relationship together. You can read Professor Cutlip’s foreword to this issue on page 6. We are also thankful to the esteemed editorial board members for their continued support of the journal and involvement in this relaunched issue. Their guidance has been invaluable in shaping this issue. We would also like to thank all of the authors who have contributed to this issue for their excellent manuscripts, each of which provides a valuable contribution to existing published literature. As readers, we hope that USC journal will be of benefit for your continued learning and treatment of your patients.

Yours sincerely, Liam O’Neill Publishing Director

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Contents

Foreword Donald E Cutlip, MD

Heart Failure

New Therapies

8 Promising New Therapies in Heart Failure: Ivabradine and the Neprilysin Inhibitors

Michelle Kittleson, MD, PhD

Pregnancy and Coronary Ischemia

1 4 Ischemic Complications of Pregnancy: Who is at Risk? Sara C Martinez, MD, PhD and Sharonne N Hayes, MD

Electrophysiology

Stroke Prevention

2 1

Emerging Strategies for Stroke Prevention in Atrial Fibrillation

Praveen Rao, MD, Olusegun Olusesi, MD and Mitchell Faddis, MD, PhD

Atrial Fibrillation Management

2 6

Optimizing Heart Rate and Controlling Symptoms in Atrial Fibrillation

Pragnesh Parikh, MD and KL Venkatachalam, MD

Venous Thromboembolic

3 0

Advanced Management Options for Massive and Submassive Pulmonary Embolism

Sonika Malik, MD, Anju Bhardwaj, MD, Matthew Eisen, MD and Sanjay Gandhi, MD

Quality and Outcomes

36 Public Reporting of Cardiovascular Data: Benefits, Pitfalls, and Vision for the Future Gregory J Dehmer, MD, MACC, MSCAI, FAHA, FACP

Guest Editorial

4 1

T he Use of Social Media In Cardiovascular Medicine

Kevin R Campbell, MD, FACC

Expert Opinion

4 3

Information Technology Data Standards in Cardiology: What, Why, and How Come

H Vernon Anderson, MD, FACC, FSCAI

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ÂŠ RADCLIFFE CARDIOLOGY 2016

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3 RD WORLD CONGRESS ON ACUTE HEART FAILURE 21-24 May Florence, Italy

Heart Failure: state of the art

21 March 18 April

Congress Key Figures 4 days of scientific exchange 4 700+ healthcare professionals from 90+ countries 1 700+ abstracts and clinical cases submitted 2 000+ m2 of exhibition 100+ scientific sessions 300+ international expert faculty members 40+ industry sessions and workshop

www.escardio.org/HFA

HFA2016-US LETTER.indd 1

#heartfailure2016

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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 is my pleasure to welcome you to the inaugural issue of the relaunch for US Cardiology Review. I am excited to take on the role of Editor in Chief and look forward to working with an outstanding

editorial board (see page 1) and staff to meet our mandate of providing timely and informative reviews and expert perspectives on current topics within the broad field of cardiovascular medicine. Cardiology practice is challenged by rapid evolution based on accumulating evidence as well as a need for guidance in areas where evidence is incomplete. While there are a number of reliable formats for presenting new evidence, textbooks for review of historical data and basic mechanisms, and newer electronic formats for providing timely and efficient summaries, there is inadequate availability of reviews that are both detailed and timely. Within the topics selected, the semiannual publication hopes to offer advantages to both traditional textbooks, by providing the most contemporary presentations, as well as the various dynamic electronic formats, by providing more detail on the current evidence and historical perspective. It is our hope that the format of US Cardiology Review, directed to a target audience of general cardiologists, will be a valuable clinical tool for optimizing patient care and clinical practice. By way of brief description, all articles published have been commissioned from or submitted by experts within a topic of interest and reviewed by established peers with expertise in the specific area.

Only original work that is produced entirely by listed authors who are fully accountable for all content is considered. In this relaunch issue we have commissioned several topical reviews and an expert perspective series. Dr Kittleson (page 8) leads with a discussion of the pathophysiologic basis for guideline directed pharmacologic management of chronic heart failure and dives deeply into the mechanisms and data supporting the use of two recently approved agents, the selective sino-atrial nodal inhibitor, ivradipine; and the combination of the neprilysin inhibitor, sacubitril, and the angiotensin receptor blocker, valsartan. Drs Martinez and Hayes (page 14) follow with a review of the ischemic complications of pregnancy, highlighting the risk factors and the acute and long-term management.

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Foreword

This is followed by two timely reviews related to management of atrial fibrillation. Dr Rao and colleagues (page 21) review current and emerging strategies for stroke prevention, including data for left atrial occlusion, and Drs Parikh and Venkatachalum provide a detailed discussion of rate control and other options for controlling symptoms (page 26). In the final review article, Dr Malik and colleagues (page 30) present a detailed review of risk stratification and contemporary management options for massive and sub-massive pulmonary embolus. This issue concludes with a series on data quality and outcomes as they impact cardiology practice. Dr Dehmer (page 36) provides an authoritative analysis of the benefits and pitfalls for public reporting of outcome data. This is especially timely as cardiology and other specialties seek guidance for measuring and rewarding high-quality care. Dr Campbell (page 41) follows with an editorial perspective on the use of social media by cardiologists and our patients for a transformation of clinical care. As he notes, these are valuable tools that are being used increasingly by emerging physicians and that more senior physicians may have to learn. Finally, Dr Anderson (page 43) presents a valuable discussion of data standards and the work of our professional societies to develop these concepts for optimal utilization of the vast amount of information we wish to record and monitor. I hope this first issue gives a flavor of the journalâ&#x20AC;&#x2122;s aims to offer timely reviews of routine practice clinical issues and perspectives on clinical and non-clinical issues that present a variety of challenges and opportunities. I trust you will find the selected papers valuable for your practice and that they will provide incentive for discussions of improving quality of care for your patients. n

US CARDIOLOGY REVIEW

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Heart Failure New Therapies

LE ATION.

Promising New Therapies in Heart Failure: Ivabradine and the Neprilysin Inhibitors M i c h e l l e Ki t t l e s o n , M D, P h D Division of Cardiology, Department of Internal Medicine, Cedars-Sinai Heart Institute, Los Angeles, CA

Abstract Current guideline-directed medical therapy for heart failure (HF) is a triumph of translation medicine. An understanding of neurohormonal activation, translated into medications to block these maladaptive systems, has culminated in improved quality of life and survival for patients with HF. The most effective drug therapies for chronic systolic HF are those that inhibit the activity of the sympathetic nervous system (SNS) and renin angiotensin aldosterone system (RAAS). These agents include the beta-blockers to inhibit SNS activity and the angiotensinconverting enzyme inhibitors (Aces), angiotensin II type 1 receptor blockers (ARBs), and mineralocorticoid receptor antagonists (MRA) to act on the RAAS pathway. Two new HF medications have recently been approved and represent a deepened understanding of neurohormonal mechanisms in HF. The first is ivabradine, which inhibits the funny current of the sinoatrial node and lowers heart rate without reducing contractility. In patients already on maximally tolerated beta-blocker dosages, ivabradine reduces the risk of HF hospitalization. The second medication is sacubitril combined with valsartan, which takes advantage of the natriuretic peptide system and other endogenous vasoactive peptides. Sacubitril, a neprilysin inhibitor, increases vasoactive peptide levels resulting in beneficial effects in HF. The angiotensin receptorneprilysin inhibitor combination sacubitril/valsartan is superior enalapril in reducing death and HF hospitalizations. This review article provides an overview of guideline-directed medical therapy in HF. It highlights the mechanisms of these two new HF agents and their pivotal clinical trials and offers practical advice for prescribing these medications to HF patients.

Keywords Heart failure, ivabradine, neprilysin inhibitor, sacubitril Disclosure: The author has no conflicts of interest to declare. Received: January 12, 2016 Accepted: January 21, 2016 Citation: US Cardiology Review, 2016;10(1):8–13 Correspondence: Michelle Kittleson, Associate Professor of Medicine, 8536 Wilshire Blvd Suite 301, Beverly Hills, CA 90211, USA. E: michelle.kittleson@cshs.org

Decades ago heart failure (HF) was primarily regarded as a hemodynamic disorder in an attempt to explain patients’ symptoms and disability. This hemodynamic model led to the widespread evaluation of peripheral vasodilators (to increase cardiac output by decreasing systemic vascular resistance against the failing heart). It also led to the development of novel positive inotropic agents (to directly increase cardiac output). Long-term use of these drugs failed to improve symptoms and was frequently accompanied by an increase in the risk of death.1–3 These clinical observations raised concerns about the validity of the hemodynamic hypothesis and led to the development of alternative models of HF—most importantly, the neurohormonal hypothesis. It is now well understood that chronic HF is associated with a complex pattern of neurohormonal activation that contributes to the relentless progression of this fatal syndrome.4 The theme of these systems is that initially beneficial mechanisms are ultimately maladaptive. The activation of the sympathetic nervous system (SNS) and the renin-angiotensinaldosterone system (RAAS) initially cause vasoconstriction and fluid retention to maintain perfusion in the face of a falling cardiac output

Kittleson_FINAL.indd 8

from the failing heart. While effective in the short term, the long-term effects of SNS and RAAS activation are adverse cardiac remodeling leading to progressive cardiac dilatation and further dysfunction of the failing heart (see Figure 1). The current guideline-directed medical therapy for HF is, in essence, a triumph of translation medicine. An understanding of this neurohormonal activation, translated into medications to block these maladaptive systems, has culminated in improved quality of life (QoL) and survival for patients with HF.5 The most effective drug therapies for chronic systolic HF are those that inhibit the activity of the SNS and RAAS. These agents include the beta-blockers to inhibit SNS activity and the angiotensin-converting enzyme inhibitors (ACEIs), angiotensin II type 1 receptor blockers (ARBs), and mineralocorticoid receptor antagonists (MRA) to act on the RAAS pathway. Recently, however, two new promising therapies for HF have emerged: ivabradine and the neprilysin inhibitors. Each capitalizes on the current paradigm of neurohormonally-focused therapies to improve outcomes in HF patients. This article will review the current management of HF patients

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Promising New Therapies in Heart Failure Figure 1: Neurohormal Systems in Heart Failure SNS

Guideline-directed Medical Therapy for Heart Failure

Adrenaline Noradrenaline

RAAS Blockers

→

The role of beta-blockers in the management of HF is an even more extraordinary example of the power of translation medicine. While one could understand the benefit of ACEIs or ARBs on a hemodynamic as well as neurohormonal level, accepting the benefit of a negative inotrope in the survival of HF patients truly required an acceptance of the maladaptive consequences of SNS activation. The most striking of all the beta-blocker trials in HF is the Carvedilol Prospective Randomized Cumulative Survival trial (COPERNICUS), which randomized patients with ambulatory NYHA Class IV symptoms and ejection fraction (EF) <25 % to carvedilol or placebo, on the background of treatment with ACEI. In 2,289 patients followed for less than a year, there was a 35 % reduction in mortality. Thus, not only did the most advanced HF patients tolerate beta-blockade in this trial, they also derived survival benefit from it. The benefit of beta-blockers has also been shown in less severe HF17,18 and HF after acute myocardial infarction.19

→

Beta-blockers

,β1,β2 receptors

→ → → →

Natriuretic peptides

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In multiple trials to follow, the benefit of ACEIs has been demonstrated in patients with less symptomatic HF,7,8 asymptomatic HF,9 and HF after an acute myocardial infarction.10 The trials of ARBs have been less definitive. While ARBs are clearly better than placebo,11 they do not appear superior to ACEIs for patients with HF.12 The combination of ACEI and ARB results in adverse effects of hypotension and hyperkalemia.13 However, the MRAs spironolactone and eplerenone have shown great promise in HF patients. The rationale behind the use of MRAs is that although ACEIs reduce the secretion of aldosterone, an “escape” phenomenon may occur and, in addition, aldosterone secretion is also independently controlled by serum potassium concentration and corticotrophin. The benefits of MRAs in addition to ACEIs have been shown in patients with severe symptomatic HF,14 less symptomatic HF,15 and HF after acute myocardial infarction.16

}

Vasoconstriction Heart rate Contractility RAAS activity Vasopressin

NPS NP receptors

→ → → → → →

In the current era it is difficult to imagine a time when ACEIs were not standard of care for HF patients. However, prior to the publication of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS) in 1987, this was not the case. In the landmark CONSENSUS trial,6 patients with New York Heart Association (NYHA) Class IV symptoms were randomized to enalapril or placebo. The trial was terminated early after 253 patients had been randomized and an average follow-up of 188 days. Six-month mortality in the enalapril group was 26 % compared with 44 % in the placebo group, giving a relative risk-reduction of 40 % (P=0.002). At 1 year these proportions were 36 and 52 % (P=0.001). While the trial is decades old, these figures are important to consider; the placebo group mortality highlights the dreadful prognosis in patients with severely symptomatic HF before the advent of modern disease-modifying therapies.

β blockers

Vasodilatation Neprilysin Blood pressure X Sympathetic tone Inactive Vasopressin fragments Aldosterone Hypertrophy Fibrosis Natriurersis/diuresis

RAAS

RAAS Inhibitors ACEI, ARB, MRA

Angiotensin II → AT1 receptor X ARNIs Vasoconstriction Blood pressure Sympathetic tone Aldosterone Hypertrophy Fibrosis

→ → → → →

and provide insight into the rationale behind these two new promising therapies for HF.

Sacubitril-valsartan is the first-in-class ARNI—a drug that combines inhibition of the angiotensin-1 receptor (AR) with neprilysin inhibition (NI). Angiotensin-converting enzyme (ACE) activity is unaffected, allowing endogenous bradykinin to be metabolized to inactive metabolites. ACEI = ACE inhibitor; ARB = angiotensin receptor blocker; MRA = mineralocorticoid antagonist; NP = natriuretic peptides; NPS = natriuretic peptide system; SNS = sympathetic nervous system; RAAS = renin angiotensin aldosterone system. Reprinted from Macdonald PS. Combined angiotensin receptor/neprilysin inhibitors: a review of the new paradigm in the management of chronic heart failure. Clin Ther 2015;37:2199.23 Copyright (2015), with permission from Elsevier.23

in patients with coronary disease and left ventricular dysfunction (BEAUTIFUL) trial comprising patients who were aged 55 and older with coronary artery disease and EF <40 % there was a strong correlation between elevated baseline resting heart rate and mortality. A baseline resting heart rate of <70 beats per minute (bpm) was associated with an increased 34 % increased risk of cardiovascular death and a 53 % increased risk of HF admission. Furthermore, for every increase of 5 bpm in baseline resting heart rate, there was an 8 % increase in cardiovascular death and a 16 % increase in admission to hospital for HF (P<0.0001).20 Similar results were demonstrated in a meta-analysis of beta-blocker HF trials including almost 23,000 patients.21 Of course, an association between lower heart rate in HF patients taking an evidence-based beta-blocker and survival does not imply causation: does a lower heart rate result in improved survival, or is a lower heart rate simply a marker of better prognosis? In addition, up-titration of beta-blockers in HF patients may be limited by hypotension and fatigue from the acute negative inotropic effects. However, a medication that could lower heart rate without affecting contractility would be the perfect test to this hypothesis. Ivabradine, through the Systolic Heart failure treatment with the lf inhibitor ivabradine Trial (SHIFT) study, has provided an opportunity to do so.

Ivabradine Effect of Heart Rate on Survival

The SHIFT Study

While beta-blockers are clearly beneficial in HF patients, there is evidence that the degree of heart rate lowering affects survival. In a subgroup analysis of the Morbidity-mortality Evaluation of the lf inhibitor ivabradine

Ivabradine is a selective inhibitor of the hyperpolarization-activated cyclic-nucleotide-gated funny current (involved in pacemaker-generation and responsiveness of the sinoatrial node, which results in heart-rate

US CARDIOLOGY REVIEW

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Heart Failure New Therapies

Patients with first hospital admission for worsening heart failure (%)

Patients with primary composite endpoint (%)

Figure 2: Outcomes in the SHIFT Study

Months Placebo (937 events)

2868 2928 Patients with cardiovascular death (%)

Ivabradine (514 events)

HR 0.82 (95% [Cl 0.75-0.90]) P<0.0001

3264 3241

Placebo (672 events)

Ivabradine (793 events)

Number at risk Placebo group Ivabradine group

18 Months

HR 0.74 (95% [Cl 0.56–0.83]) P<0.0001

2489 2600

2061 2173

1089 1191

439 447

3264 3241

2868 2928

2489 2600

2061 2173

1089 1191

439 447

Months Placebo (491 events) Ivabradine (449 events) HR 0.91 (95% [Cl 0.80–1.03]) P=0.128 Number at risk Placebo group Ivabradine group

3262 3241

3094 3085

2817 2818

2391 2428

1318 1376

534 531

Kaplan-Meier cumulative event curves for (A) the primary composite endpoint of cardiovascular death or hospital admission for worsening heart failure; (B) hospital admission for worsening heart failure; and (C) cardiovascular death. Ivabradine and outcomes in chronic heart failure (SHIFT) study. Reprinted from Swedberg K, et al. Ivabradine and outcomes in chronic heart failure (shift): a randomised placebo controlled study. Lancet 2010;376:875.22 Copyright (2010), with permission from Elsevier.22

reduction with no other apparent direct cardiovascular effects. Thus, ivabradine decreases heart rate without decreasing contractility. In the SHIFT study, 6,558 patients with EF ≤35 %, heart rate ≥70 bpm, at least one HF hospitalization, and taking maximally-tolerated beta-blockers were randomly assigned to ivabradine or placebo. Over almost a 2-year follow-up, ivabradine resulted in a significant reduction in the primary endpoint of cardiovascular death or hospital admission for worsening HF, which was mainly driven by reductions in hospitalizations for HF. HF hospitalization was 21 % in the placebo group and 16 % in the ivabradine group (see Figure 2).22

Prescribing Considerations for Ivabradine In April 2015 the US Food and Drug Administration (FDA) granted approval of ivabradine (Corlanor®). It was approved for use to reduce

Kittleson_FINAL.indd 10

the risk of hospitalization for worsening HF in patients with stable, symptomatic chronic HF with EF ≤35 %, who are in sinus rhythm with a resting heart rate of ≥70 bpm, and are either on maximally tolerated doses of beta-blockers or have a contraindication to beta-blocker use. Ivabradine is given as a starting dose of 5 mg twice daily and can be increased to 7.5 mg twice daily after 2 weeks in patients whose heart rate remains over 60 bpm. The most important consideration in deciding to prescribe ivabradine is that it is not a substitute for beta-blocker therapy. Beta-blockers have clear survival benefit in HF whereas ivabradine, in conjunction with maximally tolerated beta-blocker dosing, mainly reduces HF hospitalizations. Ivabradine is contraindicated in patients with acute decompensated HF, blood pressure <90/50 mmHg, resting heart rate below 60 bpm prior to treatment, or pacemaker dependence. The most

US CARDIOLOGY REVIEW

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Promising New Therapies in Heart Failure Figure 3: Outcomes in the PARADIGM-HF Study

Primary End Point

0.1

Cumulative probability

0.1

0.6 0.5 0.4 0.3 0.2 0.1 0.0

Death from Cardiovascular Causes

0.6 0.5 0.4 0.3 0.2 0.1

180

360

540

720

900

1080

0.0

1260

180

360

Days since randomization Enalapril

LCZ696

Enalapril

HR 0.80 (95% CI [0.73–0.87]) P<0.001 Number at risk LCZ696 4187 Enalapril 4212

3922 3883

3663 3579

3018 2922

2257 2123

1544 1488

896 853

900

1080

1260

LCZ696

Number at risk LCZ696 4187 Enalapril 4212

249 236

0.1

4056 4051

3891 3860

3282 3231

2478 2410

1716 1726

1005 280 994 279

Death from any cause 0.1

Cumulative probability

720

HR 0.80 (95% CI [0.71–0.89]) P<0.001

Hospitalization for Heart Failure

0.6 0.5 0.4 0.3 0.2 0.1 0.0

540

Days since randomization

0.6 0.5 0.4 0.3 0.2 0.1

180

360

540

900

720

1080

1260

0.0

180

360

Days since randomization Enalapril

LCZ696

Enalapril

HR 0.79 (95% CI [0.71–0.89]) P<0.001 Number at risk LCZ696 4187 Enalapril 4212

3922 3883

540

900

720

1080

1260

Days since randomization LCZ696

HR 0.84 (95% CI [0.76–0.93]) P<0.001 3663 3579

3018 2922

2257 2123

1544 1488

896 853

249 236

Number at risk LCZ696 4187 Enalapril 4212

4056 4051

3891 3860

3282 3231

2478 2410

1716 1726

1005 280 994 279

Shown are estimates of the probability of the primary composite end point (death from cardiovascular causes or first hospitalization for heart failure) (Panel A), death from cardiovascular causes (Panel B), first hospitalization for heart failure (Panel C), and death from any cause (Panel D). PARADIGM-HF = Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortalitiiy and morbidity in Heart Failure. From McMurray JJ, et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med 2014;371:993.26 Copyright © (2014) Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.26

common adverse reactions include bradycardia, hypertension, atrial fibrillation, and luminous visual phenomena (phosphenes).

Neprilysin Inhibitors The Natriuretic Peptide System and other Endogenous Vasoactive Peptides While activation of the SNS and RAAS are maladaptive in HF, activation of the natriuretic peptide system (NPS) is beneficial (see Figure 1). The NPS includes a family of three peptides known as atrial NP (ANP), brain NP (BNP; initially identified in brain but mainly secreted from ventricular myocardium), and C-type NP. NPs are released into the circulation from the atria (ANP) and from the ventricles (BNP), respectively, in response to

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atrial and ventricular distension caused by myocardial injury or overload. ANP and BNP exert a range of activities that could be beneficial in HF including vasodilatation, natriuresis, inhibition of the RAAS and SNS, and activation of the parasympathetic nervous system.23 In healthy subjects, ANP and BNP are rapidly cleared from the circulation via either binding to clearance receptors or degradation by an enzyme called neutral endopeptidase, also known as neprilysin. There has been longstanding interest in the development of drug therapies that either mimic or prolong the activity of endogenous NPs. One approach has been to develop synthetic analogues of ANP and BNP, carperitide and nesiritide, respectively. Both drugs require intravenous

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Heart Failure New Therapies Figure 4: Proposed Revision to Guideline-directed Medical Therapy in Heart Failure

Transplant/MCS evaluation Isordil/hydralazine if Afr American Digoxin if still symptomatic Spironolactone Ivabradine if HR ≥ 70 CRT if LBBB, QRS > 150 msec, sinus rhythm ICD if life expectancy > 1 year Sacubitril/valsartan ACEI or ARB if ARNI-intolerant Beta-blocker NYHA I

NYHA II

NYHA III

NYHA IV

Step-wise therapy for heart failure based on current guidelines5 and recent approval of ivabradine and sacubitril/valsartan. Medication and device therapy for heart failure due to systolic dysfunction is based on the patient’s New York Heart Association Class. Clinical trials with various therapies show mortality benefit when added to existing therapy, hence the stepwise approach. ACEI = Angiotensin converting enzyme inhibitor; ARB = angiotensin receptor blocker; ARNI = angiotensin receptor-neprilysin inhibitor; CRT = cardiac resynchonization therapy; HR= heart rate; ICD = implantable cardiac defibrillator; LBBB = left bundle branch block; MCS = mechanical circulatory support; NYHA = New York Heart Association.

administration and have a short duration of action, necessitating continuous infusion rather than bolus administration. Continuous infusion has limited the clinical application of these agents to the treatment of acute decompensated HF and no long-term benefit has been shown.24 A second approach to augmenting the activity of the NPS has been to inhibit neprilysin, with the aim of prolonging the activity of the endogenous NPs that are already elevated in patients with HF. Neprilysin, a neutral endopeptidase, degrades several endogenous vasoactive peptides including natriuretic peptides, bradykinin, and adrenomedullin. Inhibition of neprilysin increases the levels of these substances, countering the neurohormonal over-activation that contributes to vasoconstriction, sodium retention, and maladaptive remodelling. The relative role of natriuretic peptides versus the other agents is not clear but it is uncertain that augmentation in NPs is the sole cause for the benefits of neprilysin inhibition. Interestingly, a neprilysin inhibitor alone is ineffective because it blocks not only degradation of NP and other potentially beneficial vasoactive peptides but it also degrades adrenomedullin, substance P, angiotensin I and II, bradykinin, and endothelin-1. Thus, although inhibition of neprilysin would increase levels of NPs and other compensatory peptides, leading to the desirable effects noted above, there may also be increased levels of peptides, yielding undesirable effects such as vasoconstriction with angiotensin II and endothelin-1. If a neprilysin inhibitor should be combined with a RAAS blocker, an ACEI would be an obvious choice since ACEI are the cornerstone of RAAS blockade and HF management. However, the combined inhibition of ACEI and neprilysin was associated with serious angioedema in clinical trials.25 This is not surprising since ACEI block degradation of bradykinin and neprilysin inhibitors too. An increase in bradykinin, an inflammatory peptide, could result in angioedema and thus administration of ACEI

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and a neprilysin inhibitor is contraindicated. The next best approach to RAAS blockade is an ARB, which has set the stage for a new class of drugs: the angiotension receptor-neprilysin inhibitor (ARNI) in HF (see Figure 1).

PARADIGM-HF Study The Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortalitiiy and morbidity in Heart Failure (PARADIGM-HF) study was a randomized trial of the neprilysin inhibitor sacubitril and the angiotensin receptor blocker (ARB) valsartan compared to enalapril in HF.26 The trial was stopped early at 27 months due to overwhelming evidence of benefit in the sacubitril/valsartan arm. Patients receiving sacubitril-valsartan demonstrated a reduction in death and HF hospitalizations (see Figure 3). This finding is especially remarkable because sacubitril/valsartan was compared to an active control, not placebo. This is underscored by the speed with which the FDA approved this ANRI. The study was published in August 2014 and by July 2015 the first-in-class drug combination was approved for use in chronic HF under the trade name Entresto.

Prescribing Considerations for Angiotensin-neprilysin Inhibitors Sacubitril/valsartan is FDA approved to reduce the risk of cardiovascular death and hospitalization for HF in patients with chronic HF (NYHA Class II-IV) and reduced ejection fraction. The recommended starting dose is 49/51 mg (sacubitril/valsartan) twice daily. The dose can be increased after 2–4 weeks to the target maintenance dose of 97/103 mg (sacubitril/valsartan) twice daily, as tolerated. A reduced starting dose of 24/26 mg (sacubitril/valsartan) twice daily should be used for: 1) Patients not currently taking an angiotensin-converting enzyme inhibitor (ACEi) or an angiotensin II receptor blocker (ARB) or previously taking a low dose of these agents; 2) patients with severe renal impairment; or 3) patients with moderate hepatic impairment. The mg dosages of the two drugs are intentionally distinct because two-drug combinations cannot have the same mg amount, as dictated by the FDA. Sacubitril/valsartan is contraindicated in patients taking an ACEI and must be off an ACEI for at least 36 hours prior to initiation of sacubitril/ valsartan. In addition, sacubitril/valsartan should not be administered to patients with a prior history of angioedema to an ACEI or ARB. The most common adverse reactions are hypotension (expected since both blocking the RAAS and potentiating the NPS causes vasodilation) and hyperkalemia due to the ARB component.

Conclusion Guideline-directed medical therapy for HF is a triumph of translation medicine whereby an understanding of neurohormonal mechanisms of the RAAS and SNS has resulted in medications that improve QoL and survival in HF patients. Now, increased understanding of the SNS and breakthroughs in capitalizing on the NPS and other compensatory peptides has resulted in two additions to the HF armamentarium, ivabradine and sacubitril/valsartan. One can anticipate that future HF guidelines will incorporate these two new agents into the treatment algorithm and one proposed approach is shown in Figure 4. Moving forward, the goal of physicians who treat HF patients should be to ensure that all eligible patients receive these exciting new therapies. n

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Promising New Therapies in Heart Failure

Cohn JN, Archibald DG, Ziesche S, et al. Effect of vasodilator therapy on mortality in chronic congestive heart failure. Results of a veterans administration cooperative study. N Engl J Med 1986;314:1547. PMID: 3520315. 2. Oliva F, Latini R, Politi A, et al. Intermittent 6-month low-dose dobutamine infusion in severe heart failure: Dice multicenter trial. Am Heart J 1999;138:247. PMID: 10426835. 3. Packer M, Carver JR, Rodeheffer RJ, et al. Effect of oral milrinone on mortality in severe chronic heart failure. The PROMISE study research group. N Engl J Med 1991;325:1468. PMID: 1944425. 4. Swedberg K. Importance of neuroendocrine activation in chronic heart failure. Impact on treatment strategies. Eur J Heart Fail 2000;2:229. PMID: 10938480. 5. Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure: A report of the American College of Cardiology Foundation/American Heart Association task force on practice guidelines. Circulation 2013. doi: 10.1161/ CIR.0b013e31829e8776; PMID: 23741058. 6. Effects of enalapril on mortality in severe congestive heart failure. Results of the cooperative north scandinavian enalapril survival study (CONSENSUS). The CONSENSUS trial study group. N Engl J Med 1987;316:1429. PMID: 2883575. 7. Cohn JN, Johnson G, Ziesche S, et al. A comparison of enalapril with hydralazine-isosorbide dinitrate in the treatment of chronic congestive heart failure. N Engl J Med 1991;325:303. PMID: 2057035. 8. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. The SOLVD investigators. N Engl J Med 1991;325:293. PMID: 2057034. 9. Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions. The SOLVD investigators. N Engl J Med 1992;327:685. PMID: 2057034. 10. Kober L, Torp-Pedersen C, Carlsen JE, et al. A clinical trial of the

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11.

12.

13.

14.

15.

16.

17.

18.

angiotensin-converting-enzyme inhibitor trandolapril in patients with left ventricular dysfunction after myocardial infarction. Trandolapril cardiac evaluation (TRACE) study group. N Engl J Med 1995;333:1670. PMID: 7477219. Granger CB, McMurray JJ, Yusuf S, et al. Effects of candesartan in patients with chronic heart failure and reduced leftventricular systolic function intolerant to angiotensinconverting-enzyme inhibitors: The CHARM-Alternative trial. Lancet 2003;362:772. PMID: 1367887. Cohn JN, Tognoni G, Valsartan Heart Failure Trial I. A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. N Engl J Med 2001;345:1667. PMID: 11759645. Pfeffer MA, McMurray JJ, Velazquez EJ, et al. Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both. N Engl J Med 2003;349:1893. Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study investigators. N Engl J Med 1999;341:709. PMID:14610160. Zannad F, McMurray JJ, Krum H, et al. Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med 2011;364:11. doi: 10.1056/NEJMoa1009492. Epub 2010 Nov 14. PMID: 21073363. Pitt B, Remme W, Zannad F, et al. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med 2003;348:1309. PMID: 12668699. Hjalmarson A, Goldstein S, Fagerberg B, et al. Effects of controlled-release metoprolol on total mortality, hospitalizations, and well-being in patients with heart failure: The metoprolol cr/xl randomized intervention trial in congestive heart failure (MERIT-HF). MERIT-HF study group. JAMA 2000;283:1295. PMID: 10714728. The cardiac insufficiency bisoprolol study II (CIBIS-II):

A randomised trial. Lancet 1999;353:9. PMID: 10023943. 19. Dargie HJ. Effect of carvedilol on outcome after myocardial infarction in patients with left-ventricular dysfunction: The CAPRICORN randomised trial. Lancet 2001;357:1385. PMID: 11356434. 20. Fox K, Ford I, Steg PG, et al. Heart rate as a prognostic risk factor in patients with coronary artery disease and leftventricular systolic dysfunction (BEAUTIFUL): A subgroup analysis of a randomised controlled trial. Lancet 2008;372:817. doi: 10.1016/S0140-6736(08)61171-X. PMID: 18757091. 21. Flannery G, Gehrig-Mills R, Billah B, Krum H. Analysis of randomized controlled trials on the effect of magnitude of heart rate reduction on clinical outcomes in patients with systolic chronic heart failure receiving beta-blockers. Am J Cardiol 2008;101:865. doi: 10.1016/j.amjcard.2007.11.023; PMID: 18328855. 22. Swedberg K, Komajda M, Bohm M, et al. Ivabradine and outcomes in chronic heart failure (SHIFT): A randomised placebo-controlled study. Lancet 2010;376:875. doi: 10.1016/ S0140-6736(10)61198-1; PMID: 20801500. 23. Macdonald PS. Combined angiotensin receptor/neprilysin inhibitors: A review of the new paradigm in the management of chronic heart failure. Clin Ther 2015;37:2199. doi: 10.1016/j. clinthera.2015.08.013; PMID: 26386501. 24. Oâ&#x20AC;&#x2122;Connor CM, Starling RC, Hernandez AF, et al. Effect of nesiritide in patients with acute decompensated heart failure. N Engl J Med 2011;365:32. doi: 10.1056/NEJMoa1100171; PMID: 21732835. 25. Kostis JB, Packer M, Black HR, et al. Omapatrilat and enalapril in patients with hypertension: The omapatrilat cardiovascular treatment vs. Enalapril (OCTAVE) trial. Am J Hypertens 2004;17:103; PMID: 14751650. 26. McMurray JJ, Packer M, Desai AS, et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med 2014;371:993. doi: 10.1056/NEJMoa1409077; PMID: 25176015.

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Pregnancy and Coronary Ischemia

LE ATION.

Ischemic Complications of Pregnancy: Who is at Risk? Sa ra C M a r t i n e z , M D, P h D a n d S h a r o n n e N H a y e s, M D Cardiovascular Division, Mayo Clinic, Rochester, MN

Abstract The physiologic demands of pregnancy may either trigger or uncover ischemic heart disease (IHD) via largely unknown mechanisms, leading to an increased mortality compared with nonpregnant individuals. Risk factors for IHD in pregnancy are age, smoking, multiparity, and prior cardiac events. A multidisciplinary team at a referral center is key to coordinating medical or invasive management and inpatient observation. Etiologies may be revealed by experienced angiographers, and are predominantly spontaneous coronary artery dissection, followed by atherosclerotic disease and thrombus, while a significant percentage of women are found to have normal coronary arteries by angiogram. The management of these conditions is varied and, in general, conservative management is preferred with adequate coronary flow and stable hemodynamics. A woman with a history of IHD in pregnancy is at a substantial risk for further complications in future pregnancies and beyond; therefore, aggressive risk factor-reduction strategies and regular cardiology follow-up are imperative to decrease adverse events.

Keywords ACS, pregnancy, myocardial infarction, coronary artery dissection, SCAD, coronary artery disease Disclosure: The authors have no conflicts of interest to declare. Received: January 20, 2016 Accepted: February 1, 2016 Citation: US Cardiology Review, 2016;10(1):14–20 Correspondence: Sharonne N Hayes, Cardiovascular Division, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA. E: hayes.sharonne@mayo.edu

Pregnancy is a physiologic challenge, with significant hormonal, metabolic, and hemodynamic changes. Cardiac output is objectively increased by the fifth week after the last menstrual period and continues to grow by approximately 45 % by 24 weeks in the normal, singleton pregnancy. This is facilitated by elevations in heart rate and stroke volume and a decrease in systemic vascular resistance. These changes return to the prepregnant state approximately 2 weeks after delivery.1 The hemodynamic demands of these adaptations and accompanying hormonal fluctuations can create a “stress” situation, which may uncover underlying metabolic abnormalities or cardiovascular disease (CVD), the leading cause of maternal mortality in pregnancy.2 Fortunately, CVD in pregnancy is rare, however, it requires clinicians from multiple specialties to coordinate efforts to care for two patients at once. The hormonal and metabolic changes of normal pregnancy are intertwined, with insulin resistance, hypercoagulability, and immunologic dysfunction each playing important roles in fetal development while potentially contributing as risk factors for cardiovascular ischemia. Although the exact mechanisms of pregnancy-associated insulin resistance are complex, normal human pregnancy is associated initially with adipose accretion, a progressive 50 % decrease in insulin-mediated glucose disposal, and a subsequent 200–250 % increase in insulin signaling to maintain euglycemia.3,4 Pregnancy is a known prothrombotic state, with the rate of venous thromboembolism (VTE) approximately four to five times that of a nonpregnant female.5 Additionally, major shifts occur in the maternal immunologic status with the downregulation of pro-inflammatory cytokines and acceptance of the fetus and his or her immunological differences.6

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The prevalence of myocardial ischemia is low overall in pregnant women, with a variable presentation from asymptomatic to cardiogenic shock or sudden cardiac arrest.7,8 The incidence and prevalence of myocardial infarction and ischemia related to pregnancy is expected to increase more women are delaying child-bearing to later years, with a technical definition of an age >35 years as advanced maternal age (AMA).9–11 Although obstructive atherosclerotic heart disease occurs in reproductive age women, the pathophysiology of ischemic heart disease (IHD) in women also includes a greater proportion of nonobstructive coronary disease than found in men.11 However, patients with stable angina and normal coronary arteries or non-obstructive plaque burden have been shown to have increased risks for major adverse cardiovascular events (MACE).12,13 Pregnant patients may present with a medical attention with a clinical context of acute coronary syndrome (ACS) with chest discomfort, dyspnea, or other more atypical symptoms such as referred pain, nausea, or profound fatigue. Electrocardiography (ECG) and assessment of cardiac biomarkers are essential to diagnosis, per practice guidelines. The absence of ST-elevation on an ECG would likely suggest non-ST-elevation ACS (NSTEACS). NSTEACS can by further subdivided as a non-ST-elevation myocardial infarction (NSTEMI) with elevated myocardial injury biomarkers, or unstable angina (UA).14 The CVD complication rate during pregnancy is 0.2–4.0 % in Western societies, with hypertension occurring in 6–8 % of all pregnancies. Management of these complications is not standardized and is largely guided by Level of Evidence (LOE) C data, that is, consensus opinions of experts, case reports, and adaptations of care standards.15,16 Of those

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Ischemic Complications of Pregnancy with CVD during pregnancy, adult congenital heart disease comprises 75–80 % in Europe and North America, while rheumatic valvular heart disease comprises the 56–89 % of pregnancy-associated CVD in nonWestern countries.17,18 The occurrence of an acute MI has a rate of one in 35,700 pregnancies with a high mortality rate of 7.3 %.19 Pregnancy increases the risk for MI three to four times over the nonpregnancy state, which could be due in part to the physiologic “stress test” of increased cardiac output.20 The presentation of a contemporary cohort of pregnant patients with IHD was predominantly in the third trimester or postpartum period and 95 % had chest pain. Etiologies of IHD are variable between different retrospective cohorts, but the major etiologies are primarily coronary dissection (35–56 %), atherosclerosis (35 %), thrombus (22–35 %), and “normal” coronary anatomy (11 %).21,22

Figure 1: Left Coronary Artery in the Right Anterior Oblique Projection

Diagnostic Evaluation There are few data on the management of patients with pregnancyassociated MI (PAMI) and ACS. Pregnant patients presenting with ischemic symptoms should be evaluated at the emergency department with the same attention paid to history, biomarkers, and ECGs, according to the most recent guidelines.23 Additional imaging may be warranted in patients with atypical symptoms or in whom initial testing is not diagnostic. While multiple imaging modalities are available to evaluate cardiac function, nonionizing methods, especially echocardiography, are generally preferred and provide ancillary diagnostic information including myocardial and valvular function. Often, it can be difficult to delineate common symptoms of pregnancy, such as mild shortness of breath or edema, from ischemia or heart failure. A transthoracic echocardiogram should be considered in a woman who has dyspnea out of proportion to her baseline. Ionizing imaging studies in the acute setting, such as nuclear imaging, CT, and coronary angiography should be selected when it is determined that the potential information gained outweighs potential maternal and fetal risk. While cardiac MRI does not involve ionizing radiation, there are few indications for use in the acute setting. MRI has not been shown to have a harmful effect on the fetus, with teratogenesis, miscarriage, or acoustic damage, however, a strong magnetic field and substantial noise of greater than 100 dB, although attenuated by the mother’s body, are of potential concern.24–26 Gadolinium-based contrast has been shown to induce teratogenic effects in animal models in doses above any clinical indication, however, case series studies have not shown an association between gadolinium contrast and adverse fetal outcomes.27,28 The American College of Radiology (ACR) recommends that a risk–benefit analysis be performed before MRI, and that gadolinium-based agents may be given to a patient under a consensus agreement by the referring physician and radiologist when no other imaging modalities are favorable, and when the imaging cannot be performed after delivery.29,30 Concerns about exposing the mother and fetus to ionizing radiation are legitimate, as there is increased sensitivity of glandular breast tissue to ionizing effects leading to an increased risk for breast cancer, and there is no threshold radiation level below which radiation would be considered “safe” for a fetus.31 Radiation exposure is undesirable in the pregnant patient for the potential of direct and more likely scatter radiation to the developing fetus. As many precautions as possible, including minimizing low-dose fluoroscopy where appropriate, minimizing cine imaging, and perhaps shielding along the patient’s

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White arrows indicate areas and extent of spontaneous coronary dissection along the mid leftanterior descending coronary artery.

lower back if possible might mitigate fetal exposure.32 Due to the high incidence of coronary dissection in this population, special procedural precautions are recommended, including careful guide engagement of the coronary arteries and limiting the number and pressure settings of contrast injections.

Etiologies for Acute Ischemia in the Pregnant Patient Coronary Artery Dissection A review of 150 cases of PAMI revealed that the most common etiology was spontaneous coronary artery dissection (SCAD) (43 %), followed by atherosclerotic disease (27 %), and thrombus without atherosclerosis (17 %). Normal coronary anatomy was present in 11 %, however, the extent of coronary evaluation with intracoronary imaging modalities is likely underutilized.20 Patients with SCAD typically present with left anterior descending (LAD) artery involvement, and a significant proportion may present with multivessel involvement.33 SCAD is diagnosed angiographically, and emerging data suggest three different angiographic classifications of SCAD: Type 1 with multiple radiolucent lumen, Type 2 with diffuse stenosis, and an “atheroscleroticmimic”, Type 3.34 An angiogram of SCAD within the LAD artery, best classified as Type 2, is shown in Figure 1. Histology reveals that SCAD is a consequence of dissection within the coronary artery media or intima and intramural hematoma formation.35 SCAD may or may not angiographically demonstrate a double lumen, which is best appreciated by optical coherence tomography or intravascular ultrasound.36,37 The pathophysiological explanation behind SCAD is overall unknown, however, pregnancy induces a state of increased responsiveness to angiotensin II, catecholamines, and endothelial dysfunction. 38 Alterations in the coagulation–fibrinolysis system is hypothesized to contribute to SCAD with a pregnancy-induced prothrombotic state.

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Pregnancy and Coronary Ischemia Figure 2: Flowchart for Management of Acute Coronary Syndrome Presentation in a Pregnant Woman

Pregnant woman with ACS

Immediate consultation with OB and cardiology transfer to tertiary care center if stable/possible

Invasive management

Medical management

Aspirin, heparin, clopidogrel

Normal

Conservative management

TIMI flow 2-3 and stable

Angiogram by experienced operator to minimize radiation

Atherosclerosis

SCAD

TIMI flow 0-1 and unstable

thrombus

Revascularize if appropriate. Consider bare-metal stent to minimize DAPT

Revascularize via PCI or consider CABG in high volume center

Inpatient monitoring for 5–7 days with cardiology consultation and follow-up with cardiology pre and post delivery ACS = acute coronary syndrome; CABG = coronary artery bypass grafting; DAPT = dual antiplatelet therapy; OB = obestetrics; PCI = percutaneous coronary intervention; SCAD = spontaneous coronary artery dissection; TIMI = thrombolysis in myocardial infarction.

Additionally, excess estrogen and progesterone promote changes in the arterial wall, which could contribute to medial breakdown.39 The significant increase in blood volume, cardiac output, and abrupt hemodynamic stresses in delivery and postpartum have also been hypothesized to contribute to an increased chance at dissection.40 Pregnancy is a risk factor for SCAD, with a majority of the cases occurring in the third trimester or post-partum period. Additionally, case reports reveal pregnancy-associated SCAD as more frequent in women >30 years of age and in multiparous women.20 Fibromuscular dysplasia (FMD) is associated with and may be a causal factor in SCAD, although the prevalence of FMD in pregnancy-associated SCAD is unknown.41–43

Thromboembolic Thrombophilia in pregnancy is more often associated with VTE than arterial thromboembolism.44 Paradoxical embolus is an unusual cause of MI, and is more commonly associated with cryptogenic stroke.45,46 Literature on pregnancy and paradoxical embolus leading to cardiac ischemia remains limited to case reports. In two instances, the patients were documented to each have a patent foramen ovale (PFO) along with a Factor V Leiden mutation.47,48 Coronary thrombosis without atherosclerotic disease causing ischemia is rare, however, 45 % of women with pregnancies complicated by acute MIs were smokers.40

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Cigarette smoking in pregnancy is associated with increased platelet activity, further contributing to a pro-coagulant cascade.49

Atherosclerosis Atherosclerotic heart disease, or coronary artery disease (CAD), is responsible for the largest proportion of CVD among women and men, and for nearly one-third of all deaths worldwide.50 Age is strongly associated with CAD, and as more women delay childbearing to later years the number of ischemic events in pregnant women is also expected to increase.51,52 A recent study evaluated 43 women with prior MI or a history of ACS and 50 pregnancies, over a time span of 7 years and across six academic medical centers. Women with pre-existing CAD and prior MI events were at a higher risk for coronary ischemic events with pregnancy, found to comprise five patients with one death, three ACS/MI episodes, and one case of heart failure. Established risk factors were present in 80 % of those patients, and 60 % had a history of cigarette smoking.22 Figure 2 is an algorithm for the management of the pregnant patient with ACS.

Risk Factors for Pregnancy-associated Coronary Ischemia It is difficult to ascribe risk factors to one etiology of coronary ischemia versus another due to low event rates. Additionally, since many studies

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Ischemic Complications of Pregnancy are retrospective and typically from tertiary referral hospitals, many cases may be unknown in the greater community. It would appear that many clinical risk factors are shared between the two largest contributors of pregnancy-associated coronary ischemia: coronary dissection and atherosclerosis. A significant risk factor is age. Acute MI can occur in all stages of pregnancy, however, a retrospective review published in 2008 of 103 women with MI associated with pregnancy revealed that 72 % of patients were >30 years and 38 % were >35 years.40 Several years later another retrospective study of 150 women with PAMI revealed that 75 % were >30 years and 43 % were >35 years.20 The average age in ACS presentation due to SCAD was 42.6 years with an 82 % prevalence in women.53 Among women in the same cohort who had peripartum SCAD, the average age of presentation was 36 years. Smoking is a known risk factor for CAD and ischemic events in general, and it is similarly a commonly present risk factor among PAMI, varying from 25 % to 45 % within studies.20,40 Multiparity was reported to be present in 47–66 % of women with PAMI.20,40 Multiparity is known to cause increases in serum estradiol, progesterone, and other hormones of pregnancy.54,55 These two facts support the mechanism of increased doses of hormones as a direct link to abnormal endothelial function, thrombosis, and increased susceptibility to the known risk factors of atherosclerosis such as smoking, hyperlipidemia, and hypertension. Fertility treatments and hormone replacement therapy were present in two out of 15 patients with SCAD recurrence in one center.53 Preeclampsia is maternal hypertension, typically developing in the third trimester of pregnancy, characterized by proteinuria, and is progressive without treatment, possibly leading to liver and kidney failure and seizures (eclampsia).56 It is a leading cause of maternal and fetal morbidity and mortality; however, in the retrospective studies of acute MI and pregnancy, the prevalence of preeclampsia was not shown to be noticeably different than the age-adjusted rates, around 6 %.20,40,56,57 Preeclampsia is associated with future CVD, including IHD.58 A retrospective cohort of over one million women without CVD prior to first delivery were followed for cardiovascular outcomes in the Cardiovascular Health after Maternal Placental Syndromes (CHAMPS) study.59 Preeclampsia comprised 49 % of those with maternal placental syndrome, making it the most common disorder, followed by gestational hypertension (28 %) and placental abruption (15 %). The adjusted hazard ratio of preeclampsia for the development of premature CVD was 2.1 (95 % CI [1.8–2.4]). The Nationwide Inpatient Sample for 2000–2002 was queried for pregnancy-related discharges. Out of the 859 discharges with a diagnosis of acute MI, multivariable logistic regression analysis revealed that the biggest comorbidities were hypertension (OR 21.7; 95 % CI [6.8–69.1]), thrombophilia (OR 25.6; 95 % CI [0.2–71.2]), and diabetes (OR 3.6; 95 % CI [1.5–8.3]).8 Transfusion for hemorrhage was also associated with MI, although it is difficult to ascribe the increased risk for MI to the transfusion of red blood cells or to agents, such as methylergonovine, administered to women with hemorrhage due to uterine atony, and known to induce coronary vasospasm.60 This elegant analysis also highlighted the compounded impact of smoking toward an increased risk for PAMI. Although female smokers are twice as likely

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as nonsmokers to suffer from MI, pregnant smokers have an eightfold risk for MI. This is similar to the risk for MI in female smokers taking oral contraceptives.61

Treatment for Ischemic Coronary Disease in Pregnancy Medical Management After the diagnosis has been made for STEMI or NSTEACS in the pregnant patient, expedited consultation with cardiologists who have expertise in the care of pregnant patients and high-risk obstetricians is recommended. The medical management has important differences, in efforts to minimize risks to the fetus. Medications have risk factor categorical classifications for use in pregnancy based in animal and human data when available, with progressively increased fetal risk from A to D and also a category X. Category A drugs show no risk or evidence of harm in controlled human studies. Category B drugs demonstrate no risk in animal studies, however, there are no controlled human trials. Category C drugs demonstrate either unavailable or insufficient data in animals or women, or possible fetal risk in animal studies, without controlled human studies. Category D drugs have evidence of potential fetal risk in animals, however, the benefits in pregnant women may be accepted despite the risk, such as life-threatening condition to the mother. Category X drugs are contraindicated in pregnant women due to demonstrated fetal abnormalities in animals or humans.62 Fibrinolytics do not cross the placenta, and case reports exist of successful thrombolysis in pregnant patients suffering an acute MI. However, the general opinion is of relative contraindication and extensive discussion among consultants if fibrinolytic therapy is remotely considered.63–65 Additionally, due to the high prevalence of SCAD and “normal” coronary anatomy in pregnant patients with ACS, the benefit of fibrinolytic therapy may not outweigh the risk. Due to the low frequency of MI in pregnancy, anti-platelet, and anticoagulation therapies are managed similarly to nonpregnant patients, as pregnancy has never been evaluated in clinical trials of these agents. Aspirin is given a class D designation, mostly due to animal models exposed to high-doses resulting in premature fetal ductus arteriosus closing.66 Aspirin at a low dose (75–100 mg) is safe to use in pregnancy with no increased maternal or fetal bleeding risks or effects on the ductus arteriosus on meta-analysis. Additionally, aspirin was not found to increase the risk for bleeding from neuraxial anesthesia when continued through delivery.67 The platelet P2Y12 receptor blockers of clopidogrel and prasugrel are considered pregnancy class B agents, while ticagrelor is a class C agent with limited literature comprising one case report.68,69 Regarding anticoagulation, unfractionated heparin does not cross the placenta, but is a pregnancy class C agent. Due to the neurologic effects on the neonate of benzyl alcohol, which is present in some formulations of heparin as a preservative, some practices have limited the administration of heparin to pregnant patients to preservative-free heparin, if possible.70,71 Enoxaparin is a class B agent, does not cross the placenta, and is well tolerated in pregnancy from a bleeding perspective when stopped before a planned delivery. The direct thrombin inhibitors of bivalirudin and argatrobran are class B agents due to animal studies, and their use is limited to case reports of pregnant patients with heparin-induced thrombocytopenia.72,73 European guidelines on the management of pregnancy and heart disease recommend the use of clopidogrel and avoidance of glycoprotein IIb/IIIa

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Pregnancy and Coronary Ischemia inhibitors, prasugrel, ticagrelor, and bivalirudin.74 In a pregnant patient who had recently received a bare metal stent, clopidogrel was stopped 7 days prior to delivery. Eptifibatide was used as a bridging agent and discontinued 12 hours prior to neuraxial analgesia, with clopidogrel resumed within 24 hours.75

bleeding, particularly intracranial bleeding, from oral anticoagulants is reduced.74 Vaginal delivery is associated with less blood loss and a decreased infection risk compared with caesarean delivery.80 Lumbar neuraxial anesthesia is recommended for reducing pain-associated sympathetic activation and as an anesthetic should the patient require emergent delivery.

Invasive Management Percutaneous coronary intervention (PCI) with stents remain the treatment of choice in an acute STEMI, although this does not take into account the high-prevalence of SCAD in pregnant patients.76 Consultation with a high-risk obstetrician regarding the feasibility and duration of dual anti-platelet therapy should ideally occur before angiography. Additional precautions due to the high incidence of coronary dissection are to perform careful guide engagement of the coronary arteries and to minimize injections, using low-pressure. Treatment for SCAD has been a controversial topic, with no randomized controlled data on management. Retrospective studies of SCAD reveal that half of these patients with ACS present with a STEMI, and likely from guidelines advocating early and invasive management for STEMI and NSTEACs, many of these patients have been treated with PCI.53 Some studies report favorable outcomes for PCI management of SCAD, and others report a high failure rate of PCI and a better prognosis of conservative management. The largest single-center study of 189 patients with SCAD reported a PCI procedural failure rate of 53 %, and more vessel occlusion with revascularization than conservative management (44/95 versus 18/94, respectively). The conclusion from this study was that a conservative strategy with observation may be preferable in those clinically stable patients with TIMI grade 2–3 flow.77 There are no data with respect to outcomes on bare-metal versus drugeluting stents in the pregnant patient. Bare-metal stents have been used more frequently than drug-eluting devices in pregnant patients, to reduce the length of dual anti-platelet therapy and potential bleeding complications surrounding delivery.40,78 A high rate of iatrogenic coronary dissection with angiography and stenting in one study suggests that a conservative and noninvasive approach be maintained for most pregnant patients, and that revascularization attempts remain for those with severe and proximal obstruction or hemodynamic compromise.20

Mode of Delivery Pregnant women who have experienced an MI or ACS prior to or during their pregnancy should be delivered in a tertiary care center if possible, with a coordinated team consisting of a high-risk obstetrician, cardiologist, and obstetric anesthesiologist. Unless the woman is in active ACS or suffering an MI during labor, vaginal is the preferred mode of delivery. A large, retrospective study of 1,262 deliveries in women with heart disease concluded that planned caesarean delivery was of no significant benefit, and that vaginal delivery was associated with later delivery and greater birth weight.79 European guidelines advocate for vaginal delivery, with an individualized plan according to the patient’s condition. Acute heart failure decompensation, Marfan’s syndrome with an aorta >45 mm, acute or chronic aortic dissection should be considered for caesarean delivery. Additionally, patients on oral anticoagulation should ultimately be switched to unfractionated heparin and optimally delivered in a controlled manner, so that the risk of fetal

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Long-term Management All women with known heart disease or those who experience an MI or ACS and desiring pregnancy should be referred to a cardiologist ideally before stopping birth control. Pregnant women with known heart disease should be managed by a high-risk obstetrician, preferably at a tertiarycare center, with a consultant cardiologist. Women with PAMI should be followed by a cardiologist closely before and after delivery. Counseling with respect to future pregnancies after an ischemic event must be tailored with the severity of the ischemic event, coronary anatomy and the severity of atherosclerosis, the status of her right and left ventricular function, and the need for dual antiplatelet or anticoagulation therapy. Contraindicated medications during pregnancy include angiotensin converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), and statins due to teratogenic effects.81 An open dialogue about intentions for breast-feeding needs to begin before hospital discharge and continue in the postpartum appointments between the cardiologist, obstetrician, and patient to discuss the risk to benefit ratio of cardiovascular medications to both the infant and mother. Unfortunately, ACE inhibitors, ARBs, and statins as a class are likely to be avoided with respect to breast-feeding, as the data are inadequate and controversial. Metoprolol is a Category C drug for pregnancy, but is likely safe during breast-feeding. Atenolol should be avoided in all pregnant and breast-feeding patients.82

Risk in Future Pregnancies Due to the paucity of data regarding myocardial infarction in pregnancy, not much is known about the risk for future cardiovascular events in subsequent pregnancies. A case series of pregnancy after a diagnosis of SCAD was examined in a single institution. Eight women with prior SCAD became pregnant, and seven had no cardiovascular complications. However, one woman had recurrent SCAD of the left main coronary artery and underwent emergent coronary artery bypass grafting (CABG) and subsequently developed posttraumatic stress disorder.83 As such, future pregnancy is not advised after SCAD, even if the prior SCAD was not associated with pregnancy. Pregnant women with pre-existing CAD or a history of MI/ACS are at increased risk for angina, MI, ventricular arrhythmias, or cardiac arrest during their pregnancies, comprising 10 % from one retrospective review. The highest rates of cardiac complications are seen in women with atherosclerotic disease. Interestingly, the risk for neonatal adverse events, such as preterm labor, intrauterine growth restriction, or low birth weight, is greater for women with known CAD (30 %) than with known valvular or congenital heart disease (18 %), and is substantially higher than the risk in women without heart disease (7 %).22 The Cardiac Disease in Pregnancy (CARPREG) investigators reported that predictors of complications in pregnancy are: an impaired systolic function, any prior cardiovascular event including stroke, left-heart obstruction

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Ischemic Complications of Pregnancy (mitral or aortic stenosis), or New York Heart Association (NYHA) function class II or above.17 The ZAHARA (in Dutch, Zwangerschap bij vrouwen met een Aangeboren HARtAfwijking) investigators limited their risk score to pregnant women specifically with congenital heart disease.84 Neither of these risk scores evaluated women with histories of MI or ACS, likely due to the low prevalence of pregnant women with known CAD.

guidelines for this evaluation, it is reasonable to perform physical examination, ECG, echocardiography, and functional testing for inducible ischemia in most women. In addition to those with prior SCAD, women with significantly reduced left ventricular function or heart failure or ischemic symptoms should be advised against pregnancy.

Conclusion Conditions in pregnancy that predispose the mother to future cardiovascular events after pregnancy are similar to other risk factors in the general population. Women with hypertensive disorders of pregnancy became diagnosed with hypertension 7.7 years earlier than women without pregnancy complications and were at a significantly increased risk for CVD with a hazard ratio of 1.21 (95 % CI [1.10– 1.32]).85 Maternal obesity and preeclampsia predispose the mother to cardiovascular events later in life.85,86 Women with prior MI or known CAD should undergo cardiovascular evaluation as part of preconception planning. While there are no specific

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Although IHD is rare in pregnancy, the maternal mortality from heart disease is several fold above the nonpregnant population. The strongest risk factors for IHD in pregnancy are age, smoking, multiparity, and a history of MI or ACS. In this rare population, SCAD should remain high on the differential for PAMI, followed by atherosclerosis. Critical to the management of pregnant patients with IHD is a multidisciplinary and involved team of at least an obstetrician, noninvasive and interventional cardiologists, and obstetric anesthesiologists at a tertiary center. Additional cardiovascular follow-up, mitigation of risk factors, and counseling regarding plans for future pregnancy are imperative toward best possible outcomes. n

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10.1093/eurheartj/ehr218; PMID: 21873418 75. Bauer MEB, Bauer ST, Rabbani AB, Mhyre JM. Peripartum management of dual antiplatelet therapy and neuraxial labor analgesia after bare metal stent insertion for acute myocardial infarction. Anesth Analg 2012;115:613–5. DOI: 10.1213/ ANE.0b013e31825ab374; PMID: 22584549 76. O’Gara PT, Kushner FG, Ascheim DD, et al. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2013;61:e78–140. DOI: 10.1016/j. jacc.2012.11.019; PMID: 23256914 77. Tweet MS, Eleid MF, Best PJM, et al. Spontaneous coronary artery dissection: revascularization versus conservative therapy. Circ Cardiovasc Interv 2014;7:777–86. DOI: 10.1161/ CIRCINTERVENTIONS.114.001659; PMID: 25406203. 78. Pepine CJ, Ferdinand KC, Shaw LJ, et al. Emergence of nonobstructive coronary artery disease: A woman’s problem and need for change in definition on angiography. J Am Coll Cardiol 2015;66:1918–33. DOI: 10.1016/j.jacc.2015.08.876; PMID: 26493665. 79. Ruys TPE, Roos-Hesselink JW, Pijuan-Domènech A, et al. Is a planned caesarean section in women with cardiac disease beneficial? Heart 2015;101:530–6. DOI: 10.1136/ heartjnl-2014-306497; PMID: 25539946 80. Bonanno C, Gaddipati S. Mechanisms of hemostasis at cesarean delivery. Clin Perinatol 2008;35:531–47, xi. DOI: 10.1016/j.clp.2008.07.007; PMID: 18952020 81. Pacheco LD, Saade GR, Hankins GD V. Acute myocardial infarction during pregnancy. Clin Obstet Gynecol 2014;57:835–43. DOI: 10.1097/GRF.0000000000000065; PMID: 25286296 82. Spencer JP, Gonzalez LS, Barnhart DJ. Medications in the breast-feeding mother. Am Fam Physician 2001;64:119–26. DOI: 10.1161/CIRCINTERVENTIONS.114.001659; PMID: 25406203 83. Tweet MS, Hayes SN, Gulati R, et al. Pregnancy after spontaneous coronary artery dissection: a case series. Ann Intern Med 2015;162:598–600. DOI: 10.7326/L14-0446; PMID: 25894037 84. Drenthen W, Boersma E, Balci A, et al. Predictors of pregnancy complications in women with congenital heart disease. Eur Heart J 2010;31:2124–32. DOI: 10.1093/eurheartj/ehq200; PMID: 20584777 85. Heida KY, Franx A, van Rijn BB, et al. Earlier age of onset of chronic hypertension and type 2 diabetes mellitus after a hypertensive disorder of pregnancy or gestational diabetes mellitus. Hypertension 2015;66:1116–22. DOI: 10.1161/ HYPERTENSIONAHA.115.06005; PMID: 26459420 86. Charach R, Wolak T, Shoham-Vardi I, et al. Can slight glucose intolerance during pregnancy predict future maternal atherosclerotic morbidity? Diabet Med 2015; DOI: 10.1111/ dme.13036; PMID: 26606683: epub ahead of print.

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Electrophysiology Stroke Prevention

Emerging Strategies for Stroke Prevention in Atrial Fibrillation P ra v een R a o, MD, O l u s e g u n O l u s e s i , M D a n d M i t c h e l l Fa d d i s, M D, P h D Cardiovascular Division, Washington University in Saint Louis, School of Medicine, St Louis, MO

Abstract Atrial fibrillation (AF) is a common cause of stroke. In the US nearly 800,000 people suffer stroke each year and about 130,000 die as a result. Stroke care accounts for an estimated US$34 billion in health care expenditures in the US each year. Among all strokes, AF is the cause in 15–20 % of cases. The incidence of AF in the US has grown steadily over time to a current estimate of 6.1 million with the condition. With the anticipated growth in the worldwide AF population, the need for effective new therapeutic strategies for stroke prevention is clear.

Keywords Atrial fibrillation, stroke prevention, left atrial appendage occlusion, rhythm control Disclosure: The authors have no conflicts of interest to declare. Received: January 13, 2016 Accepted: February 2, 2016 Citation: US Cardiology Review, 2016;10(1):21–5 Correspondence: Mitchell N Faddis, Director of Clinical Cardiac Electrophysiology, Associate Professor of Medicine, Washington University School of Medicine, 660 S. Euclid Ave, St Louis, MO 63110, USA. E: mfaddis@dom.wustl.edu

It is presumed that the pathogenesis of stroke in atrial fibrillation (AF) patients is due to embolization of thrombus from the left atrium. Within the left atrium, the left atrial appendage is the predominant site of thrombus formation. In a study of 233 patients with new onset AF of greater than 48 hours in duration who were not anticoagulated, left atrial appendage thrombus was present in 15 % of patients.1 Among patients with a recent embolic stroke, the association of atrial fibrillation and left atrial appendage thrombus is present in more than 20 % of patients.2 In patients with documented left atrial appendage thrombus and AF discovered during transesophogeal echochardiograhy (TEE), the subsequent incidence of transient ischaemic attack (TIA) is nearly 10-fold higher than those without thrombus.3 Systemic anticoagulation with warfarin has been shown to reduce the incidence of stroke in AF patients by about two thirds.4 In spite of the proven efficacy of warfarin therapy for stroke prevention, the effective and safe use of this agent has proved challenging. In particular, frequent blood tests, dietary effects, and pharmacologic interactions with other therapeutic agents limits effective use of this agent. The requirement for tight control of the intensity of anticoagulant effect of warfarin has resulted in frequent occurrences of under- and overdosing. Despite intention-to-treat with warfarin, 50 % of patients who experience a stroke are found to have subtherapeutic anticoagulation.4 Supratherapeutic anticoagulation raises the risk of severe bleeding episodes including intracranial hemorrhage.5 Among patients prescribed warfarin, one in four discontinue the medication within the first year of use.6 Recently, the introduction of a series of novel oral anticoagulants (NOACs) has provided therapeutic alternatives to warfarin in patients

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with preserved renal function. In a meta-analysis of the major clinical trials of these agents including the direct thrombin inhibitor dabigatran and the factor Xa inhibitors apixoban, rivaroxaban and edoxaban, the incidence of stroke or systemic embolic events was reduced by 19 % relative to patients treated with warfarin.7 Although the risk reduction for ischemic stroke was similar to warfarin in the meta-analysis, the incidence of intracranial hemorrhage (a separate cause of stroke) was reduced by 52 %. In spite of the enhanced stroke prevention efficacy associated with the NOACs, a 25 % increase in gastrointestinal bleeding was observed with these agents. A new standard risk calculation has now been widely adopted because of bleeding risks inherent in systemic oral anticoagulation. This has helped guide the decision based on quantification of the risk of thromboembolic events in patients with non-rheumatic AF. Known by the acronym CHADS2-VASc (C = congestive heart failure; H = hypertension; A = age; D = diabetes mellitus; S2 = Stroke and female sex; Vasc = vascular disease), this risk calculation assigns points for the known stroke risk factors in non-rheumatic AF made up by female sex, a history of congestive heart failure, hypertension, age >65 years, age >75 years, diabetes mellitus, vascular disease, and two points for a prior history of stroke. In both men or women with one additional risk factor, oral anticoagulation is recommended. The effect of this new risk calculation scheme, relative to the older CHADS2 system, is to include a larger portion of patients with AF in the recommendation for oral anticoagulant. The predicted effect of these recommendations together with the new oral anticoagulants should be more comprehensive stroke protection in the AF patient population. Despite this, many patients have contraindications to oral

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Electrophysiology Stroke Prevention anticoagulation due to fall or bleeding risks and proven alternative stroke prevention strategies are needed.

Rhythm Control There have been several randomized trials comparing rate versus rhythm control in patients with AF. These trials have demonstrated similar rates of death or embolism regardless of the strategy.9–13 Of these, the A Comparison of Rate Control and Rhythm Control in Patients with Atrial Fibrillation (AFFIRM) trial was the largest, randomizing 4,060 patients with recurrent AF to rate control (using beta blockers, calcium channel blockers or digoxin) and anticoagulation with warfarin compared to the most effective antiarrhythmic drug. All patients were initially anticoagulated, but those in the rhythm control group who maintained sinus rhythm for at least four, but preferably 12, consecutive weeks could be withdrawn from warfarin. In the rhythm control arm the most frequently used antiarrhythmics were amiodarone (38 %) and sotalol (31 %). By the end of the 3.5 years of follow-up, 63 % had been prescribed amiodarone at least once. Patients initially assigned to rhythm control crossed over to the rate control group in 17 % of patients at one year and 38 % of patients at 5 years. This was mainly due to a failure to maintain sinus rhythm or intolerance to the antiarrhythmic medications. After the 3.5 years of follow-up the rate control arm had a trend toward a significant decrease in all-cause mortality (21.3 % versus 23.8 %; HR 0.87; 95 % CI [0.75–1.01]). There was no statistical difference between the groups in cardiac death, arrhythmic death or deaths due to ischemic or hemorrhagic stroke.9 However, groups without a history of heart failure and those aged >65 years or older had a significant reduction in mortality with rate control.14 There was a higher rate of stroke among those patients who had discontinued warfarin, suggesting that anticoagulation should be continued even if a rhythm control strategy is pursued. This is in part due to a high rate of recurrence of AF, even if asymptomatic.9 Restoration of sinus rhythm can be a valuable goal for many patients with symptoms or hemodynamic consequences from AF. Antiarrhythmic medications have potential side effects, can be proarrhythmic and can increase mortality.15 The 2014 AHA/ACC/HRS guidelines regarding the management of patients with AF suggest that catheter ablation is reasonable for patients who have failed at least one antiarrhythmic medication.16 Potential procedural risks of ablation, however, must be weighed carefully against risks of long-term use of antiarrhythmic drugs. In a multicenter Italian registry, major complications occurred in 4 % of patients (2.2 % vascular access, 0.5 % cardiac tamponade, 0.6 % pericarditis, 0.2 % transient ischemic attacks, 0.2 % stroke and 0.1 % had phrenic nerve paralysis).17 Complications such as pulmonary vein stenosis or atrial-esophageal fistulae happened rarely but were probably under recognised if they occurred late. Despite the evolution of AF ablation over the past several years, recurrence rates are still high enough to warrant continuation of long-term anticoagulation. A systematic review of six trials suggested recurrence of AF after one year occurred in 20–40 % of patients after catheter ablation and in greater than 70 % of patients on antiarrhythmic drugs.18 Hence, rhythm control with antiarrhythmic medications or catheter ablation is useful for reducing symptoms or hemodynamic consequences of AF but should not be used as a means of reducing thromboembolic risk.

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Left Atrial Appendage Occlusion The left atrial appendage (LAA) has been shown to be the location of thrombus formation 91 % of the time in patients with non-valvular AF.19 The structure of the LAA varies and consists of two lobes in 54 % of the population and three lobes in 23 % of the population.20 There have also been several studies to show the LAA has important functions in the release of atrial and brain natriuretic peptides, and loss of this may have adverse consequences on volume status after LAA occlusion.21,22 Up to one-third of patients who would benefit from anticoagulation based on their CHADS2 score cannot take warfarin due to various contraindications.23 Hence, there has been increasing interest in physically occluding the LAA to decrease risk of thromboembolic events associated with AF. Occlusion of the LAA was first achieved surgically in 1949 in patients with rheumatic AF. The surgical procedure has evolved over the past several decades in its methods and efficacy, and there has been increasing interest recently in devising less invasive methods to occlude the LAA. One of the first percutaneous methods to occlude the LAA was the Thorascopic Extracadiac Obliteration of the Left Atrial Appendage for Stroke Risk Reduction in Atrial Fibrillation (LAPTONI) procedure, which used a left lateral thoracotomy approach to ensnare the LAA to the base from the epicardial aspect.24 Since then, there have been several percutaneous methods developed to occlude the LAA from either the epicardial on endocardial approaches. The LARIAT® device (SentreHeart) was created as a catheter-based method to ensnare the LAA from the epicardial aspect. An endorcardial balloon catheter with a magnetic tip is placed via transseptal access into the LAA. With pericardial access, a separate magnetic tipped catheter is advanced to the epicardial aspect of the LAA to meet at the appendiceal tip with the endocardial magnetic balloon. The LAA ostium is identified with balloon inflation of the endocardial catheter, and a pre-tied suture is advanced from the epicardial aspect over the magnetic guidewire rail to the base of the LAA. The suture is tightened and the endocardial balloon is deflated and removed. Through this technique there is no permanent endocardial structure, which limits risk of infection or device embolization. Procedural complications can occur with access of the dry pericardium, transseptal access and perforation or laceration of the LAA. Miller et al. published a cohort of 41 patients who had undergone LARIAT. The acute success of the procedure, defined as complete occlusion of the LAA with <1 mm LAA leak on intraprocedural TEE, is approximately 93 %.25 Limitations to successful closure included large LAA size, numerous lobes, unfavorable LAA anatomy or pericardial adhesions. Long-term success has been variable and residual LAA leak seen on a CT scan or TEE at 3 months was seen in 24 % of patients.25 A larger multicenter study from the US Transcatheter LAA Consortium showed successful suture deployment in 94 % of patients.26 Major complications including death, myocardial infarction, stroke, or cardiac surgery occurred in 9.7 % of patients. Other complications included significant pericardial effusion (10.4 %) and major bleeding (9.1 %). At follow-up TEE 1–3 months post-procedure, there was a high incidence of residual leak (20 %).26 The major advantage of LARIAT is that anticoagulation

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Emerging Strategies for Stroke Prevention in Atrial Fibrillation is not required after complete occlusion of the LAA. However, due to the high incidence of residual leak afterwards, many centres will continue anticoagulation for at least 1–3 months post-procedure if there is no residual leak seen on follow-up TEE.27,28 Randomized, controlled trials are required to further evaluate the long-term safety and efficacy of the LARIAT device as an alternative to anticoagulation. Several endocardial LAA occlusion devices have also been developed. The most notable of these is the WATCHMAN™ device (Boston Scientific). This parachute-shaped device is a self-expanding nitinol cage with fixation anchors and a membrane made of polytetrafluoroethylene. It is available in various sizes (20 mm, 21 mm, 24 mm, 27 mm and 33 mm) and should be sized 10–20 % larger than the LAA. A sheath is placed via transseptal access into the LAA over a pigtail catheter. The device is then advanced through this sheath and sized and placed in the LAA ostium under TEE and fluoroscopic guidance. This device requires that patients are anticoagulated with warfarin for at least 45 days post-procedure. The WATCHMAN Left Atrial Appendage System for Embolic PROTECTion in Patients with Atrial Fibrillation (PROTECT) AF study was the first randomized, controlled trial comparing a LAA occlusion device versus warfarin.29 This was a non-inferiority study for 707 patients with non-valvular AF who were eligible for anticoagulation with warfarin. The patients were randomized in a 2:1 ratio for WATCHMAN or anticoagulation with a follow-up of 18 months. The device was successfully deployed in 91 % of patients. If follow-up TEE demonstrated residual flow ≤3 mm around the device, warfarin was discontinued in 86 % of patients at 45 days and 92 % of patients at 6 months. The primary efficacy endpoint was a composite of stroke, cardiovascular death and systemic embolism occurred in 3.0 per 100 patient-years in the device group and 4.9 per 100 patient-years in the warfarin group (RR = 0.62; 95 % CI [0.35–1.25]). The probability for non-inferiority of the intervention group was more than 99.9 %. The primary safety endpoint included major bleeding, pericardial effusion, and device embolization, which occurred more frequently in the device group than in the control group (7.4 versus 4.4 per 100 patient-years, RR = 1.69, 95 % CI [1.01–3.19]). There were five procedural-related ischemic strokes, 22 pericardial effusions and three device embolizations.11 Due to the higher rate of the primary safety endpoint in the WATCHMAN group and the lack of long-term follow-up data, the US Food and Drug Administration requested a second randomized trial prior to device approval. The Prospective Randomized Evaluation of the WATCHMAN Left Atrial Appendage Closure Device in Patients with Atrial Fibrillation Versus Long-Term Warfarin Therapy (PREVAIL) study was designed to validate the initial results of PROTECT AF.30 This trial randomized 407 patients with a mean CHADS2 score of 2.6 in a 2:1 fashion to device versus warfarin. At 18 months, the rate of the first co-primary efficacy endpoint (composite of stroke, systemic embolism and cardiovascular/unexplained death) was 0.064 in the device group and 0.063 in the control group with a RR of 1.07 with an upper bound of 1.89, which was higher than the prespecified criterion of 1.75 for non-inferiority (CI 95 %). Although this trial did not achieve non-inferiority for this endpoint, it did achieve non-inferiority for the second co-primary efficacy endpoint (stroke or systemic embolism >7 days post-randomization) at a rate of 0.0253 in the device group compared to 0.0200 in the control group (95 %

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credible interval (CrI) -0.0190–0.0273). Early safety events occurred in 2.2 % of the patients in the WATCHMAN arm, significantly lower than in PROTECT AF, achieving the pre-specified performance goal. A significant improvement in implant success rate of 95.1 % was noted compared to 90.9 % in the PROTECT AF trial. The Continued Access Protocol (CAP) registry was designed to gain further efficacy and safety data in a non-randomized fashion in patients undergoing WATCHMAN implantation. 31 Combining longerterm data from PROTECT AF and CAP, there was a significant decrease in procedure or device-related safety events. The rate of serious pericardial effusion decreased from 5.0 % in PROTECT AF to 2.2 % in CAP (p=0.019) and periprocedural stroke decreased from 0.9 % to 0 % (p=0.039).31 There was also a reduction in safety events noted from the first half of the PROTECT AF patients compared to the second half of the study. This signifies a reduction of safety events with improved operator experience.31 Newer data from the PROTECT AF study with a follow-up of 3.8 years was published in 2014. Non-inferiority of WATCHMAN compared to warfarin was repeatedly demonstrated. In addition, superiority for the primary efficacy endpoint (composite of stroke, cardiovascular death and systemic embolism) was seen for the first time. Also, the primary safety endpoint was similar to the warfarin group. The device group had a lower rate of hemorrhagic strokes in addition to a lower mortality rate with a 34 % relative risk reduction compared to warfarin.32 The results of the PROTECT AF and PREVAIL trials, in combination with the CAP registry and long-term follow up data from PROTECT AF, led to FDA approval of WATCHMAN in March 2015, in higher-risk patients (CHADS-VASc score of >2) with non-valvular AF as an alternative to long-term anticoagulation. One of the major limitations to WATCHMAN is the necessity for anticoagulation for at least the first 45 days post-implant. This is a crucial consideration since one of the main indications for LAA occlusion is a contraindication to chronic oral anticoagulation. This prompted the ASA Plavix Feasibility Study with WATCHMAN Left Atrial Appendage Closure Technology (ASAP) study,33 which was a prospective, non-randomized study in patients who underwent WATCHMAN with a contraindication to oral anticoagulation. Instead of warfarin for the first 45 days, 150 patients with non-valvular AF and a mean CHADS2 score of 2.8 who underwent WATCHMAN received continuous aspirin and clopidogrel for six months. The primary efficacy endpoint was a composite of ischemic stroke, hemorrhagic stroke, systemic embolism and cardiovascular/ unexplained death, with a mean follow-up of 14 months. Serious procedure- or device-related safety events occurred in 8.7 % of patients. All-cause stroke or systemic embolism occurred in four patients (2.3 % per year), ischemic stroke in three patients (1.7 % per year) and hemorrhagic stroke in one patient (0.6 % per year). The ischemic stroke rate was less than would be expected by CHADS2 score.33 This study suggested that

LAA occlusion with WATCHMAN could be safely performed without a warfarin transition in patients with a contraindication to anticoagulation. These results must be interpreted with caution, however, since the study was small and observational in nature. Another significant limitation to the WATCHMAN trials is that the device was compared only to warfarin. The novel oral anticoagulant

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Electrophysiology Stroke Prevention medications are non-inferior, if not superior, to warfarin in efficacy and safety. The benefit of LAA occlusion with the rising use of NOACs for stroke risk reduction of non-valvular AF is unclear. The Amplatzer™ Cardiac Plug (ACP) (St Jude) is another potential option for LAA occlusion. It was originally used for closure of a patent foramen ovale or atrial septal defect. The device was redesigned and used for the LAA. The first generation is a self-expanding nitinol wire mesh and polyester patch with a lobe and disk connected by a central waist. The device is delivered across a transseptal puncture into the LAA, and the disk unfolds to cover the appendage. There have been several small clinical studies showing successful LAA occlusion in approximately 98 % of the patients with risks of procedural complications in approximately 9.8 % of the patients.34 This device has been implanted under local anaesthesia as well as under general anaesthesia and post-procedure anticoagulation is not required. However, despite dual antiplatelet therapy post-procedure follow-up imaging detected thrombus formation on the device in 17 % of the patients. Other complications included stroke, major bleeding, pericardial effusion and device embolization. A second-generation device (ACP2 Amulet) has been developed that allows closure of larger LAA, improves stability, decreases the risk for embolization and is repositionable.35 This device is not currently available in the US. Several other LAA occlusion devices such as WaveCrest™ (Coherex Medical), LAmbre™ (Lifetech), and CellAegis Devices are in development and early stages of testing.36 There are limited clinical safety and efficacy data on these so far but studies are ongoing. LAA occlusion represents a growing therapy for thromboembolic stroke risk reduction in patients with non-valvular AF, particularly in those who are unable to take long-term anticoagulation. More prospective trials with longer follow-up durations are needed in addition to comparisons against novel oral anticoagulants.

Transient Anticoagulation at the Time of Atrial Fibrillation Detection In patients with whom rhythm control strategy is the preferred therapeutic option the duration of AF may play a critical role in determining the period of their most significant thromboembolic risk. Patients with AF lasting two days or more have a 5–7 % risk for clinical thromboembolism if cardioversion is not preceded by several weeks of warfarin therapy.37–40 The risk decreases to 0–1.6 % with 2–4 weeks of warfarin prophylaxis or short term anticoagulation therapy in addition to screening with tranesophageal echocardiogram.37,39 Hence, in patients with AF duration less than 48 hours, the benefit of thromobembolic risk reduction by anticoagulation warrants a closer examination to determine if these patients with short AF episodes require any anticoagulation therapy. A prospective observational study attempted to estimate the thromboembolic risk of patients with AF duration less than 48 hours.41 A cohort of 357 patients admitted to a hospital with AF duration less than 48 hours were followed. One hundred and eighty-one patients (48.3 %) had a prior history of AF, and 23 (6.1 %) had a prior history of thromboembolism. Three hundred and fifty seven patients (95.2 %) converted to sinus rhythm during the index admission. Spontaneous conversion occurred in 250 patients (66.7 %) and pharmacological or

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electrical cardioversion was done in one hundred and seven patients (28.5 %). Three patients (0.8 %) who had converted spontaneously had a clinical thromboembolic event. One patient had a stroke, one had a TIA and one had a peripheral thromboembolus. None of the three patients had a prior history of AF or thromboembolism and all had normal left ventricular systolic function. It was concluded that in patients presenting with AF duration less than 48 hours, the likelihood of cardioversion-related clinical thromboembolism was low. A review of the published data,42 mainly from emergency medical patient encounters, supports the practice of cardioversion and discharge from the emergency room as safe and adequate rhythm control management for patients presenting with recent onset AF of less than 48 hours. The 2014 AHA/ACC/HRS AF guidelines16 assigns a Class IIb indication for cardioversion of patients with AF or atrial flutter of less than 48 hours duration, who are at low thromboembolic risk without the need for post cardioversion oral anticoagulation. Pacemakers and cardiac defibrillators function as implanted cardiac rhythm monitors (ICMs) that provide a unique window on the occurrence of AF episodes. A targeted approach is to anticoagulate patients with ICMs during their most vulnerable period for thromboembolic risk during AF episodes may be an alternative therapy. This could potentially reduce chronic anticoagulation use, thereby reducing cost, bleeding risks and improving quality of life. The general approach of chronic anticoagulation in AF patients may be partly due to limitations in the ability to immediately and precisely respond to AF episodes when they occur. Hence, in patients with non-valvular, paroxysmal AF with brief episodes and who may otherwise be asymptomatic, the risk of bleeding from chronic anticoagulation may not be warranted. An alternative anticoagulation strategy may be supported by evidence for a temporal relationship between subclinical AF and embolic events. The Asymptomatic Stroke and Atrial Fibrillation Evaluation in Pacemaker Patients (ASSERT) trial43 followed a cohort of 2,580 patients who had ICMs and no history of AF. During follow-up, 51 patients experienced stroke or systemic embolism. Of the 51 patients 51 % had subclinical AF (SCAF) recorded by their devices. In 18 patients (35 %) SCAF was detected before stroke or systemic embolism. However, only four patients (8 %) had SCAF within 30 days of the thromboembolic event. In patients with SCAF detected greater than 30 days before their thromboembolic event, the most recent AF episode to the time of the thromboembolic event had a median interval of 339 days. The authors inferred that, although there is an increased risk of thromboembolic events in patients with SCAF, very few had SCAF in the month before the events. Hence, with remote monitoring technology and real-time monitoring for the development of AF provided by ICMs, a new approach for targeted anticoagulation therapy may be considered in low-risk, lowburden and asymptomatic non-valvular AF patients. The Rhythm Evalution for Anticoagulation with Continuous monitoring Trial (REACT.COM)44 is a pilot study that has been recently completed. It is designed as a single-arm, prospective multicenter study to test this strategy. The primary goal of the study was to reduce the duration of chronic anticoagulation therapy in addition to reducing the risk of stroke and bleeding with the use of ICM-guided novel oral anticoagulant

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Emerging Strategies for Stroke Prevention in Atrial Fibrillation (NOAC) therapy in response to specific AF episodes. Sixty-nine patients with nonpermanent AF were enrolled. Patients were initially monitored for 60 days to document that no AF episodes longer than one hour were recorded. NOACs were subsequently discontinued but reinitiated for a 30-day duration in response to an AF episode longer than one hour diagnosed through daily ICM transmissions. Over a mean follow-up of 466 ± 131 days, compliance with transmission was 98.7 %. AF episodes longer than one hour were noted in 18 (31 %) patients, resulting in a total time on NOAC of 1,472 days. The authors concluded that there was a 94 % reduction in the duration of NOAC therapy compared to chronic anticoagulation. There were three traumatic bleeding events in patients on aspirin, and three possible TIAs were observed in patients on aspirin with CHADS2 score of one. No strokes or death were noted over the study duration. This study demonstrated the feasibility of a tailored anticoagulation therapy for AF patients with the use of constant monitoring and rapid initiation of treatment to limit total anticoagulation therapy time significantly. While a larger study is necessary to validate the findings of this study, it demonstrates a potential opportunity for

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individualised management of anticoagulation therapy while potentially decreasing bleeding risks associated with chronic anticoagulation.

Conclusion Stroke due to thromboembolism is a primary concern for patients with AF. Stroke prevention by systemic anticoagulation with an oral anticoagulant remains the standard of care for management of this risk. The newer CHADS 2 -VASc thromboembolic risk estimation tool has shifted the indications for chronic anticoagulation to include a significantly greater proportion of the AF patient population. The new NOAC agents appear superior to warfarin in terms of ease of use and lower risk of intracranial bleeding. Pooled data from major clinical trials of the NOACs suggest a superior protection against stroke relative to warfarin. Despite this, a significant fraction of the AF patient population has contraindications for chronic anticoagulation. In that group, the development of strategies for occlusion of the LAA has emerged as a viable therapeutic alternative. At present, data do not support rhythm control as a means for reducing thromboembolic risk. n

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. DOI: 10.1161/CIR.0000000000000040; PMID: 24682348 Bertaglia E, Stabile G, Pappone A, et al., Updated National Multicenter Registry on Procedural Safety of Catheter Ablation for Atrial Fibrillation. J Cardiovasc Electrophysiol 2013;24:1069–74. DOI: 10.1111/jce.12194. PMID: 23799876 Nair GM1, Nery PB, Diwakaramenon S, et al. A systematic review of randomized trials comparing radiofrequency ablation with antiarrhythmic medications in patients with atrial fibrillation. J Cardiovasc Electrophysiol 2009;20:138–44. DOI: 10.1111/j.1540-8167.2008.01285.x; PMID:18775040 Blackshear JL, Odell JA. Appendage obliteration to reduce stroke in cardiac surgical patients with atrial fibrillation. Ann Thorac Surg 1996;61:755–9. PMID: 8572814 Veinot JP, Harrity PJ, Gentile F, et al. Anatomy of the normal left atrial appendage: a quantitative study of age-related changes in 500 autopsy hearts: implications for echocardiographic examination. Circulation 1997;96:3112–5. PMID: 9386182 Inoue S, Murakami Y, Sano K, et al. Atrium as a source of brain natriuretic polypeptide in patients with atrial fibrillation. J Card Fail 2000;6:92–6. PMID: 10908082 Hoit BD, Shao Y, Gabel M. Influence of acutely altered loading conditions on left atrial appendage flow velocities. J Am Coll Cardiol 1994;24:1117–23. PMID: 7930206 Hoit BD, Shao Y, Gabel M. Influence of acutely altered loading conditions on left atrial appendage flow velocities. J Am Coll Cardiol 1994;24:1117–23. PMID: 7930206 Blackshear JL, Johnson WD, Odell JA, et al. Thoracoscopic extracardiac obliteration of the left atrial appendage for stroke risk reduction in atrial fibrillation. J Am Coll Cardiol 2003;42:1249–52. PMID: 14522490 Miller MA, Gangireddy SR, Doshi SK, et al. A Multi-Center Study on Acute and Long-Term Safety and Efficacy of Percutaneous Left Atrial Appendage Closure using an Epicardial Suture Snaring Device. Heart Rhythm 2014;11:1853–9. DOI: 10.1016/j. hrthm.2014.07.032; PMID: 25068574 Price MJ, Gibson DN, Yakubov SJ, et al. Early safety and efficacy of percutaneous left atrial appendage suture ligation: results from the U.S. transcatheter LAA ligation consortium. J Am Coll Cardiol 2014;64:565–72. DOI: 10.1016/j.jacc.2014.03.057. PMID: 25104525; PMCID: PMC4524558 Di BiaseL,Burkhardt JD,Gibson DN, etal. 2Dand3D TEE evaluation of an early reopening of the LARIAT epicardial left atrial appendage closure device. Heart Rhythm 2014;11:1087–8. DOI: 10.1016/j.hrthm.2013.08.023; PMID: 23973947 Giedrimas E, Lin AC, Knight BP. Left atrial thrombus after appendage closure using LARIAT. Circ Arrhythm Electrophysiol 2013;6:e52–3. DOI: 10.1161/CIRCEP.113.000532; PMID: 23962862 Holmes DR, Reddy VY, Turi ZG, et al. Percutaneous closure of the left atrial appendage versus warfarin therapy for prevention of stroke in patients with atrial fibrillation: a randomized noninferiority trial. Lancet 2009;374:534–42. DOI: 10.1016/S01406736(09)61343-X; PMID: 19683639 Holmes DR Jr, Kar S, Price MJ, et al. Prospective randomized evaluation of the WATCHMAN left atrial appendage closure device in patients with atrial fibrillation versus long-term

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warfarin therapy: the PREVAIL trial. J Am Coll Cardiol 2014;64:1–12. DOI: 10.1016/j.jacc.2014.04.029; PMID: 24998121 Reddy VY, Holmes D, Doshi SK, et al. Safety of percutaneous left atrial appendage closure: results from the Watchman Left Atrial Appendage System for Embolic Protection in Patients with AF (PROTECTAF) clinical trial and the Continued Access Registry. Circulation 2011;123:417–24. DOI: 10.1161/ CIRCULATIONAHA.110.976449; PMID: 21242484 Reddy VY, Sievert H, Halperin J, et al. Percutaneous left atrial appendage closure vs warfarin for atrial fibrillation: a randomized clinical trial. J Am Med Assoc 2014;312:1988–98. DOI: 10.1001/jama.2014.15192; PMID: 25399274 Reddy VY, Möbius-Winkler S, Miller MA, et al. Left atrial appendage closure with the Watchman device in patients with a contraindication for oral anticoagulation: the ASAP study (ASA Plavix Feasibility Study With Watchman Left Atrial Appendage Closure Technology). J Am Coll Cardiol 2013;61:2551–6. DOI: 10.1016/j.jacc.2013.03.035; PMID: 23583249 Nietlispach F, Gloekler S, Krause R, et al. Amplatzer left atrial appendage occlusion: single center10-year experience. Catheter Cardiovasc Interv 2013;82:283–9. DOI: 10.1002/ccd.24872; PMID: 23412815 Freixa X, Chan JL, Tzikas A, et al. The Amplatzer Cardiac Plug 2 for left atrial appendage occlusion: novel features and first-inman experience. EuroIntervention 2013;8:1094–8. DOI: 10.4244/ EIJV8I9A167; PMID: 23339815 Romero J, Natale A, Engstrom K, Di Biase L. Left atrial appendage isolation using percutaneous (endocardial/ epicardial) devices: Pre-clinical and clinical experience. Trends

Cardiovasc Med 2016;26:182–99. Epub 2015 Jun 4; DOI: 10.1016/j. tcm.2015.05.009; PMID: 26141854 37. Bjerkelund CJ, Orning OM. The efficacy of anticoagulant therapy in preventing embolism related to D.C. electrical conversion of atrial fibrillation. Am J Cardiol 1969;23:208–16. PMID: 4180019 38. Lown B, Perlroth MG, Kaidbey S, et al. “Cardioversion” of atrial fibrillation: a report on the treatment of 65 episodes in 50 patients. N Engl J Med 1963;269:325–31; PMID: 13931297 39. Weinberg DM, Mancini J. Anticoagulation for cardioversion of atrial fibrillation. Am J Cardiol 1989;63:745–6; PMID: 2923062 40. Peterson P, Godtfredsen J. Embolic complications in paroxysmal atrial fibrillation. Stroke 1986;17:622–6. PMID: 3738942 41. Weigner MJ, Caulfield TA, Danias PG, et al. Risk for clinical thromboembolism associated with conversion to sinus rhythm in patients with atrial fibrillation lasting less than 48 hours. Ann Intern Med 1997;126:615–20. PMID: 9103128 42. Von Besser K, Mills AM. Is discharge to home after emergency department cardioversion safe for the treatment of recentonset atrial fibrillation? Ann Emerg Med 2011;58:517–20. doi: 10.1016/j.annemergmed.2011.06.014. PMID: 22098994. 43. Brambatti M, Connolly SJ, Gold MR, et al. ASSERT Investigators: Temporal relationship between subclinical atrial ﬁbrillation and embolic events. Circulation 2014;129:2094–9. DOI: 10.1161/ CIRCULATIONAHA.113.007825; PMID: 24633881. 44. Passman, R, Leong-Sit P, Andrei AC, et al. Targeted Anticoagulation for Atrial Fibrillation Guided by Continuous Rhythm Assessment With an Insertable Cardiac Monitor: The Rhythm Evaluation for Anticoagulation With Continuous Monitoring (REACT.COM) Pilot Study. J Cardiovasc Electrophysiol 2015 Oct 29. [epub ahead of press] DOI: 10.1111/jce.12864; PMID: 26511221.

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Electrophysiology

Atrial Fibrillation Management

LE ATION.

Optimizing Heart Rate and Controlling Symptoms in Atrial Fibrillation P ra g ne s h Pa r i k h , M D a n d KL Ve n k a t a c h a l a m , M D Mayo Clinic Florida, Jacksonville, FL

Abstract Atrial fibrillation (AF) is the most common arrhythmia noted in clinical practice and its incidence and prevalence are on the rise. The single most important intervention is the evaluation and treatment of stroke risk. Once the risk for stroke has been minimized, controlling the ventricular rate and treating symptoms become relevant. In this review article, we emphasize the importance of confirming and treating the appropriate arrhythmia and correlating symptoms with rhythm changes. Furthermore, we evaluate some of the risk factors for AF that independently result in symptoms, underlining the need to treat these risk factors as part of symptom control. We then discuss existing and novel approaches to rate control in AF and briefly cover rhythm control methods.

Keywords Atrial fibrillation, AF, risk factors, symptoms, quality of life, rate control, rhythm control Disclosure: The authors have no conflicts of interest to declare. Received: January 6, 2016 Accepted: February 3, 2016 Citation: US Cardiology Review, 2016;10(1):26–9 Correspondence: KL Venkatachalam, Department of Cardiology, Mayo Clinic Florida, 4500 San Pablo Road, Davis 7, Jacksonville, FL 32224, USA. E: Venkat.KL@mayo.edu

Atrial fibrillation (AF) is the most common pathologic clinical arrhythmia lasting more than 30 seconds, and its incidence and prevalence continue to increase. It has been estimated that 5.9 % of patients aged >65 years suffer from AF.1 In the Rotterdam study, 17.8 % of patients over 85 had AF.2 The lifetime risk for developing AF in both men and women above age 40 is one in four.3 This arrhythmia, with its attendant comorbidities, poses a substantial physical, psychologic, and financial burden on the populace and is a significant public health concern. Evaluating and managing AF appropriately at the primary care level (by minimizing risk factors) and recognizing and treating the arrhythmia immediately will play important roles in containing this epidemic. This review article addresses the recognition of AF and the importance of distinguishing it from other arrhythmias with an irregular pulse. It discusses the available options for stroke reduction and examines the correlation between symptoms and rhythms. It then reviews existing and potentially novel approaches to rate and rhythm control and their role in controlling symptoms in patients with AF.

Types of Atrial Fibrillation The type of AF determines treatment, and we will use the definitions from the most recent American Heart Association/American College of Cardiology/Heart Rhythm Society (AHA/ACC/HRS) guidelines on AF from 2014.4 Paroxysmal AF (PAF) terminates spontaneously or with intervention within 7 days of onset. Persistent AF lasts >7 days and often requires pharmacologic or electrical cardioversion. Long-standing persistent AF lasts >12 months. This is an important change to the definition since cardioversion and ablation success rates diminish substantially in patients with long-standing persistent AF. Permanent AF describes the situation where the patient and physician have decided to stop pursuing a rhythm control strategy.

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Confirming the Arrhythmia The most common clue for suspecting that a patient may be in AF is the irregularity of the pulse. As medical students, we are all taught to associate an “irregularly irregular” pulse with AF. However, there are several arrhythmias that can produce irregularly irregular pulses and a few that produce regularly irregular pulses, which can also feel irregularly irregular if they have not been assessed for an adequate period of time. Irregularly irregular pulses are present in AF, atrial flutter with variable atrioventricular (AV) conduction, wandering atrial pacemaker, multifocal atrial tachycardia, and frequent premature atrial and ventricular complexes. Regularly irregular pulses may be noted in patients with sinoatrial exit block as well as second degree AV block. If the pulse is not monitored for an adequate interval the pattern of irregularity may not be perceived, and a wrong conclusion may be drawn. An electrical rhythm strip is still the only reliable way to identify these arrhythmias. Patients now have access to home blood pressure (BP) monitors, pulse oximeters, and single lead rhythm monitors, which indicate the presence of irregularity.5,6 This does not constitute proof of AF. Even computer-based ECG diagnostics frequently get the above arrhythmias confused, and simply reading the verbal report of an ECG without looking at the rhythm strips for oneself will result in an erroneous diagnosis (see Figure 1). Implanted pacemaker and defibrillator diagnostics can also confuse supraventricular tachycardia with AF or atrial flutter and simply using the presence of atrial high rate (AHR) episodes from a pacemaker check as proof of AF is not appropriate. The stored electrograms need to be evaluated to confirm the arrhythmia before treatment can be suggested.

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Controlling Symptoms in Atrial Fibrillation Based on present knowledge, only AF and atrial flutter pose a significant stroke risk and require risk-factor-based anticoagulation. Also, the treatment for typical atrial flutter (counterclockwise isthmus dependent flutter) is significantly different from the treatment of AF since typical atrial flutter can be ablated relatively easily with excellent success rates (90 %). The clinician is obliged to offer patients the appropriate treatment choices based on risk and efficacy, and identifying the correct arrhythmia is the first step.

Evaluating and Treating Stroke Risk Once AF has been confirmed, estimating a patient’s stroke risk in AF is paramount, as an embolic stroke due to inadequately treated AF is the surest way to negatively impact quality of life (QoL) in these patients. Several algorithms have been developed over the past 25 years and the CHA2DS2-VaSc scoring system has been most recently validated.7–9 With nonvalvular AF and a CHA2DS2-VASc score of 0 (i.e., aged <65 years with lone AF), both the US and European guidelines agree that it is reasonable to omit antithrombotic therapy. However, the two guidelines differ in their recommendations for patients with a CHA2DS2-VaSc score of 1. The US guidelines allow for antiplatelet therapy, anticoagulation, or neither, based upon an assessment of the risk for bleeding complications and patient preferences; whereas the European guidelines recommend anticoagulation as the only option. Both guidelines agree that at a CHA2DS2-VaSc score of ≥2 anticoagulation should be instituted.4,10 Warfarin, dabigatran, rivaroxaban, apixaban, and edoxaban have been approved for this use. Patients who are intolerant, or have a contraindication, to the use of anticoagulants would be candidates for a left atrial appendage occlusion, whose efficacy has been validated recently.11

Symptoms Related to Atrial Fibrillation Patients may present with a variety of symptoms related to AF. The most common symptoms include palpitations, dyspnea, and fatigue. Additionally, chest pain, lightheadedness, presyncope, and syncope may be also reported. More than half of patients with AF experience a decrease in exercise tolerance defined by lowered New York Heart Association functional class. In addition to simple awareness of having an irregular rhythm, there are multiple potential mechanisms for these symptoms, including loss of atrial contraction, loss of AV synchrony, bradycardia, tachycardia, or even tachycardia-mediated cardiomyopathy. Understanding the type of symptom and the mechanism behind it are important steps in determining the optimal treatment strategy for patients with AF.

Figure 1: Electrocardiogram Rhythm Strips Showing a) Atrial Fibrillation; b) Atrial Flutter with Variable Atrioventricular Block; c) Multifocal Atrial Tachycardia; and d) Sinus Rhythm with Frequent Premature Atrial Complexes A

Figure 2: An Example of the Lack of Symptom–Arrhythmia Correlation on Event Monitoring Monitored Daily Reports Date, time Symptom 08/07/2015 21:51:55 EDT auto

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Correlating Symptoms with Rhythm While patients may present with a variety of symptoms in AF, these may also be noted in a host of other conditions including pulmonary disease, poorly controlled hypertension (or due to the BP medications themselves), obstructive sleep apnea, obesity, or deconditioning.12–14 Therefore, it is important to confirm that the patient’s symptoms are, in fact, related to AF before beginning treatment. This is typically achieved with prolonged rhythm monitoring, ranging from 1 to 30 days depending on the frequency of symptoms. This approach can identify symptomatic bradycardia, prolonged pauses, tachycardia, or simply awareness of conversion into or out of AF. However, it is important to correlate the patient’s symptoms temporally with an episode of AF, as

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noted in Figure 2. Having episodes of paroxysmal AF on a particular day should not result in symptoms on another day, and concluding that AF produced these symptoms will result in needless testing and therapy. Additionally, an exercise electrogram can be utilized to identify poor rate control or chronotropic incompetence as potential causes for dyspnea on exertion or exercise intolerance. Once the AF and symptoms have been correlated, appropriate therapy can be instituted.15 Anxiety in the presence of palpitations is common; allaying a patient’s fears regarding the arrhythmia and using a systematic approach to treating the risk factors and controlling AF will go a long way toward improving QoL in these patients.16

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Electrophysiology

Atrial Fibrillation Management

Figure 3: Rate Control Recommendations from the 2014 American Heart Association/American College of Cardiology/ Heart Rhythm Society Guideline for Atrial Fibrillation Management

Atrial fibrillation

No other CV disease

Beta blocker Diltiazem Verapamil

Hypertension or HFpEF

Beta blocker Diltiazem Verapamil

LV dysfunction or HF

Beta blocker† Digoxin‡

COPD

Beta blocker Diltiazem Verapamil

Amiodarone§ †Drugs are listed alphabetically; ‡Digoxin is not usually first-line therapy. It may be combined with a beta blocker and/or a nondihydropyridine calcium channel blocker when ventricular rate control is insufficient and may be useful in patients with heart failure (HF). §In part because of concern over its side-effect profile, use of amiodarone for chronic control of ventricular rate should be reserved for patients who do not respond to or are intolerant of beta blockers or nondihydropyridine calcium antagonists. COPD = chronic obstructive pulmonary disease; CV = cardiovascular; HFpEF = heart failure with preserved ejection fraction; LV = left ventricular.

Figure 4: Drug Selection for Rhythm Control in Atrial Fibrillation from the 2014 American Heart Association/American College of Cardiology/Heart Rhythm Society guideline for Atrial Fibrillation Management. No structural heart disease

Structural heart disease

‡

CAD

HF ‡

Dofetilide§II Dronedarone Flecainide§¶ Propafenone§¶ Sotalol§II

Catheter ablation

Amiodarone

Dofetilide§II Dronedarone Sotalol§II

Catheter ablation

Amiodarone Dofetilide§II

Amiodarone

†Drugs are listed alphabetically; ‡Depending on patient preference when performed in experienced centers; §Not recommended with severe left ventricular hypertrophy (wall thickness >1.5 cm); II Should be used with caution in patients at risk for torsades de pointes ventricular tachycardia; ¶Should be combined with atrioventricular nodal blocking agents. CAD = coronary artery disease; HF = heart failure.

for patients with AF. However multiple studies have demonstrated no association between caffeine exposure and risk for AF, and there is even evidence to suggest that caffeine consumption in moderate amounts may actually decrease the occurrence of AF.22 Finally, exercise can improve symptoms throughout the spectrum of AF. In fact, multiple studies have demonstrated that exercise training in adults with permanent AF significantly improves rate control (at rest and with exertion), functional capacity, muscle strength, activities of daily living, and QoL.23

Approaches to Rate Control in Atrial Fibrillation Controlling heart rate (ventricular response) is a well-established approach to treating patients with minimally symptomatic AF. Beta blockers, calcium channel blockers, and digitalis (see Figure 3) are commonly used to accomplish this goal.24,25 The Atrial Fibrillation Followup Investigation of Rhythm Management (AFFIRM) trial used 80 beats/ min as a reasonable resting heart rate in AF. More recently, the Rate Control Efficacy in Permanent Atrial Fibrillation II (RACE-II) trial compared strict versus lenient rate control and demonstrated that a lenient rate control strategy does not increase morbidity. The criticism levelled against this study is that most patients in the control and treatment groups had heart rates below 90 beats/min and the results were really based on an intention-to-treat analysis.26,27 In active individuals, digitalis is not as helpful for rate control since sympathetic drive during activity can overwhelm the vagotonic action of digitalis. However, it can be useful in conjunction with a beta blocker or calcium channel blocker since it can control ventricular rate without reducing BP. Anti-arrhythmic drugs (AADs), even if they fail to maintain sinus rhythm, can provide rate control without lowering BP. Amiodarone has strong AV nodal blocking activity and may be effective in this application. There is mounting evidence that the hyperpolarizationactivated cyclic nucleotide-gated (HCN) channels, responsible for funny current (If) modulation, are also present in the AV node and could be targeted to achieve rate control. The prototypical drug to modulate If in the sinus node is ivabradine.28 Recent case reports highlight the ratecontrolling effect of ivabradine in AF through its additional action on the AV node, and this may turn out to be a very useful drug for this purpose, though presently this would be an off-label use of this medication.29–31 The extreme approach in the continuum of rate control is AV node ablation, with pacemaker implantation. This technique has fallen out of favor over the past 20 years due to the rapid incorporation of AF ablation into clinical practice. Nevertheless, AV node ablation with pacemaker implantation remains a very effective technique to control symptoms and improve QoL, particularly in the elderly population, often intolerant of rate-controlling medications.32–33

Managing Rhythm Control in Atrial Fibrillation Lifestyle Modification In addition to considering pharmacologic or procedural treatment options for AF management, it is important to address modifiable risk factors. Obesity, obstructive sleep apnea, hypertension, type 2 diabetes, and alcohol consumption have all been identified as independent risk factors for the development of AF. Properly evaluating and treating these risk factors may help minimize episodes of AF and also tackle the symptoms.17–21 Caffeine intake has also often been discouraged

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In patients who are symptomatic from AF, despite good control of heart rate, a rhythm-control strategy should be implemented. Success at maintaining sinus rhythm long-term is highest with good control of underlying risk factors (hypertension, sleep apnea, and obesity). Cardioversion as a means of establishing that AF is responsible for symptoms is a very reasonable first step, even if the long-term success of this approach is only 30–35 %. Once the symptom-rhythm correlation has been established and risk factors have been controlled, AADs

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Controlling Symptoms in Atrial Fibrillation may be attempted. The 2014 ACC/AHA/HRS AF guidelines provide a systematic approach to trying AADs (see Figure 4), based on the patient’s co-morbidities.4 Ranolazine in conjunction with dronedarone or ivabradine may also play an important role in effective rate control of AF.30,34 Intolerance of AADs or breakthrough AF while on AADs should prompt consideration of an invasive approach. The specific technique (radiofrequency ablation, cryoablation, focal impulse and rotor modulation, laser ablation, or a surgical maze procedure in patients undergoing cardiac surgery) is not as important as the decision to attempt the intervention, and the risks and benefits of this approach need to be discussed with patients in detail. The success rate for all ablative methods for paroxysmal AF has been reported between

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66–89 % at 1 year. In long-standing persistent AF, multiple ablation procedures may often be required.35,36

Conclusion AF should be considered a chronic condition, and like other chronic conditions, such as hypertension and diabetes, should be treated with risk factor control and symptom management. Since the morbidity associated with this condition and with the available treatment options is considerable, exhaustive attempts to confirm the diagnosis of AF must be made early. Symptom-rhythm correlation is an important part of this evaluation. Advances in heart rate control, rhythm management, and stroke prevention over the next decade will aid in reducing the burden of AF. n

future research opportunities. Circulation 2012;125:2933–43. doi: 10.1161/CIRCULATIONAHA.111.069450; PMID: 22689930 Vermond RA, Crijns HJGM, Tijssen JGP, et al. Symptom severity is associated with cardiovascular outcome in patients with permanent atrial fibrillation in the RACE II study. Europace 2014;16:1417–25. doi: 10.1093/europace/euu151; PMID: 24938627 Patel N, Chung EH, Mounsey JP, et al. Effectiveness of atrial fibrillation monitor characteristics to predict severity of symptoms of atrial fibrillation. Am J Cardiol 2014;113 :1674–8. doi: 10.1016/j.amjcard.2014.02.022; PMID: 24698459 Kochhäuser S, Joza J, Essebag V, et al. The impact of duration of atrial fibrillation recurrences on measures of health related quality of life and symptoms. Pacing Clin Electrophysiol 2015: epub ahead of print. doi: 10.1111/pace.12772; PMID: 26516038 Pathak RK, Middeldorp ME, Meredith M, et al. Long-Term Effect of Goal-Directed Weight Management in an Atrial Fibrillation Cohort: A Long-Term Follow-Up Study (LEGACY). J Am Coll Cardiol 2015;65 :2159–69. doi: 10.1016/j.jacc.2015.03.002; PMID: 25792361 Nalliah CJ, Sanders P, Kottkamp H, Kalman JM. The role of obesity in atrial fibrillation. Eur Heart J 2015; PMID: 26371114: epub ahead of press. Chung MK, Foldvary-Schaefer N, Somers VK, et al. Atrial fibrillation, sleep apnea and obesity. Nat Clin Pract Cardiovasc Med 2004;1 :56–9. PMID: 16265261 Kanagala R, Murali NS, Friedman PA, et al. Obstructive sleep apnea and the recurrence of atrial fibrillation. Circulation 2003;107 :2589–94. PMID: 12743002 Gami AS, Hodge DO, Herges RM, et al. Obstructive sleep apnea, obesity, and the risk of incident atrial fibrillation. J Am Coll Cardiol 2007;49 :565–71. PMID: 17276180 Menezes AR, Lavie CJ, De Schutter A, et al. Lifestyle modification in the prevention and treatment of atrial fibrillation. Prog Cardiovasc Dis 2015;58 :117–25. doi: 10.1016/j. pcad.2015.07.001; PMID: 26184674 Reed JL, Mark AE, Reid RD, Pipe AL. The effects of chronic exercise training in individuals with permanent atrial fibrillation: a systematic review. Can J Cardiol 2013;29 :1721–8. Costea AI, Platonov PG. Rate modulation drugs in atrial fibrillation: what is the clinical impact? J Cardiovasc Electrophysiol 2015;26 :142–4. Waldo AL. Rate control versus rhythm control in atrial fibrillation: lessons learned from clinical trials of atrial fibrillation. Prog Cardiovasc Dis 2015;58 :168–76. Van Gelder IC, Groenveld HF, Crijns HJ, et al. Lenient versus strict rate control in patients with atrial fibrillation. N Engl J Med 2010;362:1363–73. doi: 10.1056/NEJMoa1001337; PMID: 20231232 Steinberg BA, Kim S, Thomas L, et al. Increased heart rate is associated with higher mortality in patients with atrial fibrillation (AF): Results from the Outcomes Registry for Better Informed Treatment of AF (ORBIT-AF). JAMA 2015;4 :e002031. doi: 10.1161/JAHA.115.002031 Giuseppe C, Chiara F, Giuseppe R, Maurizio V. Addition of

29.

30.

31.

32.

33.

34.

35.

36.

ivabradine to betablockers in patients with atrial fibrillation: Effects on heart rate and exercise tolerance. Int J Cardiol 2016;202 :73–4. doi: 10.1016/j.ijcard.2015.08.207; PMID: 26386926 Moubarak G, Logeart D, Cazeau S, Cohen Solal A. Might ivabradine be useful in permanent atrial fibrillation? Int J Cardiol 2014;175:187–8. doi: 10.1016/j.ijcard.2014.04.183; PMID: 24814540 Verrier RL, Silva AF, Bonatti R, et al. Combined actions of ivabradine and ranolazine reduce ventricular rate during atrial fibrillation. J Cardiovasc Electrophysiol 2015;26 :329–35. doi: 10.1111/jce.12569; PMID: 25346368 Kosiuk J, Oebel S, John S, et al. Ivabradine for rate control in atrial fibrillation. Int J Cardiol 2015;179 :27–8. doi: 10.1016/j. ijcard.2014.10.062; PMID: 25464400 Dong K, Shen K-W, Powell BD. et al. Atrioventricular nodal ablation predicts survival benefit in patients with atrial fibrillation receiving cardiac resynchronization therapy. Heart Rhythm 2010;7 :1240–5. doi: http://dx.doi.org/10.1016/j. hrthm.2010.02.011 Vlacho K, Letsas KP, Korantzopoulos P, et al. A review on atrioventricular junction ablation and pacing for heart rate control of atrial fibrillation. J Geriatr Cardiol 2015;12 :547–54. doi: 10.11909/j.issn.1671-5411.2015.05.005 Reiffel JA, Camm AJ, Belardinelli L, et al. The HARMONY Trial: Combined Ranolazine and Dronedarone in the Management of Paroxysmal Atrial Fibrillation: Mechanistic and Therapeutic Synergism. Circ Arrhythm Electrophysiol 2015;8 :1048–56. doi: 10.1161/CIRCEP.115.002856;PMID: 26226999 Packer DL, Kowal RC, Wheelan KR, et al. Cryoballoon ablation of pulmonary veins for paroxysmal atrial fibrillation: first results of the North American Arctic Front (STOP AF) pivotal trial. J Am Coll Cardiol 2013;61 :1713–23. doi: 10.1016/j.jacc.2012.11.064; PMID: 23500312 Calkins H, Kuck KH, Cappato R, et al. 2012 HRS/EHRA/ECAS expert consensus statement on catheter and surgical ablation of atrial fibrillation: recommendations for patient selection, procedural techniques, patient management and follow-up, definitions, endpoints, and research trial design: a report of the Heart Rhythm Society (HRS) Task Force on Catheter and Surgical Ablation of Atrial Fibrillation. Developed in partnership with the European Heart Rhythm Association (EHRA), a registered branch of the European Society of Cardiology (ESC) and the European Cardiac Arrhythmia Society (ECAS); and in collaboration with the American College of Cardiology (ACC), American Heart Association (AHA), the Asia Pacific Heart Rhythm Society (APHRS), and the Society of Thoracic Surgeons (STS). Endorsed by the governing bodies of the American College of Cardiology Foundation, the American Heart Association, the European Cardiac Arrhythmia Society, the European Heart Rhythm Association, the Society of Thoracic Surgeons, the Asia Pacific Heart Rhythm Society, and the Heart Rhythm Society. Heart Rhythm 2012;9 :632–696 e21. doi: 10.1016/j.hrthm.2011.12.016; PMID: 22386883

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Venous Thromboembolic

LE ATION.

Advanced Management Options for Massive and Submassive Pulmonary Embolism Sonik a Ma lik , MD, Anju B h a r d w a j , M D, M a t t h e w E i s e n , M D a n d S a n j a y G a n d h i , M D MetroHealth Hospital, Case Western Reserve University, Cleveland, OH

Abstract Pulmonary embolism (PE) is an important cause of morbidity and mortality and presents with significant diagnostic and therapeutic challenges. Clinical presentation ranges from mild, nonspecific symptoms to syncope, shock, and sudden death. Patients with hemodynamic instability and/ or signs of right ventricular dysfunction are at high risk for adverse outcomes and may benefit from aggressive therapy and support. Therapeutic anticoagulation is indicated in all patients in the absence of contraindications. Thrombolysis should be strongly considered in selected high- and intermediate-risk patients, either by systemic infusion or percutaneous catheter-directed therapy. Other therapeutic modalities, such as vena cava filters and surgical embolectomy, are options for patients who fail or cannot tolerate anticoagulation and/or thrombolysis. This article reviews the assessment and advanced management options for acute PE with focus on high- and intermediate-risk patients.

Keywords Pulmonary embolism, right ventricular dysfunction, anticoagulation, systemic thrombolysis, percutaneous catheter-directed therapy, surgical embolectomy, vena cava filter Disclosure: The authors have no conflicts of interest to declare. Received: February 1, 2016 Accepted: February 17, 2016 Citation: US Cardiology Review, 2016;10(1):30–5 Correspondence: Sanjay Gandhi, Director Endovascular Cardiology, Associate Professor of Medicine, MetroHealth Campus, Case Western Reserve University, 2500 MetroHealth Drive, H 310 Cleveland, OH 44109, USA. E: sgandhi@metrohealth.org

Pulmonary embolism (PE) is a common and serious manifestation of venous thromboembolism (VTE) and is an important cause of morbidity and mortality in the US. The incidence is estimated to be 50 per 100,000 but increases to 500 per 100,000 in the elderly.1 There is a wide spectrum of clinical severity with mortality estimates of 1–2 % in stable individuals and up to 30 % in patients presenting with hemodynamic instability.1 Massive (or high-risk) PE is a term used to designate patients with sustained hypotension (systolic blood pressure <90 mmHg for at least 15 minutes or requiring inotropic support, not due to a cause other than PE), pulselessness, or persistent profound bradycardia. Submassive (or intermediate-risk) PE refers to those patients with acute PE without systemic hypotension but with evidence of either right ventricle (RV) dysfunction or myocardial necrosis. RV dysfunction is characterized by RV dilation, hypokinesis, or elevation of brain natriuretic peptide (BNP); myocardial necrosis is suggested by elevated troponin. Careful clinical assessment must include appropriate risk stratification since this will influence both diagnostic and therapeutic decision-making.

Clinical Presentation The clinical spectrum ranges from asymptomatic individuals to those presenting with syncope, shock, or sudden death. Symptom onset is typically rapid (minutes to hours) but can develop over days or weeks. The most common presenting symptom is dyspnea, followed by symptoms of pulmonary infarction, including pleuritic pain, cough,

Gandhi_FINAL.indd 30

and, less commonly, hemoptysis. Symptoms of deep vein thrombosis (DVT), including leg swelling or pain, may be present. Many patients have only mild or nonspecific symptoms and asymptomatic PE is sometimes seen on computed tomography (CT) scanning. The most common signs of PE are tachypnea and tachycardia. Many patients appear anxious. Lung exam is often normal but may reveal rales or decreased breath sounds. An extremity exam may reveal a palpable cord, unilateral or asymmetric edema, tenderness, warmth, erythema, or superficial venous dilation. With more extensive clot burden, findings include hypotension, hypoxemia, altered mental status, and signs of RV strain (distended neck veins, tricuspid regurgitation murmur, accentuated pulmonic component of the second heart sound, right-sided third heart sound, parasternal lift). An example case is provided in Box 1.

Risk Stratification of Massive and Submassive Pulmonary Embolism Early risk stratification in patients with PE is vital to guide acute management. The presence of hypotension and shock is associated with high mortality, and warrants immediate intervention with aggressive therapy. Nevertheless, select patients with PE in absence of hemodynamic instability may also have unfavorable outcomes, and benefit from more aggressive therapy. A combination of clinical features, diagnostic studies, and biomarkers are used to risk stratify these patients.

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Advanced Management of Massive and Submassive PE Box 1: Example Clinical Case

History A 54-year-old man with history of hypertension and obesity presented with 1-week history of left calf pain and shortness of breath. He had no history of recent travel, trauma, or surgery, and no family history of venous thromboembolism. On examination in the emergency room, his blood pressure was 110/83 with a heart rate of 110 beats per minute. He was breathing at 30 times per minute with a pulse oximetry of 87 % on 5 L nasal cannula. Computed tomography of the chest showed bilateral large pulmonary embolism (PE, see Figure 1). Additional data included a lower extremity duplex that showed left femoral deep venous thrombosis and echocardiogram showed preserved left ventricular ejection fraction of 55 % with dilated right ventricle (RV) and reduced RV function. His troponin was borderline elevated at 0.18 (upper limit 0.120) and a BNP of 200 pg/ml (upper limit 100 pg/ml). How would you manage this patient?

Management Based on his clinical presentation with stable blood pressure, simplified PE severity index (PESI) score of 2, and features of RV strain by echocardiogram and elevated biomarkers, he was characterized as intermediate–high risk for mortality. The options of anticoagulation alone versus systemic and catheter directed thrombolysis were discussed with him. Given his low risk for bleeding and high-risk clinical markers he was treated with systemic alteplase with good response and improvement in symptoms over the next 24 hours and no major bleeding complications. An inferior vena cava filter was not placed as he tolerated anticoagulation. He was transitioned to warfarin therapy bridged with enoxaparin and was doing well at the time of his clinic visit in 4 weeks.

Clinical Risk Scores One of the widely used risk scores for prognostic stratification of acute PE is the PE severity index (PESI) or its simplified version (sPESI)2,3 (see Table 1). The original PE severity index identifies 11 predictors of adverse outcome that include age >80 years, male sex, cancer, chronic heart failure, chronic obstructive pulmonary disease (COPD), tachycardia, hypotension, tachypnea, hypothermia, altered mental status, and arterial hypoxemia. The modified version—the simplified PESI index— uses a 6-point scoring system for predicting adverse outcomes: 1 point each for age >80 years, heart failure or COPD, underlying malignancy, tachycardia, hypotension, and arterial hypoxemia. Patients with PESI score >85 points (Class III–V) and sPESI ≥1 point are considered to have higher risk for adverse outcomes and mortality (see Table 1).2,3

Assessment of Right Ventricular Function RV dysfunction as assessed by echocardiography is an important adverse prognostic marker in patients with PE.4,5 The most commonly used criteria for RV dysfunction on echocardiography include: right ventricular dilatation with RV end-diastolic diameter >30 mm, RV to left ventricle (LV) end diastolic ratio ≥0.9 and RV hypokinesia. Other criteria include paradoxical septal wall motion, pulmonary hypertension, and severe tricuspid regurgitation.4,6 RV dysfunction detected by echocardiography is associated with an elevated short-term mortality in patients with PE.7,8 Similarly, a right to left ventricular dimensional ratio of ≥0.9 on multidetector CT (MDCT) has been shown to have a 92 % sensitivity for detection of RV dysfunction. Right ventricular dysfunction by MDCT was shown to be an independent predictor for in-hospital death or clinical deterioration in patients with PE (hazard ratio [HR] 3.5, 95 % confidence interval [CI] 1.6–7.7; p=0.002), including hemodynamically stable patients.9

Figure 1: Axial Images through Right and Left Main Pulmonary Arteries with Large Thrombus Burden

LPA = left main pulmonary artery; RPA = right main pulmonary artery.

and adverse outcomes.10,11 In a meta-analysis of 20 studies, Becattini et al. found that elevated troponin levels were significantly associated with short-term mortality (odds ratio [OR] 5.24; 95 % CI [3.28–8.38]), with death resulting from PE (OR 9.44; 95 % CI [4.14–21.49]), and with adverse outcome events (OR 7.03; 95 % CI [2.42–20.43]). Elevated troponins also predicted high mortality in a subgroup of hemodynamically stable patients (OR 5.90; 95 % CI [2.68–12.95]). Results were consistent for both troponin I or T.12 Elevated BNP and N-terminal (NT) pro-BNP, which are reflective of RV pressure overload, have also been shown to be independent predictors of death and adverse outcomes in patients with PE.7 In a systematic review by Klok et al., patients with elevated BNP or NT pro-BNP had a 10 % risk for early death (95 % CI [8.0–13]) and a 23 % (95 % CI [20–26]) risk for an adverse clinical outcome.13

Treatment Modalities Anticoagulation

Cardiac Biomarkers Cardiac troponins when elevated in patients with acute PE is suggestive of RV myocardial injury and has been shown to predict short-term mortality

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Prompt initiation of therapeutic anticoagulation is indicated for all patients with PE unless there is a strong contraindication (e.g., active or recent severe bleeding, major surgery, or trauma). Consideration should be

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Venous Thromboembolic Table 1: The Original Pulmonary Embolism Severity Index (PESI) and the simplified PESI (s-PESI) Clinical Risk Scores Parameter Age

PESI s-PESI Age in years 1 point (if >80 years)

Male sex

+10 points

Cancer diagnosis

+30 points

Chronic heart failure

+10 points

Chronic pulmonary disease

+10 points

Pulse rate ≥110 beats per minute

+20 points

1 point

Systolic blood pressure <100 mmHg

+30 points

1 point

Respiratory rate ≥30 breaths per minute

+20 points

Temperature <36°C

+20 points

Altered mental status

+60 points

Arterial oxyhemoglobin saturation <90 %

+20 points

1 point

[

1 point 1 point

]

Risk stratification Class I: ≤65 points

Very low 30-day mortality risk (0–1.5 %)

Class II: 66–85 points

Low mortality risk (1.7–3.5 %)

Class III: 86–105 points

Moderate mortality risk (3.2–7.1 %)

Class IV: 106–125 points

High mortality risk (4–11.4 %)

Class V: >125 points

Very high mortality risk (10–24.5 %)

Simplified PESI Score 0 points = 30-day mortality risk 1 % (95 % Cl 0–2.1 %) ≥ 1 point(s) = 30-day mortality risk 10.9 % (95 % Cl 8.5–13.2 %) Modified from Aujesky et al., 20052 and Jiménez et al., 2010.3

given to starting empiric therapy if there will be a delay in diagnosis and clinical suspicion for PE is high (e.g., using a validated prediction rule such as the Wells criteria). The immediate objective of anticoagulation is to prevent clinical deterioration, recurrent PE, and death. Rapid-acting anticoagulants include parenteral drugs (unfractionated heparin [UFH], low molecular weight heparin [LMWH], fondaparinux) as well as direct oral anticoagulants (DOACs). Compared with UFH, LMWH produces a more predictable anticoagulant effect and is the preferred drug in stable, lower-risk patients (although LMWH and fondaparinux should be avoided in patients with creatinine clearance (CrCl) <30 ml per minute or extremes of body weight; anti-Xa monitoring is an option in such cases.14–16 UFH has the advantage of a short half-life so is preferred in unstable patients who may require an intervention or thrombolysis or are at high risk for bleeding. Rapid-acting parenteral drugs should be continued for at least 5 days and overlapped with oral therapy while initiating a vitamin K antagonist, such as warfarin. Two DOACs (rivaroxaban, apixaban) were studied and approved for use as monotherapy (i.e., without initial LMWH or UFH) while two others (dabigatran, edoxaban) require at least 5 days of LMWH or UFH prior to initiation.17–22 Patients with hemodynamic instability or requiring a vena cava filter or fibrinolytic therapy were excluded from DOAC trials so the role of these agents in this setting has yet to be defined. Due to superior efficacy, continued LMWH monotherapy without transitioning to warfarin is preferred in patients with malignancy.23–25 If heparin-induced thrombocytopenia (HIT) is suspected or confirmed, fondaparinux or a direct thrombin inhibitor, such as argatroban, should be used.26,27

LV output compared with anticoagulation with heparin alone.28,29 Thrombolytics approved for PE by the US Food and Drug Administration (FDA) include streptokinase, urokinase, and alteplase. Studies show similar efficacy for tenecteplase and reteplase, though they are not yet approved by the FDA for PE.30,31 The hemodynamic benefits of thrombolysis are seen in the first few days of treatment.28 Clinical and echocardiographic data indicate that >90 % of patients with PE respond to thrombolytics within the first 36 hours.32

Systemic Thrombolysis

There are conflicting data for the use of thrombolytic therapy in hemodynamically stable patients with acute PE. Konstantinides et al.33 reported that in patients with acute PE without hypotension, but with RV dysfunction, alteplase reduced the primary end point of in-hospital death or clinical deterioration requiring escalation of treatment, with no significant elevation in major hemorrhagic complications. However, the effect of thrombolysis on mortality in these intermediate-risk patients is not clear. In a meta-analysis of randomized controlled trials of thrombolytic therapy, Marti et al.34 found that thrombolytic therapy was associated with a significant reduction in overall mortality (OR 0.59; 95 % CI [0.36–0.96]). While this reduction in early mortality was not statistically significant after exclusion of studies with high-risk PE, thrombolytic therapy did significantly reduce the incidence of PE mortality, death or treatment escalation, and PE recurrence. Further, there was no significant difference between alteplase, tenecteplase, or older thrombolytics. Similar results were found in another meta-analysis by Chatterjee et al.35 though in their analysis, there was a significant reduction in mortality even among patients with intermediate-risk PE.

Use of systemic thrombolysis has been shown to decrease mortality and recurrent PE in high-risk patients who present with hemodynamic instability.28 In addition to rapid resolution of major pulmonary emboli, thrombolytic therapy is also known to decrease pulmonary artery pressure and improve RV function with a concomitant increase in

Thrombolytic therapy is also associated with increased incidence of major bleeding.34–36 The Pulmonary Embolism Thrombolysis (PEITHO) investigators found that single-dose tenecteplase poses a high risk for hemorrhagic stroke when used in hemodynamically stable patients with

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Advanced Management of Massive and Submassive PE acute PE.30 Similarly, major hemorrhage (OR 2.91; 95 % CI [1.95–4.36]) and fatal or intracranial bleeding (OR 3.18; 95 % CI [1.25–8.11]) were more likely among patients receiving thrombolysis in the meta-analysis by Marti et al.34 The Moderate Pulmonary Embolism Treated with Thrombolysis (MOPETT) trial used half the conventional dose of tissue plasminogen activator (tPA) in the treatment of intermediate PE.37 At a reduced dose, tPA was shown to significantly reduce the pulmonary artery systolic pressure without any significant increase in major bleeding.38 Careful assessment for bleeding risk is warranted in all patients being considered for thrombolytic therapy (see Table 2).

Table 2: Contraindications to Thrombolytic Therapy

The current guidelines recommend systemic thrombolysis in patients with high-risk PE with hemodynamic compromise in the absence of contraindications. However, guidelines do not recommend routine use of systemic thrombolysis in all patients with intermediate-risk PE. A careful risk/benefit analysis should be performed on an individual basis in patients with intermediate-risk PE.

Current anticoagulants

Percutaneous Catheter-directed Treatment Percutaneous catheter-directed therapy (CDT) involves the removal or disruption of obstructing thrombi from the main pulmonary arteries and/ or local administration of small dose of thrombolytics directly into the pulmonary artery. The various interventional options include thrombus fragmentation with pigtail or balloon catheter, rheolytic thrombectomy, suction thrombectomy with aspiration catheters, and rotational thrombectomy.39 Concurrent administration of local thrombolytics can be performed via multiple side-hole catheter(s) in the pulmonary artery with or without the application of ultrasound energy as used in the EKOS device (EkoSonic Endovascular). Catheter-based therapy has the advantage of being better tolerated in patients with tenuous hemodynamics compared with surgical embolectomy and requiring lower doses of thrombolytic compared with systemic therapy. However, CDT is only effective in main pulmonary artery or its major branches and with less organized thrombus. The efficacy of CDT for thrombus removal is limited by relatively small size of the aspiration catheters compared with the size of the pulmonary artery. There are limited good quality data on hard outcomes using CDT in patients with acute PE. In a systematic review on CDT in acute PE, Kuo et al.40 included 594 subjects from 35 nonrandomized studies and showed 87 % clinical success with CDT in terms of stabilization of hemodynamic parameters, resolution of hypoxia, and survival to discharge. Pooled risk for minor and major complications was 7.9 % and 2.4 %, respectively. In a recent single-arm multicenter study in patients with both massive (n=31) and submassive PE (n=119), Piazza et al.41 demonstrated that ultrasound-facilitated, catheter-directed, low-dose fibrinolysis decreased RV size, pulmonary pressures, thrombus burden, and reduced incidence of intracranial hemorrhage. The 30-day mortality in this group was 2.7 % with 10 % incidence of major bleeding.

Absolute Contraindications Any prior intracranial hemorrhage Known intracranial malformation or neoplasm Ischemic stroke <3 month Suspected dissection Recent surgery Recent head trauma Bleeding diathesis Relative Contraindications >75 years of age Pregnancy Cardiopulmonary resuscitation >10 minutes Recent internal bleed (2–4 weeks) Uncontrolled hypertension (180/110 mmHg) Remote ischemic stroke Major surgery within 3 weeks Modified from Jaff et al.39

Table 3: Risk Stratification for Patients with Acute Pulmonary Embolism (PE) Chest Guideline European Society of 2011 American Heart 52 Cardiology Guidelines Association Guidelines Update 2016 42 39 2014 2011 PE with hypotension High risk PE Massive PE PE without hypotension Intermediate–high risk PE

Intermediate–low risk PE

Low-risk PE

Submassive PE Low-risk PE

as an alternative to surgical embolectomy when systemic thrombolysis is contraindicated or has failed or in intermediate–high-risk patients if the anticipated risk for bleeding with systemic thrombolytic therapy is high.42

Surgical Embolectomy Surgical embolectomy is an open surgical procedure in which clots are removed from the right atrium or ventricle or main/proximal pulmonary arteries. It is indicated in patients with massive PE (and possibly in select patients with submassive PE) who have a contraindication to thrombolysis or when thrombolysis or catheter-based mechanical clot disruption has failed. A wide range of mortality rates have been reported (6–46 %).43,44 In a recent report describing 105 patients who underwent surgical embolectomy (49 hemodynamically unstable; 56 hemodynamically stable), overall operative mortality was 6.6 % (10.2 % for unstable patients; 3.6 % for stable patients).45 Of 11 patients requiring preoperative cardiopulmonary resuscitation, four died. Six-month, 1-year, and 3-year survival rates were 75 %, 68.4 %, and 65.8 % for unstable PE, and 92.6 %, 86.7 %, and 80.4 % for stable PE, respectively. These findings suggest that surgical embolectomy is an important option that can provide reasonably good outcomes if significant experience is locally available and patients are carefully selected.

Vena Cava Filters Nevertheless, large prospective studies are lacking, and the ideal CDT protocol, particularly for submassive PE, remains unclear. There are limited data comparing the efficacy of systemic thrombolysis and CDT for management of acute PE. CDT should be considered in high-risk patients

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In patients with acute PE who cannot safely receive anticoagulation, placement of an inferior vena cava (IVC) filter is indicated (even in the absence of lower extremity clot). Filters are placed via catheter in the infrarenal portion of the IVC; in certain circumstances, filters may

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Venous Thromboembolic Figure 2: Clinical Approach to Patient Management Following Acute Pulmonary Embolism (PE) Acute PE

High-risk PE

Yes

Contraindications to thrombolysis

Systemic thrombolysis

Shock hypotension or PEA arrest

Yes

Consider surgical embolectomy or CDT

Both RV dysfunction and elevated biomarkers

Low- or intermediaterisk PE

PESI III–V or sPESI ≥1

No RV dysfunction or either only RV dysfunction or elevated biomarker

Low-risk PE

Anticoagulation Consider thrombolysis or CDT if low bleeding risk

Intermediate–highrisk PE

Intermediate–lowrisk PE

CDT = catheter-directed thrombolysis; PEA = pulseless electrical activity; (s)PESI = (simplified) pulmonary embolism severity index; RV = right ventricle.

be placed in other locations (superior vena cava if upper extremity clot is thought to be the source of PE; suprarenal IVC for renal vein clot). Observational studies suggest IVC ﬁlters may reduce PE-related mortality in the acute setting but these studies have methodologic limitations.46,47 Eight-year follow-up of a randomized study in 400 patients with DVT (with or without PE), all of whom had initial anticoagulation for at least 3 months, showed patients who received a permanent IVC ﬁlter had a reduced risk for recurrent PE (6.2 % versus 15.1 %; p=0.008), but an increased risk for recurrent DVT (35.7 % versus 27.5 %; p=0.042), and no overall effect on survival.48 A more recent study of patients with acute PE and additional risk factors for recurrence compared retrievable IVC filters plus anticoagulation to anticoagulation alone.49 Filter retrieval was accomplished in the majority of patients at 3 months and anticoagulation was continued for at least 6 months. At 6 months, recurrent PE was seen in 3.5 % of patients in the filter group and 2.0 % of patients in the control group (RR with filter, 1.75; 95 % CI [0.52–5.88]; p=0.54). There is therefore no clearly established role for IVC filters in patients with PE who can receive anticoagulation. After filter placement, patients should be periodically reassessed for initiation of anticoagulation and filters should be removed once the risk for recurrent VTE is felt to be acceptably low, usually within several months (sometimes up to a year). Filter placement is associated with a variety of complications, including malpositioning of the filter, guide-wire entrapment, and insertion site thrombosis, hematoma, or arterial-venous fistula. Long-term complications include chronic thrombosis/occlusion of the IVC, which has been reported in 3–30 % of patients, as well as IVC perforation, filter fracture, and migration.

Approach to Patient Patients with Acute PE and Shock or Hypotension High Risk In addition to providing hemodynamic and respiratory support, high-risk unstable patients with suspected PE should be started on intravenous UFH. Early thrombolytic therapy is strongly recommended in these

Gandhi_FINAL.indd 34

patients in the absence of contraindications. Surgical embolectomy is recommended for patients in whom thrombolysis is either contraindicated or unsuccessful. At experienced centers, percutaneous CDT can be considered as an alternative to surgical pulmonary embolectomy (see Figure 2).

Intermediate Risk Parenteral anticoagulation with UFH or LMWH or fondaparinux is recommended without delay in patients with intermediate–high risk PE. Echocardiogram and cardiac biomarkers should be obtained. If there is evidence of RV dysfunction and elevated cardiac biomarkers, the patient is deemed as intermediate–high risk. Systemic thrombolysis or catheterdirected thrombolysis can be considered in selected intermediate– high risk patients who are at low risk for bleeding. Patients with RV dysfunction with normal biomarkers or elevated biomarkers with normal RV function are deemed as intermediate–low risk and treatment with anticoagulation alone may suffice (see Figure 2). Routine use of IVC filters in patients with PE is not recommended. IVC filter should be considered if there is an absolute contraindication to anticoagulation or recurrent PE despite adequate anticoagulation.

Pulmonary Embolism Response Team In order to provide individualized approach to patients with intermediateand high-risk PE, medical centers should develop a multidisciplinary team and uniform institutional protocols for management of these patients.50 In their initial experience at Massachusetts General Hospital the Pulmonary Embolism Response Team (PERT) was activated in about 400 patients over the initial 2.5 years, with 60 % of activations from emergency department and 20 % from intensive care units. While it is too early to estimate the impact of PERT on patient outcomes, it can streamline care with rapid access to multiple specialties and has the potential to provide a uniform approach to patients with massive and submassive PE.51

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Advanced Management of Massive and Submassive PE Guidelines for Management of Acute PE There are three guideline documents that address the diagnosis and management options for patients with acute PE. The 2014 European Society of Cardiology guidelines,42 the 2011 American Heart Association guidelines for massive and submassive PE,39 and the 2016 update of the Chest guidelines for venous thromboembolic disease.52 The guidelines use slightly different terminology in risk stratification for PE. This is summarized in Table 3. Broadly, the guidelines are consistent

1. 2.

10.

11.

12.

13.

14.

15.

16.

17.

18.

White RH. The epidemiology of venous thromboembolism. Circulation 2003;107:I-4–I-8. PMID: 12814979 Aujesky D, Obrosky DS, Stone RA, et al. Derivation and validation of a prognostic model for pulmonary embolism. Am J Respir Crit Care Med 2005;172:1041–6. PMID: 16020800; PMCID: PMC2718410 Jiménez D, Aujesky D, Moores L, et al. Simplification of the pulmonary embolism severity index for prognostication in patients with acute symptomatic pulmonary embolism. Arch Intern Med 2010;170:1383–9. doi: 10.1001/ archinternmed.2010.199; PMID: 20696966 Goldhaber SZ. Echocardiography in the management of pulmonary embolism. Ann Intern Med 2002;136:691–700. PMID: 11992305 Grifoni S, Olivotto I, Cecchini P, et al. Short term clinical outcome of patients with acute pulmonary embolism, normal blood pressure, and echocardiographic right ventricular dysfunction. Circulation 2000;101:2817–22. PMID: 10859287 McConnell MV, Solomon SD, Rayan ME, et al. Regional right ventricular dysfunction detected by echocardiography in acute pulmonary embolism. Am J Cardiol 1996;78:469–73. PMID: 8752195 Coutance G, Cauderlier E, Ehtisham J, et al. The prognostic value of markers of right ventricular dysfunction in pulmonary embolism: a meta-analysis. Crit Care 2011;15:R103. doi: 10.1186/cc10119; PMID: 21443777; PMCID: PMC3219376 Sanchez O, Trinquart L, Colombet I, et al. Prognostic value of right ventricular dysfunction in patients with haemodynamically stable pulmonary embolism: a systematic review. Eur Heart J 2008;29:1569–77. doi: 10.1093/eurheartj/ehn208; PMID: 18495689 Becattini C, Agnelli G, Vedovati MC, et al. Multidetector computed tomography for acute pulmonary embolism: diagnosis and risk stratification in a single test. Eur Heart J 2011;32:1657–63. doi: 10.1093/eurheartj/ehr108; PMID: 21504936 Mehta NJ, Jani K, Kham IA. Clinical usefulness and prognostic value of elevated cardiac troponin I levels in acute pulmonary embolism. Am Heart J 2003;145:821–5. PMID: 12766738 Lankeit M, Jiménez D, Kostrubiec M, et al. Predictive value of the high-sensitivity troponin T assay and the simplified pulmonary embolism severity index in hemodynamically stable patients with acute pulmonary embolism: a prospective validation study. Circulation 2011;124:2716–24. doi: 10.1161/ CIRCULATIONAHA.111.051177; PMID: 22082681 Becattini C, Vedovati MC, Agnelli G. Prognostic value of troponins in acute pulmonary embolism: a meta-analysis. Circulation 2007;116:427–33. PMID: 17606843 Klok FA, Mos IC, Huisman MV. Brain-type natriuretic peptide levels in the prediction of adverse outcome in patients with pulmonary embolism: a systematic review and meta-analysis. Am J Respir Crit Care Med 2008;178:425–30. doi: 10.1164/ rccm.200803-459OC; PMID: 18556626 Cossette B, Pelletier ME, Carrier N, et al. Evaluation of bleeding risk in patients exposed to therapeutic unfractionated or lowmolecular-weight heparin: a cohort study in the context of a quality improvement initiative. Ann Pharmacother 2010;44:994– 1002. doi: 10.1345/aph.1M615; PMID: 20442353 Büller HR, Davidson BL, Decousus H, et al. Subcutaneous fondaparinux versus intravenous unfractionated heparin in the initial treatment of pulmonary embolism. N Engl J Med 2003;349:1695–702. PMID: 14585937 Garcia DA, Baglin TP, Weitz JI, et al. Parenteral anticoagulants: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141(Suppl 2):e24S–e43S. doi: 10.1378/chest.11-2291; PMID: 22315264 Schulman S, Kearon C, Kakkar AK, et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med 2009;361:2342–52. doi: 10.1056/NEJMoa0906598; PMID: 19966341 Schulman S, Kakkar AK, Goldhaber SZ, et al. Treatment of acute

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19.

20.

21.

22.

23.

24.

25.

26.

27.

28.

29.

30.

31.

32.

33.

34.

35.

36.

in recommending systemic fibrinolysis in patients with massive PE and considering CDT or surgical embolectomy as alternatives for patients with contraindications to systemic thrombolysis at centers with local expertise. The Chest guidelines in general are more conservative and recommend against thrombolysis in patients with PE without hypotension unless the patients deteriorate after starting anticoagulation. The guidelines also consistently recommend against the routine use of IVC filters. n

venous thromboembolism with dabigatran or warfarin and pooled analysis. Circulation 2014;129:764–72. doi: 10.1161/ CIRCULATIONAHA; PMID: 24344086 Bauersachs R, Berkowitz SD, Brenner B, et al. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 2010;363:2499–510. doi: 10.1056/NEJMoa1007903; PMID: 21128814 Büller HR, Prins MH, Lensin AW, et al. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med 2012;366:1287–97. doi: 10.1056/NEJMoa1113572; PMID: 22449293 Agnelli G, Büller HR, Cohen A, et al. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med 2013;369:799–808. doi: 10.1056/NEJMoa1302507; PMID: 23808982 Hokusai-VTE Investigators, Büller HR, Decousus H, et al. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med 2013;369:1406–15. doi: 10.1056/NEJMoa1306638; PMID: 23991658 Lee AY, Levine MN, Baker RI, et al. Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med 2003;349:146–53. PMID: 12853587 Kucher N, Quiroz R, McKean S, et al. Extended enoxaparin monotherapy for acute symptomatic pulmonary embolism. Vasc Med 2005;10:251–6. PMID: 16444853 Beckman JA, Dunn K, Sasahara AA, et al. Enoxaparin monotherapy without oral anticoagulation to treat acute symptomatic pulmonary embolism. Thromb Haemost 2003;89:953–8. PMID: 12783106; PMID: 19682670 Stein PD, Hull RD, Matta F, et al. Incidence of thrombocytopenia in hospitalized patients with venous thromboembolism. Am J Med 2009;122:919–30. doi: 10.1016/j.amjmed.2009.03.026; PMID: 19682670 Warkentin TE, Maurer BT, Aster RH. Heparin-induced thrombocytopenia associated with fondaparinux. N Engl J Med 2007;356:2653–5. PMID: 17582083 Konstantinides S, Tiede N, Geibel A, et al. Comparison of alteplase versus heparin for resolution of major pulmonary embolism. Am J Cardiol 1998;82:966–70. PMID: 9794353 Goldhaber SZ, Haire WD, Feldstein ML, et al. Alteplase versus heparin in acute pulmonary embolism: randomized trial assessing right-ventricular function and pulmonary perfusion. Lancet 1993;341:507–11. PMID: 8094768 Meyer G, Vicaut E, Danays T, et al. for the PEITHO Investigators. Fibrinolysis for patients with intermediate-Risk Pulmonary embolism. N Eng J Med 2014;370:1402–11. doi: 10.1056/ NEJMoa1302097; PMID: 24716681 Kline JA, Nordenholz KE, Courtney DM, et al. Treatment of submassive pulmonary embolism with tenecteplase or placebo: cardiopulmonary outcomes at three months (TOPCOAT): Multicenter double-blind, placebo-controlled randomized trial. J Thromb Haemos 2014;12:459–68. doi: 10.1111/jth.12521 Meneveau N, Seronde MF, Blonde MC, et al. Management of unsuccessful thrombolysis in acute massive pulmonary embolism. Chest 2006;129:1043–50. PMID: 16608956 Konstantinides S, Geibel A, Heusel G, et al. Heparin plus alteplase compared with heparin alone in patients with submassive pulmonary embolism. N Engl J Med 2002;347:1143–50. PMID: 12374874 Marti C, John G, Konstantinides S, et al. Systemic thrombolytic therapy for acute pulmonary embolism: a systematic review and meta-analysis. Eur Heart J 2015;36:605–14. doi: 10.1093/ eurheartj/ehu218 Chatterjee S, Chakraborty A, Weinberg I, et al. Thrombolysis for pulmonary embolism and risk of all-cause mortality, major bleeding, and intracranial hemorrhage: A meta-analysis. JAMA 2014;311:2414–21. doi: 10.1001/jama.2014.5990 Chen H, Ren C, Chen H. Thrombolysis versus anticoagulation for the initial treatment of moderate pulmonary embolism: a meta-analysis of randomized controlled trials. Respir Care 2014;59:1880–7.

37. Sharifi M, Bay C, Skrocki L, et al. Moderate pulmonary embolism treated with thrombolysis. Am J Cardio 2013;111:273–7. 38. Fasullo, Sergio MD et al. Six-month echocardiographic study in patients with submassive pulmonary embolism and right ventricle dysfunction: Comparison of thrombolysis with heparin. Am J Med Sci 2011;341:33–9. doi: 10.1097/ MAJ.0b013e3181f1fc3e; PMID: 20890176 39. Jaff MR, McMurtry MS, Archer SL, et al. Management of massive and submassive pulmonary embolism, iliofemoral deep vein thrombosis, and chronic thromboembolic pulmonary hypertension: a scientific statement from the American Heart Association. Circulation 2011;123:1788–830. doi: 10.1161/ CIR.0b013e318214914f; PMID: 21422387 40. Kuo WT, Gould MK, Louie JD, et al. Catheter directed therapy for the treatment of massive pulmonary embolism: systematic review and meta-analysis of modern techniques. J Vasc Interv Radiol 2009;20:1431–40. doi: 10.1016/j.jvir.2009.08.002; PMID: 19875060 41. Piazza G, Hohlfelder B, Jaff MR, et al. A Prospective, Single-Arm, Multicenter Trial of Ultrasound-Facilitated, Catheter-Directed, Low-Dose Fibrinolysis for Acute Massive and Submassive Pulmonary Embolism: The SEATTLE II Study. JACC Cardiovasc Interv 2015;8:1382–92. doi: 10.1016/j.jcin.2015.04.020; PMID: 26315743 42. Konstantinides S, Torbicki A, Agnelli G, et al. 2014 ESC Guidelines on the diagnosis and management of acute pulmonary embolism. Eur Heart J 2014;35:3033–80. doi: 10.1093/ eurheartj/ehu283; PMID: 25173341 43. Malekan R, Saunders PC, Yu CJ, et al. Peripheral extracorporeal membrane oxygenation: comprehensive therapy for high risk massive pulmonary embolism. Ann Thorac Surg 2012;94:104–8. doi: 10.1016/j.athoracsur.2012.03.052; PMID: 22542068 44. Aymard T, Kadner A, et al. Massive pulmonary embolism: surgical embolectomy versus thrombolytic therapy: should surgical indications be revisited? Eur J Cardiothorac Surg 2013;43:90–4. doi: 10.1136/thoraxjnl-2013-204667; PMID: 26165484 45. Neely RC, Byrne JG, Gosev I, et al. Surgical embolectomy for acute massive and submassive pulmonary embolism in a series of 115 Patients. Ann Thorac Surg 2015;100:1245–51. doi: 10.1016/j.athoracsur.2015.03.111 46. Stein PD, Matta F, Keyes DC, et al. Impact of vena cava filters on in-hospital case fatality rate from pulmonary embolism. Am J Med 2012;125:478–84. doi: 10.1016/j.amjmed.2011.05.025; PMID: 22310013 47. Muriel A, Jiménez D, Aujesky D, et al. Survival effects of inferior vena cava filter in patients with acute symptomatic venous thromboembolism and a significant bleeding risk. J Am Coll Cardiol 2014;63:1675–83. doi: 10.1016/j.jacc.2014.01.058; PMID: 24576432 48. PREPIC Study Group. Eight-year follow-up of patients with permanent vena cava filters in the prevention of pulmonary embolism: the PREPIC (Prevention du Risque d’Embolie Pulmonaire par Interruption Cave) randomized study. Circulation 2005;112:416–22. PMID: 16009794 49. Mismetti P, Laporte S, Pellerin O, et al, for the PREPIC2 Study Group. Effect of a retrievable inferior vena cava filter plus anticoagulation vs anticoagulation alone on risk of recurrent pulmonary embolism: A randomized clinical trial. JAMA 2015;313:1627–35. doi: 10.1001/jama.2015.3780; PMID: 25919526 50. Provius T, Dudzinski DM, Jaff MR, et al. The Massachusetts General Hospital Pulmonary Embolism Response Team (MGH PERT): creation of a multidisciplinary program to improve care of patients with massive and submassive pulmonary embolism. Hosp Pract (1995) 2014;42:31–7. 51. Dudzinski DM, Piazza G. Multidisciplinary Pulmonary Embolism Response Teams. Circulation 2016;133:98–103. doi: 10.1161/ CIRCULATIONAHA.115.015086; PMID: 26719388 52. Kearon C, Akle EA, Ornelas J, et al. Antithrombotic therapy for VTE disease. Chest Guideline and Expert Panel Report. Chest 2016;149:315–52. doi: 10.1016/j.chest.2015.11.026; PMID: 26867832

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Quality and Outcomes

LE ATION.

thor: Q1 s has been anged to althcare oughout

nsistency ealth re and althcare re ginally ed), please nfirm this is rrect

Public Reporting of Cardiovascular Data: Benefits, Pitfalls, and Vision for the Future Greg ory J D e h m e r, M D, M A CC, M S CA I , FA H A , FA CP Texas A&M University Health Science Center College of Medicine, Temple, TX; Cardiovascular Services, Central Texas Division, Baylor Scott & White Health, Temple, TX

Abstract Public reporting of healthcare data is not a new concept. This initiative continues to proliferate as consumers and other stakeholders seek information on the quality and outcomes of care. Furthermore, mandates for the development of additional public reporting efforts are included in several new healthcare legislations such as the Affordable Care Act. Many current reporting programs rely heavily on administrative data as a surrogate for true clinical data, but this approach has well-defined limitations. Clinical data are traditionally more difficult and costly to collect, but more accurately reflect the clinical status of the patient, thus enhancing validity of the quality metrics and the reporting program. Several professional organizations have published policy statements articulating the main principles that should establish the foundation for public reporting programs in the future.

Keywords Public reporting, quality, outcomes, healthcare reform Disclosure: GJD reports no financial conflicts of interest related to this work. The author is the Chair of the Public Reporting Advisory Group of the National Cardiovascular Data Registry, a voluntary, unpaid position. Received: December 29, 2015 Accepted: January 11, 2016 Citation: US Cardiology Review, 2016;10(1):36–40 Correspondence: Gregory J Dehmer, MD, MACC, MSCAI, FAHA, FACP, Cardiology Division (MS-33-ST156), Baylor Scott & White Health, 2401 South 31st Street, Temple, TX 76508, USA. E: Gregory.Dehmer@BSWHealth.org

In what is often cited as the earliest public reporting of healthcare information, Florence Nightingale published mortality rates at British military hospitals caring for casualties of the Crimean War.1 Dr Ernest Codman, about 50 years later, called for the public release of surgical outcomes at his hospital, but was highly criticized for his effort eventually leading to the loss of his hospital privileges.2 His early efforts, however, contributed to the founding of the American College of Surgeons and later The Joint Commission. The next major public reporting effort occurred in the late 1980s when the Health Care Financing Administration (HCFA) published risk-adjusted death rates in US hospitals.3 Although not intended for public release, these reports eventually became public and were the subject of considerable criticism.4 Although imperfect, the HCFA experience stimulated development of other quality improvement registries and statewide reporting systems for coronary artery bypass graft surgery (CABG) and percutaneous coronary interventions (PCI) outcomes.5,6 With the implementation of the “Hospital Compare” website in 2002, the Centers for Medicare and Medicaid Services (CMS) revived public reporting of data from Medicare beneficiaries aggregated at the hospital level.7 More recently, CMS began reporting on group and individual physician performance.8 Public reporting programs now exist in many forms, including: a) federal and state initiatives; b) reports from payers and business consumer groups; c) reports from independent organizations that use their own proprietary analysis and rating schemes; and d) reports

Dehmer_FINAL.indd 36

focusing on the cost of care.9–12 Public websites also exist where patients can report their anecdotal experiences with physicians without any opportunity for physician rebuttal of their comments see Figure 1.13

Rational for Public Reporting Although there are many outstanding characteristics of the US healthcare system, it also has many shortcomings. Unacceptable gaps in care and concerns over quality issues are increasingly identified in the public domain. With the current national emphasis on quality improvement, accountability and cost-effectiveness in healthcare, stakeholders such as government agencies, purchaser and provider organizations, and consumers are seeking information to inform decisions about healthcare facilities and providers see Table 1. Some advocates would even state that public reporting is a professional ethical responsibility.14 The most persuasive justification for public reporting is the public’s right to know about the care they are likely to receive from hospitals and physicians. Public reporting is sustained by the belief that accessible, transparent, quality information will affect decisions and behaviors of the various stakeholders, ultimately resulting in an improvement in healthcare delivery and outcomes. Transparency encourages patient autonomy by providing patients with information that should allow them to make better-informed decisions about their healthcare choices. However, for this to succeed the reporting process must be accurate and fair.

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Public Reporting of Cardiovascular Metrics Figure 1: Examples of Public Reporting Efforts

Table 1: Stakeholders and Their Interest in Public Reporting

Federal Government

State Government

Independent Groups

Insurance Providers

Consumer Groups

• Hospital Compare

• Massachusetts (MASS-DAC)

• Consumer Reports

• Blue Cross Blue Shield

• Angie’s List

audience for information on the costs and quality of care.

• RateMDs.com

Consumers could use the information in public reports

• Physician Compare

• New York

• US News & World Report

• Aetna

• YELP

at various points of interaction to make more-informed

• Cigna

• Leapfrog

• DrScore

• Others

• CarePages

• Physician payments from CMS • Physician payments from industry

• California Cardiac Surgery Information project • Pennsylvania • Texas (Texas Health Care Information Collection)

• HealthGrades • ProPublica • Consumer’s Checkbook

• Vitals • Doctor Scorecard

• Truven

• Healthcare Bluebook

• Oregon Health Care Q Corp

• Castlight

• Others

• Catalyst for Payment Reform

Stakeholder

Reasons for Interest

Consumers

Consumers of healthcare services are the most obvious

decisions about choosing facilities and providers for a specific service Employers/

Employers act as intermediaries in selecting health

purchasers

insurance for most privately insured Americans. Employers may want information to use in selecting from among various health plans or self-insured options, including the cost and outcomes of providers included in a given plan’s network and the plan’s record of performance in meeting service and quality standards

Health plans

Health plans likely have their own claims data, but in certain markets may not have sufficient information to evaluate the price and quality of all physicians, hospitals,

CMS = Centers for Medicare and Medicaid Services; MASS-DAC = Massachusetts Data Analysis Center; Q Corp = Quality Corporation.

and other providers. Plans may also want to benchmark their performance on service and quality measures against

Moving forward, there is also a clear mandate to begin changing reimbursement models so they are based on the quality and value of care, rather than the quantity of care. For that to succeed, quality measures that are meaningful and validated must exist. Employers continue to allocate an increasing portion of their budget for the provision of healthcare benefits to their employees similar to what the federal government has experienced for Medicare beneficiaries. This increasing financial burden on employers has several effects. It results in employees saddled with a greater percentage of their healthcare cost and, as that occurs, patients become more conscious of the care they are receiving. Insurers are pressured to provide lower cost, higher value products and ultimately this translates into pressure on providers to demonstrate the quality and value of their care. To remain competitive, healthcare systems and providers must then accelerate their quality improvement efforts. Public reporting of physician, health plan, and institutional performance is being leveraged in an attempt to steer patients to the best performing providers and facilities on the assumption that patients will receive better and more cost-effective care. The public release of performance data has been proposed as a mechanism for improving the quality of care by providing more transparency and greater accountability of healthcare providers.15 However, there are data showing that areas with comprehensive, but confidential, data reporting had improvements in outcomes similar to those in public reporting states and that public reporting added to existing confidential feedback reporting resulted in little incremental improvement in outcomes.16–18 Moreover, the use of publically reported information by various segments of the population is variable and the impact of this information on patients’ decision-making is uncertain.19,20 Rather than identifying the absolute best hospital or provider in the country, patients’ seem more focused on access to empathetic, interactive providers and the availability of local services for common conditions that meet an acceptable standard of care.21

Public Reporting of Cardiovascular Data Public reporting developed in the cardiovascular arena well before many other areas of medicine. Beginning in the mid-1990s, New York and

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their competitors Providers

Hospitals, physicians, nursing homes, and other healthcare providers could benefit from more transparent quality information for benchmarking their own performance and as a feedback loop for improved performance

Policymakers

Federal and state officials’ responsibility for oversight and monitoring of performance could benefit from accurate and timely information on providers, health plans, and facilities to monitor changes in the overall system, identify areas that warrant closer investigation, and encourage the reporting groups to monitor their own performance. Policymakers are seeking to promote healthcare “value,” which necessitates the measurement of both cost and quality

Reprinted from Dehmer GJ et al., Public reporting of clinical quality data: an update for cardiovascular specialists (J Am Coll Cardiol 2014;63:1239–45), copyright (2014), with the permission of Elsevier.

Pennsylvania started publicly reporting outcomes from cardiac surgery followed by similar programs in Massachusetts and California.22–25 Several of these same states now have analogous programs for publically reporting PCI data.26,27 In 2005, an independent group of seven New England hospitals started collecting data for patients undergoing several cardiovascular procedures and began providing a public report of CABG results on their website.5 More recently, the Clinical Outcomes Assessment Program (COAP) program was launched in the State of Washington reporting both CABG and PCI outcomes.28 Cardiovascular professional organizations have also joined the growing public reporting effort. The Society of Thoracic Surgeons (STS) has maintained a clinical database on cardiac surgical procedures since 1989 and in 2011 began a voluntary public reporting program that has been well received.6,14,29 Likewise, the American College of Cardiology (ACC) recently launched a public reporting program using clinical data from the National Cardiovascular Data Registry.30,31

Benefits of Public Reporting Public reporting is intended to improve healthcare delivery and patient outcomes and studies showing the positive impact of public reporting are emerging. For example, the use of aspirin prophylaxis was 95 % in a state where this metric was publically reported compared with much

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Quality and Outcomes

Mean Expected Mortality Rate (%) All PCI Patients

Figure 2: Change in Expected Mortality Rates After Identification as an Outlier Hospital Outlier hospitals Non-outlier hospitals

2.0

1.5

1.0

0.5 2003

2004

2005

2006

2007

2008

2009

2010

Year Fir ho st ‘ou sp ita tlier l id ’ en tifi e

Fo Se ho urth ho cond sp ‘ou sp a ita ita nd l id tlier’ l id th en en ird tifi tifi ‘ou ed e t d d lie r’ The expected mortality estimate at outlier hospitals (red line) decreased after being identified indicating the development of risk-aversive behavior by the physicians at the facility. Reproduced from McCabe JM, et al. Impact of public reporting and outlier status identification on percutaneous coronary intervention case selection in Massachusetts (JACC Cardiovasc Interv 2013;6:625–30). Copyright (2016), with permission of Elsevier and the American College of Cardiology.

lower aspirin use in a large national survey.32,33 Likewise, data from the Wisconsin Collaborative for Healthcare Quality shows increases in quality performance when data from groups are displayed publically on a website.34 Survey data from administrators and providers endorse the benefits derived from public reporting such as a greater involvement of leadership in performance improvement, creation of a sense of accountability to internal and external customers, improved awareness of performance measure data throughout the hospital, and a stronger focus on organizational priorities.35 The STS has recently published their 4-year experience since beginning their public reporting program.36 Facility participation in public reporting varied from 22 % to 46 % during their reporting periods. Risk-adjusted, patient-level mortality rates for isolated CABG were consistently lower at public reporting versus nonreporting sites and reporting centers had higher composite performance scores and higher mean annualized CABG volumes than non-reporting sites. Importantly, no evidence of risk aversion was found. However, systematic reviews of public reporting programs note that rigorous evaluations of many major public reporting programs are lacking.37,38 These reviews cite some evidence that publicly releasing performance data stimulates quality improvement activity at the hospital level, but also conclude that the overall the effect of public reporting on effectiveness, safety, and patient-centeredness remains uncertain. Even less data are available to show a benefit from the public reporting individual or group data.

Pitfalls of Public Reporting Several potential problems are often cited related to public reporting efforts. First, data used in public reporting are derived from either administrative or clinical data sets. Administrative, financial (claims), and other descriptive data are readily available and thus attractive sources of information, but are only surrogates for clinical data. Several studies have shown that administrative data are: a) payer and market specific; b) use old and sometimes nonactionable data; and c) may poorly reflect the severity of illness, correct

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diagnosis, and clinical outcomes.39–41 For example, in two separate studies that compared cardiac surgery performance using administrative versus clinical data sources there were substantial inconsistencies in the comparisons leading to the conclusion that report cards using administrative data are flawed compared with those derived from validated clinical data.42,43 Clinical registry data have several advantages over administrative data.39,40,43 Clinical data more directly mirror the clinical care received by patients and thus are more representative of actual performance than data derived solely from claims. Administrative data frequently have a lag time of 2 years whereas clinical data are timelier and thus provide an excellent source of nationally benchmarked data to providers. Receiving timely data allows providers to construct better quality-improvement activities with feedback available soon after subsequent data submissions. Furthermore, data submission to clinical registries can be incorporated into provider workflow, thus potentially reducing the burden of data collection. Clinical data from registry programs also can be used for research or educational programs that focus on quality improvement. Second, concern has been expressed that public reporting programs may lead to unintended consequences that could offset their benefits.44,45 The majority of these reports highlight the development of risk-adverse behavior among physicians and facilities subject to public reporting. One of the earliest examples of this behavior was observed after New York State started publishing mortality related to CABG surgery. Following the release of these data, there was a reduction in risk-adjusted CABG mortality resulting in the impression that the public reporting program was highly successful. However, a different perspective emerged when referrals from New York to the Cleveland Clinic were examined after public reporting began in New York.46 Patients referred from New York had a worse risk profile and a higher expected mortality rate than other referrals. The authors speculated that the beginning of public reporting in New York likely triggered the referral of high-risk patients out of state, explaining the reduction of CABG mortality in New York. A similar experience was reported related to the public reporting of CABG outcomes in Pennsylvania.47 Public reporting of PCI data has a shorter history compared with that of cardiac surgery, but similar trends in physician behavior are being observed. Compared with New York, which has public reporting of PCI mortality, patients in Michigan, which does not have public reporting, more frequently were treated with PCI for acute MI (14.4 % versus 8.7 %) and cardiogenic shock (2.56 % versus 0.38 %) and had a higher prevalence of congestive heart failure and extracardiac vascular disease.48 The unadjusted in-hospital mortality rate was lower in New York than in Michigan reflecting the exclusion of high-risk patients, but there was no significant difference in mortality between the two states after adjustment for comorbidities. The authors concluded that the lower use of PCI among these higher-risk patients in New York was likely related to physician concerns over being identified as an outlier in a public report. In a separate study, patients from New York presenting with cardiogenic shock were less likely to receive angiography, PCI, or CABG compared with patients from other states.49 These patients experienced an in-hospital mortality 1.5 times higher, suggesting that life-saving treatments were being avoided in this high-risk group in an effort to elude identification as an outlier in a public report. Survey data from New York physicians confirmed this, with 83 % of practitioners agreeing that

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Public Reporting of Cardiovascular Metrics patients who were at high risk were denied PCI because of fear of public reporting and 79 % confirming that their own decisions on performing PCIs was influenced by a fear of public reporting.50 Similar concerns were raised about the public reporting of PCI data in Massachusetts and indirectly confirmed by examining the risk profile of patients undergoing PCI at hospitals after the facility was identified as an outlier in a public report.51,52 After being publically identified as an outlier, the risk profile of PCI patients at the institution became significantly lower compared with non-outlier institutions (see Figure 2). This observation implies the presence of risk-aversive behaviors among PCI operators at these outlier institutions as an unintended consequence of public reporting.

Table 2: American College of Cardiology Foundation’s Principles of Public Reporting

Third, risk-adjustment methods currently available are suboptimal and may not include all relevant variables. To minimize risk-avoidance behaviors, some reporting efforts now specifically exclude extremely high-risk and salvage patients. In the Massachusetts PCI registry, a “compassionate use” data element has been added to capture these types of cases.53 It has also been suggested that mortalities be adjudicated to determine if they were truly procedure related or related to the natural history of a disease process. This recommendation is supported by the fact that after further blinded review, about 80 % of the mortalities at one Massachusetts hospital were felt to not be directly related to the procedure and more related to the natural history of disease in the patient.51 Payers are often focused more on cost profiling physicians,

Number

Principle

The driving force behind physician performance measurement and reporting systems should be to promote quality improvement

Public reporting programs should be based on performance measures with scientific validity

Public reporting programs should be developed in partnership with physicians

Every effort should be made to use standardized data elements to assess and report performance and to make the submission uniform across all public reporting programs

but the accuracy of these methods have also been questioned.54 Finally, the manner in which information is presented in some public reports is overly complex and can be confusing to consumers. Everyone desires transparent and accurate reporting presented in a fair and understandable format. The information provided in public reporting should be understandable and usable. The amount of, and manner in which, information is displayed determines whether consumers can actually process and use it in decision-making.55,56 Information displays that aid consumers in quickly understanding the meaning of data increase consumer motivation to use the information in contrast to a bewildering display that will quickly be dismissed as too complicated.

Public Reporting in the Future With the current national emphasis on quality measurement, accountability, transparency, and value-based purchasing, stakeholders and consumers of healthcare are eager to obtain information about healthcare facilities and providers. This has created a rich environment for public reporting that, at present, is uncoordinated, often perplexing to patients, and further confused by divergent public rankings of the same facility in different reporting systems.57,58 Despite this, the public release of information about the performance of healthcare systems and individual providers continues to grow, although it lags behind the reporting of commercial products and services in many other industries. Hospital-level public reporting in its various formats is now familiar to most clinicians with individual provider reporting becoming more prevalent. Physician-level reporting has additional challenges. Attributing process and outcome of care metrics to a single provider when patients interact with multiple different providers during an encounter can be difficult. Moreover, determining if differences in outcomes are statistically significant becomes more difficult when the number of patients treated for a specific condition at a facility is divided among multiple providers.

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Performance reporting should occur at the appropriate level of accountability

Public reporting programs should include a formal process for evaluating the impact of the program on the quality and cost of healthcare, including an assessment of unintended consequences.

Reprinted from Dehmer GJ et al., Public reporting of clinical quality data: an update for cardiovascular specialists (J Am Coll Cardiol 2014;63:1239–45) with the permission of Elsevier.

Passage of the Patient Protection and Affordable Care Act of 2010 created a new framework by mandating a national strategy for quality improvement, including public reporting of health quality information. More recently, the Medicare Access and Children’s Health Insurance Program Reauthorization Act of 2015 (known as MACRA) incorporates a merit-based incentive payment system that will encourage alternative payment models compared with the traditional fee-for-service model. Payment adjustments will be based on performance in four categories (clinical quality, meaningful use, resource use, and clinical practice improvement) creating an environment with many additional public reporting opportunities, but with an unproved impact on access and quality or care. Professional organizations including the ACC and the STS have articulated the main principles to guide public reporting initiatives (see Table 2).59,60 Although there are challenges to developing accurate and meaningful public reports, a thoughtful, measured public reporting program using clinical data with transparent and scientifically sound methodology, and oversight by professional organizations, has benefits and can minimize the potential unintended consequences. Providing these data demonstrates a good faith effort to deliver high-quality information to assist patients’ healthcare decisions. Value-based purchasing will be dominant in several years and will include public access to provider performance. Failure to understand and use clinical data to improve operations now may result in facilities facing unfair public judgments based on administrative or proprietary-derived data and falling behind in their adaptation to the changing healthcare environment.61 The medical community continues to have concerns over the unintended consequences of public reporting and the ability of patients and other stakeholders to misuse or misinterpret the results. By voluntarily reporting results based on the best available data and analytics public reporting has the potential to enhance a healthcare facility’s standing and linkage to their community. The public reporting of healthcare outcomes exists now and will only expand into the future as the public becomes more engaged in the quality and cost of their healthcare. n

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22, 2015). 24. Adult Coronary Artery Bypass Graft Surgery in the Commonwealth of Massachusetts Fiscal Year 2012 Report. Available at: http://www.massdac.org/wp-content/uploads/ CABG-FY2012-Update.pdf (accessed December 22, 2015). 25. California Healthcare Information Division. Coronary Artery Bypass Graft (CABG) Surgery in California. Available at: http:// www.oshpd.ca.gov/HID/Products/Clinical_Data/CABG/index. html (accessed December 22, 2015). 26. New York State Department of Health. Percutaneous Coronary Interventions in New York State: 2010- 2012. Available at: http:// www.health.ny.gov/statistics/diseases/cardiovascular/docs/ pci_2010-2012.pdf (accessed December 23, 2015). 27. Adult Percutaneous Coronary Intervention in the Commonwealth of Massachusetts Fiscal Year 2012 Report. Available at: http://www.massdac.org/wp-content/uploads/PCIFY2012.pdf (accessed December 22, 2015). 28. Clinical Outcomes Assessment Program (COAP). Available at www.COAP.org (accessed December 20, 2015). 29. Ferris TG, Torchiana DF. Public release of clinical outcomes data—online CABG report cards. N Engl J Med 2010;363:1593–5. doi: 10.1056/NEJMp1009423. Epub 2010 Sep 7 PMID: 20961241 30. Dehmer GJ, Drozda JP Jr, Brindis RG, et al. Public reporting of clinical quality data: an update for cardiovascular specialists. J Am Coll Cardiol 2014;63 :1239–45. doi: 10.1016/j.jacc.2013.11.050 PMID: 24509280 31. Dehmer GJ, Jennings J, Madden RA, et al. The National Cardiovascular Data Registry voluntary public reporting program: an interim report from the NCDR public reporting advisory group. J Am Coll Cardiol 2016;67:205–15. doi:10.1016/j. jacc.2015.11.001. 32. Recommended use of aspirin and other antiplatelet medications among adults —National Ambulatory Medical Care Survey and National Hospital Ambulatory Medical Care Survey, United States, 2005–2008. MMWR Morb Mortal Wkly Rep 2012;61(Suppl.):11–8. 33. Minnesota Health Scores. Available at: http://www. mnhealthscores.org/?p=our_reports&sf=clinic&category_ section=category_condition&category=2&sub_ category=9&name_id=&compare=&search_ phrase=&zipcode=&within=5 (accessed December 21, 2015). 34. Lamb GC, Smith MA, Weeks WB, et al. Publicly reported qualityof-care measures influenced Wisconsin physician groups to improve performance. Health Aff (Millwood) 2013;32 :536–43. doi: 10.1377/hlthaff.2012.1275 PMID: 23459733 PMID: 21840943 35. Hafner JM, Williams SC, Koss RG, et al. The perceived impact of public reporting hospital performance data. Int J Qual Health Care 2011;23 :697–704. doi: 10.1093/intqhc/mzr056 PMID: 21840943 36. Shahian DM, Grover FL, Prager RL, et al. The Society of Thoracic Surgeons voluntary public reporting initiative: the first 4 years. Ann Surg 2015;262 :526–35. doi: 10.1097/SLA.0000000000001422 PMID: 26258322 37. Ketelaar NABM, Faber MJ, Flottorp S, et al. Public release of performance data in changing the behaviour of healthcare consumers, professionals or organisations. Cochrane Database of Systematic Reviews 2011;11 :CD004538. 38. Fung CH, Lim Y-W, Mattke S, et al. Systematic review: Evidence that publishing patient care performance data improves quality of care. Ann Intern Med 2008;148 :111–23. PMID: 18195336 39. Hammill BG, Curtis LH, Fonarow GC, et al. Incremental value of clinical data beyond claims data in predicting 30-day outcomes after heart failure hospitalization. Circ Cardiovasc Qual Outcomes 2011;4 :60–7. DOI: http://dx.doi.org/10.1016/j. genhosppsych.2015.12.001 40. Tang PC, Ralston M, Arrigotti MF, et al. Comparison of methodologies for calculating quality measures based on administrative data versus clinical data from an electronic health record system: implications for performance measures. J Am Med Inform Assoc 2007;14 :10–5. PMID: 17068349 PMCID: PMC2215069 41. Jollis JG, Ancukiewicz M, DeLong ER, et al. Discordance of databases designed for claims payment versus clinical information systems, implications for outcomes research. Ann Intern Med 1993;118 :844–50. PMID: 8018127 42. Hannan EL, Racz MJ, Jollis JG, et al. Using Medicare claims data to assess provider quality for CABG surgery: does it work well enough? Health Serv Res 1997;31 :659–78. PMID: 9018210 PMCID: PMC1070152 43. Shahian DM, Silverstein T, Lovett AF, et al. Comparison of clinical and administrative data sources for hospital coronary artery bypass graft surgery report cards. Circulation 2007;115 :1518–27.

PMID: 17353447 44. Werner RM, Asch DA. The unintended consequences of publicly reporting quality information. JAMA 2005;293 :1239–44. DOI: 10.1001/jama.293.10.1239 45. Marshall MN, Shekelle PG, Leatherman S, et al. The public release of performance data: what do we expect to gain? A review of the evidence. JAMA 2000;283 :1866–74. 46. Omoigui NA, Miller DP, Brown KJ, et al. Outmigration for coronary bypass surgery in an era of public dissemination of clinical outcomes. Circulation 1996;93 :27–33. PMID: 8616936 47. Schneider EC, Epstein AM. Use of public performance reports: A survey of patients undergoing cardiac surgery. JAMA 1998;279 :1638–42. doi:10.1001/jama.279.20.1638 48. Moscucci M, Eagle KA, Share D, et al. Public reporting and case selection for percutaneous coronary interventions: an analysis from two large multicenter percutaneous coronary intervention databases. J Am Coll Cardiol 2005;45 :1759–65. doi:10.1016/j. jacc.2015.01.008 49. Apolito RA, Greenberg MA, Menegus MA, et al. Impact of the New York State Cardiac Surgery and Percutaneous Coronary Intervention Reporting System on the management of patients with acute myocardial infarction complicated by cardiogenic shock. Am Heart J 2008;155 :267–73. doi: 10.1016/j. ahj.2007.10.013 PMID: 18215596 50. Narins CR, Dozier AM, Ling FS, et al. The influence of public reporting of outcome data on medical decision making by physicians. Arch Intern Med 2005;165 :83–87. PMID: 15642879 51. Resnic FS, Welt FG. The public health hazards of risk avoidance associated with public reporting of risk-adjusted outcomes in coronary intervention. J Am Coll Cardiol 2009;53 :825–30. doi:10.1016/j.jcin.2013.02.017 52. McCabe JM, Joynt KE, Welt FG, et al. Impact of public reporting and outlier status identification on percutaneous coronary intervention case selection in Massachusetts. JACC Cardiovasc Interv 2013;6 :625–30. doi: 10.1016/j.jcin.2013.01.140 PMID: 23787236 53. Resnic FS, Normand S-LT, Piemonte TC, et al. Improvement in mortality risk prediction after percutaneous coronary intervention through the addition of a “compassionate use” variable to the National Cardiovascular Data Registry CathPCI Dataset: a study from the Massachusetts Angioplasty Registry. J Am Coll Cardiol 2011;57 :904–11. doi: 10.1016/j.jacc.2010.09.057 PMID: 21329835 PMCID: PMC3061352 54. Adams JL, Mehrotra A, Thomas JW, et al: Physician cost profiling—reliability and risk of misclassification. N Engl J Med 2010;362 :1014–21. doi: 10.1056/NEJMsa0906323 PMID: 20237347 PMCID: PMC2878194 55. Hibbard J, Sofaer S. Best Practices in Public Reporting No. 1: How to effectively present health care performance data to consumers. Available at: http://archive.ahrq.gov/professionals/ quality-patient-safety/quality-resources/tools/pubrptguide1/ pubrptguide1.pdf (accessed December 10, 2015). 56. Hibbard J, Sofaer S. Best Practices in Public Reporting No. 2: Maximizing consumer understanding of public comparative quality reports: Effective use of explanatory information. Available at: http://archive.ahrq.gov/professionals/qualitypatient-safety/quality-resources/tools/pubrptguide2/ pubrptguide2 (accessed December 10, 2015). 57. Austin JM, Jha AK, Romano PS, et al. National hospital ratings systems share few common scores and may generate confusion instead of clarity. Health Aff (Millwood) 2015;34 :423– 30. doi: 10.1377/hlthaff.2014.0201 PMID: 25732492 58. HANYS’ Report on Report Cards; Understanding publicly reported hospital quality measures. Available at: http://www. hanys.org/quality/data/report_cards/2013/ (accessed December 22, 2015). 59. Drozda JP Jr, Hagan EP, Mirro MJ, et al. American College of Cardiology Foundation Writing Committee. ACCF 2008 health policy statement on principles for public reporting of physician performance data: A Report of the American College of Cardiology Foundation Writing Committee to develop principles for public reporting of physician performance data. J Am Coll Cardiol 2008;51 :1993–2001. doi: 10.1016/j.jacc.2008.03.004 PMID: 18482675 60. The Society of Thoracic Surgeons. Rational for Public Reporting. Available at: http://www.sts.org/quality-research-patient-safety/ sts-public-reporting-online/rationale-public-reporting (accessed December 24, 2015). 61. Hibbard JJH, Stockard J, Tusler M. Hospital performance reports: Impact on quality, market share, and reputation. Health Aff (Millwood) 2005;24 :1150–60. PMID: 16012155

US CARDIOLOGY REVIEW

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Guest Editorial

The Use of Social Media In Cardiovascular Medicine

Dr Kevin R Campbell, MD, FACC is Assistant Professor of Medicine, Division of Cardiology at the University of North Carolina. Twitter @DrKevinCampbell Blog drkevincampbellmd.wordpress.com Website www.drkevincampbellmd.com

Social Media utilization and online social networking is booming. Nearly 83 % of all Fortune 500 companies are active on Twitter and nearly 420K C-level executives engage on social media channels daily1. For decades, cardiovascular professionals have led the way for innovation and research in healthcare and social media use and engagement should be no exception.

Our Patients Are Active in Cyberspace and That is Where They Need Us to Be… Patients and physicians have the opportunity to engage online like never before—nearly 87 % of all American adults use the internet on a daily basis. The growing number of mobile devices and tools that are available to consumers today facilitates this widespread internet use. According to a research poll conducted by Pew2, nearly 65 % of all Americans own a smartphone and almost 90 % own a mobile device of some type. Most users engage online daily and the internet has become a major source of information for patients. The widespread use of online resources by patients has created the concept of the “electronic patient” or e-patient. The e-patient is a healthcare consumer who is fully invested in their care—they consider themselves an equal partner with their physician in the management of their disease. They are well informed and use online resources on a regular basis. Electronic patients are changing the landscape of medical care. According to Pew, 60 % of all e-patients consume social media and nearly 30 % contribute content. Internet use is not limited to the millennial generation—71 % of all seniors go online every single day and more than half of these seniors go online in order to access health information3. Moreover, nearly 75 % of all patients visit the internet either immediately before or immediately after a visit to their healthcare provider in order to either seek advice or gather information to better understand a new diagnosis or treatment. Much of this online interaction is now occurring via mobile devices— enabling healthcare consumers to access information instantly, even while on the go. Social media facilitates instant communication and two-way interaction between healthcare professionals and patients. This ease of access and the opportunity for real-time dialogue and information exchange provides an enormous opportunity to impact the cardiovascular health of millions of Americans.

Campbell_Editorial FINAL.indd 41

How Can Cardiovascular Professionals Use Social Media to Transform Care and Improve Outcomes? Cardiovascular disease is the number one killer of Americans today. As a society we must do more to educate the public and increase awareness of the risk factors for cardiovascular disease. As healthcare providers we have a responsibility to work to prevent disease and modify risk factors within the populations whom we serve. Social Media can be an effective platform to promote wellness and positive lifestyle changes as well as a better way to interact with colleagues as well as patients in order to positively affect outcome. A systemic review of over 98 publications concerning the use of social media in medicine was conducted in 2013 and found that there were six significant benefits when social media was used in medicine:4 • • • • • •

Increased meaningful interactions with colleagues More available, tailored, and shared information Increased accessibility and widening access to health information Increased peer/emotional/social support Public health surveillance Potential to influence healthcare policy

I believe that each of these findings is certainly relevant and easily applicable to the prevention and treatment of cardiovascular disease. By increasing our opportunities for meaningful interactions with colleagues, we are more likely to share ideas and innovate. Innovations will provide better treatments and will have the potential to reduce morbidity and mortality related to cardiovascular disease worldwide. Clinical trials can be promoted via social media and potential subjects can be recruited via online platforms. Social media engagement can promote collaborations in research as well as in patient care, ultimately improving outcomes. Providing wider access to health information allows patients all over the world to learn more about their risk for heart disease and may very well motivate them to make necessary lifestyle changes such as smoking cessation, weight loss and increasing physical activity. Given that the majority of Americans now have access to the internet, online depositories of information have the potential to impact millions of people with a wide range of medical problems. Even patients who live

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Guest Editorial in relatively rural areas have the opportunity to learn and engage from an online platform rather than remain isolated from major medical innovations. Social media promotes camaraderie because patients have common, shared experiences. Patients with cardiovascular disease often struggle with the day-to-day challenges of living with a chronic disease and many feel lonely and isolated—often depressed and hopeless. Social media can provide patients with much needed support and the virtual peer-to-peer interaction may very well improve compliance and reduce disease related emotional stress and depression. Given that cardiovascular disease is the leading cause of death in the US today, social media can be a great way to track disease and identify patterns in order to better focus on prevention. In addition, social media can help report outbreaks of disease and can assist government officials in disseminating important information during a health crisis. Primarily for medical professionals, social media provides a platform where physicians can work to influence public opinion and potentially lawmakers for policy change. Blogs—short essays of between 750 and 1000 words that are posted online—offer cardiovascular healthcare providers the opportunity to advocate for patients, discuss healthcare policy, and spur debate among legislators and other political leaders. These discussions can be the vehicle by which changes are made that improve healthcare and outcomes for all patients. In addition, physician involvement in online platforms serves to develop one’s reputation as a key opinion leader in a particular discipline or area of expertise. However, even the most innovative and respected senior physicians have been slow to adapt social media for professional use. This is not the case with emerging healthcare professionals—the newer generation of physicians has been quick to adopt mobile technology and is making great progress in social media use. Data obtained from a survey in the Journal of General Internal Medicine in 2011 shows that while there is far less engagement online by older physicians, there is significant use of social media by fellows, residents and medical students5. Nearly 95 % of emerging physicians report daily social media engagement—this is worth noting as these medical professionals will be the physician leaders of tomorrow and will likely set the standard for physician practices on social media platforms.

Social Media Provides Physicians With an Opportunity for Real Impact—Right Now Patients trust their doctors, due in large part to the development of a meaningful doctor-patient relationship, but also due to a physician’s

1. 2. 3. 4.

Source: Twitter.com, MediaBistro October–December 2013 http://www.pewinternet.org/2015/04/01/us-smartphone-usein-2015/ Pew Research Center’s Internet & American Life Project Moorhead SA, Hazlett DE, Harrison L, et al. A new dimension

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excellent care, years of training, and reputation as an expert. Trust between doctor and patient is critical—each holds one another accountable and both are engaged in the patient’s treatment plan and invested in the patient’s outcome. This important patient trust also extends to cyberspace. A recent survey carryied out by PricewaterhouseCoopers demonstrated that most healthcare consumers are much more likely to trust online information provided by physicians as compared to hospitals, insurers, or drug companies. 6 The online credibility of physicians offers a powerful opportunity to educate and influence. Physicians have an obligation to engage patients and colleagues in an online environment. In order to maximize the potential of social media in medicine we must improve cardiovascular outcomes. In order to successfully develop an online presence, it is important to understand how to master the meaningful use of social media in cardiovascular care: • To treat—engaging directly with patients about a particular disease process, treatment options, and cardiovascular care. The information should be provided generally and not specific to a particular patient. Avoid engaging in an online doctor-patient relationship. • To teach—provide timely and credible information and diseasespecific education to patients as well as colleagues. • To consult—share medical information and disease-specific knowledge with colleagues around the world. Develop a network to engage with colleagues and discuss best practices. • To market—share your expertise and abilities with the world. Highlight your skill set and those of your colleagues. • Become a key opinion leader—establish a national/international reputation. Become a thought leader and influence policy and practice guidelines. Social media use by patients for health care and disease management is at an all-time high. The numbers of electronic patients continues to grow. While physicians have been slow to wade in to the waters of cyberspace, we are beginning to see more provider engagement. It is clear that the physicians of tomorrow will be fluent with multiple social media channels and it is apparent that older healthcare providers must begin to embrace change and engage with patients in cyberspace in order to meet the healthcare needs of a new tech savvy population. The time to get involved is now. Remember, cyberspace is where our patients are now and where we need to be. n

of health care: systematic review of the uses, benefits, and limitations of social media for health communication. J Med Internet Res 2013 Apr 23;15:e85. doi: 10.2196/jmir.1933. PMID: 23615206 PMCID: PMC3636326. Bosslet GT, Torke AM, Hickman SE, et al. The patient-doctor

relationship and online social networks: results of a national survey. J Gen Intern Med 2011 Oct;26:1168–74. Epub 2011 Jun 25. doi: 10.1007/s11606-011-1761-2. PMID: 21706268 PMCID: PMC3181288. Source: PwC HRI Social Media Consumer Survey, 2012

US CARDIOLOGY REVIEW

13/03/2016 20:26

Quality and Outcomes Expert Opinion

Information Technology Data Standards in Cardiology What, Why, and How Come H Ve r n o n A n d e r s o n , M D, FA CC, F S CA I University of Texas Health Science Center, McGovern Medical School, Memorial Hermann Heart & Vascular Institute, Houston, TX; Member, Health Informatics Task Force, American College of Cardiology

Abstract Computers are the necessary substrate for everything that occurs in cardiology and all of medicine, yet computer technology has been implemented in a piecemeal manner. Multiple single solutions have been introduced to solve individual problems, with no coherent planning for integration and communication across all the multiple computer platforms. Data and data elements are the building blocks of what we call information. In order to maximally utilize the enormous capacities that computers offer in handling information, the data elements must be precisely defined and stored in computers in a uniform manner. This requires data standards. In cardiology, national professional societies led by the American College of Cardiology are developing data standards along with necessary technical specifications that will help achieve the desired goal of a fully interoperable health information network.

Keywords Informatics, data standards, electronic medical records Disclosure: The author has no conflicts of interest to declare. Received: January 22, 2016 Accepted: February 8, 2016 Citation: US Cardiology Review, 2016;10(1):43–5 Correspondence: H Vernon Anderson, Cardiology Division, UTHSCH, 6431 Fannin St, Suite 1.246, Houston, TX 77030, USA. E: h.v.anderson@uth.tmc.edu

By now everyone is aware of the involvement of computers in cardiology. This involvement ranges from imaging (image capture, image display, image management), to tabulating simple clinical data items, to enormous electronic health records systems. Computers are the necessary substrate for everything that occurs in cardiology, not to mention all the rest of the healthcare system. However, for a great variety of reasons, information technology (IT) in cardiology, and in medical care in general, have been implemented in a very piecemeal manner. This has occurred because small, isolated problems are solved in a single, non-integrated manner, with a single solution developed for a single problem. Each solution typically is developed by a single commercial vendor, mostly using proprietary equipment and software. As time passes, what results is an enormous confused mess of isolated, stand-alone systems, each unable to communicate with the others (or, at best, only with a few others). This is the current state of affairs. We all conceptualize cardiology, and healthcare in general, as dependent on data. Data are conceived of as specific data elements, which are the building blocks of information. This is somewhat analogous to the way that complex organic molecules are composed of individual single elements called atoms. The difficulty for us is that, unlike atoms, data and data elements have lacked precise definitions and exact structures. To make matters worse, the way that one computer system stores and handles data elements may be, and most often is, completely different

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from the way another computer system does. Couple that with the proliferation of multiple isolated computers, and the result is chaos. So the ‘what’ of data standards in cardiology involves the identification and definition of the data elements that make up the much larger structure of what we call information. Data standards require both the choice of elements as well as the definitions of the terms in them. For some items, this will be quite simple; for example, for certain numeric data, it means making certain that all weights are recorded in either pounds or kilograms, and all heights in either inches or centimeters, insuring that the number scales are not intermingled. Beyond that, clinicians must be certain that when a term is used, it means the same thing everywhere: we need precise, written definitions of terms like ‘myocardial infarction,’ ‘hypertension,’ ‘diabetes,’ and ‘chronic lung disease.’ The complexity increases when we realize that we also need categories or classes included in some data elements. A well-known example of this is the New York Heart Association Functional Class (NYHA). This simple scheme has four classes, I–IV, and each class has a clinical definition. In order to be maximally useful and computable (interoperable), we must adhere to the precise definitions of these four classes and everyone must use them as written. Otherwise, when captured into a computer dataset, that data element will be unreliable. In another element, we might have mitral regurgitation classified as: none, mild, moderate, severe. The same rules would apply here too. So IT data

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Quality and Outcomes Expert Opinion standards begin with a choice of elements to be used along with clear element definitions that are used by all. When confronted with the request to list specific elements and use standard definitions of terms, many cardiologists ask: Why? The common (mis)conception is that computers are smart enough to decode the words we use and sort them into the appropriate meaning we want, or meant, or intended. But this is not true or possible. Most material stored as information in electronic health records is not stored as usable, computable, and exchangeable (that is, interoperable) data items. Most clinical material is stored in prose text files; for example, as portable document format (PDF) files or equivalent file structures. This includes notes, test reports, and procedure reports. The data or the true information in such files is not contained in single words or numbers, but exists in higher-order human-language structures like sentences or paragraphs or even several paragraphs. Despite their complexity and sophistication, computers have not been able, and likely never will be able, to comprehend human prose language and extract the kind of computable data elements that we, as clinicians, all want to be able to use. This is especially so if every prose text file contains multitudes of data elements with non-standardized definitions. So the ‘why’ of IT data standards in cardiology involves the redirection away from prose text with its higher-order human-language structures, toward a different model based on the computational power and speed of electronic systems. The trade-off we must confront is the discipline we need for working with standardized data elements, structured data files, and adherence to formats, for the combining power, calculating power, communication power, and interoperability of computer networks. The prose text human-language model of data and information just will not work on the large-scale, integrated computer networks that have been developed. The good news is that computers themselves can help us with the transition away from prose text to the digital model. When railroads first began to be built in the period 1820–70, every railroad used a different gauge (i.e. width) of track. There were no track standards and railroad builders designed the tracks to solve individual, local problems of terrain and freight loads. As the rail networks grew, they began to bump into one another. Since the track gauges did not match, the engine and cars of one railroad train could not be transferred over to another. At the junctions, all the passengers and freight had to be unloaded by hand off of one train and moved onto the next train. Of course, this was found to be terribly inefficient. In the US, it was only with the construction of the national transcontinental railroads during the 1860s–80s that the standard track gauge came into being. From that we developed a national transportation network. We are facing the same problem with data standards for healthcare IT today. The ‘how come’ of IT data standards in cardiology is the same as the railroad track gauge issue. We have to adapt our work to take advantage of the astronomical speed and processing advantages of computer networks. These computer systems and networks cannot become merely giant storage depots of millions or billions or even trillions of prose text documents, each containing information in the form of higher-order human-language structures that cannot be decoded or deconstructed into atomic data elements for transmission, reception, combining,

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calculating, and display. No person, and no machine, can sort through and understand millions of pages of prose text documents. In order to derive the maximal benefit of computer networks, indeed, in order to not drown in a rapidly rising ocean of prose text documents that cannot be compiled into a coherent whole, the medical community must define the data elements, write the definitions, and store the data, which is the true information, as atomic elements. These atomic data elements then can be transmitted, received, combined, analyzed, calculated, and displayed. Just imagine for a moment trying to do modern polymer chemistry without the precisely structured periodic table of chemical elements. It would not be possible. The key to the future then, is to understand that we in the clinical community cannot continue to do what we have been doing. Instead of the existing Tower of Babel, with all the poorly defined (but beautiful!) prose text language, we will have to create the precise atomic data elements that we need in order to describe the clinical attributes that we want described. Once we have these atomic data elements, and can use them to model the more complex clinical conditions we confront, then we will be able to take advantage of all the enormous capabilities and opportunities that the computer systems can offer. Yes, the task is enormous, but the goal is achievable, and worthwhile. Just as we all learned the alphabet, to read and write, and to add, subtract, multiply, and divide, we will all learn how to define precise clinical terms and create unique atomic data elements that can be built into larger and more complex clinical data structures. The data elements will become the fundamental building blocks that can be stored in a uniform manner in computers, and then also transmitted, combined, and analyzed. The alternative to this is an unpleasant and ultimately fruitless future of billions and billions of prose text files that will strain the human mind to store, index, read, and understand. In addition to this paradigm shift away from prose text, we will have to redesign workflow processes to accommodate structured clinical data collection into routine activities. This has been referred to as the digitization of healthcare.1 Several new and evolving technologies will make it possible to collect patient data, including physician and other provider inputs, at virtually every step in the care process. Small wearable monitors with wireless (Wi-Fi) connectivity, barcode labels and barcode scanners, radiofrequency (RFID) chips, wireless tablet computers, even personal cellphones, and many other devices, can be and will be integrated into patient care. Exactly when, where, and what data should be collected will have to be determined, and that will be part of the challenging future that awaits us. The possibilities are infinite, so careful design will be required. Cardiac procedures such as catheterizations and interventions are likely to be tackled first because of their more limited scope of activities and controlled environment. Cardiac electrophysiology procedures should be close behind. As we learn more about how to reconfigure the procedure-based world, with team-based structured data capture at multiple points along the care pathway, it will then be possible to build on that knowledge and move to other areas within the hospital environment, such as routine bedside care and consultations. Eventually this can and will be carried to the outpatient office environment. There are many groups currently at work creating the IT structures we will need in the future. At the federal level, the Office of the National Coordinator

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Data Standards in Cardiology for Health Information Technology has outlined a roadmap for a fully interoperable healthcare network.2 Within cardiology, some of the most productive work is being done by professional societies like the American College of Cardiology (ACC) and its component, the National Cardiovascular Data Registries (NCDR). The large NCDR registries have been based on standardized data elements and data dictionaries from the very beginning.3,4 Additionally, collaborative efforts with the American Heart Association to create comprehensive data standards for specific clinical cardiovascular areas have been underway for many years.5 The Society for Thoracic Surgery (STS) has developed a standardized dataset for adult cardiac surgery patients.6 Minimal yet comprehensive datasets needed to describe overall cardiovascular conditions for entire patients, and not just one limited and specific area, have been developed and are undergoing continuing review and refinement.7,8 Precisely defined clinical cardiovascular endpoints for clinical trials have been developed, and may become the basis for reporting to the Food and Drug Administration.9 In addition to this, as mentioned above, work is ongoing on developing standardized team-based reporting for procedures done in cardiac catheterization laboratories.10

Steinhubl SR, Topol EJ. Moving from digitalization to digitization in cardiovascular care. J Am Coll Cardiol 2015;66 :1489–96. DOI: 10.1016/j.jacc.2015.08.006; PMID: 26403346 The Office of the National Coordinator for Health Information Technology. Connecting Health and Care for the Nation. A Shared Nationwide Interoperability Roadmap. Available at: https://www.healthit.gov/sites/default/files/hie-interoperability/ nationwide-interoperability-roadmap-final-version-1.0.pdf (accessed February 5, 2016) Anderson HV, Shaw RE, Brindis RG, et al. A contemporary overview of percutaneous coronary interventions: the American College of Cardiology – National Cardiovascular Data Registry (ACC-NCDR). J Am Coll Cardiol 2002;39 :1096–103. DOI: 10.1016/S0735-1097(02)01733-3; PMID: 11923031 Shaw RE, Anderson HV, Brindis RG, et al. Development of a risk adjustment mortality model using the American College of Cardiology National Cardiovascular Data Registry (ACC-NCDR)

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The vendor community that provides all of the necessary hardware and software for IT has a fundamentally important role to play in this endeavor. A partnership organization has been formed with 135 members composed of IT companies, government and nonprofit organizations, professional societies, healthcare provider firms, and standards development organizations. Known as Integrating the Healthcare Enterprise (IHE), it is facilitating the necessary collaborations needed to improve the way computer systems in healthcare share information.11 IHE promotes the coordinated use of established standards to enable care providers to use information more effectively. All of the efforts described here will only continue to grow and advance in the years to come. While IT data standards in cardiology may appear at first glance to be an obscure and inscrutable subject, it is central to development of healthcare computer networks. It is going to be a long road to travel, but in the end, with help and guidance and leadership from clinicians, the goals of a fully interoperable electronic health information system will be achieved. n

experience: 1998–2000. J Am Coll Cardiol 2002;39 :1104–12. DOI: 10.1016/S0735-1097(02)01731-X; PMID: 11923032 Hendel RC, Bozkurt B, Fonarow GC, et al. ACC/AHA 2013 methodology for developing clinical data standards: a report of the American College of Cardiology/American Heart Association task force on clinical data standards. J Am Coll Cardiol 2014;63 :2323–34. DOI: 10.1016/j.jacc.2013.11.006; PMID: 24246166 The Society of Thoracic Surgeons. Adult Cardiac Surgery Database. Available at: http://www.sts.org/national-database/ database-managers/adult-cardiac-surgery-database (accessed January 24, 2016) Weintraub WS, Karlsberg RP, Tcheng JE, et al. ACCF/AHA 2011 key data elements and definitions of a base cardiovascular vocabulary for electronic health records. J Am Coll Cardiol 2011;58 :202–22. DOI: 10.1016/j.jacc.2011.05.001; PMID: 21652161

Anderson HV, Weintraub WS, Radford MJ, et al. Standardized cardiovascular data for clinical research, registries, and patient care. A report from the Data Standards Workgroup of the National Cardiovascular Research Infrastructure Project. J Am Coll Cardiol 2013;61 :1835–46. DOI: 10.1016/j.jacc.2012.12.047; PMID: 23500238 9. Hicks KA, Tcheng JE, Bozkurt B, et al. 2014 ACC/AHA key data elements and definitions for cardiovascular endpoint events in clinical trials. J Am Coll Cardiol 2015;66 :403–69. DOI: 10.1016/j. jacc.2014.12.018; PMID: 25553722 10. Sanborn TA, Tcheng JE, Anderson HV, et al. ACC/AHA/SCAI 2014 Health Policy Statement on Structured Reporting for the Cardiac Catheterization Laboratory. J Am Coll Cardiol 2014;63 :2591–623. DOI:10.1016/j.jacc.2014.03.020; PMID: 24685667 11. IHE International website. Available at: www.ihe.net. (accessed February 5, 2016)

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