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J O U R N A L O F T H E A M E R I C A N C O L L E G E O F C A R D I O L O G Y V O L . 7 4 , N O . 1 , 2 0 1 9

ª 2 0 1 9 B Y T H E A M E R I C A N H E A R T A S S O C I A T I O N , I N C . , T H E AM E R I C A N C O L L E G E O F

C A R D I O L O G Y F O UN DA T I O N , A N D T H E H E A R T R H Y T H M S O C I E T Y

P U B L I S H E D B Y E L S E V I E R

CLINICAL PRACTICE GUIDELINE: FOCUSED UPDATE

ISSN 0735-1097/$36.0

2019 AHA/ACC/HRS Focused Update of the 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society

Developed in Collaboration With the Society of Thoracic Surgeons

Writing Group Craig T. January, MD, PHD, FACC, Chair

Members*

L. Samuel Wann, MD, MACC, FAHA, Vice Chair

Hugh Calkins, MD, FACC, FAHA, FHRS*y Lin Y. Chen, MD, MS, FACC, FAHA, FHRSy Joaquin E. Cigarroa, MD, FACCz Joseph C. Cleveland JR, MD, FACC*x Patrick T. Ellinor, MD, PHD*y Michael D. Ezekowitz, MBCHB, DPHIL, FACC, FAHA*k Michael E. Field, MD, FACC, FAHA, FHRSk Karen L. Furie, MD, MPH, FAHAk Paul A. Heidenreich, MD, FACC, FAHA{

0

This document was approved by the American College of Cardiology Clin

Advisory and Coordinating Committee, and the Heart Rhythm Society Boar

ecutive Committee in January 2019.

The American College of Cardiology requests that this document be cited as

JC Jr, Ellinor PT, Ezekowitz MD, Field ME, Furie KL, Heidenreich PA, Murray

the 2014 AHA/ACC/HRS guideline for the management of patients with atria

American Heart Association Task Force on Clinical Practice Guidelines and t

This article has been copublished in Circulation and HeartRhythm.

Copies: This document is available on the websites of the American

(professional.heart.org), and the Heart Rhythm Society (www.hrsonline.org

Department via fax (212-633-3820) or e-mail ([email protected]).

Permissions: Multiple copies, modification, alteration, enhancement, and

permission of the American College of Cardiology. Requests may be compl

author-agreement/obtaining-permission).

Katherine T. Murray, MD, FACC, FAHA, FHRSk Julie B. Shea, MS, RNCS, FHRS*k Cynthia M. Tracy, MD, FAHAk Clyde W. Yancy, MD, MACC, FAHAk

*Writing group members are required to recuse themselves from voting on

sections to which their specific relationships with industry may apply;

see Appendix 1 for detailed information. zACC/AHA Task Force on

Clinical Practice Guidelines Liaison. kACC/AHA Representative. yHRS

Representative. xSTS Representative. {ACC/AHA Task Force on

Performance Measures Representative.

ACC/AHA Task Force Members

Glenn N. Levine, MD, FACC, FAHA, Chair Patrick T. O’Gara, MD, MACC, FAHA, Chair-Ele

ct Jonathan L. Halperin, MD, FACC, FAHA, Immediate Past Chair#

Sana M. Al-Khatib, MD, MHS, FACC, FAHA

Joshua A. Beckman, MD, MS, FAHA

Kim K. Birtcher, PharmD, MS, AACC Biykem Bozkurt, MD, PhD, FACC, FAHA# Ralph G. Brindis, MD, MPH, MACC# Joaquin E. Cigarroa, MD, FACC Lesley H. Curtis, PhD, FAHA# Anita Deswal, MD, MPH, FACC, FAHA Lee A. Fleisher, MD, FACC, FAHA

https://doi.org/10.1016/j.jacc.2019.01.011

ical Policy Approval Committee, the American Heart Association Science

d of Trustees in September 2018, and the American Heart Association Ex-

follows: January CT, Wann LS, Calkins H, Chen LY, Cigarroa JE, Cleveland

KT, Shea JB, Tracy CM, Yancy CW. 2019 AHA/ACC/HRS focused update of

l fibrillation: a report of the American College of Cardiology Foundation/

he Heart Rhythm Society. J Am Coll Cardiol 2019;74:104–132.

College of Cardiology (www.acc.org), the American Heart Association

). For copies of this document, please contact the Elsevier Inc. Reprint

/or distribution of this document are not permitted without the express

eted online via the Elsevier site (http://www.elsevier.com/about/policies/

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Federico Gentile, MD, FACC Samuel Gidding, MD, FAHA# Zachary D. Goldberger, MD, MS, FACC, FAHA Mark A. Hlatky, MD, FACC, FAHA John Ikonomidis, MD, PhD, FAHA# José A. Joglar, MD, FACC, FAHA Laura Mauri, MD, MSc, FAHA# Mariann R. Piano, RN, PhD, FAAN, FAHA

Susan J. Pressler, PhD, RN, FAHA# Barbara Riegel, PhD, RN, FAHA# Duminda N. Wijeysundera, MD, PhD

#Former Task Force member; current member during the

writing effort.

TABLE OF CONTENTS

PREAMBLE (FULL VERSION) . . . . . . . . . . . . . . . . . . . . . 105

1. INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107

1.1. Methodology and Evidence Review . . . . . . . . . . . 107

1.2. Organization of the Writing Group . . . . . . . . . . . . 108

1.3. Document Review and Approval . . . . . . . . . . . . . . 109

1.4. Abbreviations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109

4. PREVENTION OF THROMBOEMBOLISM . . . . . . . . . . 109

4.1. Risk-Based Anticoagulant Therapy (Modified From Section 4.1., “Risk-Based Antithrombotic Therapy,” in the 2014 AF Guideline) . . . . . . . . . . 109

4.1.1. Selecting an Anticoagulant Regimen— Balancing Risks and Benefits (Modified From Section 4.1.1., “Selecting an Antithrombotic Regimen—Balancing Risks and Benefits,” in the 2014 AF Guideline) . . . . . . . . . . . . . . . . . . . . . . . . . . . 109

4.2. Anticoagulant Options (Modified From Section 4.2., “Antithrombotic Options,” in the 2014 AF Guideline) . . . . . . . . . . . . . . . . . . . 114

4.3. Interruption and Bridging Anticoagulation . . . . . 114

4.4. Nonpharmacological Stroke Prevention . . . . . . . . 115

4.4.1. Percutaneous Approaches to Occlude the LAA . . . . . . . . . . . . . . . . . . . . . 115

4.4.2. Cardiac Surgery—LAA Occlusion/Excision . . 116

6. RHYTHM CONTROL . . . . . . . . . . . . . . . . . . . . . . . . . . . 116

6.1. Electrical and Pharmacological Cardioversion of AF and Atrial Flutter . . . . . . . . . . . . . . . . . . . . . . . 116

6.1.1. Prevention of Thromboembolism . . . . . . . . 116

6.3. AF Catheter Ablation to Maintain Sinus Rhythm . 118

6.3.4. Catheter Ablation in HF . . . . . . . . . . . . . . . 118

7. SPECIFIC PATIENT GROUPS AND AF . . . . . . . . . . . . 119

7.4. AF Complicating ACS . . . . . . . . . . . . . . . . . . . . . . 119

7.12. Device Detection of AF and Atrial Flutter (New) . . 122

7.13. Weight Loss (New) . . . . . . . . . . . . . . . . . . . . . . . . 122

REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124

APPENDIX 1

Author Relationships With Industry and Other Entities (Relevant) . . . . . . . . . . . . . . . . . . . . . . . . 129

APPENDIX 2

Abbreviated Reviewer Relationships With Industry and Other Entities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131

PREAMBLE (FULL VERSION)

Since 1980, the American College of Cardiology (ACC) and American Heart Association (AHA) have translated sci- entific evidence into clinical practice guidelines with recommendations to improve cardiovascular health. These guidelines, which are based on systematic methods to evaluate and classify evidence, provide a foundation for the delivery of quality cardiovascular care. The ACC and AHA sponsor the development and publication of clinical practice guidelines without commercial support, and members volunteer their time to the writing and re- view efforts. Guidelines are official policy of the ACC and AHA. For some guidelines, the ACC and AHA partner with other organizations. This guideline is a collaboration of the ACC and AHA with the Heart Rhythm Society (HRS) as a partner and the Society of Thoracic Surgeons as a collaborator.

Intended Use

Clinical practice guidelines provide recommendations applicable to patients with or at risk of developing car- diovascular disease. The focus is on medical practice in the United States, but these guidelines are relevant to patients throughout the world. Although guidelines may be used to inform regulatory or payer decisions, the intent is to improve quality of care and align with pa- tients’ interests. Guidelines are intended to define

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practices meeting the needs of patients in most, but not all, circumstances, and should not replace clinical judgment.

Clinical Implementation

Management, in accordance with guideline recommen- dations, is effective only when followed by both prac- titioners and patients. Adherence to recommendations can be enhanced by shared decision-making between clinicians and patients, with patient engagement in selecting interventions on the basis of individual values, preferences, and associated conditions and comorbidities.

Methodology and Modernization

The ACC/AHA Task Force on Clinical Practice Guidelines (Task Force) continuously reviews, updates, and modifies guideline methodology on the basis of published stan- dards from organizations, including the Institute of Medicine (P-1, P-2), and on the basis of internal reevaluation. Similarly, presentation and delivery of guidelines are reevaluated and modified in response to evolving technologies and other factors to optimally facilitate dissemination of information to healthcare professionals at the point of care.

Beginning in 2017, numerous modifications to the guidelines have been and continue to be implemented to make guidelines shorter and enhance “user friendli- ness.” Guidelines are written and presented in a modular knowledge chunk format, in which each chunk includes a table of recommendations, a brief synopsis, recommendation-specific supportive text and, when appropriate, flow diagrams or additional tables. Hyper- linked references are provided for each modular knowl- edge chunk to facilitate quick access and review. More structured guidelines—including word limits (“targets”) and a web guideline supplement for useful but noncritical tables and figures—are 2 such changes. Also, to promote conciseness, the Preamble is presented in abbreviated form in the executive summary and full-text guideline documents.

In recognition of the importance of cost–value consid- erations in certain guidelines, when appropriate and feasible, an analysis of value for a drug, device, or inter- vention may be performed in accordance with the ACC/ AHA methodology (P-3).

To ensure that guideline recommendations remain current, new data are reviewed on an ongoing basis, with full guideline revisions commissioned ideally in approximate 6-year cycles. Publication of potentially

practice-changing new study results relevant to an existing or new drug, device, or management strategy prompts evaluation by the Task Force, in consultation with the relevant guideline writing committee, to determine whether a focused update should be commissioned. For additional information and policies on guideline development, we encourage readers to consult the ACC/AHA guideline methodol- ogy manual (P-4) and other methodology articles (P-5—P-8).

Selection of Writing Committee Members

The Task Force strives to ensure that the guideline writing committee both contains requisite expertise and is representative of the broader medical commu- nity by selecting experts from a broad array of back- grounds, representing different geographic regions, sexes, races, ethnicities, intellectual perspectives/ biases, and scopes of clinical practice, and by inviting organizations and professional societies with related interests and expertise to participate as partners or collaborators.

Relationships With Industry and Other Entities

The ACC and AHA have rigorous policies and methods to ensure that documents are developed without bias or improper influence. The complete policy on relationships with industry and other entities (RWI) can be found online. Appendix 1 of the guideline lists writing commit- tee members’ relevant RWI; for the purposes of full transparency, their comprehensive disclosure informa- tion is available online. Comprehensive disclosure informa- tion for the Task Force is also available online.

Evidence Review and Evidence Review Committees

In developing recommendations, the writing committee uses evidence-based methodologies that are based on all available data (P-4—P-6). Literature searches focus on randomized controlled trials (RCTs) but also include reg- istries, nonrandomized comparative and descriptive studies, case series, cohort studies, systematic reviews, and expert opinion. Only key references are cited.

An independent evidence review committee is commissioned when there are one or more questions deemed of utmost clinical importance that merit formal systematic review to determine which patients are most likely to benefit from a drug, device, or treatment strat- egy, and to what degree. Criteria for commissioning an evidence review committee and formal systematic review

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include absence of a current authoritative systematic review, feasibility of defining the benefit and risk in a timeframe consistent with the writing of a guideline, relevance to a substantial number of patients, and likeli- hood that the findings can be translated into actionable recommendations. Evidence review committee members may include methodologists, epidemiologists, clinicians, and biostatisticians. Recommendations developed by the writing committee on the basis of the systematic review are marked “

SR ”.

Guideline-Directed Management and Therapy

The term guideline-directed management and therapy encompasses clinical evaluation, diagnostic testing, and both pharmacological and procedural treatments. For these and all recommended drug treatment regimens, the reader should confirm dosage with product insert material and evaluate for contraindications and in- teractions. Recommendations are limited to drugs, de- vices, and treatments approved for clinical use in the United States.

Class of Recommendation and Level of Evidence

The Class of Recommendation (COR) indicates the strength of recommendation, encompassing the esti- mated magnitude and certainty of benefit in proportion to risk. The Level of Evidence (LOE) rates the quality of scientific evidence supporting the intervention on the basis of the type, quantity, and consistency of data from clinical trials and other sources (Table 1) (P-5).

Glenn N. Levine, MD, FACC, FAHA Chair, ACC/AHA Task Force on Clinical Practice Guidelines

1. INTRODUCTION

The purpose of this document is to update the “2014 AHA/ ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation” (S1.3-1) (2014 AF Guideline) in areas for which new evidence has emerged since its publication. The scope of this focused update of the 2014 AF Guideline includes revisions to the section on anticoagulation (because of the approval of new medications and throm- boembolism protection devices), revisions to the section on catheter ablation of atrial fibrillation (AF), revisions to the section on the management of AF complicating acute coronary syndrome (ACS), and new sections on device detection of AF and weight loss. The areas of the 2014 AF Guideline that were updated were limited to those for which important new data from clinical trials had emerged and/or new U.S. Food and Drug Administration (FDA) indications for thromboembolism protection

devices have appeared in the data available to the writing group up to August 2018.

All recommendations (new, modified, and unchanged) for each updated clinical section are included to provide a comprehensive assessment. The text explains new and modified recommendations, whereas recommendations from the previous guideline that have been deleted or superseded no longer appear. Please consult the full-text version of the 2014 AF Guideline (S1.3-1) for text and evidence tables supporting the unchanged recommen- dations and for clinical areas not addressed in this focused update. Individual recommendations in this focused update will be incorporated into the full-text guideline in the future. Recommendations from the prior guideline that remain current have been included for completeness, but the LOE reflects the COR/LOE system used when initially developed. New and modified recommendations in this focused update reflect the lat- est COR/LOE system, in which LOE B and C are sub- categorized for greater specificity (S1.3-2—S1.3-4). The section numbers correspond to the full-text guideline sections.

1.1. Methodology and Evidence Review

Clinical trials presented at the annual scientific meetings of the ACC, AHA, Heart Rhythm Society (HRS), and Eu- ropean Society of Cardiology, as well as other selected data published in a peer-reviewed format through August 2018, were reviewed by the Task Force and members of the 2014 AF Guideline writing group to identify trials and other key data that might affect guideline recom- mendations. The information considered important enough to prompt updated recommendations is included in evidence tables in the Online Data Supplement. The complete section of recommendations (new, modified, and unchanged) for each clinical section is included to provide a comprehensive overview for the reader. Rec- ommendations that have been deleted or superseded are not incorporated. The text supporting the new and modified recommendations is provided.

After the preliminary recommendation and text were drafted for percutaneous approaches to occlusion of the left atrial appendage (LAA), it was appreciated that the primary author of the section had, by strict criteria, an RWI relevant to the section. Task Force and organiza- tional leadership directed that both the recommendation and text be discarded and the section be constructed de novo by both a new primary author and new primary reviewer, both without RWI. This new section was thoroughly reviewed by the entire writing group, and the de novo formulated recommendation, as with all

TABLE 1 Applying Class of Recommendation and Level of Evidence to Clinical Strategies, Interventions, Treatments, or Diagnostic Testing in Patient Care* (Updated August 2015)

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recommendations in the focused update, was formally voted on by the writing group.

1.2. Organization of the Writing Group

For this focused update, representative members of the 2014 AF writing committee were invited to participate, and they were joined by additional invited members to

form a new writing group, referred to as the 2018 AF Guideline Focused Update Writing Group. Members were required to disclose all RWI relevant to the data under consideration. The group was composed of clinicians with broad expertise related to AF and its treatment, including the areas of adult cardiology, electrophysiology, cardio- thoracic surgery, and heart failure (HF). The writing group

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included representatives from the ACC, AHA, HRS, and the Society of Thoracic Surgeons.

1.3. Document Review and Approval

The focused update was reviewed by 2 official reviewers each nominated by the ACC, AHA, and HRS; 1 AHA/ACC lay reviewer; 1 organizational reviewer from the Society of Thoracic Surgeons; and 29 individual content reviewers. Reviewers’ abbreviated RWI information is published in this document (Appendix 2), and their detailed disclo- sures are available online.

This document was approved for publication by the governing bodies of the ACC, AHA, and HRS and was endorsed by the Society of Thoracic Surgeons.

1.4. Abbreviations

Abbreviation Meaning/Phrase

ACS acute coronary syndrome

AF atrial fibrillation

AHRE atrial high-rate episodes

CHADS2 congestive heart failure, hypertension, age >75 years, diabetes mellitus, stroke/ transient ischemia attack/ thromboembolism

CHA2DS2-VASc congestive heart failure, hypertension, age $75 years (doubled), diabetes mellitus, prior stroke or transient ischemic attack or thromboembolism (doubled), vascular disease, age 65 to 74 years, sex category

CI confidence interval

CKD chronic kidney disease

CMS U.S. Centers for Medicare & Medicaid Services

CrCl creatinine clearance

DAPT dual-antiplatelet therapy

FDA U.S. Food and Drug Administration

HF heart failure

HFrEF heart failure with reduced left ventricular ejection fraction

HR hazard ratio

INR international normalized ratio

LAA left atrial appendage

LV left ventricular

MI myocardial infarction

NOAC non–vitamin K oral anticoagulant

PCI percutaneous coronary intervention

RCT randomized controlled trial

TIMI Thrombolysis in Myocardial Infarction

4. PREVENTION OF THROMBOEMBOLISM

4.1. Risk-Based Anticoagulant Therapy (Modified From Section 4.1., “Risk-Based Antithrombotic Therapy,” in the 2014 AF Guideline)

4.1.1. Selecting an Anticoagulant Regimen—Balancing Risks

and Benefits (Modified From Section 4.1.1., “Selecting an

Antithrombotic Regimen—Balancing Risks and Benefits,”

in the 2014 AF Guideline)

Introductory Text

The distinction between nonvalvular and valvular AF has confused clinicians, varying among AF clinical trials of non–vitamin K oral anticoagulants (NOACs) (i.e., dabi- gatran [a direct thrombin inhibitor] and rivaroxaban, apixaban, and edoxaban [factor Xa inhibitors]; also referred to as direct-acting oral anticoagulants [DOACs]) and between North American and European AF guide- lines. Valvular AF generally refers to AF in the setting of moderate-to-severe mitral stenosis (potentially requiring surgical intervention) or in the presence of an artificial (mechanical) heart valve. Valvular AF is considered an indication for long-term anticoagulation with warfarin. In contrast, nonvalvular AF does not imply the absence of valvular heart disease. Instead, as used in the present focused update, nonvalvular AF is AF in the absence of moderate-to-severe mitral stenosis or a mechanical heart valve. This is because in most AF NOAC clinical trials, up to approximately 20% of patients were enrolled with various valvular defects, including mild mitral stenosis, mitral regurgitation, aortic stenosis, aortic regurgitation, and tricuspid regurgitation (S4.1.1-1, S4.1.1-2); some trials enrolled small numbers of patients with valve repair, valvuloplasty, and bioprosthetic valves. Furthermore, meta-analysis–derived data from the original clinical tri- als suggest that, among patients with AF and these valvular lesions and operations, NOACs reduce stroke and systemic embolism compared with warfarin, but with differences in bleeding risk (S4.1.1-3). For recommenda- tions from the 2014 AF guideline that were modified only to define the exclusion criteria for valvular AF or to change “antithrombotic” to “anticoagulant,” LOE and supportive text have not been updated. A fifth NOAC, betrixaban, has not been approved by the FDA for use in patients with AF. Antithrombotic (anticoagulant com- bined with antiplatelet) therapy is discussed in Sections 4.4.1. and 7.4. (S4.1.1-4).

Recommendations for Selecting an Anticoagulant Regimen—Balancing Risks and Benefits Referenced studies that support new or modified recommendations are summarized in Online Data Supplements 1 and 2.

COR LOE RECOMMENDATIONS

I

A 1. For patients with AF and an elevated CHA2DS2-VASc score of 2 or greater in men or 3 or greater in women,

oral anticoagulants are recommended. Options include:

n Warfarin (LOE: A) (S4.1.1-5–S4.1.1-7) n Dabigatran (LOE: B) (S4.1.1-8) n Rivaroxaban (LOE: B) (S4.1.1-9) n Apixaban (LOE: B) (S4.1.1-10), or n Edoxaban (LOE: B-R) (S4.1.1-11)

MODIFIED: This recommendation has been updated in response to the approval of edoxaban, a new factor Xa inhibitor. More precision in the use of CHA2DS2-VASc scores is specified in subsequent recommenda- tions. The LOEs for warfarin, dabigatran, rivaroxaban, and apixaban have not been updated for greater granularity as per the new LOE system. (Section 4.1. in the 2014 AF Guideline) The original text can be found in Section 4.1 of the 2014 AF guideline. Additional information about the comparative effectiveness and bleeding risk of NOACs can be found in Section 4.2.2.2.

B

B

B

B-R

I A 2. NOACs (dabigatran, rivaroxaban, apixaban, and edoxaban) are recommended over warfarin in

NOAC-eligible patients with AF (except with moderate-to-severe mitral stenosis or a mechanical heart valve) (S4.1.1-8–S4.1.1-11). NEW: Exclusion criteria are now defined as moderate-to-severe mitral stenosis or a mechanical heart valve. When the NOAC trials are considered as a group, the direct thrombin inhibitor and factor Xa inhibitors were at least noninferior and, in some trials, superior to warfarin for preventing stroke and systemic embolism and were associated with lower risks of serious bleeding.

I A 3. Among patients treated with warfarin, the international normalized ratio (INR) should be determined

at least weekly during initiation of anticoagulant therapy and at least monthly when anticoagulation (INR in range) is stable (S4.1.1-12–S4.1.1-14). MODIFIED: “Antithrombotic” was changed to “anticoagulant.”

I B 4. In patients with AF (except with moderate-to-severe mitral stenosis or a mechanical heart valve), the

CHA2DS2-VASc score is recommended for assessment of stroke risk (S4.1.1-5–S4.1.1-7). MODIFIED: Exclusion criteria are now defined as moderate-to-severe mitral stenosis or a mechanical heart valve. Patients with AF with bioprosthetic heart valves are addressed in the supportive text. (Section 4.1. in the 2014 AF guideline)

I B 5. For patients with AF who have mechanical heart valves, warfarin is recommended (S4.1.1-15–S4.1.1-19).

MODIFIED: New information is included in the supportive text.

I B 6. Selection of anticoagulant therapy should be based on the risk of thromboembolism, irrespective of

whether the AF pattern is paroxysmal, persistent, or permanent (S4.1.1-20–S4.1.1-23). MODIFIED: “Antithrombotic” was changed to “anticoagulant.”

I B-NR 7. Renal function and hepatic function should be evaluated before initiation of a NOAC and should be

reevaluated at least annually (S4.1.1-11, S4.1.1-24–S4.1.1-28). MODIFIED: Evaluation of hepatic function was added. LOE was updated from B to B-NR. New evidence was added. (Section 4.1. in the 2014 AF Guideline)

I C 8. In patients with AF, anticoagulant therapy should be individualized on the basis of shared decision-

making after discussion of the absolute risks and relative risks of stroke and bleeding, as well as the patient’s values and preferences. MODIFIED: “Antithrombotic” was changed to “anticoagulant.”

I C 9. For patients with atrial flutter, anticoagulant therapy is recommended according to the same risk profile

used for AF. MODIFIED: “Antithrombotic” was changed to “anticoagulant.”

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I C 10. Reevaluation of the need for and choice of anticoagulant therapy at periodic intervals is recommended

to reassess stroke and bleeding risks. MODIFIED: “Antithrombotic” was changed to “anticoagulant.”

I C-EO 11. For patients with AF (except with moderate-to-severe mitral stenosis or a mechanical heart valve) who

are unable to maintain a therapeutic INR level with warfarin, use of a NOAC is recommended. MODIFIED: Exclusion criteria are now defined as moderate-to-severe mitral stenosis or a mechanical heart valve, and this recommendation has been changed in response to the approval of edoxaban. (Section 4.1. in the 2014 AF Guideline)

IIa B 12. For patients with AF (except with moderate-to-severe mitral stenosis or a mechanical heart valve) and a

CHA2DS2-VASc score of 0 in men or 1 in women, it is reasonable to omit anticoagulant therapy (S4.1.1-24, S4.1.1-25). MODIFIED: Exclusion criteria are now defined as moderate-to-severe mitral stenosis or a mechanical heart valve. (Section 4.1. in the 2014 AF Guideline)

IIb B-NR 13. For patients with AF who have a CHA2DS2-VASc score of 2 or greater in men or 3 or greater in women and

who have end-stage chronic kidney disease (CKD; creatinine clearance [CrCl] <15 mL/min) or are on dialysis, it might be reasonable to prescribe warfarin (INR 2.0 to 3.0) or apixaban for oral anticoagulation (S4.1.1-26, S4.1.1-29, S4.1.1-30). MODIFIED: New evidence has been added. LOE was updated from B to B-NR. (Section 4.1. in the 2014 AF Guideline)

IIb B-R 14. For patients with AF (except with moderate-to-severe mitral stenosis or a mechanical heart valve) and

moderate-to-severe CKD (serum creatinine ‡1.5 mg/dL [apixaban], CrCl 15 to 30 mL/min [dabigatran], CrCl £50 mL/min [rivaroxaban], or CrCl 15 to 50 mL/min [edoxaban]) with an elevated CHA2DS2-VASc score, treatment with reduced doses of direct thrombin or factor Xa inhibitors may be considered (e.g., dabigatran, rivaroxaban, apixaban, or edoxaban) (S4.1.1-11). MODIFIED: Exclusion criteria are now defined as moderate-to-severe mitral stenosis or a mechanical heart valve, and this recommendation has been changed in response to the approval of edoxaban. LOE was updated from C to B-R. (Section 4.1. in the 2014 AF Guideline)

IIb C- LD 15. For patients with AF (except with moderate-to-severe mitral stenosis or a mechanical heart valve) and a

CHA2DS2-VASc score of 1 in men and 2 in women, prescribing an oral anticoagulant to reduce throm- boembolic stroke risk may be considered (S4.1.1-31–S4.1.1-35). MODIFIED: Exclusion criteria are now defined as moderate-to-severe mitral stenosis or a mechanical heart valve, and evidence was added to support separate risk scores by sex. LOE was updated from C to C-LD. (Section 4.1. in the 2014 AF Guideline)

III: No Benefit C-EO 16. In patients with AF and end-stage CKD or on dialysis, the direct thrombin inhibitor dabigatran or the

factor Xa inhibitors rivaroxaban or edoxaban are not recommended because of the lack of evidence from clinical trials that benefit exceeds risk (S4.1.1-8–S4.1.1-11, S4.1.1-36–S4.1.1-38). MODIFIED: New data have been included. Edoxaban received FDA approval and has been added to the recommendation. LOE was updated from C to C-EO. (Section 4.1. in the 2014 AF Guideline)

III: Harm B-R 17. The direct thrombin inhibitor dabigatran should not be used in patients with AF and a mechanical heart

valve (S4.1.1-39). MODIFIED: Evidence was added. LOE was updated from B to B-R. Other NOACs are addressed in the supportive text. (Section 4.1. in the 2014 AF Guideline)

(Continued)

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Recommendation-Specific Supportive Text

(New or Modified)

1. New data are available for edoxaban. Edoxaban (30 or 60 mg once daily) was studied in a large randomized prospective AF trial; it was found to be noninferior to warfarin with regard to the prevention of stroke or systemic embolization and was associated with significantly lower rates of bleeding and death from

cardiovascular causes (S4.1.1-11). Treatment of pa- tients with AF with edoxaban, either 30 mg or 60 mg, should be based on assessment of the risks of stroke and bleeding. In ENGAGE-TIMI 48 (Effective Anti- coagulation With Factor Xa Next Generation in Atrial Fibrillation—Thrombolysis in Myocardial Infarction 48), the rate of systemic embolism and stroke was 1.5% with warfarin, compared with 1.2% with 60 mg of edoxaban (hazard ratio [HR]: 0.79; 97.5% CI: 0.63–

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0.99; p<0.001 for noninferiority) and 1.6% with 30 mg of edoxaban (HR: 1.07; 97.5% CI: 0.87–1.31; p¼0.005 for noninferiority). The rate of major bleeding was 3.4% with warfarin, versus 2.8% with 60 mg of edox- aban (HR: 0.80; 95% CI: 0.71–0.91; p<0.001) and 1.6% with 30 mg of edoxaban (HR: 0.47; 95% CI: 0.41–0.55; p<0.001) (S4.1.1-11). In the 2014 AF Guideline, the presence of a prior stroke, a prior transient ischemic attack, or a CHA2DS2-VASc score of 2 or greater was an indication to consider oral anticoagulants. In the present focused update, we are adding precision to the CHA2DS2-VASc scoring system on the basis of new published information. The COR and LOE of warfarin, dabigatran, rivaroxaban, and apixaban are unchanged from the 2014 AF Guideline.

2. There have been 4 RCTs (S4.1.1-8–S4.1.1-11) comparing NOACs with warfarin. There was consis- tent evidence of at least noninferiority for the com- bined endpoint of stroke or systemic embolism. When combined with a superior safety profile, they are recommended as firstline therapy for eligible patients.

4. The recommendation is similar to the 2014 AF Guideline. New evidence has appeared that empha- sizes the substantial variation across different cohorts of patients with AF, including various non-European populations, in overall stroke rates for a given CHA2DS2-VASc point score (S4.1.1-40). Additional ap- proaches to stroke risk prediction and serious net clinical outcome prediction in selected patients with AF, including for specific anticoagulant management, have been published (S4.1.1-41–S4.1.1-42). Anti- coagulation for AF and hypertrophic cardiomyopathy remain the same as in the 2014 AF Guideline.

Patients with bioprosthetic heart valves were not included in studies validating the CHA2DS2-VASc scoring system. For bioprosthetic valves, very limited published experience exists for the use of the CHA2DS2- VASc scoring system for long-term assessment of thromboembolism risk in patients with AF. In 1 brief report in patients with AF, increasing age and the CHA2DS2-VASc score were independent predictors of thromboembolic events. In these patients with AF, a low CHA2DS2-VASc score was associated with low thrombo- embolic risk regardless of whether the patients had bioprosthetic valves (S4.1.1-43). In addition, in the ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation; apixaban) and ENGAGE AF-TIMI 48 (edoxaban) AF tri- als, small numbers of these patients (with mitral or aortic bioprosthetic valve implants) were included. In these small subgroups, the findings suggested that apixaban (41 patients) and edoxaban (191 patients)

appeared to be equitable alternatives to warfarin in patients with AF and remote bioprosthetic valve im- plantation (S4.1.1-44–S4.1.1-45). Although short-term anticoagulation of bioprosthetic valves after implanta- tion is standard practice, further study is needed before the routine long-term use of the CHA2DS2-VASc score can be recommended in AF patients with bioprosthetic heart valves (S4.1.1-18, S4.1.1-19).

5. One mechanical aortic valve replacement has FDA- approved recommendations of an INR of 1.5 to 2.0 (3 months after implantation) along with low-dose aspirin, based on a limited clinical trial (S4.1.1-46). This trial was designed to test whether it is safe and effective to treat patients with less aggressive anti- coagulant therapy after implantation of an approved mechanical valve prosthesis (On-X). Although pa- tients with AF were not excluded, very few were enrolled (see also the AHA/ACC valvular heart disease guidelines (S4.1.1-18–S4.1.1-19)).

7. All 4 NOACs with FDA approval for use in patients with AF have dosing defined by renal function (creatinine or CrCl using the Cockcroft-Gault equation). Apixaban adds additional dosing considerations of age$80 years or weight#60 kg (S4.1.1-47). Edoxaban is not approved for use in patients with poor renal function (CrCl <30 mL/min) or upper-range renal function (CrCl >95 mL/ min) (S4.1.1-27). Renal function should be regularly monitored and CrCl calculated at an interval that de- pends on the individual degree of renal dysfunction and likelihood of fluctuation, and dose adjustments should be made according to FDA dosing guidelines (S4.1.1-48). In addition, for the factor Xa inhibitors, hepatic function should occasionally be monitored. NOACs are not recommended for use in patients with severe hepatic dysfunction.

11. Edoxaban (30 mg or 60 mg once daily) was studied in a large randomized prospective AF trial (ENGAGE AF- TIMI 48); it was noninferior to warfarin with regard to the prevention of stroke or systemic embolization and was associated with significantly lower rates of bleeding and death from cardiovascular causes (S4.1.1-11).

12. Many risk factors contribute to the increased risk of stroke in patients with AF as expressed in the CHA2DS2-VASc score. The evidence for female sex as a risk factor has been assessed in many studies. Most studies support the finding that females with AF are at increased risk of stroke. One meta-analysis found a 1.31-fold (95% CI: 1.18–1.46) elevated risk of stroke in females with AF, with the risk appearing greatest for females $75 years of age (S4.1.1-35). Recent studies have suggested that female sex, in the absence of other AF risk factors (CHA2DS2-VASc score of 0 in

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males and 1 in females), carries a low stroke risk that is similar to males. The excess risk for females was especially evident among those with $2 non–sex- related stroke risk factors; thus, female sex is a risk modifier and is age dependent (S4.1.1-49). Adding fe- male sex to the CHA2DS2-VASc score matters for age >65 years or $2 non–sex-related stroke risk factors (S4.1.1-49).

13. Patients with end-stage CKD who receive dialysis have increased prevalence of AF and other associated risk factors for stroke (S4.1.1-50) and have increased bleeding risk (S4.1.1-50–S4.1.1-52). Warfarin, when studied in large retrospective studies, has been shown to offer protection from cardiovascular events without increasing bleeding (S4.1.1-29); however, in a recent meta-analysis, warfarin did not offer reduc- tion in deaths, ischemic events, or strokes but increased the incidence of major bleeding (S4.1.1-26, S4.1.1-53).

Limited data exist on single- and multiple-dose apixaban (2.5 mg or 5 mg) in patients with AF and CKD on dialysis compared to healthy patients (S4.1.1-54– S4.1.1-57). Patients with CKD on dialysis accumulate apixaban (increase in apixaban area-under-the-plasma- concentration-versus-time-curve and trough drug levels), and apixaban 2.5 mg twice daily resulted in steady-state drug exposure comparable to 5 mg twice daily in patients with preserved renal function. Dialysis had a limited impact on apixaban clearance. Bleeding complications were decreased. A recent trial compared apixaban (5 mg versus 2.5 mg twice daily) and warfarin in dialysis-dependent patients with AF. Patients receiving standard-dose apixaban (5 mg) had a lower risk of stroke/ embolism than those receiving low-dose apixaban (2.5 mg) and warfarin. Standard-dose apixaban was associated with a lower risk of death than that observed with low-dose apixaban and warfarin, and there was a lower risk of major bleeding with apixaban than with warfarin (S4.1.1-30). Use of warfarin or apixaban might be reasonable in dialysis-dependent patients with AF, but further study is warranted.

14. Edoxaban (30 mg or 60 mg once daily) was studied in ENGAGE AF-TIMI 48; it was found to be noninferior to warfarin with regard to the prevention of stroke or systemic embolization and was associated with significantly lower rates of bleeding and death from cardiovascular causes (S4.1.1-11).

15. There has been uncertainty about whether anti- coagulation is warranted in men and women who have AF with a CHA2DS2-VASc score of 1 or 2, respec- tively. Women with AF are likely to be older and have

an increased risk of stroke (S4.1.1-31–S4.1.1-33). Fe- male sex alone, however, does not convey increased risk in the absence of other factors (S4.1.1-34, S4.1.1- 35, S4.1.1-58). Recent studies of a large community- based cohort of patients with AF addressed the benefit of anticoagulation among patients with AF who have 1 non–sex-related AF risk factor (CHA2DS2- VASc score of 1 in males and 2 in females) (S4.1.1-58). The authors found that nonanticoagulated patients with AF who had 1 non–sex-related stroke risk factor (CHA2DS2-VASc score of 1 versus 0 in males and 2 vs. 1 in females) had an increased risk of serious cardio- vascular events during follow-up. Importantly, warfarin anticoagulation use was associated with a small positive net clinical benefit (measured as ischemic stroke reduction balanced against increased intracranial hemorrhage) compared with no anti- coagulation or antiplatelet therapy use. Similar studies with NOACs in such patients are needed.

16. Edoxaban is 50% renally excreted and dosed once a day; it is not recommended in patients with end-stage renal disease or on dialysis (S4.1.1-11). Limited single- dose pharmacokinetic data have been published for rivaroxaban use in patients with end-stage kidney disease on dialysis (S4.1.1-59, S4.1.1-60). Dabigatran and rivaroxaban have been studied by using pre- scription patterns in a dialysis population (S4.1.1-61). Dabigatran and rivaroxaban were associated with a higher risk of hospitalization or death from bleeding than that of warfarin (S4.1.1-61).

17. The RE-ALIGN trial (Randomized, Phase II Study to Evaluate the Safety and Pharmacokinetics of Oral Dabigatran Etexilate in Patients After Heart Valve Replacement) was a multicenter, prospective, ran- domized, phase II dose-validation study of dabiga- tran versus warfarin that enrolled patients (18-75 years of age) with one of the following: mechanical valve replacement in the aortic or mitral position (or both) within the prior 7 days (population A) or mechanical mitral valve (with or without aortic valve) replacement more than 3 months before randomization (population B). The trial was stopped after it had enrolled 252 patients because of unacceptable thromboembolic and bleeding event rates in the dabigatran group. Similar drug safety and efficacy information is lacking for me- chanical heart valves and rivaroxaban, apixaban, and edoxaban. On the basis of the outcomes of the RE-ALIGN trial, the presence of a mechanical heart valve is considered a contraindication to all NOACs (S4.1.1-39, S4.1.1-62).

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I

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4.2. Anticoagulant Options (Modified From Section 4.2., “Antithrombotic Options,” in the 2014 AF Guideline)

4.2.2.2. Non–Vitamin K Oral Anticoagulants (Modified From Section 4.2.2.2., “New Target-Specific Oral Anticoagulants,” in the 2014 AF Guideline)

Most NOACs represent an advance in therapeutic safety when compared with warfarin for prevention of throm- boembolism in patients with AF. The NOAC AF trials demonstrated that NOACs are noninferior (S4.2.2.2-1, S4.2.2.2-2) or superior (S4.2.2.2-3, S4.2.2.2-4) to warfarin in preventing stroke or thromboembolism. NOACs reduce intracranial bleeding as compared with warfarin (S4.2.2.2- 1–S4.2.2.2-5). Although no direct RCT data are available, limited data comparing individual NOACs to one another are emerging from meta-analyses of the original NOAC clinical trials (S4.2.2.2-6) and registries and patient databases (S4.2.2.2-6–S4.2.2.2-14), and more data are expected. Specific NOACs, such as apixaban, may have lower risks of bleeding (including intracranial hemor- rhage) and improved efficacy for stroke prevention, whereas the risk of bleeding for rivaroxaban is compara- ble to that of warfarin. In other studies, uninterrupted dabigatran had a more favorable outcome than warfarin in ablation of AF (RE-CIRCUIT Trial [Uninterrupted Dabiga- tran Etexilate in Comparison to Uninterrupted Warfarin in Pulmonary Vein Ablation]) (S4.2.2.2-15). Over time, NOACs (particularly dabigatran and rivaroxaban) may be associated with lower risks of adverse renal outcomes than warfarin in patients with AF (S4.2.2.2-16). Among older adults with AF receiving anticoagulation,

endations for Interruption and Bridging Anticoagulation ced studies that support new or modified recommendations are

LOE RECOMMENDATIONS

C 1. Bridging therapy with unfractionated hep

patients with AF and a mechanical heart warfarin. Decisions on bridging therapy s

B-R 2. For patients with AF without mechanical h

decisions about bridging therapy (unfrac balance the risks of stroke and bleeding (S4.3-1). MODIFIED: LOE was updated from C to B Guideline)

B-NR 3. Idarucizumab is recommended for the rev

an urgent procedure (S4.3-2). NEW: New evidence has been published

B-NR 4. Andexanet alfa can be useful for the reve

or uncontrolled bleeding (S4.3-3, S4.3-4 NEW: New evidence has been published

dabigatran was associated with a lower risk of osteopo- rotic fracture than warfarin (S4.2.2.2-17). Data on drug interactions with NOACs are emerging (S4.2.2.2-18). Interpretation of these data requires careful consideration of trial design, including factors such as absence of con- trol groups, incomplete laboratory and historical data, missing data for some drugs (particularly edoxaban), and varying NOAC drug doses (some approved doses in the United States differ from those in Europe). Head-to-head prospective RCT data for NOACs are needed for further evaluation of comparative bleeding risk and effectiveness.

Commercial assays to measure NOAC serum levels are now available, but reference ranges derived from pub- lished literature are variable and are not well correlated with safety, efficacy, and clinical outcomes. Indications for measurement of NOAC serum levels might include:

n Measurement of drug levels in patients undergoing urgent surgical procedures.

n Uncovering accumulation of potentially toxic drug levels in patients with CKD or those undergoing dialysis.

n Detection of potential drug–drug interactions to guide dose adjustment.

n Evaluation of drug absorption in severely obese pa- tients (body mass index >35 or weight >120 kg)

n Assessment of patient adherence.

4.3. Interruption and Bridging Anticoagulation

summarized in Online Data Supplement 3.

arin or low-molecular-weight heparin is recommended for valve undergoing procedures that require interruption of hould balance the risks of stroke and bleeding.

eart valves who require interruption of warfarin for procedures, tionated heparin or low-molecular-weight heparin) should and the duration of time a patient will not be anticoagulated

-R because of new evidence. (Section 4.1. in the 2014 AF

ersal of dabigatran in the event of life-threatening bleeding or

about idarucizumab to support LOE B-NR.

rsal of rivaroxaban and apixaban in the event of life-threatening ). about andexanet alfa to support LOE B-NR.

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Recommendation-Specific Supportive Text (New or

Modified)

2. The BRIDGE (Bridging Anticoagulation in Patients who Require Temporary Interruption of Warfarin Therapy for an Elective Invasive Procedure or Surgery) study was a randomized, double-blind, placebo-controlled trial of bridging versus no bridging in 1,884 patients with AF (except with moderate to severe mitral ste- nosis or a mechanical heart valve) requiring peri- procedural interruption of warfarin therapy (S4.3-1). Absence of bridging was found to be noninferior to bridging with low-molecular-weight heparin for pre- vention of arterial thromboembolism and was found to decrease the risk of bleeding. Bridging anticoagulation may be appropriate only in patients (on warfarin) with a very high thromboembolic risk.

3. The analysis of 503 patients from the RE-VERSE AD (Reversal Effects of Idarucizumab on Active Dabiga- tran) trial found that idarucizumab, a monoclonal

Recommendation for Percutaneous Approaches to Occlude the L Referenced studies that support the new recommendation are s

COR LOE RECOMMENDATION

IIb B-NR 1. Percutaneous LAA occlusion may

contraindications to long-term a NEW: Clinical trial data and FDA

antibody fragment that binds dabigatran, rapidly normalized hemostasis and reduced levels of circu- lating dabigatran in subjects on dabigatran who had serious bleeding or required an urgent procedure (S4.3- 2). Idarucizumab has received full FDA approval.

4. Andexanet alfa (coagulation factor Xa [recombinant], inactivated-zhzo) is a bioengineered, recombinant modified protein designed to serve as an antidote against direct factor Xa inhibitors. It was reported to reverse the effects of rivaroxaban and apixaban (S4.3- 3, S4.3-4) and was approved under the FDA’s accelerated-approval pathway on the basis of effects in healthy volunteers. Continued approval may be contingent on postmarketing studies to demonstrate an improvement in hemostasis in patients.

4.4. Nonpharmacological Stroke Prevention

4.4.1. Percutaneous Approaches to Occlude the LAA

AA ummarized in Online Data Supplement 4.

be considered in patients with AF at increased risk of stroke who have nticoagulation (S4.4.1-1–S4.4.1-5). approval of the Watchman device necessitated this recommendation.

RCT (S4.4.1-8).

Recommendation-Specific Supportive Text (New)

1. Percutaneous LAA occlusion with the Watchman device has been compared with warfarin in patients with AF (in the absence of moderate to severe mitral stenosis or a mechanical heart valve) at increased risk of stroke in 2 RCTs: the PROTECT AF (WATCHMAN Left Atrial Appendage System for Embolic Protection in Patients With Atrial Fibrillation) (S4.4.1-1) and the PREVAIL (Evaluation of the WATCHMAN LAA Closure Device in Patients With Atrial Fibrillation Versus Long Term Warfarin Therapy) (S4.4.1-2) trials. A meta-analysis combining data from these 2 trials and their registries demonstrated that patients receiving the device had significantly fewer hemorrhagic strokes than did those receiving warfarin, but there was an increase in ischemic strokes in the device group (S4.4.1-3). However, when periprocedural events were excluded, the difference in ischemic strokes was not significant.

Oral anticoagulation remains the preferred therapy for stroke prevention for most patients with AF and elevated stroke risk. However, for patients who are poor candidates for long-term oral anticoagulation (because of the pro- pensity for bleeding or poor drug tolerance or adherence), the Watchman device provides an alternative. There are

important differences in wording between the FDA approval and the Centers for Medicare & Medicaid Services (CMS) approval. In the FDA approval, the device was restricted to patients who were deemed suitable for long- term warfarin (mirroring the inclusion criteria for enroll- ment in the clinical trials) but had an appropriate rationale to seek a nonpharmacological alternative to warfarin. Conversely, CMS states that the device is an option for patients who are suitable for short-term warfarin but deemed unable to take long-term oral anticoagulation. CMS has specified that patients should have a CHADS2 score $2 or a CHA2DS2-VASc score $3 to be considered for

the device. A number of unresolved issues remain,

including the optimal patient selection and periprocedural

antithrombotic regimen. The current FDA labeling spec-

ifies that patients should be deemed suitable for anti- coagulation and, in particular, a period of periprocedural

anticoagulation. Patients unable to take oral anti-

coagulation were excluded from the Watchman RCTs. However, there is increasing experience outside the United States with LAA closure in oral anticoagulation– ineligible patients using an antiplatelet regimen only (S4.4.1-6, S4.4.1-7), and this is the focus of an ongoing

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4.4.2. Cardiac Surgery—LAA Occlusion/Excision

endation for Cardiac Surgery—LAA Occlusion/Excision ced studies that support the modified recommendation are summarized in Online Data Supplement 5.

LOE RECOMMENDATION

B-NR 1. Surgical occlusion of the LAA may be considered in patients with AF undergoing cardiac surgery

(S4.4.2-1), as a component of an overall heart team approach to the management of AF. MODIFIED: LOE was updated from C to B-NR because of new evidence.

Recommendation-Specific Supportive Text (Modified)

1. New evidence exists supporting surgical LAA occlusion in patients with a history of AF. An observational study evaluated the association between surgical LAA occlu- sion (usually with surgical atrial ablation) performed concurrently with cardiac operations in older patients with a history of AF and the risk of postoperative thromboembolic complications (S4.4.2-1). The authors used patient information from the Society of Thoracic Surgeons Adult Cardiac Surgery Database registry, which contains perioperative information with short- term (mainly 30-day) outcomes. The study linked the Society of Thoracic Surgeons Adult Cardiac Surgery Database patient information to Medicare claims data (age $65 years), with the primary outcome of read- mission within 3 years of operation for thromboembo- lism (stroke, transient ischemic attack, or systemic embolism). The study identified 10,524 patients who underwent cardiac surgical procedures, including 3,892 patients (37%) with surgical LAA occlusion. At a mean follow-up of 2.6 years, surgical LAA occlusion, compared with no LAA occlusion, was associated with lower unadjusted rates of readmission for thrombo- embolism (4.2% versus 6.2%), all-cause mortality (17.3% versus 23.9%), and the composite endpoint (20.5% versus 28.7%) but no significant difference in rates of hemorrhagic stroke (0.9% each). These findings suggest that surgical LAA occlusion may be associated with reduced postoperative thromboembolic events in older patients with a history of AF.

endations for Prevention of Thromboembolism ced studies that support modified recommendations are summarized in Online Data Supplement 6.

LOE RECOMMENDATIONS

B-R 1. For patients with AF or atrial flutter of 48 hours’ duration or longer, or when the duration of AF is unk

anticoagulation with warfarin (INR 2.0 to 3.0), a factor Xa inhibitor, or direct thrombin inhibitor is re mended for at least 3weeks before and at least 4weeks after cardioversion, regardless of the CHA2DS2 score or the method (electrical or pharmacological) used to restore sinus rhythm (S6.1.1-1–S6.1.1- MODIFIED: The 2014 AF Guideline recommendation for use of warfarin around the time of cardiov was combined with the 2014 AF Guideline recommendation for NOACs to create a single recommend This combined recommendation was updated to COR I/LOE B-R from COR IIa/LOE C for NOACs in the AF Guideline on the basis of additional trials that have evaluated the use of NOACs with cardiover

In subgroup analyses stratified by anticoagulation sta- tus at hospital discharge, patients with a history of AF who received LAA occlusion without postoperative anti- coagulation had a significantly lower thromboembolism rate than those who received neither LAA occlusion nor anticoagulation. There also was no significant difference in the risk of thromboembolism among patients with a history of AF discharged with anticoagulation therapy, whether they received surgical LAA occlusion or not. These data support a role for anticoagulation in patients with a history of AF, particularly in patients not receiving LAA occlusion.

A propensity-matched analysis of prophylactic surgical LAA occlusion in patients undergoing cardiac surgery did not demonstrate an association betweenLAAocclusion and long-term thromboembolic events (S4.4.2-2). The propensity-matched LAAocclusion andnon–LAAocclusion groups were relatively small (461 patients per group), and fewer than half the patients in each group had a history of AF. The study did show that surgical LAA occlusion, which oftenwas incomplete, was associatedwith increased risk of early postoperative AF, but it did not influence the risk of stroke or death.

There are several important limitations to these studies, and future RCTs may be valuable.

6. RHYTHM CONTROL

6.1. Electrical and Pharmacological Cardioversion of AF and Atrial Flutter

6.1.1. Prevention of Thromboembolism

nown, com- -VASc 12). ersion ation. 2014 sion.

Re

I C 2. For patients with AF or atrial flutter of more than 48 hours’ duration or unknown duration that requires

immediate cardioversion for hemodynamic instability, anticoagulation should be initiated as soon as possible and continued for at least 4 weeks after cardioversion unless contraindicated.

I C-EO 3. After cardioversion for AF of any duration, the decision about long-term anticoagulation therapy should

be based on the thromboembolic risk profile and bleeding risk profile. MODIFIED: The 2014 AF Guideline recommendation was strengthened with the addition of bleeding risk profile to the long-term anticoagulation decision-making process.

IIa B-NR 4. For patients with AF or atrial flutter of less than 48 hours’ duration with a CHA2DS2-VASc score of 2 or

greater in men and 3 or greater in women, administration of heparin, a factor Xa inhibitor, or a direct thrombin inhibitor is reasonable as soon as possible before cardioversion, followed by long-term anti- coagulation therapy (S6.1.1-13, S6.1.1-14). MODIFIED: Recommendation COR was changed from I in the 2014 AF Guideline to IIa, and LOE was changed from C in the 2014 AF Guideline to B-NR. In addition, a specific CHA2DS2-VASc score is now specified.

IIa B 5. For patients with AF or atrial flutter of 48 hours’ duration or longer or of unknown duration who have not

been anticoagulated for the preceding 3 weeks, it is reasonable to perform transesophageal echocardi- ography before cardioversion and proceed with cardioversion if no left atrial thrombus is identified, including in the LAA, provided that anticoagulation is achieved before transesophageal echocardiography and maintained after cardioversion for at least 4 weeks (S6.1.1-15).

IIb B-NR 6. For patients with AF or atrial flutter of less than 48 hours’ duration with a CHA2DS2-VASc score of 0 in

men or 1 in women, administration of heparin, a factor Xa inhibitor, or a direct thrombin inhibitor, versus no anticoagulant therapy, may be considered before cardioversion, without the need for post- cardioversion oral anticoagulation (S6.1.1-13, S6.1.1-14, S6.1.1-16). MODIFIED: Recommendation LOE was changed from C in the 2014 AF Guideline to B-NR to reflect evi- dence from 2 registry studies and to include specific CHA2DS2-VASc scores derived from study results.

(Continued)

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commendation-Specific Supportive Text

(New or Modified)

1. Three prospective RCTs have evaluated the safety and efficacy of newly initiated factor Xa inhibitors (rivar- oxaban and apixaban) for cardioversion as an alterna- tive to warfarin (S6.1.1-7, S6.1.1-8, S6.1.1-17). In addition, retrospective analyses have been performed on the subset of patients undergoing cardioversion within the context of the larger randomized trials that compared each of the FDA-approved NOACs with warfarin for thromboembolism prevention with AF. The results were consistent and support the assertion that NOACs are an effective and safe alternative to warfarin for patients undergoing cardioversion. An alternative to waiting 3 weeks before cardioversion is to perform transesophageal echocardiography to exclude thrombus (see separate recommendation in this section). The decision about long-term anticoag- ulant therapy (beyond 4 weeks) is based on the thromboembolic risk profile (Section 4) and bleeding risk profile. The “48-hour rule” has also been ques- tioned, because delay to cardioversion of 12 hours or longer from symptom onset was associated with a greater risk of thromboembolic complications compared to cardioversion of less than 12 hours

(1.1% versus 0.3%) (S6.1.1-18) and the risk of thrombo- embolic complications with cardioversion of 12 hour or longer increases substantially in patients >75 years of age and in women (S6.1.1-19).”

4. The data supporting the safety of current practices of cardioversion of AF without oral anticoagulation in patients with AF duration <48 hours are limited. Two recent retrospective studies demonstrate that the risk of thromboembolic complication after a cardioversion for AF lasting <48 hours is in the range of 0.7% to 1.1%, with higher risk in patients with risk factors that include female sex, HF, and diabetes mellitus, whereas patients <60 years of age without throm- boembolic risk factors and those with postoperative AF appear to have a lower risk (S6.1.1-13, S6.1.1-14). In 1 study (567 cardioversions in 484 patients), the risk of thromboembolism was nearly 5 times higher in patients without therapeutic anticoagulation than in those on therapeutic anticoagulation with either warfarin or heparin. All events in that study occurred in patients with a CHA2DS2-VASc score of $2 (S6.1.1- 14). In the absence of randomized trials, the risk of

thromboembolic events should be weighed against

the risk of anticoagulant-related bleeding for the in- dividual patient.

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6. Two recent retrospective studies evaluated the risk of thromboembolism in patients after cardioversion for AF lasting <48 hours. In 1 study (567 cardioversions in 484 patients), the risk of thromboembolism was nearly 5 times higher in patients without therapeutic anticoagulation than in those on therapeutic anti- coagulation with either warfarin or heparin, with no events in patients with a CHA2DS2-VASc score of <2 (S6.1.1-14). In the second study, for patients with AF lasting <48 hours and a CHA2DS2-VASc score #1, the overall event rate was low (0.4%), but this group

endation for Catheter Ablation in HF ced studies that support the new recommendation are summariz

LOE RECOMMENDATION

B-R 1. AF catheter ablation may be reasonable i

left ventricular (LV) ejection fraction (HF hospitalization for HF (S6.3.4-1, S6.3.4-2 NEW: New evidence, including data on im ablation compared with medical therapy

accounted for 10 of the 38 thromboembolic events (26%) that occurred in the study (S6.1.1-13). These studies agree with prior studies of cardioversion in short-term AF (S6.1.1-20). In the absence of random- ized trials, the risk of thromboembolic events should be weighed against the risk of anticoagulant-related bleeding for the individual patient.

6.3. AF Catheter Ablation to Maintain Sinus Rhythm

6.3.4. Catheter Ablation in HF

ed in Online Data Supplement 7.

n selected patients with symptomatic AF and HF with reduced rEF) to potentially lower mortality rate and reduce ). proved mortality rate, has been published for AF catheter in patients with HF.

S6.3.4-6).

Recommendation-Specific Supportive Text (New)

1. In an RCT (CASTLE-AF [Catheter Ablation vs. Standard Conventional Treatment in Patients With LV Dysfunc- tion and AF]), selected patients with HFrEF with paroxysmal or persistent AF and an implanted cardioverter-defibrillator or cardiac resynchronization therapy defibrillator device who did not respond to or could not take antiarrhythmic drugs were randomized to receive AF catheter ablation versus medical therapy (rate or rhythm control) in addition to guideline- directed management and therapy for HFrEF (S6.3.4- 1). Patients in the AF catheter ablation group had significantly reduced overall mortality rate, reduced rate of hospitalization for worsening HF, and improved LV ejection fraction as compared with the medical therapy group, and according to device interrogation, more patients in the AF catheter ablation group were in sinus rhythm. An additional RCT in a population of patients with persistent AF, HFrEF, and an implanted cardioverter-defibrillator or cardiac resynchronization therapy defibrillator device demonstrated that AF

catheter ablation was superior to amiodarone for maintenance of sinus rhythm, with secondary endpoint analyses suggesting a lower rate of unplanned hospi- talization and death (S6.3.4-2). Both studies have limi- tations, including relatively small and highly selected patient populations. Further, larger studies are needed to validate these findings.

Other small studies conducted in patients with AF and HFrEF have shown the superiority of AF ablation over antiarrhythmic drugs in the maintenance of sinus rhythm and in outcomes such as improved LV ejection fraction, performance in a 6-minute walk test, and quality of life (S6.3.4-3, S6.3.4-4). However, the recent CABANA (Cath- eter Ablation verses Anti-arrhythmic Drug Therapy for Atrial Fibrillation) trial (n¼2,204 patients randomized to

either catheter ablation or drug therapy) showed that AF

ablation was not superior to drug therapy for the primary

cardiovascular outcomes of death, disabling stroke, serious

bleeding, or cardiac arrest at 5 years among patients with

new-onset or untreated AF that required therapy (S6.3.4-5,

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7. SPECIFIC PATIENT GROUPS AND AF

7.4. AF Complicating ACS

Recommendations for AF Complicating ACS Referenced studies that support new or modified recommendations are summarized in Online Data Supplement 8.

COR LOE RECOMMENDATIONS

I B-R 1. For patients with ACS and AF at increased risk of systemic thromboembolism (based on CHA2DS2-VASc

risk score of 2 or greater), anticoagulation is recommended unless the bleeding risk exceeds the expected benefit (S7.4-1–S7.4-3). MODIFIED: New published data are available. LOE was updated from C in the 2014 AF Guideline to B-R. Anticoagulation options are described in supportive text.

I C 2. Urgent direct-current cardioversion of new-onset AF in the setting of ACS is recommended for patients

with hemodynamic compromise, ongoing ischemia, or inadequate rate control.

I C 3. Intravenous beta blockers are recommended to slow a rapid ventricular response to AF in patients with

ACS who do not display HF, hemodynamic instability, or bronchospasm.

IIa B-NR 4. If triple therapy (oral anticoagulant, aspirin, and P2Y12 inhibitor) is prescribed for patients with AF at

increased risk of stroke (based on CHA2DS2-VASc risk score of 2 or greater) who have undergone percutaneous coronary intervention (PCI) with stenting for ACS, it is reasonable to choose clopidogrel in preference to prasugrel (S7.4-4, S7.4-5). NEW: New published data are available.

IIa B-R 5. In patients with AF at increased risk of stroke (based on CHA2DS2-VASc risk score of 2 or greater) who

have undergone PCI with stenting for ACS, double therapy with a P2Y12 inhibitor (clopidogrel or tica- grelor) and dose-adjusted vitamin K antagonist is reasonable to reduce the risk of bleeding as compared with triple therapy (S7.4-3, S7.4-6–S7.4-8). NEW: New RCT data and data from 2 registries and a retrospective cohort study are available.

IIa B-R 6. In patients with AF at increased risk of stroke (based on CHA2DS2-VASc risk score of 2 or greater) who

have undergone PCI with stenting for ACS, double therapy with P2Y12 inhibitors (clopidogrel) and low- dose rivaroxaban 15 mg daily is reasonable to reduce the risk of bleeding as compared with triple therapy (S7.4-2). NEW: New published data are available.

IIa B-R 7. In patients with AF at increased risk of stroke (based on CHA2DS2-VASc risk score of 2 or greater) who

have undergone PCI with stenting for ACS, double therapy with a P2Y12 inhibitor (clopidogrel) and dabigatran 150 mg twice daily is reasonable to reduce the risk of bleeding as compared with triple therapy (S7.4-1). NEW: New published data are available.

IIb B-R 8. If triple therapy (oral anticoagulant, aspirin, and P2Y12 inhibitor) is prescribed for patients with AF who

are at increased risk of stroke (based on CHA2DS2-VASc risk score of 2 or greater) and who have un- dergone PCI with stenting (drug eluting or bare metal) for ACS, a transition to double therapy (oral anticoagulant and P2Y12 inhibitor) at 4 to 6 weeks may be considered (S7.4-9, S7.4-10). NEW: New published data are available.

IIb C 9. Administration of amiodarone or digoxin may be considered to slow a rapid ventricular response in pa-

tients with ACS and AF associated with severe LV dysfunction and HF or hemodynamic instability.

IIb C 10. Administration of nondihydropyridine calcium antagonists may be considered to slow a rapid ventricular

response in patients with ACS and AF only in the absence of significant HF or hemodynamic instability.

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Synopsis

The incidence of AF in patients with ACS ranges from 10% to 21% and increases with patient age and severity of myocardial infarction (MI) (S7.4-11, S7.4-12). In the Medicare population, AF is associated with increased in- hospital mortality rate (25.3% with AF versus 16.0% without AF), 30-day mortality rate (29.3% versus 19.1%), and 1-year mortality rate (48.3% versus 32.7%) (S7.4-12). With multivariate adjustment, AF remains an indepen- dent predictor of death: in hospital (odds ratio: 1.21), at 30 days (odds ratio: 1.20), and at 1 year (odds ratio: 1.34) (S7.4-12). Patients who develop AF during hospitalization have a worse prognosis than those with AF on admission (S7.4-12). Stroke rates are higher in patients with MI and AF than in those without AF (3.1% for those with AF versus 1.3% for those in sinus rhythm) (S7.4-11). Thus, AF is an independent predictor of poor long-term outcome in patients with ACS (S7.4-13, S7.4-14).

Patients treated for ACS normally require dual- antiplatelet therapy (DAPT) with aspirin plus a platelet P2Y12 receptor inhibitor and may require the addition of warfarin or a NOAC (“triple therapy”) for primary pre- vention for patients with AF at increased risk of stroke (S7.4-3) (Section 4.3.). An option is to consider double therapy—the use of an oral anticoagulant plus a P2Y12 in- hibitor without aspirin (S7.4-3). If triple therapy is used, efforts may be directed to minimize duration of triple therapy to a period of 4 to 6 weeks, as this is the period of greatest risk of stent thrombosis, especially in patients with ACS, such as ST-segment–elevation MI. Use of DAPT alone may be considered for patients with ACS who have AF and a CHA2DS2-VASc score of 0 to 1, with reconsider- ation of the indications for anticoagulation over time (S7.4-15, S7.4-16). Whereas Section 4.1.1. provides specific guidance on the presence/absence of stroke risk associ- ated with female sex in the CHA2DS2-VASc score, the randomized data set referenced in this section on double versus triple therapy in patients undergoing PCI (subset with ACS) does not present the data analysis stratified by sex; therefore, the recommendation is provided in the context of overall CHA2DS2-VASc score. The HAS-BLED score can be used to assess bleeding risk in patients for whom anticoagulation is being considered (S7.4-17).

Urgent direct-current cardioversion is appropriate in patients with ACS presenting with new-onset AF and intractable ischemia, hemodynamic instability, or inade- quate rate control. Intravenous administration of a beta blocker is indicated for rate control in patients with ACS to reduce myocardial oxygen demands. Intravenous amiodarone is an appropriate alternative for rate control and may facilitate conversion to sinus rhythm. Digoxin may be considered in those with severe LV dysfunction and HF or hemodynamic instability. However, recent data from the ARISTOTLE AF NOAC trial study population

show that digoxin was independently associated with higher mortality rate in patients with AF regardless of HF, and in patients with AF taking digoxin, the risk of death increased with higher serum digoxin concentrations (S7.4-18). Other meta-analysis studies support these conclusions (S7.4-19). Treatment with angiotensin- converting enzyme inhibitors appears to reduce the inci- dence of AF in patients with LV dysfunction after ACS (S7.4-20, S7.4-21).

Recommendation-Specific Supportive Text

(New or Modified)

1. This recommendation is modified to incorporate the data from WOEST (What is the Optimal Antiplatelet & Anticoagulant Therapy in Patients With Oral Anti- coagulation and Coronary Stenting) (S7.4-3) and the recent evidence from PIONEER AF-PCI (Open-Label, Randomized, Controlled, Multicenter Study Exploring two Treatment Strategies of Rivaroxaban and a Dose- Adjusted Oral Vitamin K Antagonist Treatment Strat- egy in Subjects With Atrial Fibrillation who Undergo Percutaneous Coronary Intervention) (S7.4-2) and RE- DUAL PCI (Randomized Evaluation of Dual Antith- rombotic Therapy With Dabigatran Versus Triple Therapy With Warfarin in Patients With Nonvalvular Atrial Fibrillation Undergoing Percutaneous Coronary Intervention) (S7.4-1) (see supportive text for recom- mendations 6 and 8 below). These 3 clinical trials enrolled both patients with stable ischemic disease and patients with ACS treated with PCI. These trials did not include patients with ACS managed medically. On the basis of these clinical trials, options for anticoagulants in this patient population include warfarin, rivarox- aban, and dabigatran. Although the use of the CHA2DS2-VASc score has been validated only in several small studies of patients with AF and ACS, we believe it is reasonable to use this methodology to estimate the risk of systemic thromboembolism (S7.4-22, S7.4-23).

4. A single-center prospective cohort study found that, as compared with triple therapy with clopidogrel, triple therapy with prasugrel was associated with a higher incidence of Thrombolysis in Myocardial Infarction (TIMI) major or minor bleeding events (S7.4-4). This finding was corroborated by the TRANSLATE-ACS (Treatment with Adenosine Diphosphate Receptor In- hibitors: Longitudinal Assessment of Treatment Pat- terns and Events After Acute Coronary Syndrome) study (S7.4-5), a multicenter prospective cohort study of patients who underwent PCI for an acute MI. That study found that, as compared with triple therapy with clopidogrel, triple therapy with prasugrel was associ- ated with a higher incidence of BARC (Bleeding Aca- demic Research Consortium)–defined bleeding events.

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These events, however, were patient-reported bleeding events that did not require hospitalization.

5. WOEST was an RCT that showed that, as compared with triple therapy (aspirin, clopidogrel, and warfarin), double therapy with warfarin and clopidogrel was associated with fewer bleeding complications. WOEST, however, was not powered to assess stent thrombosis (S7.4-3). Two other registry-based studies similarly showed that double therapy with warfarin and clopi- dogrel was not associated with higher risk of coronary ischemia than triple therapy (S7.4-6, S7.4-7). Further- more, a hospital-based retrospective cohort study found that double therapy with warfarin and ticagrelor had thrombotic and bleeding rates that were similar to those observed with triple therapy (S7.4-8). The aforementioned studies were not based exclusively on patients with AF and ACS; patients with AF undergoing elective PCI for stable coronary artery disease were also included.

6. PIONEER AF-PCI was an international, multicenter, randomized, open-label trial of 2,124 patients with AF (without moderate to severe mitral stenosis or a me- chanical heart valve) who had undergone PCI with stenting. Patients were randomized in a 1:1:1 ratio to low-dose rivaroxaban (15 mg once daily) plus a P2Y12

inhibitor for 12 months (Group 1); very-low-dose rivaroxaban (2.5 mg twice daily) plus DAPT for 1, 6, or 12 months (Group 2); or standard therapy with a dose- adjusted vitamin K antagonist (once daily) plus DAPT for 1, 6, or 12 months (Group 3). Clopidogrel was the most common P2Y12 inhibitor used (>90%). The rates of clinically significant bleeding were lower in Groups 1 and 2 than in Group 3 (S7.4-2). The rates of death from cardiovascular causes, MI, or stroke were similar in the 3 groups (S7.4-2). It is important to note that the dose of rivaroxaban used in that study was lower than the dose recommended for stroke prophylaxis in AF. The study was not powered to evaluate risk of stent thrombosis or systemic thromboembolism (S7.4-2).

7. RE-DUAL PCI was an international, multicenter, ran- domized open-label trial of 2,725 patients with non- valvular AF who had undergone PCI with stenting. Patients were randomized to receive 1 of 3 treatments: double therapy with dabigatran (110 mg twice daily) plus either clopidogrel or ticagrelor (110-mg dual- therapy group), double therapy with dabigatran (150 mg twice daily) plus either clopidogrel or ticagrelor (150-mg dual-therapy group), or triple therapy with warfarin plus aspirin (#100 mg daily) and either clo- pidogrel or ticagrelor (triple-therapy group). The inci- dence of major or clinically relevant nonmajor bleeding was higher in the triple-therapy group than in the 110- mg dual-therapy group and the 150-mg dual-therapy group. In addition, the 2 dual-therapy groups

combined were noninferior to the triple-therapy group with regard to the composite efficacy endpoint of thromboembolic events (MI, stroke, or systemic em- bolism), death, or unplanned revascularization. Clopi- dogrel was the most common P2Y12 inhibitor used (88%). Notably, the study was not powered to evaluate risk of stent thrombosis or systemic thromboembolism (S7.4-1).

In aggregate, the data to date on comparisons of double versus triple therapy demonstrate that double therapy significantly reduces the risk of bleeding without a signal of harm with regard to stent thrombosis in clinical trials that enrolled both patients with stable ischemic disease and patients with ACS. With regard to the antithrombotic dosages studied, only the RE-DUAL PCI trial and WOEST trials studied antithrombotic dosages known to reduce the risk of systemic thromboembolism (S7.4-1, S7.4-3). The ongoing AUGUSTUS (A Study of Apixaban in Patients With Atrial Fibrillation, not Caused by a Heart Valve Problem, who are at Risk for Thrombosis due to Having had a Recent Coronary Event, Such as a Heart Attack or a Procedure to Open the Vessels of the Heart) trial is an open-label 2�2 factorial RCT to evaluate the safety of apixaban versus vitamin K antagonist and aspirin versus aspirin placebo in patients with AF and ACS or PCI (S7.4-24). The ENTRUST-AF-PCI (Edoxaban Treat- ment Versus Vitamin K Antagonist in Patients With Atrial Fibrillation Undergoing Percutaneous Coronary Interven- tion) is an ongoing trial evaluating edoxaban treatment versus vitamin K antagonist treatment in patients with AF undergoing PCI (S7.4-25). These trials will provide further evidence on treatment approaches designed to mitigate bleeding while reducing the risks of stent thrombosis and systemic thromboembolism.

8. The ISAR-TRIPLE (Triple Therapy in Patients on Oral Anticoagulation After Drug Eluting Stent Implantation) trial (S7.4-9) was a randomized, open-label trial of pa- tients receiving anticoagulation who underwent PCI with drug-eluting stents. Patients received concomi- tant anticoagulant and aspirin and were randomized to 6 weeks versus 6 months of clopidogrel. There was no difference between the 2 groups in terms of the pri- mary composite endpoint of death, MI, definite stent thrombosis, stroke, or TIMI major bleeding or in terms of the secondary bleeding endpoint of TIMI major bleeding at 9 months (S7.4-9). The Bern PCI Registry (S7.4-10) is a prospective registry of consecutive pa- tients who have undergone PCI for stable coronary artery disease or ACS at Bern University Hospital since 2009. Among patients who were discharged on triple therapy, there was no difference between #1 month versus >1 month of triple therapy in the primary composite endpoint of cardiac death, MI, stroke, defi- nite stent thrombosis, or TIMI major bleeding at 1 year

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(S7.4-10). Although both the ISAR-TRIPLE trial and the Bern PCI Registry have limitations, the consistent finding in both patients with ACS and patients with stable ischemic heart disease suggests that with cur- rent drug-eluting stents, selecting bare metal stents to shorten the duration of DAPT is no longer indicated. Of

endations for Device Detection of AF and Atrial Flutter ced studies that support new recommendations are summarized

LOE RECOMMENDATIONS

B-NR 1. In patients with cardiac implantable elect

defibrillators), the presence of recorded evaluation to document clinically relevan

B-R 2. In patients with cryptogenic stroke (i.e.,

monitoring is inconclusive, implantation optimize detection of silent AF (S7.12-6)

endation for Weight Loss in Patients with AF ced studies that support the new recommendation are summariz

LOE RECOMMENDATION

B-R 1. For overweight and obese patients with A

recommended (S7.13-1–S7.13-3). NEW: New data demonstrate the benefici controlling AF.

the patients treated with triple therapy for 1 month in the Bern PCI Registry, 60% were treated with a current- generation drug-eluting stent.

7.12. Device Detection of AF and Atrial Flutter (New)

in Online Data Supplement 9.

ronic devices (pacemakers or implanted cardioverter- atrial high-rate episodes (AHREs) should prompt further t AF to guide treatment decisions (S7.12-1–S7.12-5).

stroke of unknown cause) in whom external ambulatory of a cardiac monitor (loop recorder) is reasonable to .

Recommendation-Specific Supportive Text (New)

1. Patients with AHREs detected by implanted devices are at increased risk of stroke and abundant data now link device-detected atrial tachycardia or AF (or AHREs) with the development of thromboembolic events (S7.12- 1–S7.12-5). Remote monitoring with AHRE alerts in- creases the likelihood of detecting silent AF. However, it is unclear whether patients with AHREs benefit from oral anticoagulation. Careful review of stored electro- grams may confirm the presence of AF and rule out false positive events. Occasionally, the addition of extended external electrocardiographic monitoring may be needed if data from the implanted device are uncertain. Prospective clinical trials of prophylactic anti- coagulation based on device-detected AF are under way but have not been completed. Although increased duration of AHREs is associated with increased stroke risk, the threshold duration of AHREs that warrants anticoagulation is unclear. Current approaches factor in the duration of device-detected AF and the patient’s

stroke risk profile, bleeding risk, and preferences to determine whether to initiate long-term anticoagulation.

2. The cause of ischemic stroke remains unknown in 20% to 40% of patients, leading to a diagnosis of cryptogenic stroke. Prolonged electrocardiogram monitoring with an implantable cardiac monitor in these patients (age >40 years) has the advantage of increasing the likeli- hood of detecting silent AF that would escape detection with short-term monitoring. A recent RCT established the superiority of an implantable cardiac monitor over conventional monitoring for detecting silent AF, a finding with major clinical ramifications for these pa- tients (S7.12-6). A role in screening for silent AF may also exist for remote electrocardiographic acquisition and transmission with a “smart” worn or handheld WiFi-enabled device with remote interpretation (S7.12- 7, S7.12-8).

7.13. Weight Loss (New)

ed in Online Data Supplement 10.

F, weight loss, combined with risk factor modification, is

al effects of weight loss and risk factor modification on

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Recommendation-Specific Supportive Text (New)

1. Obesity is associated with atrial electrostructural remodeling (S7.13-4) and AF (S7.13-5–S7.13-7). One RCT demonstrated that a structured weight management program for obese patients (body mass index >27) with symptomatic AF reduced symptom burden and severity and reduced the number of AF episodes and their cu- mulative duration when compared with attempts to optimally manage risk factors alone (S7.13-1). Risk fac- tor modification included assessment and treatment of underlying sleep apnea, hypertension, hyperlipidemia, glucose intolerance, and alcohol and tobacco use. A second nonrandomized observational study reported improved outcomes of AF catheter ablation among obese patients who enrolled in a weight loss program (S7.13-2). Observational studies have revealed that the degree of improvement in the AF type and symptoms were related to thedegree ofweight loss (S7.13-3, S7.13-8). Taken together, these studies support a treatment approach that addresses the risk factors for AF.

PRESIDENTS AND STAFF

American College of Cardiology

C. Michael Valentine, MD, FACC, President

Timothy W. Attebery, DSc, MBA, FACHE, Chief Executive Officer

William J. Oetgen, MD, MBA, FACC, FACP, Executive Vice President, Science, Education, Quality, and Publishing

MaryAnne Elma, MPH, Senior Director, Science, Education, Quality, and Publishing

Amelia Scholtz, PhD, Publications Manager, Science, Education, Quality, and Publishing

American College of Cardiology/American Heart Association

Katherine A. Sheehan, PhD, Director, Guideline Strategy and Operations

Abdul R. Abdullah, MD, Senior Manager, Guideline Science

Thomas S. D. Getchius, Manager, Guideline Science Zainab Shipchandler, MPH, Associate Guideline Advisor American Heart Association

Ivor J. Benjamin, MD, President Nancy Brown, Chief Executive Officer Rose Marie Robertson, MD, FAHA, Chief Science and

Medicine Officer Gayle R. Whitman, PhD, RN, FAHA, FAAN, Senior Vice

President, Office of Science Operations Anne Leonard, MPH, RN, CCRC, FAHA, Senior Science and

Medicine Advisor, Office of Science Operations Jody Hundley, Production and Operations Manager,

Scientific Publications, Office of Science Operations

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R EF E RENCE S

PREAMBL E

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P-2. Committee on Standards for Systematic Reviews of Comparative Effectiveness Research, Institute of Medicine (U.S.). Finding What Works in Health Care: Standards for Systematic Reviews. Washington, DC: National Academies Press, 2011.

P-3. Anderson JL, Heidenreich PA, Barnett PG, et al. ACC/AHA statement on cost/value methodology in clinical practice guidelines and performance measures: a report of the American College of Cardiology/ American Heart Association Task Force on Perfor- mance Measures and Task Force on Practice Guide- lines. J Am Coll Cardiol. 2014;63:2304–22.

P-4. ACCF/AHA Task Force on Practice Guidelines. Methodology Manual and Policies From the ACCF/ AHA Task Force on Practice Guidelines. American College of Cardiology and American Heart Association. 2010. Available at: http://assets.cardiosource.com/ Methodology_Manual_for_ACC_AHA_Writing_Committees. pdf and http://professional.heart.org/idc/groups/ ahamah-public/@wcm/@sop/documents/downloadable/ ucm_319826.pdf. Accessed October 31, 2018.

P-5. Halperin JL, Levine GN, Al-Khatib SM, et al. Further evolution of the ACC/AHA clinical practice guideline recommendation classification system: a report of the American College of Cardiology/Amer- ican Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol. 2016;67:1572–4.

P-6. Jacobs AK, Anderson JL, Halperin JL. The evolu- tion and future of ACC/AHA clinical practice guidelines: a 30-year journey: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2014;64: 1373–84.

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1.3. Document Review and Approval

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S1.3-2. ACCF/AHA Task Force on Practice Guidelines. Methodology Manual and Policies From the ACCF/AHA Task Force on Practice Guidelines. American College of Cardiology and American Heart Association. 2010. Avail- able at: http://assets.cardiosource.com/Methodology_ Manual_for_ACC_AHA_Writing_Committees.pdf and http:// professional.heart.org/idc/groups/ahamah-public/@wcm/ @sop/documents/downloadable/ucm_319826.pdf. Accessed October 31, 2018.

S1.3-3. Halperin JL, Levine GN, Al-Khatib SM, et al. Further evolution of the ACC/AHA clinical practice guideline recommendation classification system: a report of the American College of Cardiology/Amer- ican Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol. 2016;67:1572–4.

S1.3-4. Jacobs AK, Kushner FG, Ettinger SM, et al. ACCF/AHA clinical practice guideline methodology summit report: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2013;61:213–65.

4.1.1. Selecting an Anticoagulant Regimen— Balancing Risks and Benefits (Modified From Section 4.1.1. Selecting an Antithrombotic Regimen—Balancing Risks and Benefits in the 2014 AF Guideline) S4.1.1-1. Di Biase L. Use of direct oral anticoagulants in patients with atrial fibrillation and valvular heart le- sions. J Am Heart Assoc. 2016;5:e002776.

S4.1.1-2. Ezekowitz MD, Nagarakanti R, Noack H, et al. Comparison of dabigatran and warfarin in patients with atrial fibrillation and valvular heart disease: the RE-LY Trial (Randomized Evaluation of Long-Term Anticoagulant Therapy). Circulation. 2016;134:589– 98.

S4.1.1-3. Pan K-L, Singer DE, Ovbiagele B, et al. Effects of non-vitamin K antagonist oral anticoagulants versus warfarin in patients with atrial fibrillation and valvular heart disease: a systematic review and meta-analysis. J Am Heart Assoc. 2017;6:e005835.

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4.2.2.2. Non-Vitamin K Oral Anticoagulants (Modi- fied From Section 4.2.2.2. New Target-Specific Oral Anticoagulants in the 2014 AF Guideline)

S4.2.2.2-1. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365:883–91.

S4.2.2.2-2. Giugliano RP, Ruff CT, Braunwald E, et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2013;369:2093–104.

S4.2.2.2-3. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361:1139–51.

S4.2.2.2-4. Granger CB, Alexander JH, McMurray JJV, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365:981–92.

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S4.2.2.2-7. Abraham NS, Noseworthy PA, Yao X, et al. Gastrointestinal safety of direct oral anticoagulants: a large population-based study. Gastroenterology. 2017; 152:1014–22.e1.

S4.2.2.2-8. Graham DJ, Reichman ME, Wernecke M, et al. Stroke, bleeding, and mortality risks in elderly Medicare beneficiaries treated with dabigatran or rivaroxaban for nonvalvular atrial fibrillation. JAMA Intern Med. 2016;176:1662–71.

S4.2.2.2-9. Larsen TB, Skjøth F, Nielsen PB, et al. Comparative effectiveness and safety of non-vitamin K antagonist oral anticoagulants and warfarin in patients with atrial fibrillation: propensity weighted nationwide cohort study. BMJ. 2016;353:i3189.

S4.2.2.2-10. Lip GYH, Keshishian A, Kamble S, et al. Real-world comparison of major bleeding risk among non-valvular atrial fibrillation patients initiated on apixaban, dabigatran, rivaroxaban, or warfarin. A pro- pensity score matched analysis. Thromb Haemost. 2016;116:975–86.

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4.3. Interruption and Bridging Anticoagulation

S4.3-1. Douketis JD, Spyropoulos AC, Kaatz S, et al. Perioperative bridging anticoagulation in patients with atrial fibrillation. N Engl J Med. 2015;373:823–33.

S4.3-2. Pollack CV Jr., Reilly PA, van Ryn J, et al. Idarucizumab for dabigatran reversal - full cohort analysis. N Engl J Med. 2017;377:431–41.

S4.3-3. Siegal DM, Curnutte JT, Connolly SJ, et al. Andexanet alfa for the reversal of factor Xa inhibitor activity. N Engl J Med. 2015;373:2413–24.

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4.4.1. Percutaneous Approaches to Occlude the Left Atrial Appendage

S4.4.1-1. Reddy VY, Sievert H, Halperin J, et al. Percutaneous left atrial appendage closure vs warfarin for atrial fibrillation: a randomized clinical trial. JAMA. 2014;312:1988–98.

S4.4.1-2. 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 warfarin therapy: the PREVAIL trial. J Am Coll Car- diol. 2014;64:1–12.

S4.4.1-3. HolmesDR Jr., Doshi SK, Kar S, et al. Left atrial appendage closure as an alternative to warfarin for stroke Prevention in atrial fibrillation: a patient-level meta-analysis. J Am Coll Cardiol. 2015;65:2614–23.

S4.4.1-4. Reddy VY, Gibson DN, Kar S, et al. Post- approval U.S. experience with left atrial appendage closure for stroke prevention in atrial fibrillation. J Am Coll Cardiol. 2017;69:253–61.

S4.4.1-5. Boersma LVA, Schmidt B, Betts TR, et al. Implant success and safety of left atrial appendage closure with the WATCHMAN device: peri-procedural outcomes from the EWOLUTION registry. Eur Heart J. 2016;37:2465–74.

S4.4.1-6. 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.

S4.4.1-7. Boersma LV, Ince H, Kische S, et al. Efficacy and safety of left atrial appendage closure with WATCHMAN in patients with or without contraindica- tion to oral anticoagulation: 1-year follow-up outcome data of the EWOLUTION trial. Heart Rhythm. 2017;14: 1302–8.

S4.4.1-8. Holmes DR, Reddy VY, Buchbinder M, et al. The assessment of the Watchman device in patients unsuitable for oral anticoagulation (ASAP-TOO) trial. Am Heart J. 2017;189:68–74.

4.4.2. Cardiac Surgery—LAA Occlusion/Excision

S4.4.2-1. Friedman DJ, Piccini JP, Wang T, et al. As- sociation between left atrial appendage occlusion and readmission for thromboembolism among patients

with atrial fibrillation undergoing concomitant cardiac surgery. JAMA. 2018;319:365–74.

S4.4.2-2. Melduni RM, Schaff HV, Lee H-C, et al. Impact of left atrial appendage closure during cardiac surgery on the occurrence of early postoperative atrial fibrillation, stroke, and mortality: a propensity score- matched analysis of 10 633 patients. Circulation. 2017;135:366–78.

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S6.1.1-2. Jaber WA, Prior DL, Thamilarasan M, et al. Ef- ficacy of anticoagulation in resolving left atrial and left atrial appendage thrombi: a transesophageal echocar- diographic study. Am Heart J. 2000;140:150–6.

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S6.1.1-4. Nagarakanti R, Ezekowitz MD, Oldgren J, et al. Dabigatran versus warfarin in patients with atrial fibrillation: an analysis of patients undergoing cardio- version. Circulation. 2011;123:131–6.

S6.1.1-5. Piccini JP, Stevens SR, Lokhnygina Y, et al. Outcomes after cardioversion and atrial fibrillation ablation in patients treated with rivaroxaban and warfarin in the ROCKET AF trial. J Am Coll Cardiol. 2013;61:1998–2006.

S6.1.1-6. Flaker G, Lopes RD, Al-Khatib SM, et al. Ef- ficacy and safety of apixaban in patients after cardio- version for atrial fibrillation: insights from the ARISTOTLE Trial (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation). J Am Coll Cardiol. 2014;63:1082–7.

S6.1.1-7. Cappato R, Ezekowitz MD, Klein AL, et al. Rivaroxaban vs. vitamin K antagonists for cardiover- sion in atrial fibrillation. Eur Heart J. 2014;35:3346–55.

S6.1.1-8. Goette A, Merino JL, Ezekowitz MD, et al. Edoxaban versus enoxaparin-warfarin in patients un- dergoing cardioversion of atrial fibrillation (ENSURE- AF): a randomised, open-label, phase 3b trial. Lancet. 2016;388:1995–2003.

S6.1.1-9. Pallisgaard JL, Lindhardt TB, Hansen ML, et al. Cardioversion and risk of adverse events with dabigatran versus warfarin—a nationwide cohort study. PLoS ONE. 2015;10:e0141377.

S6.1.1-10. Plitt A, Ezekowitz MD, De Caterina R, et al. Cardioversion of atrial fibrillation in ENGAGE AF-TIMI 48. Clin Cardiol. 2016;39:345–6.

S6.1.1-11. Dentali F, Botto GL, Gianni M, et al. Efficacy and safety of direct oral anticoagulants in patients undergoing cardioversion for atrial fibrillation: a sys- tematic review and meta-analysis of the literature. Int J Cardiol. 2015;185:72–7.

S6.1.1-12. Ezekowitz MD, Pollack CV Jr., Halperin JL, et al. Apixaban compared to heparin/vitamin K antagonist in patients with atrial fibrillation scheduled for cardioversion: the EMANATE trial. Eur Heart J. 2018;39:2959–71.

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S6.1.1-14. Garg A, Khunger M, Seicean S, et al. Inci- dence of thromboembolic complications within 30 days of electrical cardioversion performed within 48 hours of atrial fibrillation onset. J Am Coll Cardiol EP. 2016;2:487–94.

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S6.1.1-18. Nuotio I, Hartikainen JEK, Grönberg T, et al. Time to cardioversion for acute atrial fibril- lation and thromboembolic complications. JAMA. 2014;312:647–9.

S6.1.1-19. Bah A, Nuotio I, Gronberg T, et al. Sex, age, and time to cardioversion. Risk factors for cardiover- sion of acute atrial fibrillation from the FinCV study. Ann Med. 2017;49:254–9.

S6.1.1-20. Kleemann T, Becker T, Strauss M, et al. Prevalence of left atrial thrombus and dense sponta- neous echo contrast in patients with short-term atrial fibrillation < 48 hours undergoing cardioversion: value of transesophageal echocardiography to guide car- dioversion. J Am Soc Echocardiogr. 2009;22:1403–8.

6.3.4. Catheter Ablation in HF

S6.3.4-1. Marrouche NF, Brachmann J, Andresen D, et al. Catheter ablation for atrial fibrillation with heart failure. N Engl J Med. 2018;378:417–27.

S6.3.4-2. Di Biase L, Mohanty P, Mohanty S, et al. Ablation versus amiodarone for treatment of persis- tent atrial fibrillation in patients with congestive heart failure and an implanted device: results from the AATAC multicenter randomized trial. Circulation. 2016; 133:1637–44.

S6.3.4-3. Prabhu S, Taylor AJ, Costello BT, et al. Catheter ablation versus medical rate control in atrial fibrillation and systolic dysfunction: the CAMERA-MRI Study. J Am Coll Cardiol. 2017;70:1949–61.

S6.3.4-4. Al Halabi S, Qintar M, Hussein A, et al. Catheter ablation for atrial fibrillation in heart failure patients: a meta-analysis of randomized controlled trials. J Am Coll Cardiol EP. 2015;1:200–9.

S6.3.4-5. Packer DL, Mark DB, Robb RA, et al. Catheter ablation versus antiarrhythmic drug therapy for atrial fibrillation (CABANA) trial: study rationale and design. Am Heart J. 2018;199:192–9.

S6.3.4-6. Packer DL, Mark DB, Robb RA, et al. Catheter ablation vs. antiarrhythmic drug therapy for atrial fibrillation: the results of the Cabana Multicenter

International Randomized Clinical Trial [abstract B- LBCT01-05]. Heart Rhythm. 2018;15. 940-141.

7.4. AF Complicating ACS

S7.4-1. Cannon CP, Bhatt DL, Oldgren J, et al. Dual antithrombotic therapy with dabigatran after PCI in atrial fibrillation. N Engl J Med. 2017;377:1513–24.

S7.4-2. Gibson CM, Mehran R, Bode C, et al. Preven- tion of bleeding in patients with atrial fibrillation un- dergoing PCI. N Engl J Med. 2016;375:2423–34.

S7.4-3. Dewilde WJM, Oirbans T, Verheugt FWA, et al. Use of clopidogrel with or without aspirin in patients taking oral anticoagulant therapy and undergoing percutaneous coronary intervention: an open-label, randomised, controlled trial. Lancet. 2013;381:1107–15.

S7.4-4. Sarafoff N, Martischnig A, Wealer J, et al. Triple therapy with aspirin, prasugrel, and vitamin K antagonists in patients with drug-eluting stent im- plantation and an indication for oral anticoagulation. J Am Coll Cardiol. 2013;61:2060–6.

S7.4-5. Jackson LR, Ju C, Zettler M, et al. Outcomes of patients with acute myocardial infarction undergoing percutaneous coronary intervention receiving an oral anticoagulant and dual antiplatelet therapy: a com- parison of clopidogrel versus prasugrel from the TRANSLATE-ACS Study. J Am Coll Cardiol Intv. 2015;8: 1880–9.

S7.4-6. Lamberts M, Gislason GH, Olesen JB, et al. Oral anticoagulation and antiplatelets in atrial fibril- lation patients after myocardial infarction and coro- nary intervention. J Am Coll Cardiol. 2013;62:981–9.

S7.4-7. Rubboli A, Schlitt A, Kiviniemi T, et al. One- year outcome of patients with atrial fibrillation un- dergoing coronary artery stenting: an analysis of the AFCAS registry. Clin Cardiol. 2014;37:357–64.

S7.4-8. Braun OÖ, Bico B, Chaudhry U, et al. Concom- itant use of warfarin and ticagrelor as an alternative to triple antithrombotic therapy after an acute coronary syndrome. Thromb Res. 2015;135:26–30.

S7.4-9. Fiedler KA, Maeng M, Mehilli J, et al. Duration of triple therapy in patients requiring oral anti- coagulation after drug-eluting stent implantation: the ISAR-TRIPLE Trial. J Am Coll Cardiol. 2015;65:1619–29.

S7.4-10. Koskinas KC, Räber L, Zanchin T, et al. Dura- tion of triple antithrombotic therapy and outcomes among patients undergoing percutaneous coronary intervention. J Am Coll Cardiol Intv. 2016;9:1473–83.

S7.4-11. Crenshaw BS, Ward SR, Granger CB, et al. Atrial fibrillation in the setting of acute myocardial infarction: the GUSTO-I experience. Global Utilization of Streptokinase and TPA for Occluded Coronary Ar- teries. J Am Coll Cardiol. 1997;30:406–13.

S7.4-12. Rathore SS, Berger AK, Weinfurt KP, et al. Acute myocardial infarction complicated by atrial fibrillation in the elderly: prevalence and outcomes. Circulation. 2000;101:969–74.

S7.4-13. Goldberg RJ, Seeley D, Becker RC, et al. Impact of atrial fibrillation on the in-hospital and long- term survival of patients with acute myocardial infarction: a community-wide perspective. Am Heart J. 1990;119:996–1001.

S7.4-14. Behar S, Zahavi Z, Goldbourt U, et al. Long- term prognosis of patients with paroxysmal atrial

fibrillation complicating acute myocardial infarction. SPRINT Study Group. Eur Heart J. 1992;13:45–50.

S7.4-15. ACTIVE Investigators, Connolly SJ, Pogue J, et al. Effect of clopidogrel added to aspirin in pa- tients with atrial fibrillation. N Engl J Med. 2009; 360:2066–78.

S7.4-16. You JJ, Singer DE, Howard PA, et al. Antithrombotic therapy for atrial fibrillation: antith- rombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence- based clinical practice guidelines. Chest. 2012;141: e531S–75S.

S7.4-17. Pisters R, Lane DA, Nieuwlaat R, et al. A novel user-friendly score (HAS-BLED) to assess 1- year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey. Chest. 2010;138: 1093–100.

S7.4-18. Lopes RD, Rordorf R, De Ferrari GM, et al. Digoxin and mortality in patients with atrial fibrillation. J Am Coll Cardiol. 2018;71:1063–74.

S7.4-19. Vamos M, Erath JW, Hohnloser SH. Digoxin- associated mortality: a systematic review and meta- analysis of the literature. Eur Heart J. 2015;36:1831–8.

S7.4-20. Pedersen OD, Bagger H, Køber L, et al. The occurrence and prognostic significance of atrial fibrillation/-flutter following acute myocardial infarc- tion. TRACE Study group. TRAndolapril Cardiac Eval- uation. Eur Heart J. 1999;20:748–54.

S7.4-21. McMurray J, Køber L, Robertson M, et al. Antiarrhythmic effect of carvedilol after acute myocardial infarction: results of the Carvedilol Post- Infarct Survival Control in Left Ventricular Dysfunc- tion (CAPRICORN) trial. J Am Coll Cardiol. 2005;45: 525–30.

S7.4-22. Fauchier L, Lecoq C, Ancedy Y, et al. Evalua- tion of 5 prognostic scores for prediction of stroke, thromboembolic and coronary events, all-cause mor- tality, and major adverse cardiac events in patients with atrial fibrillation and coronary stenting. Am J Cardiol. 2016;118:700–7.

S7.4-23. Álvarez-Álvarez B, Raposeiras-Roubín S, Abu- Assi E, et al. Is 6-month GRACE risk score a useful tool to predict stroke after an acute coronary syndrome? Open Heart. 2014;1:e000123.

S7.4-24. Bristol-Myers Squibb. A study of apixaban in patients with atrial fibrillation, not caused by a heart valve problem, who are at risk for thrombosis (blood clots) due to having had a recent coronary event, such as a heart attack or a procedure to open the vessels of the heart. Available at: https://www. clinicaltrials.gov. Identifier: NCT02415400. Accessed November 1, 2017.

S7.4-25. Daiichi Sankyo, Inc. Edoxaban treatment versus vitamin K antagonist in patients with atrial fibrillation undergoing percutaneous coronary inter- vention (ENTRUST-AF-PCI). Available at: https://www. clinicaltrials.gov. Identifier: NCT02866175. Accessed November 1, 2017.

7.12. Device Detection of AF and Atrial Flutter

(New Section)

S7.12-1. Boriani G, Glotzer TV, Santini M, et al. Device- detected atrial fibrillation and risk for stroke: an analysis of >10,000 patients from the SOS AF

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project (Stroke prevention Strategies based on Atrial Fibrillation information from implanted devices). Eur Heart J. 2014;35:508–16.

S7.12-2. Glotzer TV, Daoud EG, Wyse DG, et al. The relationship between daily atrial tachyarrhythmia burden from implantable device diagnostics and stroke risk: the TRENDS study. Circ Arrhythm Electrophysiol. 2009;2:474–80.

S7.12-3. Glotzer TV, Hellkamp AS, Zimmerman J, et al. Atrial high rate episodes detected by pace- maker diagnostics predict death and stroke: report of the Atrial Diagnostics Ancillary Study of the MOde Selection Trial (MOST). Circulation. 2003;107: 1614–9.

S7.12-4. Healey JS, Connolly SJ, Gold MR, et al. Sub- clinical atrial fibrillation and the risk of stroke. N Engl J Med. 2012;366:120–9.

S7.12-5. Martin DT, Bersohn MM, Waldo AL, et al. Randomized trial of atrial arrhythmia monitoring to guide anticoagulation in patients with implanted defibrillator and cardiac resynchronization devices. Eur Heart J. 2015;36:1660–8.

S7.12-6. Sanna T, Diener H-C, Passman RS, et al. Cryptogenic stroke and underlying atrial fibrillation. N Engl J Med. 2014;370:2478–86.

S7.12-7. Halcox JPJ, Wareham K, Cardew A, et al. Assessment of remote heart rhythm sampling using

the AliveCor heart monitor to screen for atrial fibril- lation: the REHEARSE-AF Study. Circulation. 2017;136: 1784–94.

S7.12-8. Bumgarner JM, Lambert CT, Hussein AA, et al. Smartwatch algorithm for automated detec- tion of atrial fibrillation. J Am Coll Cardiol. 2018;71: 2381–8.

7.13. Weight Loss (New Section)

S7.13-1. Abed HS, Wittert GA, Leong DP, et al. Effect of weight reduction and cardiometabolic risk factor management on symptom burden and severity in pa- tients with atrial fibrillation: a randomized clinical trial. JAMA. 2013;310:2050–60.

S7.13-2. Pathak RK, Middeldorp ME, Lau DH, et al. Aggressive risk factor reduction study for atrial fibril- lation and implications for the outcome of ablation: the ARREST-AF cohort study. J Am Coll Cardiol. 2014; 64:2222–31.

S7.13-3. Pathak RK, Middeldorp ME, Meredith M, et al. Long-term effect of goal-directed weight manage- ment in an atrial fibrillation cohort: a long-term follow-up study (LEGACY). J Am Coll Cardiol. 2015; 65:2159–69.

S7.13-4. Abed HS, Samuel CS, Lau DH, et al. Obesity results in progressive atrial structural and electrical remodeling: implications for atrial fibrillation. Heart Rhythm. 2013;10:90–100.

S7.13-5. Wang TJ, Parise H, Levy D, et al. Obesity and the risk of new-onset atrial fibrillation. JAMA. 2004; 292:2471–7.

S7.13-6. Wong CX, Ganesan AN, Selvanayagam JB. Epicardial fat and atrial fibrillation: current evidence, potential mechanisms, clinical implications, and future directions. Eur Heart J. 2017;38:1294–302.

S7.13-7. Wong CX, Abed HS, Molaee P, et al. Peri- cardial fat is associated with atrial fibrillation severity and ablation outcome. J Am Coll Cardiol. 2011;57: 1745–51.

S7.13-8. Middeldorp ME, Pathak RK, Meredith M, et al. PREVEntion and regReSsive Effect of weight-loss and risk factor modification on Atrial Fibrillation: the REVERSE-AF study. Europace. 2018;20:1929–35.

KEY WORDS ACC/AHA Clinical Practice Guidelines, focused update, acute coronary syndrome, anticoagulants, anticoagulation agents, antiplatelet agents, apixaban, atrial fibrillation, atrial flutter, cardioversion, coronary artery disease, coronary heart disease, stents, dabigatran, edoxaban, hypertension, idarucizumab, myocardial infarction, obesity, percutaneous coronary intervention, risk factors, rivaroxaban, sleep apnea, stroke, thromboembolism, warfarin

Committee Member Employment Consultant Speakers Bureau

Ownership/ Partnership/ Principal

Personal Research

Institutional, Organizational, or Other

Financial Benefit Expert Witness

Voting Recusals by Section*

Craig T. January (Chair) University of Wisconsin-Madison— Professor of Medicine, Cardiovascular

Medicine Division

None None None None None None None

L. Samuel Wann (Vice Chair) Columbia St. Mary’s Cardiovascular Physicians—Clinical Cardiologist

n Astellas None None None None None None

Hugh Calkins Johns Hopkins Hospital—Professor of Medicine, Director of Electrophysiology

n Abbott n AltaThera n AtriCure n Boehringer Ingelheim†

n King Pharmaceuticals, Inc. (Pfizer)

n Medtronic† n St. Jude Medical‡

None None n Boehringer Ingelheim†

n Boston Scientific†

n St. Jude Medical†

None None 4.1.1, 4.2.2.2, 4.3, 4.4.1, 4.4.2,

6.1.1, 6.3.4, 7.4, 7.12

Lin Y. Chen§ University of Minnesota Medical School, Cardiovascular Division—Associate

Professor of Medicine

None None None None None None None

Joaquin E. Cigarroa Oregon Health & Science University— Professor of Medicine; Clinical Chief of

Knight Cardiovascular Institute Division Head of Cardiology

None None None None None None None

Joseph C. Cleveland, Jr University of Colorado—Professor of Surgery; Denver Veteran’s Administration

Hospital—Chief, Cardiac Surgery

None None None n St. Jude Medical None None 4.4.1, 4.4.2, 6.3.4, 7.4, 7.12

Patrick T. Ellinor Massachusetts General Hospital Heart Center, Cardiac Arrhythmia

Service—Director

n Bayer None None n Bayer† None None 4.1.1, 4.2.2.2, 4.3, 6.1.1, 7.4

Michael D. Ezekowitz Sidney Kimmel Medical College at Thomas Jefferson University— Professor of Medicine; Lankenau Medical Center,

Bryn Mawr Hospital—Attending Cardiologist

n Armetheon† n Bayer† n Boehringer Ingelheim†

n Bristol-Myers Squibb† n Coherex n Daiichi-Sankyo† n Janssen Pharmaceuticals† n Johnson & Johnson† n Medtronic† n Merck† n Pfizer† n Portola Pharmaceuticals n Sanofi-aventis†

None None n Boehringer Ingelheim (PI)†

n Pfizer (PI)† n Portola

Pharmaceuticals†

None None 4.1.1, 4.2.2.2, 4.3, 4.4.1, 4.4.2, 6.1.1, 6.3.4,

7.4, 7.12

Continued on the next page

APPENDIX 1. AUTHOR RELATIONSHIPS WITH INDUSTRY AND OTHER ENTITIES (RELEVANT)—2019 AHA/ACC/HRS FOCUSED UPDATE OF THE

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Committee Member Employment Consultant Speakers Bureau

Ownership/ Partnership/ Principal

Personal Research

Institutional, Organizational, or Other

Financial Benefit Expert Witness

Voting Recusals by Section*

Michael E. Field Medical University of South Carolina and Ralph H. Johnson VA Medical Center—

Associate Professor of Medicine

None None None None None None None

Karen L. Furie Rhode Island Hospital, the Miriam Hospital and Bradley Hospital— Neurologist-in-Chief; The Warren Alpert Medical School of Brown University—Chair of Neurology

None None None None None None None

Paul A. Heidenreich Stanford VA Palo Alto Health Care System—Professor of Medicine

None None None None None None None

Katherine T. Murray Vanderbilt University School of Medicine, Divisions of Clinical Pharmacology and

Cardiology—Professor of Medicine

None None n Metabolic Technologies, Inc.

None None None None

Julie B. Shea Brigham and Women’s Hospital n Medtronic n St. Jude Medical

None None None None None 4.4.1, 4.4.2, 7.4, 6.3.4, 7.12

Cynthia M. Tracy George Washington University Medical Center—Associate Director and Professor

of Medicine

None None None None None None None

Clyde W. Yancy Northwestern University, Feinberg School of Medicine—Magerstadt Professor of Medicine; Division of Cardiology—Chief

None None None None None None None

This table represents the relationships of committee members with industry and other entities that were determined to be relevant to this document. These relationships were reviewed and updated in conjunction with all meetings and/or conference calls of the writing committee during the document development process. The table does not necessarily reflect relationships with industry at the time of publication. A person is deemed to have a significant interest in a business if the interest represents ownership of $5% of the voting stock or share of the business entity, or ownership of $$5,000 of the fair market value of the business entity; or if funds received by the person from the business entity exceed 5% of the person’s gross income for the previous year. Relationships that exist with no financial benefit are also included for the purpose of transparency. Relationships in this table are modest unless otherwise noted.

According to the ACC/AHA, a person has a relevant relationship IF: a) the relationship or interest relates to the same or similar subject matter, intellectual property or asset, topic, or issue addressed in the document; or b) the company/entity (with whom the relationship exists) makes a drug, drug class, or device addressed in the document, or makes a competing drug or device addressed in the document; or c) the person or a member of the person’s household, has a reasonable potential for financial, professional or other personal gain or loss as a result of the issues/content addressed in the document.

The Atrial Fibrillation Guideline was initiated in September 2016. Over the initial years of the CMS Open Payment System, understandably, there have been many issues related to the accurate reporting of food and beverage payments. For this reason, the ACC and AHA have not considered these minor charges relevant relationships with industry. *Writing committee members are required to recuse themselves from voting on sections to which their specific relationships with industry and other entities may apply. †Significant relationship. ‡No financial benefit. §CMS reported payments related to medical education from Medtronic Vascular to a third party, University of Minnesota Foundation, under Dr. Chen’s name in 2016. Medtronic has confirmed that there was no payment made to Dr. Chen, and the entry was made in error. The sections authored by Dr. Chen have been reviewed, and it was affirmed that there was no implication of any influence of industry.

ACC indicates American College of Cardiology; AHA, American Heart Association; CMS, Centers for Medicare & Medicaid Services; HRS, Heart Rhythm Society; PI, principal investigator; and VA, Veterans Affairs.

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APPENDIX 2. ABBREVIATED REVIEWER RELATIONSHIPS WITH INDUSTRY AND OTHER ENTITIES—2019

AHA/ACC/HRS FOCUSED UPDATE OF THE 2014 AHA/ACC/HRS GUIDELINE FOR THE MANAGEMENT OF

PATIENTS WITH ATRIAL FIBRILLATION (AUGUST 2018)*

Reviewer Representation Employment Comprehensive

RWI?

Samuel C. Dudley, Jr Official Reviewer—AHA University of Minnesota—Director, Cardiology Division Yes

Federico Gentile Official Reviewer—ACC/AHA Task Force on Clinical Practice Guidelines

Centro Cardiologico Gentile No

Augustus O. Grant Official Reviewer—AHA Duke University School of Medicine—Professor of Medicine; Vice Dean, Faculty Enrichment

No

Eric Stecker Official Reviewer—ACC Science and Quality Committee

OHSU—Associate Professor of Medicine, Division of Cardiovascular Medicine, School of Medicine

Yes

Eugene Yang Official Reviewer—ACC Board of Governors University of Washington School of Medicine Yes

James R. Edgerton Organizational Reviewer—STS The Heart Hospital Baylor—Director of Education Yes

Fred Morady Organizational Reviewer—HRS University of Michigan—McKay Professor of Cardiovascular Disease and Professor of Medicine

Yes

Hakan Oral Organizational Reviewer—HRS University of Michigan Hospital—Frederick G. L. Huetwell Professor of Cardiovascular Medicine; Director, Cardiac Arrhythmia Service

Yes

Sana M. Al-Khatib Content Reviewer—ACC/AHA Task Force on Clinical Practice Guidelines

Duke Clinical Research Institute—Professor of Medicine Yes

Joseph S. Alpert Content Reviewer University of Arizona Health Sciences Center—Professor of Medicine; Head, Department of Medicine

Yes

Anastasia L. Armbruster Content Reviewer—ACC Surgeons’ Council

St. Louis College of Pharmacy—Associate Professor, Department of Pharmacy Practice

No

Nisha Bansal Content Reviewer University of Washington—Associate Professor, Division of Nephrology; Associate Program Director, Nephrology Fellowship

Yes

Coletta Barrett Content Reviewer—AHA/ACC Lay Reviewer Our Lady of the Lake Regional Medical Center—Vice President, Mission

No

Kim K. Birtcher Content Reviewer—ACC/AHA Task Force on Clinical Practice Guidelines

University of Houston College of Pharmacy—Clinical Professor Yes

John A. Bittl Content Reviewer Ocala Heart Institute; Munroe Regional Medical Center No

Yong-Mei Cha Content Reviewer Mayo Clinic, Division of Cardiovascular Diseases No

Jamie B. Conti Content Reviewer University of Florida—Professor of Medicine (Cardiology); Chief, Division of Cardiovascular Diseases, Department of Medicine

Yes

Anita Deswal Content Reviewer—ACC/AHA Task Force on Clinical Practice Guidelines

Baylor College of Medicine—Professor of Medicine; Michael E. DeBakey VA Medical Center—Chief of Cardiology

Yes

Michael S. Firstenberg Content Reviewer—ACC Surgeons’ Council The Summa Health System Yes

Zachary D. Goldberger Content Reviewer—ACC/AHA Task Force on Clinical Practice Guidelines

University of Wisconsin School of Medicine and Public Health—Associate Professor of Medicine, Division of

Cardiovascular Medicine/Electrophysiology

No

Maya E. Guglin Content Reviewer—ACC HF and Transplant Section Leadership Council

University of Kentucky—Professor of Medicine; Director, Mechanical Assisted Circulation, Gill Heart Institute

Yes

Jonathan L. Halperin Content Reviewer Mount Sinai Medical Center—Professor of Medicine Yes

José A. Joglar Content Reviewer—ACC/AHA Task Force on Clinical Practice Guidelines

UT Southwestern Medical Center University— Associate Professor of Internal Medicine

No

Gautam Kumar Content Reviewer—ACC Interventional Section Leadership Council

Emory University; Atlanta VA Medical Center Yes

Valentina Kutyifa Content Reviewer—ACC EP Section Leadership Council

University of Rochester Medical Center— Associate Professor of Medicine

Yes

Glenn N. Levine Content Reviewer—ACC/AHA Task Force on Clinical Practice Guidelines

Baylor College of Medicine—Professor of Medicine; Michael E. DeBakey Medical Center—Director,

Cardiac Care Unit

Yes

Grace Lin Content Reviewer—ACC HF and Transplant Section Leadership Council

Mayo Clinic; Mayo Foundation Yes

Gregory Y. H. Lip Content Reviewer University of Birmingham Centre For Cardiovascular Sciences Yes

Patrick T. O’Gara Content Reviewer—ACC/AHA Task Force on Clinical Practice Guidelines

Harvard Medical School—Prof of Medicine; Brigham and Women’s Hospital—Director, Strategic Planning

Yes

Continued on the next page

Reviewer Representation Employment Comprehensive

RWI?

Ratika Parkash Content Reviewer Dalhousie University and Nova Scotia Health Authority— Professor of Medicine, Division of Cardiology (Arrhythmia);

Director of Research, Division of Cardiology

Yes

Mariann Piano Content Reviewer—ACC/AHA Task Force on Clinical Practice Guidelines

Vanderbilt University School of Nursing—Nancy and Hilliard Travis Professor of Nursing;

Senior Associate Dean for Research

Yes

Win-Kuang Shen Content Reviewer Mayo Clinic Arizona, Phoenix Campus— Professor of Medicine; Consultant

No

Giuseppe Stabile Content Reviewer Clinica Mediterranea, Naples, Italy Yes

William G. Stevenson Content Reviewer Vanderbilt Medical Center—Director, Director of Arrhythmia Research Yes

James Tisdale Content Reviewer—AHA Purdue University—Professor, College of Pharmacy; Indiana University School of Medicine—Adjunct Professor

Yes

Shane Tsai Content Reviewer—ACC Adult Congenital and Pediatric Cardiology

Section Leadership Council

University of Nebraska Medical Center—Assistant Professor, Internal Medicine and Pediatrics, Division of Cardiovascular Medicine;

Section Chief, Electrophysiology

Yes

Kathryn Wood Content Reviewer—AHA Emory University—Associate Professor, Nell Hodgson Woodruff School of Nursing

No

This table represents all relationships of reviewers with industry and other entities that were reported at the time of peer review, including those not deemed to be relevant to this document, at the time this document was under review. The table does not necessarily reflect relationships with industry at the time of publication. A person is deemed to have a significant interest in a business if the interest represents ownership of$5% of the voting stock or share of the business entity, or ownership of$$5,000 of the fair market value of the business entity; or if funds received by the person from the business entity exceed 5% of the person’s gross income for the previous year. Relationships that exist with no financial benefit are also included for the purpose of transparency. Relationships in this table are modest unless otherwise noted. Names are listed in alphabetical order within each category of review. Please refer to http://www.acc.org/guidelines/about-guidelines-and-clinical-documents/relationships-with-industry-policy for definitions of disclosure categories or additional information about the ACC/AHA Disclosure Policy for Writing Committees. *Detailed reviewer disclosures can be found at this link: http://jaccjacc.acc.org/Clinical_Document/2019_AFib_Focused_Update_Comp_Author-Reviewer_RWI_Table_Final.pdf.

ACC indicates American College of Cardiology; AHA, American Heart Association; EP, electrophysiology; HF, heart failure; HRS, Heart Rhythm Society; OHSU, Oregon Health & Science University; RWI, relationships with industry and other entities; STS, Society of Thoracic Surgeons; UT, University of Texas; and VA, Veterans Affairs.

APPENDIX 2. CONTINUED

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