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Circulation. 2024;149:e1–e156. DOI: 10.1161/CIR.0000000000001193 January 2, 2024 e1

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*Writing committee 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. †ACC/AHA Joint Committee on Clinical Practice Guidelines liaison. ‡ACC/AHA Joint Committee on Performance Measures liaison. §Lay stakeholder representative. ‖American College of Clinical Pharmacy representative. ¶Heart Rhythm Society representative. #Joint ACC/AHA staff representative. **ACC/AHA Joint Committee on Clinical Data Standards liaison. Peer Review Committee Members and AHA/ACC Joint Committee on Clinical Practice Guidelines Members, see page e113. The American Heart Association requests that this document be cited as follows: Joglar JA, Chung MK, Armbruster AL, Benjamin EJ, Chyou JY, Cronin EM, Deswal A, Eckhardt L, Goldberger ZD, Gopinathannair R, Gorenek B, Hess PL, Hlatky M, Hogan G, Ibeh C, Indik JH, Kido K, Kusumoto F, Link MS, Linta KT, Marcus GM, McCarthy PM, Patel N, Patton KK, Perez MV, Piccini JP, Russo AM, Sanders P, Streur MM, Thomas KL, Times S, Tisdale JE, Valente AM, Van Wagoner DR. 2023 ACC/ AHA/ACCP/HRS guideline for the diagnosis and management of atrial fibrillation: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. 2024;149:e1–e156. doi: 10.1161/CIR.0000000000001193 © 2023 by the American College of Cardiology Foundation and the American Heart Association, Inc.

CLINICAL PRACTICE GUIDELINES

2023 ACC/AHA/ACCP/HRS Guideline for the Diagnosis and Management of Atrial Fibrillation: A Report of the American College of Cardiology/ American Heart Association Joint Committee on Clinical Practice Guidelines Developed in Collaboration With and Endorsed by the American College of Clinical Pharmacy and the Heart Rhythm Society

Writing Committee Members*

José A. Joglar, MD, FACC, FAHA, FHRS, Chair; Mina K. Chung, MD, FACC, FAHA, FHRS, Vice Chair; Anastasia L. Armbruster, PharmD, FACC†; Emelia J. Benjamin, MD, ScM, FACC, FAHA; Janice Y. Chyou, MD, FACC, FAHA, FHRS; Edmond M. Cronin, MB, BCh, BAO, FHRS; Anita Deswal, MD, MPH, FACC, FAHA†; Lee L. Eckhardt, MD, MS, FHRS; Zachary D. Goldberger, MD, FACC, FAHA, FHRS; Rakesh Gopinathannair, MD, MA, FACC, FAHA, FHRS; Bulent Gorenek, MD, FACC; Paul L. Hess, MD, MHS‡; Mark Hlatky, MD, FACC, FAHA; Gail Hogan§; Chinwe Ibeh, MD; Julia H. Indik, MD, PhD, FACC, FAHA, FHRS; Kazuhiko Kido, PharmD, PhD, MS, FCCP‖; Fred Kusumoto, MD, FACC, FAHA, FHRS; Mark S. Link, MD, FACC, FAHA, FHRS; Kathleen T. Linta § Gregory M. Marcus, MD, MAS, FACC, FAHA, FHRS; Patrick M. McCarthy, MD, FACC; Nimesh Patel, MD; Kristen K. Patton, MD, FACC, FAHA, FHRS; Marco V. Perez, MD, FAHA; Jonathan P. Piccini, MD, MHS, FACC, FAHA, FHRS; Andrea M. Russo, MD, FACC, FAHA, FHRS¶; Prashanthan Sanders, MBBS, PhD, FAHA, FHRS; Megan M. Streur, PhD, MN, ARNP; Kevin L. Thomas, MD, FACC, FHRS; Sabrina Times, DHSC, MPH#; James E. Tisdale, PharmD, FACC, FAHA, FCCP; Anne Marie Valente, MD, FACC, FAHA**; David R. Van Wagoner, PhD, FAHA, FHRS

AIM: The “2023 ACC/AHA/ACCP/HRS Guideline for the Diagnosis and Management of Atrial Fibrillation” provides recommendations to guide clinicians in the treatment of patients with atrial fibrillation.

METHODS: A comprehensive literature search was conducted from May 12, 2022, to November 3, 2022, encompassing studies, reviews, and other evidence conducted on human subjects that were published in English from PubMed, EMBASE, the Cochrane Library, the Agency for Healthcare Research and Quality, and other selected databases relevant to this guideline. Additional relevant studies, published through November 2022, during the guideline writing process, were also considered by the writing committee and added to the evidence tables, where appropriate.

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January 2, 2024 Circulation. 2024;149:e1–e156. DOI: 10.1161/CIR.0000000000001193e2

Joglar et al 2023 Guideline for the Diagnosis and Management of Atrial Fibrillation

STRUCTURE: Atrial fibrillation is the most sustained common arrhythmia, and its incidence and prevalence are increasing in the United States and globally. Recommendations from the “2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation” and the “2019 AHA/ACC/HRS Focused Update of the 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation” have been updated with new evidence to guide clinicians. In addition, new recommendations addressing atrial fibrillation and thromboembolic risk assessment, anticoagulation, left atrial appendage occlusion, atrial fibrillation catheter or surgical ablation, and risk factor modification and atrial fibrillation prevention have been developed.

Key Words: AHA Scientific Statements ◼ acute coronary syndrome ◼ alcohol ◼ anticoagulants ◼ anticoagulation agents ◼ antiplatelet agents ◼ apixaban ◼ atrial fibrillation ◼ atrial flutter ◼ cardioversion ◼ catheter ablation ◼ coronary artery disease ◼ coronary heart disease

◼ dabigatran ◼ edoxaban ◼ exercise ◼ heart failure ◼ hypertension ◼ idarucizumab ◼ left atrial appendage occlusion ◼ myocardial infarction ◼ obesity ◼ percutaneous coronary intervention ◼ pulmonary vein isolation ◼ risk factors ◼ rivaroxaban ◼ sleep apnea ◼ stents ◼ stroke

◼ surgical ablation ◼ thromboembolism ◼ warfarin

TABLE OF CONTENTS Top 10 Take-Home Messages . . . . . . . . . . . . . . . . . . . . . . e4 Preamble . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . e4 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . e6

1.1. Methodology and Evidence Review . . . . . . . e6 1.2. Organization of the Writing

Committee . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . e6 1.3. Document Review and Approval . . . . . . . . . . e6 1.4. Scope of the Guideline . . . . . . . . . . . . . . . . . . . e6 1.5. Class of Recommendations and

Level of Evidence . . . . . . . . . . . . . . . . . . . . . . . . e6 1.6. Abbreviations . . . . . . . . . . . . . . . . . . . . . . . . . . . . e7

2. Background and Pathophysiology . . . . . . . . . . . . . . . e8 2.1. Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . e8

2.1.1. Prevalence, Incidence, Morbidity, and Mortality . . . . . . . . . . . e9

2.1.2. Risk Factors and Associated Heart Disease. . . . . . . . . . . . . . . . . . . . e9

2.2. Atrial Arrhythmia Classification and Definitions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . e9 2.2.1. AF Classification . . . . . . . . . . . . . . . . . e9 2.2.2. Associated Arrhythmias . . . . . . . . . .e10

2.3. Mechanisms and Pathophysiology . . . . . . .e11 2.3.1. Electrophysiological

Mechanisms and Electrical Remodeling . . . . . . . . . . . . . . . . . . . . .e11

2.3.2. Atrial Structural Abnormalities, Remodeling, and Atrial Myopathy . . . . . . . . . . . . . . . . . . . . . . .e16

2.3.3. Role of the Autonomic Nervous System . . . . . . . . . . . . . . . . .e18

2.4. Genetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .e19 2.5. Addressing Health Inequities and

Barriers to AF Management . . . . . . . . . . . . .e20 3. Shared Decision-Making (SDM) in

AF Management. . . . . . . . . . . . . . . . . . . . . . . . . . . . . .e21 4. Clinical Evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . .e21

4.1. Risk Stratification and Population Screening . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .e21

4.2. Basic Evaluation . . . . . . . . . . . . . . . . . . . . . . . .e22

4.2.1. Basic Clinical Evaluation . . . . . . . . .e22 4.2.2. Rhythm Monitoring Tools

and Methods . . . . . . . . . . . . . . . . . . . .e23 5. Lifestyle and Risk Factor Modification

(LRFM) for AF Management . . . . . . . . . . . . . . . . . .e24 5.1. Primary Prevention . . . . . . . . . . . . . . . . . . . . . .e24 5.2. Secondary Prevention: Management

of Comorbidities and Risk Factors . . . . . . .e25 5.2.1. Weight Loss in Individuals Who

Are Overweight or Obese . . . . . . . .e25 5.2.2. Physical Fitness . . . . . . . . . . . . . . . . .e25 5.2.3. Smoking Cessation . . . . . . . . . . . . . .e26 5.2.4. Alcohol Consumption . . . . . . . . . . . .e26 5.2.5. Caffeine Consumption . . . . . . . . . . .e26 5.2.6. Diet and Dietary

Supplementation . . . . . . . . . . . . . . . .e27 5.2.7. Diabetes . . . . . . . . . . . . . . . . . . . . . . . .e27 5.2.8. Treatment of Hypertension . . . . . . .e27 5.2.9. Sleep . . . . . . . . . . . . . . . . . . . . . . . . . . .e28 5.2.10. Comprehensive Care . . . . . . . . . . . .e28

6. Prevention of Thromboembolism . . . . . . . . . . . . . . .e29 6.1. Risk Stratification Schemes . . . . . . . . . . . . .e29 6.2. Risk-Based Selection of Oral

Anticoagulation: Balancing Risks and Benefits . . . . . . . . . . . . . . . . . . . . . . . . . . .e31

6.3. Oral Anticoagulants . . . . . . . . . . . . . . . . . . . . .e32 6.3.1. Antithrombotic Therapy . . . . . . . . . .e33

6.4. Silent AF and Stroke of Undetermined Cause . . . . . . . . . . . . . . . . . . .e38 6.4.1. Oral Anticoagulation for

Device-Detected Atrial High-Rate Episodes Among Patients Without a Previous Diagnosis of AF . . . . . . . . . . . . . . . . .e40

6.5. Nonpharmacological Stroke Prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . .e42 6.5.1. Percutaneous Approaches to

Occlude the LAA . . . . . . . . . . . . . . . .e42 6.5.2. Cardiac Surgery—LAA

Exclusion/Excision . . . . . . . . . . . . . .e43

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Joglar et al 2023 Guideline for the Diagnosis and Management of Atrial Fibrillation

6.6. Active Bleeding on Anticoagulant Therapy and Reversal Drugs . . . . . . . . . . . . .e44 6.6.1. Management of Patients With

AF and ICH . . . . . . . . . . . . . . . . . . . . . e47 6.7. Periprocedural Management . . . . . . . . . . . . .e50 6.8. Anticoagulation in Specific

Populations . . . . . . . . . . . . . . . . . . . . . . . . . . . .e52 6.8.1. AF Complicating ACS or

Percutaneous Coronary Intervention (PCI) . . . . . . . . . . . . . . .e52

6.8.2. Chronic Coronary Disease (CCD) . . . . . . . . . . . . . . . . . . . . . . . . . .e53

6.8.3. Peripheral Artery Disease (PAD) . . . . . . . . . . . . . . . . . . . . . . . . . .e54

6.8.4. Chronic Kidney Disease (CKD)/Kidney Failure . . . . . . . . . . .e55

6.8.5. AF in VHD . . . . . . . . . . . . . . . . . . . . . .e56 6.8.6. Anticoagulation of Typical

AFL . . . . . . . . . . . . . . . . . . . . . . . . . . . . e57 7. Rate Control . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .e59

7.1. Broad Considerations for Rate Control . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .e59

7.2. Specific Pharmacological Agents for Rate Control . . . . . . . . . . . . . . . . . . . . . . . . . . .e59 7.2.1. Acute Rate Control . . . . . . . . . . . . . .e60 7.2.2. Long-Term Rate Control . . . . . . . . .e63

7.3. Atrioventricular Nodal Ablation (AVNA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .e64

8. Rhythm Control . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .e66 8.1. Goals of Therapy With Rhythm

Control . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .e66 8.2. Electrical and Pharmacological

Cardioversion . . . . . . . . . . . . . . . . . . . . . . . . . .e69 8.2.1. Prevention of

Thromboembolism in the Setting of Cardioversion . . . . . . . . .e69

8.2.2. Electrical Cardioversion . . . . . . . . . . e72 8.2.3. Pharmacological

Cardioversion . . . . . . . . . . . . . . . . . . . e73 8.3. Antiarrhythmic Drugs for Maintenance

of Sinus Rhythm . . . . . . . . . . . . . . . . . . . . . . . . e76 8.3.1. Specific Drug Therapy for

Long-Term Maintenance of Sinus Rhythm . . . . . . . . . . . . . . . . . . . e76

8.3.2. Inpatient Initiation of Antiarrhythmic Agents . . . . . . . . . . . e79

8.3.3. Antiarrhythmic Drug Follow-Up. . . . . . . . . . . . . . . . . . . . . . .e81

8.3.4. Upstream Therapy . . . . . . . . . . . . . . .e83 8.4. AF Catheter Ablation . . . . . . . . . . . . . . . . . . .e84

8.4.1. Patient Selection . . . . . . . . . . . . . . . .e86 8.4.2. Techniques and Technologies

for AF Catheter Ablation . . . . . . . . .e86

8.4.3. Management of Recurrent AF After Catheter Ablation . . . . . . . . . . e87

8.4.4. Anticoagulation Therapy Before and After Catheter Ablation . . . . . . . . . . . . . . . . . . . . . . . .e88

8.4.5. Complications After AF Catheter Ablation . . . . . . . . . . . . . . .e89

8.5. Role of Pacemakers and ICDs for the Prevention and Treatment of AF . . . . . . . . .e89

8.6. Surgical Ablation . . . . . . . . . . . . . . . . . . . . . . .e90 9. Management of Patients With HF . . . . . . . . . . . . .e91

9.1. General Considerations for AF and HF . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .e91

9.2. Management of AF in Patients With HF . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .e92

10. AF and Specific Patient Groups . . . . . . . . . . . . . . . e97 10.1. Management of Early Onset AF,

Including Genetic Testing . . . . . . . . . . . . . . . e97 10.2. Athletes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .e98 10.3. Management Considerations in

Patients With AF and Obesity . . . . . . . . . . . .e98 10.4. Anticoagulation Considerations in

Patients With Class III Obesity . . . . . . . . . . .e98 10.5. AF and VHD . . . . . . . . . . . . . . . . . . . . . . . . . . .e99 10.6. WPW and Preexcitation

Syndromes . . . . . . . . . . . . . . . . . . . . . . . . . . . . .e99 10.7. Hypertrophic Cardiomyopathy . . . . . . . . . e100 10.8. Adult Congenital Heart

Disease (ACHD) . . . . . . . . . . . . . . . . . . . . . e100 10.9. Prevention and Treatment of AF

After Cardiac Surgery . . . . . . . . . . . . . . . . . e102 10.9.1. Prevention of AF After

Cardiac Surgery . . . . . . . . . . . . . . . e102 10.9.2. Treatment of AF After

Cardiac Surgery . . . . . . . . . . . . . . . e102 10.10. Acute Medical Illness or Surgery

(Including AF in Critical Care) . . . . . . . . e104 10.11. Hyperthyroidism . . . . . . . . . . . . . . . . . . . . . e106 10.12. Pulmonary Disease . . . . . . . . . . . . . . . . . . e106 10.13. Pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . e107 10.14. Cardio-Oncology and Anticoagulation

Considerations . . . . . . . . . . . . . . . . . . . . . . e108 10.15. CKD and Kidney Failure . . . . . . . . . . . . . e110 10.16. Anticoagulation Use in Patients

With Liver Disease . . . . . . . . . . . . . . . . . . e110 11. Future Research Needs . . . . . . . . . . . . . . . . . . . . . e111 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . e114 Appendix 1

Author Relationships With Industry and Other Entities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . e150

Appendix 2 Reviewer Relationships With Industry and Other Entities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . e155

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January 2, 2024 Circulation. 2024;149:e1–e156. DOI: 10.1161/CIR.0000000000001193e4

Joglar et al 2023 Guideline for the Diagnosis and Management of Atrial Fibrillation

TOP 10 TAKE-HOME MESSAGES 1. Stages of atrial fibrillation (AF): The previous clas-

sification of AF, which was based only on arrhyth- mia duration, although useful, tended to emphasize therapeutic interventions. The new proposed clas- sification, using stages, recognizes AF as a disease continuum that requires a variety of strategies at the different stages, from prevention, lifestyle and risk factor modification, screening, and therapy.

2. AF risk factor modification and prevention: This guideline recognizes lifestyle and risk factor modification as a pillar of AF management to pre- vent onset, progression, and adverse outcomes. The guideline emphasizes risk factor management throughout the disease continuum and offers more prescriptive recommendations, accordingly, includ- ing management of obesity, weight loss, physical activity, smoking cessation, alcohol moderation, hypertension, and other comorbidities.

3. Flexibility in using clinical risk scores and expand- ing beyond CHA2DS2-VASc for prediction of stroke and systemic embolism: Recommendations for anticoagulation are now made based on yearly thromboembolic event risk using a validated clini- cal risk score, such as CHA2DS2-VASc. However, patients at an intermediate annual risk score who remain uncertain about the benefit of anticoagulation can benefit from consideration of other risk variables to help inform the decision, or the use of other clini- cal risk scores to improve prediction, facilitate shared decision making, and incorporate into the electronic medical record.

4. Consideration of stroke risk modifiers: Patients with AF at intermediate to low (<2%) annual risk of ischemic stroke can benefit from consideration of factors that might modify their risk of stroke, such as the characteristics of their AF (eg, burden), nonmodifiable risk factors (sex), and other dynamic or modifiable factors (blood pressure control) that may inform shared decision-making discussions.

5. Early rhythm control: With the emergence of new and consistent evidence, this guideline emphasizes the importance of early and continued management of patients with AF that should focus on maintaining sinus rhythm and minimizing AF burden.

6. Catheter ablation of AF receives a Class 1 indi- cation as first-line therapy in selected patients: Recent randomized studies have demonstrated the superiority of catheter ablation over drug ther- apy for rhythm control in appropriately selected patients. In view of the most recent evidence, we upgraded the Class of Recommendation.

7. Catheter ablation of AF in appropriate patients with heart failure with reduced ejection fraction receives a Class 1 indication: Recent randomized

studies have demonstrated the superiority of cath- eter ablation over drug therapy for rhythm control in patients with heart failure and reduced ejection failure. In view of the data, we upgraded the Class of Recommendation for this population of patients.

8. Recommendations have been updated for device-detected AF: In view of recent studies, more prescriptive recommendations are provided for patients with device-detected AF that consider the interaction between episode duration and the patient's underlying risk for thromboembolism. This includes considerations for patients with AF detected via implantable devices and wearables.

9. Left atrial appendage occlusion devices receive higher level Class of Recommendation: In view of additional data on safety and efficacy of left atrial appendage occlusion devices, the Class of Recommendation has been upgraded to 2a com- pared with the 2019 AF Focused Update for use of these devices in patients with long-term contra- indications to anticoagulation.

10. Recommendations are made for patients with AF identified during medical illness or surgery (precipitants): Emphasis is made on the risk of recurrent AF after AF is discovered during noncar- diac illness or other precipitants, such as surgery.

PREAMBLE Since 1980, the American College of Cardiology (ACC) and American Heart Association (AHA) have translated scientific evidence into clinical practice guidelines with recommendations to improve cardiovascular health. These guidelines, which are based on systematic meth- ods to evaluate and classify evidence, provide a founda- tion for the delivery of quality cardiovascular care. The ACC and AHA sponsor the development and publication of clinical practice guidelines without commercial sup- port, and members volunteer their time to the writing and review efforts. Guidelines are the official policy of the ACC and AHA. For some guidelines, the ACC and AHA collaborate with other organizations.

Intended Use Clinical practice guidelines provide recommendations applicable to patients with or at risk of developing cardio- vascular disease. The focus is on medical practice in the United States, but these guidelines are relevant to pa- tients 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 patients’ inter- ests. Guidelines are intended to define practices meeting the needs of patients in most, but not all, circumstances and should not replace clinical judgment.

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Joglar et al 2023 Guideline for the Diagnosis and Management of Atrial Fibrillation

Clinical Implementation Management, in accordance with guideline recommenda- tions, is effective only when followed by both practitioners and patients. Adherence to recommendations can be enhanced by shared decision-making between clinicians and patients, with patient engagement in selecting inter- ventions on the basis of individual values, preferences, and associated conditions and comorbidities.

Methodology and Modernization The ACC/AHA Joint Committee on Clinical Practice Guidelines (Joint Committee) continuously reviews, up- dates, and modifies guideline methodology on the basis of published standards from organizations, including the Institute of Medicine,1,2 and on the basis of internal re- evaluation. Similarly, presentation and delivery of guide- lines are reevaluated and modified in response to evolving technologies and other factors to optimally facilitate dis- semination of information to health care professionals at the point of care.

Numerous modifications to the guidelines have been implemented to make them shorter and enhance “user friendliness.” 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.

In recognition of the importance of cost–value con- siderations, 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.3

To ensure that guideline recommendations remain cur- rent, new data will be reviewed on an ongoing basis by the writing committee and staff. Going forward, targeted sections/knowledge chunks will be revised dynamically after publication and timely peer review of potentially practice-changing science. The previous designations of “full revision” and “focused update” will be phased out. For additional information and policies on guideline devel- opment, readers may consult the ACC/AHA guideline methodology manual4 and other methodology articles.5–7

Selection of Writing Committee Members The Joint Committee strives to ensure that the guide- line writing committee contains requisite content exper- tise and is representative of the broader cardiovascular community by selection of experts across a spectrum of backgrounds, representing different geographic regions, sexes, races, ethnicities, intellectual perspectives/biases, and clinical practice settings. Organizations and profes-

sional societies with related interests and expertise are invited 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 committee mem- bers’ comprehensive and relevant RWI; for the purposes of full transparency, comprehensive and relevant disclo- sure information for the Joint Committee 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.4,5 Literature searches focus on randomized controlled trials (RCTs) but also include registries, nonran- domized comparative and descriptive studies, case series, cohort studies, systematic reviews, and expert opinion. Only key references are cited.

An independent evidence review committee is com- missioned when there are ≥1 questions deemed of utmost clinical importance and merit formal systematic review to determine which patients are most likely to ben- efit from a drug, device, or treatment strategy, and to what degree. Criteria for commissioning an evidence review committee and formal systematic review include absence of a current authoritative systematic review, feasibility of defining the benefit and risk in a time frame consistent with the writing of a guideline, relevance to a substantial number of patients, and likelihood that the findings can be translated into actionable recommendations. Evidence review committee members may include methodologists, epidemiologists, clinicians, and biostatisticians. Recom- mendations 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 (GDMT) encompasses clinical evaluation, diagnostic testing, and both pharmacological and procedural treat- ments. For these and all recommended drug treatment regimens, the reader should confirm dosage with prod- uct insert material and evaluate for contraindications and interactions. Recommendations are limited to drugs, devices, and treatments approved for clinical use in the United States.

Joshua A. Beckman, MD, MS, FAHA, FACC Chair, ACC/AHA Joint Committee on

Clinical Practice Guidelines

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1. INTRODUCTION 1.1. Methodology and Evidence Review The recommendations listed in this guideline are, whenever possible, evidence based. An initial exten- sive evidence review, which included literature derived from research involving human subjects, published in English, and indexed in MEDLINE (through PubMed), EMBASE, the Cochrane Library, the Agency for Healthcare Research and Quality, and other selected databases relevant to this guideline, was conduct- ed from May 2022 to November 2022. Key search words included but were not limited to the following: atrial fibrillation; pregnancy; heart defects, congeni- tal; smoking; cardiomyopathy, hypertrophic; alcohol; caffeine; sleep; diet; fitness; obesity; anticoagulants; diabetes; rhythm monitoring; heart failure; genetics; heart valve diseases; rate control; catheter ablation; social determinants of health; chronic kidney disease; sinus rhythm; chronic coronary syndromes; left atrial appendage occlusion; left atrial appendage exclu- sion; cardiac surgical procedures; amiodarone; elec- trical cardioversion; thromboembolism; rhythm control; Wolff-Parkinson-White syndrome. Additional relevant studies, published through November 2022 during the guideline writing process, were also considered by the writing committee and added to the evidence tables when appropriate. The final evidence tables are includ- ed in the Online Data Supplement and summarize the evidence used by the writing committee to formulate recommendations. References selected and published in the present document are representative and not all-inclusive.

1.2. Organization of the Writing Committee The writing committee consisted of cardiologists, car- diac electrophysiologists, surgeons, pharmacists, and patient representatives/lay stakeholders. The writing committee included representatives from the ACC and AHA, ACCP, and HRS. Appendix 1 of the current docu- ment lists writing committee members’ comprehensive and relevant RWI.

1.3. Document Review and Approval The Joint Committee appointed a peer review commit- tee to review the document. The peer review committee comprised individuals nominated by the ACC, AHA, and the collaborating organizations. Reviewers’ RWI informa- tion was distributed to the writing committee and is pub- lished in this document (Appendix 2).

This document was approved for publication by the governing bodies of the ACC and the AHA and was endorsed by ACCP and HRS.

1.4. Scope of the Guideline In developing the “2023 ACC/AHA/ACCP/HRS Guide- line for the Diagnosis and Management of Atrial Fibrillation” (2023 atrial fibrillation guideline), the writing committee re- viewed previously published guidelines. Table 1 contains a list of these publications deemed pertinent to this writing effort and is intended for use as a resource, thus obviating the need to repeat existing guideline recommendations.

1.5. Class of Recommendations and Level of Evidence The Class of Recommendation (COR) indicates the strength of recommendation and encompasses the esti- mated magnitude and certainty of benefit in proportion to risk. The Level of Evidence (LOE) rates the quality of sci- entific evidence supporting the intervention on the basis of the type, quantity, and consistency of data from clinical trials and other sources (Table 2).

Table 1. Associated ACC/AHA Guidelines

Title Organization

Publication Year (Reference)

Guidelines

Atrial fibrillation AHA/ACC/HRS 20191* 20142

Atrial fibrillation ESC/EACTS/EHRA 20213

Atrial fibrillation CCS 20204

Management of adults with congenital heart disease

AHA/ACC 20185

Diagnosis and treatment of patients with hypertrophic cardiomyopathy

AHA/ACC 20206

Management of patients with valvular heart disease

ACC/AHA 20217

Coronary artery revascularization ACC/AHA/AATS/ STS/SCAI

20218

Evaluation and diagnosis of chest pain

AHA/ACC/ASE/ CHEST/SAEM/ SCCT/SCMR

20219

Prevention of stroke in patients with stroke and transient ischemic attack

AHA/ASA 202110

Management of heart failure AHA/ACC/HFSA 202211

Management of arrhythmias in pregnancy

HRS 202312

*The full-text AF guideline is from 2014.2 A focused update was published in 2019.1

AATS indicates American Association for Thoracic Surgery; ACC, American Col- lege of Cardiology; AF, atrial fibrillation; AHA, American Heart Association; ASA, American Stroke Association; ASE, American Society of Echocardiography; CCS, Canadian Cardiovascular Society; CHEST, American College of Chest Physicians; EACTS, European Association for Cardio Thoracic Surgery; EHRA, European Heart Rhythm Association; ESC, European Society of Cardiology; HFSA, Heart Failure Society of America; HRS, Heart Rhythm Society; SAEM, Society for Academic Emergency Medicine; SCAI, Society for Cardiovascular Angiography and Interven- tions; SCCT, Society of Cardiovascular Computed Tomography; SCMR, Society for Cardiovascular Magnetic Resonance; and STS, Society of Thoracic Surgery.

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Table 2. Applying American College of Cardiology/American Heart Association Class of Recommendation and Level of Evidence to Clinical Strategies, Interventions, Treatments, or Diagnostic Testing in Patient Care* (Updated May 2019)

1.6. Abbreviations

Abbreviation Meaning/Phrase

ACE angiotensin-converting enzyme

ACHD adult congenital heart disease

ACS acute coronary syndrome

AF atrial fibrillation

AFL atrial flutter

AHRE atrial high-rate episodes

ANS autonomic nervous system

AP accessory pathway

APT antiplatelet therapy

Abbreviation Meaning/Phrase

ARB angiotensin receptor blocker

AT atrial tachycardia

AVNA atrioventricular nodal ablation

BiVP biventricular pacing

BMI body mass index

BP blood pressure

bpm beats per minute

BTK Bruton’s tyrosine kinase

CABG coronary artery bypass graft surgery

CAD coronary artery disease

CCD chronic coronary disease

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Abbreviation Meaning/Phrase

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

CHD congenital heart disease

CHF congestive heart failure

CKD chronic kidney disease

COPD chronic obstructive pulmonary disease

COR Class of Recommendation

CrCl creatinine clearance

CRT cardiac resynchronization therapy

CTI cavotricuspid isthmus

CVD cardiovascular disease

DAT dual antithrombotic therapy

DOAC direct oral anticoagulant

ECG electrocardiogram

EF ejection fraction

eGFR estimated glomerular filtration rate

FDA US Food and Drug Administration

GDMT guideline-directed management and therapy

HF heart failure

HFpEF heart failure with preserved ejection fraction

HFrEF heart failure with reduced ejection fraction

HR hazard ratio

ICD implantable cardioverter-defibrillator

ICH intracranial hemorrhage

LA left atrium

LAA left atrial appendage

LAAO left atrial appendage occlusion

LOE Level of Evidence

LRFM lifestyle risk factor modification

LV left ventricular

LVEF left ventricular ejection fraction

MI myocardial infarction

MRA mineralocorticoid receptor antagonist

NYHA New York Heart Association

OAC oral anticoagulant

PAC premature atrial contraction

PAD peripheral artery disease

PCI percutaneous coronary intervention

PCC prothrombin complex concentrate

PE pulmonary embolism

PH pulmonary hypertension

PHPVD pulmonary hypertension with pulmonary vascular disease

Abbreviation Meaning/Phrase

PITP pill-in-the-pocket

pLAAO percutaneous left atrial appendage occlusion

PV pulmonary veins

PVI pulmonary vein isolation

QOL quality of life

RAAS renin-angiotensin-aldosterone system

RCT randomized controlled trial

RV right ventricular

RVP right ventricular pacing

SDB sleep-disordered breathing

SDOH social determinants of health

SDM shared decision-making

S-LAAO surgical removal of the left atrial appendage occlusion

SVT supraventricular tachycardia

TEE transesophageal echocardiogram

TIA transient ischemic attack

UREG underrepresented racial and ethnic groups

VF ventricular fibrillation

VHD valvular heart disease

VKA vitamin K antagonist

VT ventricular tachycardia

WPW Wolff-Parkinson-White

2. BACKGROUND AND PATHOPHYSIOLOGY 2.1. Epidemiology Atrial fibrillation (AF) is the most sustained common ar- rhythmia, and its incidence and prevalence are increas- ing in the United States and globally (Figures 1 to 3).1,2 The increasing burden is multifactorial; causes include the aging of the population, rising tide of obesity, increas- ing detection, and increasing survival with AF and other forms of cardiovascular disease (CVD). The estimated global prevalence was 50 million in 2020.2,3 Although the prevalence of undiagnosed AF in the community is unknown, using back-calculation methodology, investiga- tors have estimated that, in 2015, about 11% (591 000 cases) of the >5.6 million AF cases in the United States were undiagnosed.4

AF is associated with higher health care utilization and costs.2 Using US data from Optum (an administra- tive claims database for commercially insured [United Healthcare] patients in the United States), compared with patients without AF, patients with incident AF had an increased risk of inpatient visits and more cardiovas- cular-related emergency department visits (relative risk [RR], 2.41 [95% CI, 2.35–2.47]).5 AF is costly. Examining Optum data, individuals with AF have annual health care

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costs of $63 031, which is $27 896 more than individu- als without AF.5 Investigators examining public and pri- vate health insurer data estimated that in US dollars in 2016, AF accounted for $28.4 billion (95% CI, $24.6 billion–$33.8 billion) in health care spending.6

2.1.1. Prevalence, Incidence, Morbidity, and Mortality AF prevalence in the United States was estimated to be 5.2 million in 2010, with an expectation to rise to 12.1 million in 2030.1 Corresponding estimates for US incidence was 1.2 million cases in 2010, with an ex- pectation to rise to 2.6 million cases in 2030.1 The rate of AF diagnosis varies by education, income,2 clinical,3,4 and genetic3 factors. Overall lifetime risk is about 30% to 40% in White individuals,2–4 about 20% in African American individuals,2 and about 15% in Chinese5 individuals.

AF is associated with a 1.5- to 2-fold increased risk of death6,7; studies suggest that the mortality risk may be higher in women than in men.6 In meta-analyses, AF is also associated with increased risk of multiple adverse outcomes, including a 2.4-fold risk of stroke,7 1.5-fold risk of cognitive impairment or dementia,8 1.5-fold risk of myocardial infarction (MI),9 2-fold risk of sudden cardiac death,10 5-fold risk of heart failure (HF),7 1.6-fold risk of chronic kidney disease (CKD),7

and 1.3-fold risk of peripheral artery disease (PAD).7 In Medicare beneficiaries, the most frequent outcome in the 5 years after AF diagnosis was death (19.5% at 1 year; 48.8% at 5 years)11; the next most common diag- nosis was HF (13.7%), followed by new-onset stroke (7.1%), gastrointestinal hemorrhage (5.7%), and MI (3.9%).11

2.1.2. Risk Factors and Associated Heart Disease In Table 3, we present the evidence for the most widely reported and validated factors for AF from single stud- ies, meta-analyses, and Mendelian randomization stud- ies. Risk factors include demographic, anthropometric, and cardiovascular risk factors, CVD, noncardiac con- ditions, biomarkers (eg, electrocardiographic, imaging, circulating), and genetic markers.1 Models predicting risk of AF onset are presented in Section 4.1 (“Risk Stratification and Population Screening”). Most stud- ies of AF risk factors and outcomes have been reported from high-income countries and in individuals of Euro- pean ancestry.

2.2. Atrial Arrhythmia Classification and Definitions 2.2.1. AF Classification The previous classification of AF, which was based only on arrhythmia duration, although useful, tended to em- phasize AF once it was diagnosed and focused mainly on therapeutic interventions. The new proposed classi- fication using stages aims to correct the deficiencies of the previous classification by recognizing AF as a pro- gressive disease that requires different strategies at the different stages, from prevention to screening, to rate and rhythm control therapies. The different stages bet- ter define AF as a progressive disease and highlight the need to address it at the earliest stages, especially em- phasizing the importance of prevention, risk factor man- agement, and timing for screening in those patients at the highest risk. The stages are not mutually exclusive (eg, risk factors should be managed through multiple stages) (Figure 4).

AF is the most common arrhythmia in the world and accounts for significant morbidity and mortality. Over the past decade, evidence has consistently shown that the best treatment of atrial fibrillation requires multiple stakeholders committed to providing comprehensive patient-centered care. In addition, as emphasized in this guideline, AF should be thought of in a more holistic sense over an individual patient’s lifetime.

The foundation of optimal AF management is the treat- ment of risk factors and implementing lifestyle changes to decrease the likelihood of developing AF (Figure 5). Once AF develops, patient care should focus on assessing the risk of stroke and implementing any necessary treatment, continued optimization of all modifiable risk factors, and

Figure 1. Temporal Trends in Counts and Age-Standardized Rates of AF-Prevalent Cases by Social Demographic Index Quintile for Both Sexes Combined, 1990–2017. Trends in counts of AF-prevalent cases by SDI quintile, 1990–2017. SDI was made up of the geometric mean of 3 common indicators: the lag distributed income per capita, mean educational achievement for those aged ≥15 y, and total fertility rate <25 y. SDI ranged from 0 to 1, where 0 represents the theoretical minimum level of development, whereas 1 represents the theoretical maximum level of development. Modified from Dai et al7 by permission of Oxford University Press on behalf of the European Society of Cardiology. Copyright 2020 Oxford University Press. AF indicates atrial fibrillation; and SDI, Social Demographic Index.

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managing potential symptoms of AF, with an initial focus on evaluating and minimizing AF burden. However, as outlined in this guideline, access to all aspects of health care to all patients is necessary for any true improvement to be realized.

When AF develops, holistic and optimal care of the patient at risk for AF, or who has developed AF, can be simply modeled using a building. The foundation of care is treatment of comorbidities and risk factors and implementing behavioral change in all individuals to decrease the likelihood of developing AF and reducing its burden (Screening for all risk factors from HEAD 2 TOES). Once AF develops, there are 3 important care processes that must be specifically addressed with all patients and aligned with their goals of therapy: Stroke risk assessment and treatment, if appropriate, Opti- mizing all modifiable risk factors, and Symptom man- agement using rate- and rhythm-control strategies

that consider AF burden in the context of an individual patient’s needs (SOS). The overarching principle for AF management is Access to All Aspects of care to All (4 As).

2.2.2. Associated Arrhythmias Other atrial arrhythmias are often encountered in pa- tients with AF.

Atrial Tachycardia (AT): It is a regular atrial rhythm at a constant rate of >100 beats per minute (bpm) with dis- crete P waves and atrial activation sequences originating outside of the sinus node.1 The mechanism can be auto- maticity, triggered activity, or a microreentry circuit. Focal ATs arise from a single discrete site within the left or right atrium, in contrast to macroreentrant atrial arrhythmias and AF, which involve multiple sites or larger circuits. In multifocal AT, the atrial activation sequence and P-wave morphology vary.

Figure 2. Prevalence of AF Among Medicare Beneficiaries, 1993–2007. (A) In the overall cohort, (B) by age group, (C) by sex, and (D) by race. The dashed lines in panel A represent 95% CIs. Reproduced with permission from Piccini et al.8 Copyright 2012 American Heart Association, Inc. AF indicates atrial fibrillation.

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Atrial Flutter (AFL) and Macroreentrant AT: They occur in many of the same situations as AF. Typical AFL, also known as “typical AFL” or “cavotricuspid isthmus (CTI)-dependent AFL,”2 involves a macroreentrant circuit around the tricuspid annulus traversing the CTI on the right side of the heart (Figure 6). This is the arrhythmia associated with the classic electrocardiogram (ECG) finding of sawtooth flutter waves in the inferior leads when the circuit goes in the counterclockwise direc- tion. The same circuit in the clockwise direction is called “reverse typical AFL.” If the flutter involves a different circuit than tricuspid valve/isthmus, then it is called “atypical” AFL, which is also known as “noncavotricuspid isthmus–dependent macroreentrant AT.”2 AFL was previ- ously classified as either type I or type II. That terminol- ogy is no longer used.

2.3. Mechanisms and Pathophysiology AF is a chaotic, rapid (300-500 bpm), and irregu- lar atrial rhythm. Although normal rhythms are con- ducted through the atria in smooth waves initiated by the sinoatrial node, AF is the result of either elec- trophysiological abnormalities that underlie impulse generation and/or structural abnormalities of cellular connections that typically facilitate rapid and uniform

impulse conduction. AF often stems from waves of electrical activity originating from ectopic action po- tentials most commonly generated in the pulmonary veins (PVs) of the left atrium (LA),1 or in response to reentrant activity promoted by heterogeneous conduction due to interstitial fibrosis.2 Atrial ectopy can generate runs of tachycardia, while persistent AF requires a substrate that is either sufficiently large or conduction that is sufficiently heterogeneous to enable reentrant activity to persist. The electrical abnormalities evident on the ECG during AF likely represent a shared phenotype of a condition with many distinct etiologies (genetic, environmental, and metabolic) (Figure 7).

2.3.1. Electrophysiological Mechanisms and Electrical Remodeling The observation by Haissaguerre et al1 that ectopic fir- ing from PVs triggers AF revolutionized treatments for AF. PV features that increase vulnerability for initiating ectopy include a higher resting membrane potential, stretch-activated channels,2 and pattern of cross myofi- ber orientation.

Electrical remodeling, which can contribute to and result from AF, includes perturbations that culminate in abnormal Ca2+ handling and shortened, proarrhyth- mic triangulated action potentials (eg, from decreased

Figure 3. Age-Standardized Global Prevalence Rates of AF and Atrial Flutter per 100 000, Both Sexes, 2020. During each annual GBD Study cycle, population health estimates are produced for the full-time series. Improvements in statistical and geospatial modeling methods and the addition of new data sources may lead to changes in past results across GBD Study cycles. Modified with permission from Tsao et al.2 Copyright 2023 American Heart Association, Inc. Source: Institute for Health Metrics Evaluation. Used with permission. All rights reserved. AF indicates atrial fibrillation; and GBD, Global Burden of Disease.

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(Continued )

Table 3. Risk Factors for Diagnosed AF

Condition Study Type Effect on Risk of AF

Summary Risk of Incident AF Effect of LRFM

Risk Factors

Advancing age SR/MA Age per 5 y: ↑ risk (HR, 1.43-1.66)2,3 ↑ Risk N/A

MR Accelerated epigenetic age by MR: no association4

Smoking Single study Current smoking: ↑ risk (9.8%)5 ↑ Risk N/A

SR/MA Smoking: ↑ risk (HR, 1.21-1.43)2,6

MR Smoking initiation: ↑ risk (OR, 1.11)7

Physical activity SR/MA Sedentary lifestyle: ↑ risk (OR, 2.47)8

Guideline-recommended physical activity: ↓ risk (HR, 0.94)9

Elite athletes vs nonathletes: ↑ risk (OR, 2.46)10

U curve: Sed- entary lifestyle and elite/extreme exercise: ↑ risk

Exercise: ↓ AF burden, recurrence, symptoms; ↑ quality of life, functional capacity11–16

Alcohol Single studies Risk of AF episode within 4 h of 1 drink: ↑ risk (OR, 2.02)17

Greater access to alcohol law: ↑ risk18

↑ Risk Randomized abstinence: ↓ AF recurrence and burden19

N-of-1 studies of alcohol avoidance: ↓ near-term AF20

Alcohol avoidance or reduction as part of a comprehensive LRFM program: ↓ AF burden, symptoms, pro- gression of AF21–24

SR/MA Dose response (#drinks/d): ↑ risk (RR) 1: 1.08; 2: 1.17; 3: 1.33; 4: 1.36; 5: 1.4725

MR Genetically predicted heavy alcohol consumption (>35 U/wk for women and >50 U/wk for men): ↑ risk (OR, 1.11)7

Adiposity markers: weight, BMI, obesity

Single study Obesity: population attributable fraction 12.7%-16.9%5,26

↑ Risk Weight loss in overweight or obese patients with AF as part of a comprehensive LRFM program: ↓ AF symptoms, burden, recurrence, progression21–24

Bariatric surgery in class III obesity: associated with reversal of AF type, ↑ sinus rhythm postablation27–29

Weight loss in long-lasting persistent AF and obesity: ↔30

SR/MA BMI: RR, 1.28 per 5-unit ↑ in BMI31

Weight:2 HR, 1.12 per 15 kg ↑

MR Obesity3

Birthweight: 1.26 per SD ↑32

Childhood BMI (OR, 1.18)32

BMI 1.31 per unit BMI33

Height MA Height per 10 cm: ↑ risk (HR, 1.28)2 ↑ Risk N/A

SR/MA Increasing height: ↑ risk3

MR Increasing height: ↑ risk (OR per unit, 1.33)33

Hypertension and BP

Single studies Elevated BP: ↑ risk, population attributable fraction, 21.6%5

Presence of hypertension treatment: ↑ risk (HR, 1.35-1.68), incidence 9.8%-19.5%; both AF and SBP decreased over time26

Hypertension: ↑ risk SBP: ↑ risk DBP: ↑↓↔ risk

Renal denervation: ↓ AF postablation34

Mineralocorticoid receptor antagonists: ↓ AF burden35

BP control postablation: ↔36

Intensive BP control to SBP <120 mm Hg in patients with hypertension at high risk for CVD: ↓ AF risk37

BP control as part of a comprehensive LRFM program: ↓ AF burden21–24,38

MA BP: SBP: ↑ risk (HR per 20 mm Hg, 1.22);

DBP per 10 mm Hg ↓ risk (HR, 0.90); use of BP medications ↑ risk (HR, 1.42)2

SR/MA Hypertension: ↑ risk3

MR SBP33,39 ↑ risk; DBP mixed results ↔↑ risk39,40; pulse pressure ↑ risk40

Resting heart rate

SR/MA Resting heart rate: J-shaped relationship with incident AF. Lowest risk at 68-80 bpm; <70 bpm (RR, 1.09 per 10 bpm ↓); >70 bpm (RR, per 10 bpm ↑ RR 1.06)41

Slow heart rate: ↑↓ variable risk

Higher heart rate: ↑↓ variable risk

N/A

MR Heart rate: <65 bpm slower (HR ↑ risk); heart rate per 5 bpm ↑, 0.8242

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Table 3. Continued

(Continued )

Condition Study Type Effect on Risk of AF

Summary Risk of Incident AF Effect of LRFM

Diabetes Single study Diabetes: ↑ risk, population attributable fraction 3.1%5

Diabetes: ↑ risk, population attributable fraction ↑ over time 3.2%-5.9%26

↑ Risk Optimal glycemic control preablation may ↓ AF recurrence postablation43

MA Diabetes: ↑ risk (HR, 1.27 [95% CI, 1.10-1.46])2

SR/MA Diabetes: ↑ risk (RR, 1.28, excluding large outlying study)44

Pre-diabetes: ↑ risk (RR, 1.20)44

Blood glucose; ↑ risk (RR per 20 mg/dL ↑, 1.11)44

Cardiovascular disease

HF or CAD Single study HF or CAD: population attributable fraction 5.4%5 ↑ Risk N/A

HF Single studies HF: ↑ risk but population attributable fraction ↓ d over time 7.8%-1.4%26

Bidirectional relation between AF and HF45

↑ Risk N/A

MA History of HF: ↑ risk (HR, 2.02)2

MR Genetically predicted HF: ↑ risk (OR, 1.86)46

CAD Single study MI: Population attributable fraction 3.6%26 ↑ Risk N/A

MA History of MI: HR, 1.642

MR Genetically predicted CAD: OR, 1.1833

VHD Single studies Significant heart murmur: ↑ risk (HR, 2.38)47

Significant heart murmur (any diastolic and grade ≥3/6 systolic murmur): ↑ risk, population attributable fraction 21.9% ↓ d over time to 3.1%26

↑ Risk N/A

MR Genetically predicted risk of AF in individuals of

European ancestry: associated with VHD with rheumatic fever (OR, 1.26) and nonrheumatic VHD (OR, 1.27)48

Cardiac surgery

Single study Multicenter validated risk prediction model: ↑ risk AF after CABG49

↑ Risk Prophylactic amiodarone, beta blockers: ↓↔ postop AF50–54

Posterior left pericardiotomy during CABG, aortic valve, ascending aortic aneurysm surgery: ↓ postop AF55,56

SR/MA Postop AF incidence: 23.7%-25.5%56 of cardiac surgery patients57

Other conditions

CKD SR/MA CKD: ↑ risk (HR, 1.47)58 ↑↔ Risk N/A

MR Bidirectional relation between CKD and AF59

AF causal for CKD; CKD not causal for AF60

Obstructive sleep apnea

SR/MA OSA: ↑ risk (OR, 1.71), with potential dose response relation by severity61

↑ Risk Observational studies of SDB treatment: ↓ AF burden62–67

Small RCTs of SDB treatment: ↔68–70 MR Genetically predicted OSA: ↑ risk (OR, 1.21)71

Thyroid disease SR/MA Clinical hyperthyroidism: ↑ risk (RR, 2.35)72 ↑ Risk

MR Hyperthyroidism: ↑ risk (OR, 1.31)73

Sepsis Single study Severe sepsis: ↑ risk (OR, 6.82)74; Medicare population75 ↑ Risk N/A

SR/MA Sepsis severity: ↑ risk76

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Table 3. Continued

(Continued )

Condition Study Type Effect on Risk of AF

Summary Risk of Incident AF Effect of LRFM

Markers on ECG

PR interval SR/MA Prolonged PR: ↑ risk (RR, 1.45)77 Prolonged PR: ↑ risk

PR interval polygenic risk score: ↓ risk

PR interval risk SNPs: variable ↑↓ risk

N/A

MR Polygenic risk score PR interval prolongation: ↓ AF risk (OR, 0.95; P=4.30×10−8) with some variants associated with ↑ and some with ↓ AF risk78

LVH Single study ECG LVH: Population attributable fraction 10.4% ↓ d over time to 1.8%26

↑ Risk N/A

SR/MA LVH: ↑ risk (RR, 1.46)79

Biomarkers

Natriuretic peptides

MA BNP: ↑ risk (HR per 1-SD ln-BNP, 1.66)80 ↑↔ Risk N/A

MR Natriuretic peptides not associated81

Inflammatory markers

SR/MA CRP: ↑ risk (SMD, 0.95)82

IL-6: ↑ risk (SMD, 0.89)82

TNF-α: ↑ risk (SMD, 2.20)82

CRP, IL-6, TNF-α, DUSP13, FKBP7, Spon- din-1: ↑ risk

IL-6R, TNFS12: ↓ risk

N/A

MR DUSP13, FKBP7, Spondin-1 ↑ risk33

IL-6R, TNFS12 ↓ risk33

Lp(a) SR/MA Lp(a): HR, 1.03; only 39% of Lp(a) risk mediated via ASCVD83

↑ Risk N/A

MR Genetically predicted ↑ Lp(a): ↑ risk (HR per 23 mg/dL ge- netically predicted ↑ Lp(a), 1.04)83

Imaging markers

LA size or function

Single studies LA anterior-posterior dimension: ↑ risk (HR per 5 mm ↑, 1.39)84

End diastolic LA volume (min): ↑ risk (HR, 1.12)85

LA emptying fraction: ↑ risk (HR, 1.03)85

↑ LA size, emptying fraction: ↑ risk

Surgical LA reduction in conjunction with cardiac surgery or surgical AF ablation in patients with persistent AF may ↑ rates of sinus rhythm86–89

MR Genetic susceptibility to AF (independent measure) is associated with ↑indexed LA size and ↓ LA ejection

fraction (dependent measures)90

LV wall thickness

Single study LV posterior wall thickness: ↑ risk (HR per 4-mm ↑, 1.28)84

↑ Risk N/A

SR/MA LVH: ↑ risk (RR, 1.46)79

Social determinants of health

Education Single studies Higher education: ↑ lifetime risk of AF (US-based ARIC study)91

Higher education in young individuals: ↓ risk of AF diagnosis (Danish study)92

Variable ↑↓ risk N/A

MR AF risk related but largely mediated via BMI (57.5%), type 2 diabetes (9.8%), SBP (18.7%), and smoking (7.1%)93

Income Single studies Higher income: ↑ lifetime risk of AF (US-based ARIC study)91

Higher income in young individuals: ↓ risk of AF diagnosis (Danish study)92

Variable ↑↓ risk N/A

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L-type Ca2+ current3 and increase in IK1). 4 Heterogene-

ity in IK1 between left and right atria further promotes arrhythmogenicity.5 Downregulation of connexin results in decreased gap junctions, leading to slow heteroge- neous atrial conduction velocity and repolarization,6

promoting regional functional conduction block that can support reentry. Connexin remodeling can be due to genetic7 or acquired factors, such as inflamma- tory state,8,9 older age, or sleep-disordered breathing (SDB).10

Figure 4. AF Stages: Evolution of Atrial Arrhythmia Progression. *Heart failure, valve disease, coronary artery disease, hypertrophic cardiomyopathy, neuromuscular disorders, thyroid disease. Original figure created by the 2023 Atrial Fibrillation Guideline Writing Committee. AF indicates atrial fibrillation.

Table 3. Continued

Condition Study Type Effect on Risk of AF

Summary Risk of Incident AF Effect of LRFM

SES Single studies Cumulative socioeconomic disadvantage: ↑ risk (HR, 1.57)94

Individual’s poorest areas: 12% ↑ d risk95

Low SES:

↑↔ risk

N/A

SR/MA Heterogeneous results96

Genetics

Family history/ heritability

Single studies Family history of AF: ↑ risk97–99 ↑ Risk N/A

MR Proportion heritability explained by loci in European ancestry analysis, 42%100

GWAS MA Number of AF risk loci ↑s with ↑ number of subjects studied. In 2018, 97-111 loci explained ∼11%-42% of the heritability of AF in individuals of European ancestry100,101

↑ Risk N/A

Population attributable fraction: the proportional disease incidence in the population that is estimated to be due to the risk factor.Statistically significant associations reported, unless otherwise indicated.

↓ indicates decreased; ↑, increased; ↔ no significant change in risk; AF, atrial fibrillation; ASCVD, atherosclerotic cardiovascular disease; BMI, body mass index; BNP, brain naturiuretic peptide; BP, blood pressure; CABG, coronary artery bypass graft surgery; CAD, coronary artery disease; CI, confidence interval; CKD, chronic kidney disease; DBP, diastolic blood pressure; ECG, electrocardiogram; GWAS, genome-wide association study; HF, heart failure; HR, hazard ratio; LA, left atrial; LRFM, lifestyle and risk factor modification; LV, left ventricular; LVH, left ventricular hypertrophy; MA, meta-analysis; MR, Mendelian randomization; N/A, not available/applicable; OR, odds ratio; RR, relative risk; OSA, obstructive sleep apnea; SMD, standardized mean difference; SBP, systolic blood pressure; SES, socioeconomic status; SR, systematic review; and VHD, valvular heart disease.

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Calcium mishandling from remodeling increases cal- cium load in the sarcoplasmic reticulum and dysfunc- tion of ryanodine receptors, which regulate intracellular calcium release. Remodeling in AF of sarcoplasmic reticulum calcium ATPase underlies sequestration of intracellular calcium between beats, and/or altered reg- ulation of sarcoplasmic reticulum calcium ATPase by phospholamban and sarcolipin.11 Increased intra- cellular sodium from calcium-calmodulin II-induced increased late sodium current or cardiac glycosides can also increase sarcoplasmic reticulum calcium through the sodium-calcium exchanger.12,13 Several upstream mechanisms (eg, oxidative stress, inflammatory signal- ing) promote calcium-calmodulin II -activation. CaM- KII-mediated and hyperphosphorylation of ryanodine receptor 2 promotes spontaneous diastolic Ca2+ leak by increasing ryanodine receptor 2 channel open prob- ability, leading to higher intracellular Ca2+ levels and the milieu for delayed afterdepolarizations, the most likely trigger for AF initiation.14 Electrogenic action of sodium- calcium exchanger drives afterdepolarizations, and expression of sodium-calcium exchanger is increased in HF and AF. Action potential alternans related to Ca2+ mishandling can be noted to precede AF onset and increases with age.

2.3.1.1. Triggers of AF The atria of patients with AF tend to have both shorter effective refractory periods and slower conduction, which enhances dispersion of repolarization and favor reentry. This substrate is sensitive to AF initiation, frequently af- ter premature atrial contractions (PACs).1 PAC burden is associated with development of AF.2 Larger LA volume, increased NT-proBNP levels, and impaired LA emptying are associated with increased PAC burden.3 In a study of 100 patients undergoing PV isolation, PACs induced 41 episodes of AF in 22 patients, with most episodes

originating in the PVs.4 Earlier studies also reported an LA gradient of background potassium currents, resulting in shorter LA than right atrial effective refractory period in patients with AF.5 Mapping studies of AF electrograms in canine models documented a left-right gradient of high frequency sources (drivers), with the highest frequency regions located near the PVs in the LA.6

2.3.2. Atrial Structural Abnormalities, Remodeling, and Atrial Myopathy Atrial cardiomyopathy has been identified as “any com- plex of structural, architectural, contractile or electrophysi- ological changes affecting the atria with the potential to produce clinically relevant manifestations.”1 Atrial cardio- myopathy is common, associated with aging and other comorbidities with metabolic or hemodynamic stress, and often leads to or results from AF. Structural and electrical remodeling promote AF and include interstitial changes, increased myofibroblast activity, and collagen deposi- tion, fibrofatty deposits, altered ion channel expression, calcium signaling and contractility, and inflammatory in- filtrates.1 Myeloperoxidase, an oxidase in neutrophils and macrophages, is associated with fibroblast activa- tion, interstitial fibrosis, and inducibility of AF in a mouse model.2 Prothrombotic changes are often evident in the LA, including increased endocardial expression of von Willebrand factor, vascular cell adhesion molecule-1 and monocyte chemoattractant protein-1 changes, which may increase risk of thrombus formation and stroke.1

Experimental hemodynamic overload, such as revers- ible aortopulmonary artery shunting promotes atrial dilation, atrial myocyte hypertrophy, interstitial fibrosis, alterations in extracellular matrix composition and vas- cular dysfunction, and increased vulnerability to atrial ectopy and AF inducibility.3 Electrical remodeling similar to that seen during AF is observed, with characteristic

Figure 5. Pillars for AF Management. AF indicates atrial fibrillation.

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loss of calcium currents. Shunt closure reverses elec- trophysiological changes.3 Clinically, the hemodynamic structural changes are difficult or impossible to reverse.

2.3.2.1. Upstream Pathways Upstream pathways include inflammatory, oxidative stress, fibrosis, calcium handling, genetic, metabolic, obesity, and other mechanisms implicated in increasing suscep- tibility to or progression of AF. The renin-angiotensin-al- dosterone system (RAAS), oxidative stress, inflammatory signaling, and calcium overload are discussed here and in Section 2.3.1 (“Electrophysiological Mechanisms and Electrical Remodeling”). Upstream therapies are discussed in Section 8.3.4 (“Upstream Therapy”).

The RAAS regulates blood pressure (BP) and is activated in hypertension and obesity. RAAS activation promotes vascular smooth muscle constriction (increas- ing BP), activates fibroblasts (increasing atrial intersti-

tial collagen), and increases reactive oxygen species in the sympathetic nervous system. BP and weight control, including treatment with angiotensin-converting enzyme (ACE) inhibitors or angiotensin-II receptor blockers, attenuate pathologic changes.

Oxidative stress is associated with: (1) activation of calcium-dependent calmodulin kinase II1,2 and jun kinase 2,3 which promotes ryanodine receptor phosphoryla- tion and leads to spontaneous calcium release4; (2) increased late sodium current, INa,L, and lower calcium current amplitude; (3) formation of reactive lipid products (isolevuglandins) in hypertension5 and AF6; (4) activation of the redox-sensitive transcription factor nuclear factor- kappa B and the NLRP3 inflammasome7; (5) increase in mitochondrial and metabolic stress; (6) inflamma- tory changes; and (7) myofilament protein degradation, impairing atrial contractility, which may increase throm- boembolism risk.8

Table 4. Definitions

Term Definition

AF A supraventricular tachyarrhythmia with uncoordinated atrial activation and ineffective atrial contraction

Electrocardiographic characteristics include (1) irregular R-R intervals (when atrioventricular conduction is present), (2) absence of distinct P waves, and (3) irregular atrial activity also known as fibrillatory waves. AF can be documented by, for example, 12-lead ECG, rhythm strips, wearables, intracardiac electrograms, but will always require visual confirmation that the diagnosis is accurate.

Clinical AF With the increasing availability of wearable devices and other continuous monitoring technologies, the distinction between clinical and subclinical AF has become increasingly blurred, thus the writing committee felt the term clinical AF has become less useful. Yet, the term was kept because most of the evidence from randomized trials that have led to guideline recommendations for the treatment of AF refer to “clinical AF.” These trials required electrocardiographic documentation of the arrhythmia for inclusion and most patients presented for clinical evaluation and/or therapy of the arrhythmia.

Subclinical AF Subclinical AF refers to this arrhythmia identified in individuals who do not have symptoms attributable to AF and in whom there are no previous ECGs documenting AF This includes AF identified by implanted devices (pacemakers, defibrillators, or implantable loop recorders) or wearable monitors

Atrial high-rate episodes

These are defined as atrial events exceeding the programmed detection rate limit set by the device. These are recorded by implanted devices but require visual inspection to confirm AF and exclude other atrial arrhythmias, artifact or oversensing.

AF burden AF burden encompasses both frequency and duration and refers to the amount of AF that an individual has. AF burden has been defined differently across studies. For the purpose of this guideline, AF burden will be defined as the durations of an an episode or as a percentage of AF duration during the monitoring period depending on how it was defined in the individual studies.

First detected AF The first documentation of AF, regardless of previous symptoms

Paroxysmal AF AF that is intermittent and terminates within ≤7 d of onset

Persistent AF AF that is continuous and sustains for >7 d and requires intervention. Of note, patients with persistent AF who, with therapy, become parox- ysmal should still be defined as persistent as this reflects their original pattern and is more useful to predict outcomes and define substrate.

Long-standing persistent AF

AF that is continuous for >12 mo in duration

Permanent AF A term that is used when the patient and clinician make a joint decision to stop further attempts to restore and/or maintain sinus rhythm Acceptance of AF represents a therapeutic decision and does not represent an inherent pathophysiological attribute of AF

Terms considered obsolete

Chronic AF This historical term has had variable definitions and should be abandoned. It has been replaced by the “paroxysmal,” “persistent,” “long- standing persistent,” and “permanent” terminology.

Valvular and nonvalvular AF

The distinction between “valvular” and “nonvalvular “AF remains a matter of debate. Their definitions may be confusing. Recent trials comparing vitamin K antagonists with non-vitamin K antagonist oral anticoagulants in AF were performed among patients with so-called “nonvalvular” AF. These trials have all allowed native valvular heart disease other than mitral stenosis (mostly moderate and severe) and prosthetic heart valves to be included. We should no longer consider the classification of AF as ‘‘valvular’’ or “nonvalvular” for the purpose of defining the etiology of AF, since the term was specific for eligibility of stroke risk reduction therapies. Valvular and nonvalvular terminology should be abandoned.

Lone AF This term has been used in the past to identify AF in younger patients without structural heart disease who are at a lower risk for thromboembolism. This term does not enhance patient care, is not currently used, and should be abandoned.

AF indicates atrial fibrillation.

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Systemic inflammatory activation, first documented with AF after cardiac surgery,9 has also been associated with nonsurgical AF.10 NLRP3 knockdown prevented AF inducibility in a mouse model, implicating the NLRP3 inflammasome in AF pathophysiology.11 NLRP3-block- ing drugs are in development.

2.3.2.2. Persistence of AF In general, persistence of AF reflects the substrate for AF. A suitable substrate for AF has a wavelength (wave- length = refractory period × conduction velocity) that is shorter than the dimensions of the tissue, with heterog- enous conduction velocity and/or repolarization dura- tion. Thus, an individual with large, fibrotic, and/or fatty atria is more likely to have persistent AF than one with a normal-sized atria with little interstitial fibrosis or adipose infiltration. Electrophysiologic remodeling is typically a response to persistent AF rather than the trigger.

2.3.3. Role of the Autonomic Nervous System The autonomic nervous system (ANS) has an important role as trigger and substrate (Figure 8).

ANS triggers AF The ANS as AF trigger is detailed in several reviews.1–6 Sympathetic efferent stimulation releases noradrenaline, stimulating G-coupled β-adrenergic receptors, enhancing L-type calcium channels, and increasing inward current (automaticity/early afterdepolarization). Delayed afterde- polarization occurs via calcium overload and ryanodine-2 receptor dysfunction. Parasympathetic stimulation short- ens atrial effective refractory period by increasing IKACh (acetyl-choline receptor mediated inward rectifying po- tassium channel) activity. Atrial effective refractory period heterogeneity follows the pattern of autonomic innerva- tion. Sympathetic and parasympathetic activity, alone or combined, can trigger AF.

Figure 6. Types of Atrial Flutter and Macroreentrant Atrial Tachycardia. The typical, reverse typical, and the lower-loop flutter all have the low right atrial isthmus incorporated in the flutter circuit. Other macroreentrant flutters include scar-mediated reentrant tachycardia and left mitral isthmus flutter. Modified with permission from Wellens et al.3 Copyright 2002 American Heart Association, Inc. Fl indicates flutter; LA, left atrium; and MRT, macroreentrent.

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ANS maintains AF Atrial sympathetic and parasympathetic hyperinnerva- tion and spatial heterogeneity, coupled with electri- cal fractionation and altered atrial electrophysiology, contribute to substrate.7–10 Modifiable AF risk factors promote ANS dysfunction.3 AF produces autonomic af- ferent reflex deficiencies elicited by decreased cardiac volume11,12 and increases sympathetic activity.13 Affer- ent abnormalities disrupt blood volume and pressure homeostasis. Similar abnormalities to AF were identi- fied in HF.14 Afferent ANS dysfunction could link au- tonomic with anatomic remodeling (atrial dilatation15), contributing to AF self-perpetuation.

2.4. Genetics Both common forms and familial AF are heritable.1–3 Multiple recent genome-wide association studies have documented >100 loci specific for AF.4,5 Numerous AF loci appear consistent across multiethnic groups,5

with some population variation.6,7 With large genome- wide genotyped cohorts such as the UK Biobank and the US National Heart, Lung, and Blood Institute’s (NHLBI’s) Trans Omics for Precision Medicine, the ge- netic architecture of AF is now emerging. A UK Bio- bank study identified TTN loss of function variants in 0.44% of participants, 14% of whom had AF.8 In a Trans Omics for Precision Medicine study of nearly 1300 par- ticipants <66 years of age with AF, 10.1% harbored a disease-associated genetic variant in genes associated with inherited cardiomyopathy or arrhythmia syndromes (most common were TTN, MYH7, MYH6, LMNA, and KCNQ1), and 62.8% had variants of undetermined sig- nificance. Disease-associated variants were more prev- alent at younger age of AF onset, 16.8% in those <30 years.9 A smaller study of persons of Hispanic or African American descent reported 7% of persons with AF on- set at ≤66 years of age harbored rare likely pathogenic or pathogenic sequence variants, mostly in myocardial structural proteins and ion channels.10

Figure 7. Mechanisms and Pathways Leading to AF. The pathways that contribute to the development of AF create a substrate for reentry and provide triggers that can initiate arrhythmic activity. AF indicates atrial fibrillation; PAC, premature atrial contraction; NLRP3, NOD-, LRR- and pyrin domain-containing protein 3; and RAAS, renin- angiotensin-aldosterone system.

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2.5. Addressing Health Inequities and Barriers to AF Management

Recommendation to Address Health Inequities and Barriers to AF Management Referenced studies that support the recommendation are summarized in the Online Data Supplement.

COR LOE Recommendation

1 B-NR

1. Patients with AF, regardless of sex1 and gender diversity, race and ethnicity,2 or adverse social determinants of health (SDOH),3,4* should be equitably offered guideline-directed stroke risk reduction therapies as well as rate or rhythm control strategies and LRFM as indicated to improve quality of life (QOL) and prevent adverse outcomes.

*Including lower income, lower education, inadequate or lack of insurance cov- erage, or rurality.3–5

Synopsis Inequities in AF care and outcomes in individuals who are women, from underrepresented racial and ethnic groups (UREGs),2 or who have adverse SDOH have been docu- mented.3,4 Sex differences in AF treatment have been described with respect to anticoagulation6,7 and rhythm control therapy approaches.7–9 Racial and ethnic differ- ences in clinical presentation, management, and progno- sis, including stroke, HF, and death, in patients with AF are widely reported.2,10

To avoid guidelines having the unintended con- sequence of widening inequities in clinical care and

outcomes in individuals with AF, it is essential to longitu- dinally measure the receipt of AF GDMT and outcomes at the clinical practice and health system levels stratified by specific populations who have historically experienced inequitable care. If inequities are identified, barriers to GDMT should be eliminated. Data are needed to assess the impact of addressing SDOH in patients with AF on process measures, health care utilization, costs, and clinical outcomes.11 In other health contexts, there are observational and randomized data12 that screening and addressing SDOH leads to improved medication adher- ence,13 risk factor control,14 and clinical outcomes.15

Recommendation-Specific Supportive Text 1. Despite the elevated risk of stroke in women and

several UREGs, many are less likely to be treated with stroke risk reduction therapies.6,7 Although women and individuals from UREGs with AF are more symptomatic and report worse QOL than their counterparts, they also are less likely to be referred to an electrophysiologist7 and receive catheter ablation.2,7–9,16 Women are referred for ablation later in the disease course and at older ages than men.7,17,18 These differences or delays in therapy may result in worse outcome given early rhythm control of AF improves outcomes1,19 in select patients. In addition, in the Catheter

Figure 8. Contemporary Summary of the Role of the ANS in AF. Original figure created by the 2023 Atrial Fibrillation Guideline Writing Committee. AF indicates atrial fibrillation; ANS, autonomic nervous system; HRV, heart rate variability; and LA, left atrium.

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Ablation versus Antiarrhythmic Drugs in AF trial, individuals from UREGs treated with catheter ablation had a 72% relative reduction in the all- cause mortality rate.20 Therefore, ensuring timely and equitable referral of women, individuals from UREG, and those with adverse SDOH for rhythm control therapy is important. In patients with AF, indicators of lower socioeconomic status were associated with lower oral anticoagulation rates,21 lower rate of adherence during direct oral antico- agulant (DOAC) initiation,22 specialty care,21,23 and less use of cardioversion4,21 and catheter abla- tion.4,21,24 Indicators of socioeconomic disadvan- tages, such as increased risk of hospitalization,25 stroke,4,21 HF,4,21,26 and death, were also associated with complications in patients with AF.4,21,27

3. SHARED DECISION-MAKING (SDM) IN AF MANAGEMENT

Recommendation for SDM in AF Management Referenced studies that support the recommendation are summarized in the Online Data Supplement.

COR LOE Recommendation

2b B-R

1. In patients with AF, the use of evidence-based decision aids might be useful to guide stroke reduction therapy treatment decisions throughout the disease course to improve engagement, decisional quality, and patient satisfaction.1–4

Synopsis There are wide variations in how SDM is implemented in clinical care settings.5,6 Decision aids may provide standardization of SDM approaches for better informing patients about stroke reduction therapies and improve patient-reported measures but to date have not consis- tently been developed with recommended frameworks, have rarely been tested in systemically disadvantaged populations (low health literacy, UREGs, low socioeco- nomic status, rural geography, older adults), and have had variable impact on adherence and clinical outcomes.1–8 Ongoing work will measure health and digital literacy and strengthen the evidence for the impact of decision aids on decisional quality, adherence to treatment, and health outcomes.9

Symptom severity strongly correlates with QOL; thus, minimizing symptoms is an essential component of patient-centered AF management decisions. Rhythm control strategies improve QOL, particularly when main- tenance of sinus rhythm or low AF burden is achieved.10 Notably, few SDM decision aids are focused on rate or rhythm control treatment options, and few have mea- sured QOL as an outcome.3,5

Recommendation-Specific Supportive Text 1. Recently, 2 comprehensive reviews of deci-

sion aids for stroke reduction therapies were

conducted to determine the impact of these tools on patient-reported measures of decisional qual- ity, while considering other important outcomes including oral anticoagulant (OAC) uptake, medi- cation adherence, and the effect on bleeding and stroke.3,4 Most decision aids focused on patient- reported measures, and few underwent rigorous pilot testing or correlated the aid with clinical out- comes, such as stroke and bleeding. Decision aids consistently demonstrate improvements in patient knowledge. The pooled analysis by Song et al noted lower decisional conflict using decision aids and enhanced OAC uptake (risk ratio, 1.03 [95% CI, 1.01-1.05]).4 Decision aids have historically shown marginal improvement in 3-month mea- sures of adherence, and the 2 largest randomized trials to date showed no improvement in adher- ence between decision aids and usual care at 1 year.1,2 There is a paucity of data on the impact of decision aids on stroke, thromboembolic events, or bleeding, and when assessed the benefit has been minimal or neutral.4,11 Despite the US Centers for Medicaid & Medicare Services coverage decision requirement for SDM for percutaneous left atrial appendage occlusion (LAAO), only 1 tool was identified that incorporated this option (Table 5).5

4. CLINICAL EVALUATION 4.1. Risk Stratification and Population Screening There are >20 risk prediction models for incident AF in the community.1 The most widely replicated risk prediction model for newly diagnosed AF is CHARGE-AF (Cohorts for Heart and Aging Research in Genomic Epidemiology model for atrial fibrillation; Table 6),2 while the C2HEST score (coronary artery disease or chronic obstructive pul- monary disease [1 point each]; hypertension [1 point]; elderly [age ≥75 years, 2 points]; systolic HF [2 points];

Table 5. Publicly Available Decision Aids

Agency Website Focus Area

American College of Cardiology Colorado Program for Patient Centered Decisions

https://patientdecisionaid.org/icd/ atrial-fibrillation/

Stroke risk reduction therapies

Anticoagulation Choice Decision Aid

https://anticoagulationdecisionaid. mayoclinic.org/

Stroke risk reduction therapies

Ottawa Hospital Research Institute Developer Healthwise

https://decisionaid.ohri.ca/AZlist. html

AF ablation Stroke risk reduction

Stanford https://afibguide.com/ Stroke risk reduction therapies

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thyroid disease [hyperthyroidism, 1 point]) was derived and validated in Asian cohorts (Table 7).3,4

Screening for AF has been investigated, mostly in patients >65 years of age, using various protocols that include both 1-time electrocardiographic recordings, recurring intermittent ECGs (including consumer-based devices), or continuous electrocardiographic external monitors. Most screening trials have shown higher AF detection using intermittent or continuous electrocardio- graphic recordings5 and higher AF detection in patients with higher predicted risk for AF.6 A recent study also showed that an AI algorithm able to risk-stratify a rel- atively uniform population (eg, older adults at risk for stroke) to detect undiagnosed AF during short-term car- diac monitoring was associated with increased AF.7 Con- versely, mass population screening with a smartwatch app only rarely detected a new diagnosis of AF.8 Ultimately, for risk stratification models and screening programs to be useful, they would need to improve outcomes and be

cost-effective.9 It is not yet established that patients at high risk of developing AF by a validated risk score ben- efit from screening and interventions to improve rates of ischemic stroke, systemic embolism, and survival.

4.2. Basic Evaluation 4.2.1. Basic Clinical Evaluation

Recommendations for Basic Clinical Evaluation Referenced studies that support the recommendations are summarized in the Online Data Supplement.

COR LOE Recommendations

1 B-NR

1. In patients with newly diagnosed AF, a transthoracic echocardiogram1–4 to assess cardiac structure, laboratory testing to include a complete blood count, metabolic panel, and thyroid function,5–7 and when clinical suspicion exists, targeted testing to assess for other medical conditions associated with AF are recommended to determine stroke and bleeding risk factors, as well as underlying conditions that will guide further management.

3: No benefit

B-NR

2. In patients with newly diagnosed AF, protocolized testing for ischemia, acute coronary syndrome (ACS), and pulmonary embolism (PE) should not routinely be performed to assess the etiology of AF unless there are additional signs or symptoms to indicate those disorders.8–10

Synopsis The initial clinical evaluation of the patient with newly diagnosed or suspected AF should be focused on con- firming the diagnosis and identifying relevant clinical factors that will impact management. A targeted history and physical examination should be performed at the ini- tial assessment and repeated during periodic follow-up, especially given the evolving risk of thromboembolism and the cadence of symptoms in response to therapy (see Section 11, “Future Research Needs”). An ECG can assess other electrical abnormalities, including pos- sible substrates such as Wolff-Parkinson-White (WPW) syndrome, coexisting atrial arrhythmias, as well as ab- normalities that may affect decision-making in pharma- cological management (eg, bradycardia, QT duration). Basic laboratory tests should be performed to deter- mine if other clinically relevant disorders are present and impact on management, particularly with respect to stroke and bleeding risk. A transthoracic echocardio- gram provides information on chamber size, thickness, function, and the presence of valvular pathology. Addi- tional testing, including multimodality advanced imaging and further ambulatory electrocardiographic monitoring, may be pursued based on the results of these initial evaluations. AF itself does not increase the likelihood of myocardial ischemia, ACS or PE, and therefore routine testing for these disorders in the absence of signs or symptoms is of no benefit.

Recommendation-Specific Supportive Text 1. A transthoracic echocardiogram is essential to

evaluate chamber size and function, valve function,

Table 6. CHARGE-AF Risk Score for Detecting Incident AF*

Variable (X) Estimated β Coefficient (SE) HR (95% CI)

Age (per 5-y increment) 0.508 (0.022) 1.66 (1.59-1.74)

White race 0.465 (0.093) 1.59 (1.33-1.91)

Height (per 10-cm increment) 0.248 (0.036) 1.28 (1.19-1.38)

Weight (per 15-kg increment) 0.115 (0.033) 1.12 (1.05-1.20)

Systolic BP (per 20-mm Hg increment)

0.197 (0.033) 1.22 (1.14-1.30)

Diastolic BP (per 10-mm Hg increment)

–0.101 (0.032) 0.90 (0.85-0.96)

Smoking (current versus former/never)

0.359 (0.063) 1.42 (1.25-1.60)

Diabetes (yes) 0.237 (0.073) 1.27 (1.64-2.48)

Myocardial infarction (yes) 0.496 (0.089) 1.64 (1.38-1.96)

Table 6 does not encompass all complications. *Five-year risk is given by: 1 – 0.9718412736exp(ΣβX – 12.4411305), where β is the

regression coefficient (column 2) and X is the level of each variable risk factor.2

AF indicates atrial fibrillation; BP, blood pressure; CHARGE-AF, Cohorts for Heart and Aging Research in Genomic Epidemiology model for atrial fibrillation; HR, hazard ratio; and SE, standard error.

Table 7. C2HEST Risk Score for Detecting Incident AF*

Acronym Risk Factor Points

C2 CAD/COPD 1-2

H Hypertension 1

E Elderly (age ≥75 y) 2

S Systolic heart failure 2

T Thyroid disease (hyperthyroidism)

*Total points 0-8. For the C2HEST score, the C statistic was 0.749, with 95% CI of 0.729–0.769.10 The incident rate of AF increased significantly with higher C2HEST scores.

AF indicates atrial fibrillation; CAD, coronary artery disease; C2HEST, coronary artery disease or chronic obstructive pulmonary disease [1 point each]; hyperten- sion [1 point]; elderly [age ≥75 y, 2 points]; systolic HF [2 points]; thyroid disease [hyperthyroidism, 1 point]; and COPD, chronic obstructive pulmonary disease.

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and right ventricular (RV) pressure. Left ventricular ejection fraction (LVEF) impacts decisions for anti- arrhythmic drug therapy and whether to prioritize other rhythm control therapies, including catheter ablation. Additionally, strain imaging may suggest an underlying infiltrative cardiomyopathy, such as amyloidosis.1 Echocardiography also provides information on LA size and function. Altered LA compliance is known to be associated with AF11 and progression toward persistent-type AF.2 In a meta-analysis, AF recurrence after ablation was associated with a lower LA strain,3 while LA vol- ume was a stronger predictor of recurrence after ablation than the characterization of AF as parox- ysmal or persistent.4 Laboratory testing can detect other medical conditions that are associated with AF and would impact therapeutic decision-making, such as CKD,5 liver dysfunction,6 and hyperthyroid- ism.7,12 Laboratory testing may also reveal electro- lyte abnormalities, including from medications such as diuretics. Laboratory testing is also needed to determine stroke risk and bleeding risk factors, which will guide management decisions. When clinical suspicion exists, additional testing might be needed to evaluate for potentially related condi- tions, such as significant valvular disease.

2. The presence of AF itself should not prompt rou- tine protocolized testing for myocardial ischemia, ACS, or PE, in the absence of signs or symptoms to suggest those diseases. A retrospective analysis of asymptomatic patients with AF compared with age- and sex-matched controls that were referred for myocardial stress imaging found no difference in mean summed stress score or rate of abnormal studies.8 A retrospective analysis of 1700 asymp- tomatic AF patients (no chest pain or dyspnea) found that 4.6% had >5% ischemic myocardium, and the yield to detect ischemia that resulted in revascularization was only 0.4%.9 Among patients suspected of PE, a retrospective analysis showed that the presence of AF did not increase the prob- ability of PE.10 Certainly, this would not preclude from evaluating patients with signs and/or symp- toms of ischemia and PE.

4.2.2. Rhythm Monitoring Tools and Methods Recommendations for Rhythm Monitoring Tools and Methods Referenced studies that support the recommendations are summarized in the Online Data Supplement.

COR LOE Recommendations

1 B-NR

1. Among individuals without a known history of AF, it is recommended that an initial AF diagnosis be made by a clinician using visual interpretation of the electrocardiographic signals, regardless of the type of rhythm or monitoring device.1–5

1 B-NR

2. In patients with an intracardiac rhythm device capable of a diagnosis of AF, such as from an atrial pacemaker lead, a diagnosis of AF should only be made after it is visually confirmed by reviewing intracardiac tracings to exclude signal artifacts and other arrhythmias.6–9

2a B-R

3. For patients who have had a systemic thromboembolic event without a known history of AF and in whom maximum sensitivity to detect AF is sought, an implantable cardiac monitor is reasonable.10,11

2a B-NR

4. Among patients with a diagnosis of AF, it is reason- able to infer AF frequency, duration, and burden using automated algorithms available from electrocardio- graphic monitors, implantable cardiac monitors, and cardiac rhythm devices with an atrial lead, recognizing that periodic review can be required to exclude other arrythmias.1,4,5,12

2a B-R

5. Among patients with AF in whom cardiac monitor- ing is advised, it is reasonable to recommend use of a consumer-accessible electrocardiographic device that provides a high-quality tracing to detect recur- rences.13

Synopsis Monitoring options for AF include a standard 12-lead ECG, continuously recording or loop-recording electro- cardiographic monitors using separate electrodes or as patches, implantable cardiac monitors (sometimes referred to as implantable loop recorders), cardiac rhythm management devices with an atrial lead (eg, pacemakers and defibrillators), handheld ECGs, and smartwatches. Photoplethysmography has been used to infer AF from irregular pulse patterns using a variety of devices, predominately smartphone cameras14 and smartwatches.15–18 Electrocardiographic monitors of- ten deploy automated algorithms for AF detection, but due to variable accuracy,1–5 the initial diagnosis should rely on a health care professional’s examination of the electrocardiographic tracing. Although photoplethys- mography monitors may alert individuals to obtain an electrocardiographic tracing, it is not sufficiently reliable to establish an AF diagnosis.14–18 AF detected from an atrial lead has been validated versus surface ECGs6,7 and independently predicts stroke.8,9 RCTs have dem- onstrated that implantable cardiac monitors exhibit the highest sensitivity in detecting AF compared with ex- ternal ambulatory monitors, likely related to the longer duration of monitoring.10,11 Automated algorithms to an- alyze electrocardiographic devices have generally been found to be sufficiently reliable to infer the frequency, duration, and burden of AF among those with an AF di- agnosis.1,4,5,12 A randomized trial showed that a handheld electrocardiographic monitor resulted in earlier detec- tion of recurrent AF.13

Recommendations for Rhythm Monitoring Tools and Methods (Continued)

COR LOE Recommendations

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Recommendation-Specific Supportive Text 1. Although automated algorithms in various devices

are generally reliable, health care profes- sional overread of electrocardiographic trac- ings remains necessary given the imperfect test characteristics of those algorithms.1–5 Similarly, while algorithms utilizing photoplethysmography signals (derived using smartphones or smart- watches) to infer irregular heart rates can dis- criminate AF from normal sinus rhythm, these are not sufficiently reliable to establish an AF diagnosis.14–18

2. Cardiac rhythm devices with an atrial lead have been shown to detect AF validated against con- ventional surface electrocardiographic tracings.6–8 In addition, both the presence and duration of AF detected solely by these devices predict stroke in a manner that would be expected of AF.8,9 It is still essential that the intracardiac tracings are reviewed for confirmation because false-positives are possible. The duration of AF that mandates intervention with anticoagulation will be dis- cussed in Section 6.4.1 (“Oral Anticoagulation for Device-Detected Atrial High-Rate Episodes Among Patients Without a Previous Diagnosis of AF”).

3. The more frequent and longer monitoring for AF is deployed, the greater the sensitivity in detecting AF.10,19 Randomized trials, predominately among cryptogenic stroke patients, have revealed that implantable cardiac monitors exhibit the highest sensitivity in detecting AF in view of extended monitoring periods compared with external monitors.10,11

4. It is often not feasible to manually review all elec- trocardiographic strips from various monitoring devices, either due to inaccessibility or time and resource constraints on health care professionals. Although variability in accuracy across different devices may be present, the validity demonstrated in automated algorithms is generally sufficient to infer frequency, duration, and burden of AF using electrocardiographic devices such as con- tinuously wearable monitors, implantable cardiac monitors, and cardiac rhythm devices with an atrial lead.1,4,5,12

5. Cardiac monitoring may be advised to AF patients for various reasons, such as for detecting recur- rences, screening, or response to therapy. Among patients with AF who are undergoing cardiover- sion or AF ablation, a single-center, randomized trial demonstrated that use of a self-administered handheld ECG resulted in earlier detection of recurrent AF13 and possibly improvement in sur- vey-determined AF-related QOL20 compared with usual care.

5. LIFESTYLE AND RISK FACTOR MODIFICATION (LRFM) FOR AF MANAGEMENT 5.1. Primary Prevention

Recommendation for Primary Prevention Referenced studies that support the recommendation are summarized in the Online Data Supplement.

COR LOE Recommendation

1 B-NR

1. Patients at increased risk of AF should receive com- prehensive guideline-directed LRFM for AF, targeting obesity,1 physical inactivity,2 unhealthy alcohol con- sumption,3 smoking,4 diabetes,5 and hypertension.6

Synopsis The clinical, family history, and genetic risk factors for AF are well established (Table 3), and risk prediction models (Section 4.1, “Risk Stratification and Pop- ulation Screening”) for AF have been reported and replicated.7–9 Multiple reports have established that maintenance of optimal risk factors and ideal cardiovas- cular health are associated with substantially reduced risk of AF10,11 onset and complications (Section 5, “Lifestyle and Risk Factor Modification [LRFM] for AF Management”). To reduce risk of AF onset, indi- viduals in the general population, particularly those at increased risk of AF, should receive comprehensive in- tegrated LRFM, including maintenance of ideal weight and weight loss if overweight or obese1,12; pursue a physically active lifestyle,2 particularly if sedentary; re- ceive smoking cessation counseling and/or medica- tions4; moderate (≤1 standard alcoholic drink/day) or abstain from alcohol and avoidance of binge drinking3; control diabetes5; and control BP in accordance with GDMT.6,13 There is also an association of cannabis, co- caine, methamphetamine, or opiate use with increased incidence of AF.14

Recommendation-Specific Supportive Text 1. Most cardiovascular risk factors are associated

with increased risk of new-onset AF. Observational studies have demonstrated that obesity and physi- cal inactivity each independently increase the risk of newly diagnosed AF.1,2,12,15–20 However, caution should be considered in pursuing years of regular, high-volume (≥3 h/day) high-intensity endurance training given observational data linking it with increased AF risk21–23 in men and similar “J” curve risk curve observed for high or vigorous activity in both men and women in another study.24 Alcohol consumption enhances the risk of AF in a fairly linear fashion, with clear evidence that binge drink- ing heightens the risk.3,25–29 Uncertainty persists regarding harms or benefits of no more than 1 regular drink per day.28,29 Self-reported,4 biomarker- verified,30 and genetically predicted31 smoking is

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associated with increased risk, and smoking ces- sation is associated with decreased risk of incident AF.4 The presence of either type 1 or type 2 diabe- tes increases AF risk,5,32 with evidence that worse glucose control correlates with a higher probability of developing AF.33 Hypertension is the risk factor with the highest attributable risk for AF10; intensive BP control lowers the risk of incident AF in obser- vational and randomized data.6 Effective strategies to manage risk factors and prevent CVD have been reported elsewhere.12,13

5.2. Secondary Prevention: Management of Comorbidities and Risk Factors 5.2.1. Weight Loss in Individuals Who Are Overweight or Obese

Recommendation for Weight Loss in Individuals Who Are Overweight or Obese Referenced studies that support the recommendation are summarized in the Online Data Supplement.

COR LOE Recommendation

1 B-R

1. In patients with AF who are overweight or obese (with body mass index [BMI] >27 kg/m2), weight loss is recommended, with an ideal target of at least 10% weight loss to reduce AF symptoms, burden, recurrence, and progression to persistent AF.1–4

Synopsis Obesity is associated with the development and pro- gression of AF.5 It results in direct changes to the atrial myocardium forming the substrate for AF.6–8 In addition, obesity is also associated with several comorbidities that have been independently associated with the develop- ment of AF.9,10 Obesity has a significant adverse impact on attempts to maintain sinus rhythm, with each 5-unit increase in BMI being associated with a 10% and 13% greater risk of postoperative and postablation AF, re- spectively.5,11,12 Management of weight is important in the prevention and treatment of AF.

Recommendation-Specific Supportive Text 1. In an RCT in overweight and obese individuals with

BMI >27 kg/m2 and AF, weight loss, as part of a comprehensive LRFM program, was associated with reduction in arrhythmia symptoms, recurrence, and burden.1 Observational studies demonstrated graded responses commensurate with the degree of weight loss, with achievement of at least 10% weight loss associated with greater maintenance of sinus rhythm,2 improved ablation outcomes,3 and reversal of AF type.4 In observational stud- ies, bariatric surgery in Class III obese individuals (BMI ≥40 kg/m2) with AF was associated with improved sinus rhythm maintenance after catheter ablation13,14 and reversal of AF type.15 The greater number of risk factors managed associated with likelihood of maintaining sinus rhythm.16 However,

a small observational study in individuals with obe- sity (BMI ≥30 kg/m2) with long-lasting persistent AF observed no difference in symptoms or sinus rhythm maintenance despite significant weight loss, suggesting that there may be extreme sub- strates in which a weight loss strategy may not be effective.17

Structured programs with regular review of prog- ress facilitate achievement of weight loss and appear essential, as demonstrated by inability to reduce AF burden in a small RCT that achieved only 4.5% weight loss in the intervention arm.

5.2.2. Physical Fitness Recommendation for Physical Fitness Referenced studies that support the recommendation are summarized in the Online Data Supplement.

COR LOE Recommendation

1 B-R

1. In individuals with AF,* moderate-to-vigorous exercise training to a target of 210 minutes per week is rec- ommended to reduce AF symptoms1–3 and burden,2,3 increase maintenance of sinus rhythm,3–5 increase functional capacity, and improve QOL.3,5,6

*In patients without AF related to excessive exercise training.

Synopsis Randomized trials provide evidence that prescribed aero- bic exercise interventions may reduce arrhythmia burden in those with nonpermanent AF2 and improve functional capacity and health-related QOL in both permanent1,6 and nonpermanent AF.2 In the ACTIVE-AF (An Exercise and Physical Activity Program in Patients With Atrial Fi- brillation) study, an exercise intervention combining home and supervised aerobic exercise over 6 months resulted in greater freedom from arrhythmia recurrence, reduced burden, and improved QOL.3

Recommendation-Specific Supportive Text 1. In patients with nonpermanent AF, aerobic exercise

training may contribute to a reduction in AF bur- den and improve maintenance of sinus rhythm.2–5 Aerobic exercise interventions reduce severity of AF symptoms, increase functional capacity, and improve health-related QOL among patients with both nonpermanent and permanent AF.1,3,6 Initiation of or continuing regular exercise after develop- ment of AF was associated with a lower risk of HF and mortality in a population-based cohort study.7 Exercise training should be moderate- to vigorous- intensity aerobic exercise, with a target of 210 min- utes per week, and should be prescribed to reduce the frequency and duration of AF episodes, while improving cardiorespiratory fitness and symptom severity.3 Exercise prescription may be further modified to patient comorbidities, such as obesity, hypertension, and diabetes.4 Caution should be applied to ensure adequate ventricular rate con- trol during exercise training and absence of atrial

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myopathy related to excessive exercise training. To date, there is little evidence that high-intensity aerobic exercise may be favorable over moderate- intensity activities,8 and extreme levels of exer- cise have been associated with higher incidence of AF.9,10 Exercise training may be delivered as a stand-alone intervention or as a component of mul- tidisciplinary cardiac rehabilitation. Exercise-based cardiac rehabilitation improves QOL and functional capacity among patients with AF undergoing abla- tion,11,12 although available studies have not been adequately powered to assess AF-specific out- comes, such as arrhythmia recurrence.13 There is mixed evidence for a reduction in hospitalization or all-cause mortality with exercise training or exer- cise-based cardiac rehabilitation.12,14,15

5.2.3. Smoking Cessation Recommendation for Smoking Cessation Referenced studies that support the recommendation are summarized in the Online Data Supplement.

COR LOE Recommendation

1 B-NR

1. Patients with a history of AF who smoke cigarettes should be strongly advised to quit smoking and should receive GDMT for tobacco cessation1,2 to mitigate increased risks of AF-related cardiovascular complications and other adverse outcomes.3–6

Synopsis Observational data support that cigarette smoking in individuals with AF is associated with worse cardiovas- cular outcomes and death and that individuals with AF who quit smoking are less likely to develop stroke or die. Despite the benefits of smoking cessation, individu- als with AF are less likely to receive smoking cessation management than counterparts without AF.7,8 Patients with AF should be strongly advised to quit cigarette smoking9 and should receive GDMT for tobacco ces- sation, including behavioral interventions10,11 and phar- macotherapy.2

Recommendation-Specific Supportive Text 1. In individuals with AF, cigarette smoking was asso-

ciated with poorer outcomes. For individuals who have undergone AF catheter ablation, current cigarette smoking was associated with increased risk for AF recurrence.12,13 Cigarette smoking was associated with less time in therapeutic range for patients on warfarin.14 Although some heteroge- neity exists, the preponderance of studies have reported that individuals with AF who smoked ciga- rettes had increased risks of stroke,3,4 HF,5 hospi- talization,6 and death.6,15 Of concern, studies have reported that individuals with AF (versus those without) were less likely to receive smoking cessa- tion interventions.7,8 Observational studies suggest that compared with current smokers, individuals with AF who quit smoking after AF diagnosis were

less likely to experience CVD,3 stroke,3,16 and all- cause mortality.16

5.2.4. Alcohol Consumption Recommendation for Alcohol Consumption Referenced studies that support the recommendation are summarized in the Online Data Supplement.

COR LOE Recommendation

1 B-R 1. Patients with AF seeking a rhythm-control strategy

should minimize or eliminate alcohol consumption to reduce AF recurrence and burden.1–3

Synopsis Among patients with a diagnosis of AF, randomized trials have demonstrated a reduction in AF burden on assign- ment to abstinence,1 that alcohol acutely changes human electrophysiology in a fashion that renders the atria more prone to fibrillate,2 and suggest that avoiding alcohol can reduce the risk of a near-term AF event.3

Recommendation-Specific Supportive Text 1. Among patients with AF, a case-crossover study

revealed a higher risk of a discrete AF episode hours after objectively confirmed alcohol consump- tion.4 In the context of a structured comprehensive management of risk factors, alcohol abstinence1 or reduction to ≤3 standard drinks per week has been demonstrated to reduce AF symptoms,5 AF burden,6,7 and progression of AF from paroxysmal to persistent.8

5.2.5. Caffeine Consumption Recommendation for Caffeine Consumption Referenced studies that support the recommendation are summarized in the Online Data Supplement.

COR LOE Recommendation

3: No Benefit

B-NR

1. For patients with AF, recommending caffeine abstention to prevent AF episodes is of no benefit, although it may reduce symptoms in patients who report caffeine triggers or worsens AF symptoms.1–9

Synopsis A randomized N-of-1 trial,2 as well as longitudinal, ob- servational studies, have generally found that caffeine consumed within normal limits is either associated with no heightened risk3–6 or a reduced risk of incident AF.3,5,7–9 Patients often report caffeine as a trigger of AF,10 although this has not been supported by objec- tive data.

Recommendation-Specific Supportive Text 1. A randomized trial of caffeine failed to show any

difference in postoperative AF risk,1 and paroxys- mal AF patients experienced no detectable differ- ence in AF episodes when exposing themselves to versus avoiding caffeine in randomized N-of-1 trials.2 Longitudinal, observational studies have generally found that caffeine consumed in usual amounts is either associated with no heightened

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risk3–6 or a reduced risk of incident AF.3,5,7–9Also, Mendelian randomization studies examining caf- feine metabolism-related genetic variants as instrumental-variable surrogates of caffeine consumption have not shown either a harm- ful or protective effect related to incident AF.8,11 Several case reports have described a relation- ship between excessive consumption of caffeine (involving overdoses or highly caffeinated energy drinks)12,13 and AF in young, healthy individuals. Individuals should not begin or increase their caf- feine consumption with the intent of reducing their AF risk.Patients often report that caffeine triggers their AF,10,14 although this has neither been supported by nor extensively studied in an objective manner. Current studies cannot exclude the possibility of individual-level idiosyncratic relationships between caffeine and AF. It is also possible that caffeine exacerbates symptoms of AF, or causes similar symptoms of palpitations, or enhances heart rhythm awareness.

5.2.6. Diet and Dietary Supplementation Promoting a healthy diet is an effective strategy for pre- vention of cardiovascular disease. The evidence pertain- ing to the prevention of AF using dietary supplements is inconsistent, complicated by substantial misclassification and difficulties controlling for potential confounding fac- tors associated with dietary interventions.

Several studies have evaluated the role of omega-3 fatty acids and AF, demonstrating an inverse relation- ship between plasma omega-3 polyunsaturated fatty acid levels and prevalent AF.1,2 However, with supple- mentation there has been no effect or a potential for greater AF.3–7 Although vitamin D supplementation is not useful on a population basis,8,9 its use in the peri- operative period in deficient individuals reduces AF.10 Similarly, ascorbic acid has been beneficial in reduc- ing postoperative AF in some studies, although not uniformly.11

The importance of weight management on AF symptoms, burden, and recurrence is increasingly rec- ognized,12,13 leading to various dietary interventions. Although evidence on diets is still evolving, analyses of the ARIC (Atherosclerosis Risk in Communities) study caution using low-carbohydrate diets, which were found to increase the risk of incident AF, regardless of the type of protein or fat used to replace carbohydrate.14

5.2.7. Diabetes AF and diabetes are associated with increased risk of car- diovascular mortality and sudden death.1 In patients with diabetes, vascular mortality was lower in patients treated with DOACs compared with warfarin.2 In patients with AF and diabetes undergoing catheter ablation, optimal glyce- mic control preablation may lessen the risk of AF recur- rence postablation.3

5.2.8. Treatment of Hypertension Recommendation for the Treatment of Hypertension Referenced studies that support the recommendation are summarized in the Online Data Supplement.

COR LOE Recommendation

1 B-NR 1. For patients with AF and hypertension, optimal BP

control is recommended to reduce AF recurrence and AF-related cardiovascular events.1–7

Synopsis Renal denervation and mineralocorticoid receptor antagonists (MRAs) have been associated with de- creased AF burden in clinical trials.1,2 The only ran- domized trial singularly targeting BP control as a mechanism to reduce the recurrence of AF8 showed no significant difference in the primary outcome of recurrent symptomatic atrial arrhythmia beyond 3 months’ postablation among the 2 groups. However, clinical trials of integrated comprehensive LRFM pro- grams in conjunction with rhythm control therapies for AF have resulted in longer arrhythmia-free survival and decreased AF burden.3,5,9 Among patients with AF, treating elevated BP to guideline-directed goals re- duces major cardiovascular events.9

Recommendation-Specific Supportive Text 1. In patients with AF, treatment of hypertension

should aim for current BP guidelines to reduce stroke, bleeding, and other adverse outcomes.5,10 An RCT of patients with paroxysmal AF and hypertension noted fewer recurrences among participants treated with renal denervation and pulmonary vein isolation (PVI) compared with PVI alone.2 Randomized studies of mineralo- corticoid receptor antagonists for hypertension have been shown to reduce AF burden, and ACE inhibitors and angiotensin II receptor blockers have been associated with lower AF incidence in secondary analyses of RCTs (see Section 8.3.4, “Upstream Therapy”). In addition, several inte- grated LRFM programs that have resulted in a decrease in BP have been associated with a decreased recurrence of AF.3,11The SMAC (Substrate Modification With Aggressive Blood Pressure Control) AF trial randomized hyperten- sive patients scheduled for AF ablation to stan- dard or aggressive BP treatment with a systolic BP target of 120 or 140 mm Hg.8 No significant difference was shown in recurrent symptomatic atrial arrhythmia beyond 3 months postablation (median follow-up, 14 months), and this is the only RCT to date singularly targeting BP control as a mechanism to reduce AF recurrence.8 Post hoc analyses of DOAC clinical trials to reduce the risk of stroke in patients with AF have con- sistently found lower rates of stroke in patients with controlled BP.6,7

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5.2.9. Sleep Recommendation for Sleep Referenced studies that support the recommendation are summarized in the Online Data Supplement.

COR LOE Recommendation

2b B-NR

1. Among patients with AF, it may be reasonable to screen for obstructive sleep apnea, given its high prevalence in patients with AF, although the role of treatment of sleep-disordered breathing (SDB) to maintain sinus rhythm is uncertain.1–13

Synopsis SDB is a risk factor for the development of incident AF, and more severe SDB acutely increases the risk of a discrete AF episode.14–18 Independent of SDB, poor sleep quality is associated with an increased risk of developing incident AF.19–21 When formal testing for SDB is used, the disease is frequently observed in >20% of patients with an AF di- agnosis.1–5 Observational studies suggest that treatment of SDB may reduce the risk of AF recurrence and AF burden, but RCTs have not been adequately powered to reveal a relationship between treating SDB and reduced AF.6–13

Recommendation-Specific Supportive Text 1. The prevalence of SDB is remarkably and consis-

tently high in patients with AF (generally substan- tially >20% and sometimes >50% regardless of the type of AF population assessed), is often unde- tected, and, as conventional symptoms of SDB may be absent, may require formal study to establish a diagnosis of SDB.1–5,11 Multiple observational stud- ies have described fewer recurrences of AF and a reduction in AF burden, including after cardiover- sion and catheter ablation procedures, among those undergoing treatment for SDB compared with those not treated for their SDB.6–11,22 However, small trials randomizing patients with AF and SDB treatment versus usual care have not shown significant differ- ences in AF burden or AF recurrence, including after cardioversion or PVI ablation,12,13,22 although stud- ies tended to exclude patients who might benefit most from SDB treatment (eg, those who had more symptomatic sleep apnea [Epworth Sleepiness Scale score >10 or 15], severe cardiovascular dis- ease [LVEF <40% or 45%], or severe obesity).

5.2.10. Comprehensive Care Recommendations for Comprehensive Care Referenced studies that support the recommendations are summarized in the Online Data Supplement.

COR LOE Recommendations

1 A

1. Patients with AF should receive comprehensive care addressing guideline-directed LRFM, AF symptoms, risk of stroke, and other associated medical conditions to reduce AF burden, progression, or consequences.1–3

2a B-R

2. In patients with AF, use of clinical care pathways, such as nurse-led AF clinics, is reasonable to promote comprehensive, team-based care and to enhance adherence to evidence-based therapies for AF and associated conditions.4–6

Synopsis Almost all patients with AF have multiple conditions that either increase AF risk or are exacerbated by AF. Patients with AF are also at risk of developing thromboembolism, stroke, and HF, so a comprehensive approach tailored to the needs of the individual patient should improve out- comes. Randomized trials have shown that interventions aimed at AF risk factors, such as alcohol use, overweight, and HF, reduce AF burden. Clinical care pathways and algorithms for AF management, including LRFM, have shown promise in randomized trials through coordinat- ing care and facilitating comprehensive AF management.

Although comprehensive care of the multiple condi- tions associated with AF is logical, it is unclear whether integrated care by a multidisciplinary team leads to better outcomes than comprehensive care by a single clinician applying an evidence-based AF clinical care algorithm or pathway. Nevertheless, coordination of care among mul- tiple clinicians should also improve care, even though it has not been evaluated rigorously.7

Recommendation-Specific Supportive Text 1. Randomized trials have shown the efficacy of many

individual components of patient-centered care for AF, as discussed earlier in this section. Several randomized and nonrandomized studies have uti- lized comprehensive programs for patients with AF.2,8,9 The RACE 3 (Rate Control versus Electrical cardioversion for persistent atrial fibrillation) trial3 found that multifaceted treatment for patients with AF and early HF (with mineralocorticoid receptor antagonists, statins, ACE inhibitors and/or angio- tensin receptor blockers [ARBs], and cardiac reha- bilitation) improved maintenance of sinus rhythm.

2. Various clinical care pathways, algorithms, and electronic clinical decision support systems for the care of patients with AF have been tested in clinical trials, with mixed results. Care provided by specialty nurses using a clinical support system aimed at enhancing adherence to guideline-directed thera- pies improved cardiovascular outcomes in a single center study4 but not in the subsequent multicenter RACE 4 trial, where results were associated with experience of the center, although adherence to guideline-based recommendations was still greatly improved.10 In a cluster randomized trial of elderly patients with AF where integrated care intervention consisting of (a) quarterly AF check-ups by trained nurses in primary care, also focusing on comorbidi- ties, (b) monitoring of anticoagulation therapy in pri- mary care, and finally (c) easy-access availability of consultations from cardiologists and anticoagula- tion clinics, the patients assigned to integrated care experienced a 45% reduction in all-cause mortality when compared with usual care.11 In another study (SAFETY [Standard versus Atrial Fibrillation spe- cific management study]), a posthospital discharge

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management program specific to AF was associ- ated with proportionately more days alive and out of hospital but not prolonged event-free survival relative to standard management.12 On the other hand, data on technology-based clinical decision support systems are mixed, with a reduction in stroke and thromboembolism in the mAF-App 2 (Mobile Health Technology for Improved Screening and Optimized Integrated Care in Atrial Fibrillation) trial5 and improved anticoagulation use in the CDS-AF (clinical decision support tool for stroke prevention) trial,6 but no significant effect on pri- mary outcomes in 3 other randomized trials.13–15 Educational interventions for both providers and patients can improve use of anticoagulation.16

6. PREVENTION OF THROMBOEMBOLISM 6.1. Risk Stratification Schemes

Recommendations for Risk Stratification Schemes Referenced studies that support the recommendations are summarized in the Online Data Supplement.

COR LOE Recommendations

1 B-NR 1. Patients with AF should be evaluated for their annual

risk of thromboembolic events using a validated clinical risk score, such as CHA2DS2-VASc.1–4

1 B-NR

2. Patients with AF should be evaluated for factors that specifically indicate a higher risk of bleeding, such as previous bleeding and use of drugs that increase bleeding risk, in order to identify possible interven- tions to prevent bleeding on anticoagulation.5–7

2a C-LD

3. Patients with AF at intermediate annual risk of thromboembolic events by risk scores (eg, equiva- lent to CHA2DS2-VASc score of 1 in men or 2 in women), who remain uncertain about the benefit of anticoagulation, can benefit from consideration of factors that might modify their risk of stroke to help inform the decision.*

3: No Benefit

B-NR

4. In patients who are deemed at high risk for stroke, bleeding risk scores should not be used in isolation to determine eligibility for oral anticoagulation but instead to identify and modify bleeding risk factors and to inform medical decision-making.8–10

*Factors may include AF burden or other features in Table 3.

Synopsis Patients with AF have an increased risk of stroke that varies widely among individuals. Several risk scores based on clinical factors have been developed.1–3 Risk scores should be evaluated using accepted criteria11: their ability to discriminate between high- and low-risk individuals (eg, as assessed by the c-index), their accu- rate calibration to actual risk levels, and their validation in independent populations. A patient’s absolute risk of stroke is central to recommendations about anticoagu- lation and can be characterized as low (∼<1%/y), inter- mediate (∼1 to ∼2%/y), and high (∼>2%/y). Currently used risk scores discriminate moderately well between patients at higher and lower risk yet can greatly overes-

timate or underestimate absolute risk levels4 in differ- ent populations. Current risk scores may be inaccurate because they omit other factors that alter risk of stroke, especially characteristics of AF12–14; consequently, risk scores should be calibrated against the actual annual rates of stroke in the target population to assure an ac- curate, unbiased risk prediction. Newer risk scores may modestly improve risk discrimination (c-index) compared with CHA2DS2-VASc and may offer potential advantag- es in specific populations (Table 8). Online calculators are available for the ATRIA (Anticoagulation and Risk Factors in Atrial Fibrillation),1 CHA2DS2-VASc,2 and GARFIELD-AF3 (Global Anticoagulant Registry in the Field-Atrial Fibrillation) risk scores.

Anticoagulation increases the risk of bleeding, so patients with AF are generally evaluated for bleeding risk as part of SDM about anticoagulation. Currently used bleeding risk scores—HAS-BLED (hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile international normalized ratio [INR], elderly [age ≥65 years], drugs/alcohol concomitantly]),5 HEMORR2HAGES (hepatic or renal disease, etha- nol abuse, malignancy, older age [≥75 years], reduced platelet count or function, re-bleeding risk, hypertension [uncontrolled], anemia, genetic factors, excessive fall risk, stroke),6 and ATRIA (anemia, renal disease, elderly [age ≥75 years], any prior bleeding, hypertension)7—discrimi- nate poorly between patients with and without bleed- ing15 and include many nonspecific factors that predict an increased risk of stroke as well as an increased risk of bleeding (eg, age, hypertension, renal disease, and previ- ous stroke). Assessment of factors that specifically pre- dict an increased risk of bleeding without predicting an increased risk of stroke is more helpful when balancing risks and benefits of anticoagulation.

Recommendation-Specific Supportive Text 1. Several risk scores based on clinical factors have

been developed1–3; in general, risk discrimina- tion is improved by including more predictors (eg, CHA2DS2-VASc improved on the original CHADS2

2 [congestive heart failure, hypertension, age >75 years, diabetes, stroke/transient ischemia attack/ thromboembolism] by adding additional risk fac- tors and age categories). However, the absolute risk associated with any particular score level var- ies widely across populations; among 15 cohort studies, patients with a CHA2DS2-VASc score of 2 had annual rates of stroke that ranged from low to high: <1% in 4 cohorts, 1% to 2% in 6 cohorts, and >2% in 5 cohorts,4 although higher scores were associated with higher stroke risk in each cohort (Figure 9). The CHA2DS2-VASc score is consid- ered the most validated score, most therapies have used that score to prove efficacy, and thus CHA2DS2-VASc is generally the preferred score.

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Yet, despite its extensive use, CHA2DS2-VASc has shown suboptimal performance in selected popu- lations, such as those with renal disease, prompt- ing the creation of other scores. Newer risk scores, such as the ATRIA1,16,17 and GARFIELD-AF3,18 scores, modestly improve risk discrimination (c-index) compared with CHA2DS2-VASc, but their calibration and risk reclassification performance has not been as rigorously evaluated. A recent meta-analysis reported that 19 risk scores, 329 external validations, and 76 risk score updates have been conducted to predict ischemic stroke in patients with AF.19 Potential differences of the most studied risk scores are listed in Table 9. Some potential advantages of other scores, for example, the GARFIELD-AF score, includes mortality and bleeding risk to facilitate discussion with patients in a more comprehensive way. Also, when uncer- tainty exists, a score such as GARFIELD-AF adds additional variables to consider, such as smoking status, renal disease, and dementia. This guideline does not intend to preclude the future development of more accurate scores for stratifying patients.

2. Clinical decisions surrounding stroke prevention therapy in patients with AF must balance the risks of ischemic stroke, the risks of bleeding with treat- ment, net clinical benefit, and patient preferences. The most studied bleeding risk scores (HAS-BLED,5 HEMORR2HAGES,6 and ATRIA7) discriminate poorly between patients with and without bleeding20 (c-index 0.58 to 0.59 in a French nationwide study21). These scores are problematic to use in clinical deci- sion-making because they incorporate several clini- cal factors that increase the risks of both stroke and bleeding (eg, age, hypertension, renal disease, and previous stroke), which makes it difficult to balance the benefits and risks of anticoagulation because the same risk factors also predict higher risk of stroke. Consideration of factors that specifically indicate a higher risk of bleeding without predicting higher risk of stroke (eg, previous bleeding, anemia, and certain medications) may better inform decision-making about the balance of benefits and harms expected from anticoagulation. Assessment of risk factors specific for bleeding may suggest interventions to reduce bleeding risk, such as discontinuing antiplate- let medications or nonsteroidal anti-inflammatory medications or the use of LAAO devices.10

3. The decision to treat with OACs for stroke pre- vention in patients with a CHA2DS2-VASc of 1 (CHA2DS2-VASc of 2 in women) may at times require additional discussion with patients as the strength or recommendation is less robust (2a), and often patients might be more reluctant. Also, the 1-point-concept of risk estimation in the subgroup of patients with a CHA2DS2-VASc score of 1 has shown to be simplistic because the magnitude of risk for each factor is heterogeneous and because data have shown a wide range of risk depending on the studied cohort.22 Thus, as part of SDM discus- sions with patients, other factors, such as AF bur- den, can be considered when interpreting a stroke risk score.12–14,23 Additional factors, such as degree of hypertension control, can also affect the risk of stroke; in the ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial, a single elevated BP mea- surement during the study was associated with a 50% increased risk of stroke.23,24 Additional patient- specific risk factors, such as certain biomarkers (eg, proBNP), LA or left atrial appendage (LAA) func- tion and anatomy, or electrocardiographic features, among others, have been demonstrated to influence stroke risk, yet it is unclear how to incorporate them into clinical practice.12 Antithrombotic treatment with DOACs seems to offer a superior net-benefit with regard to prevention of thromboembolic events and the risk of major bleeding compared with vita- min K antagonists (VKAs). Consideration of these

Table 8. Three Validated Risk Models for Stroke

Risk Factor CHA2DS2-VASc2 ATRIA1 GARFIELD3

Age ≥85 y 6 0.98

Age ≥75 y 2 5 0.59

Age 65-74 y 1 3 0.20

Female sex 1 1

Hypertension 1 0.16

Renal disease 1 0.35

Diabetes 1 1 0.21

Current smoking 0.48

Congestive heart failure

1 1 0.23

Previous stroke or TIA 2 2–8* 0.80

Vascular disease 1 0.20

Dementia 0.51

Previous bleeding 0.30

Proteinuria 1

Low risk score 0 0–5 0–0.89

Intermediate risk score 1 6 0.90–1.59

High risk score ≥2 7–15 ≥1.60

C-index (11) 0.63 0.66 -

C-index (13) 0.67 - 0.71

*8 points if age <65 y; 4 points if age 65-74 y; 2 points if age 75-84 y; and 3 points if ≥85 y.

ATRIA indicates Anticoagulation and Risk Factors in Atrial Fibrillation: anemia, renal disease, elderly (age ≥75 y), any previous bleeding, hypertension; CHA2DS2- VASc, indicates congestive heart failure, hypertension, age ≥75 y (doubled), diabetes mellitus, prior stroke or transient ischemic attack or thromboembolism (doubled), vascular disease, age 65 to 74 y, sex category; GARFIELD-AF, Global Anticoagulant Registry in the Field-Atrial Fibrillation; and TIA, transient ischemic attack.

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additional factors may inform decision-making for patients with an intermediate risk of stroke who remain uncertain on deciding anticoagulation.

4. Unless an absolute contraindication to antico- agulation is present, bleeding risk scores have limitation in clinical decision-making because the most commonly used scores (HAS-BLED,5 HEMORR2HAGES,6 and ATRIA7) are based on several clinical factors that indicate higher risks of both stroke and bleeding, and patients with higher risk of bleeding also tend to have a higher risk of stroke. Furthermore, a bleeding risk score can- not be interpreted in isolation because it does not assess the net clinical benefit of anticoagulation or balance the risk of bleeding against the risk of stroke. Population-based studies suggest that the benefits of stroke prevention with oral anticoagula- tion generally outweigh the risks of bleeding, even in patients determined to be at high risk for bleed- ing.8,9 Decision-making about oral anticoagulation should be based on consideration of both benefits

and harms, not by using bleeding risk scores in iso- lation, and the best utility of these scores may be identifying potential modifying risk factors.8,9

6.2. Risk-Based Selection of Oral Anticoagulation: Balancing Risks and Benefits

Recommendations for Risk-Based Selection of Oral Anticoagulation: Balancing Risks and Benefits Referenced studies that support the recommendations are summarized in the Online Data Supplement.

COR LOE Recommendations

1 B-R

1. In patients diagnosed with AF who have an estimated annual risk of stroke or thromboembolic events ≥2%, selection of therapy to reduce the risk of stroke should be based on the risk of thromboembolism, regardless of whether the AF pattern is paroxysmal, persistent, long-standing persistent, or permanent.1–3

1 B-NR

2. In patients with AF at risk for stroke, reevaluation of the need for and choice of stroke risk reduction therapy at periodic intervals is recommended to reassess stroke and bleeding risk, net clinical benefit, and proper dosing.4,5

Figure 9. Rates of Stroke by Stroke Risk Score Levels in Different Cohorts. Overall stroke rate in atrial fibrillation cohorts in order of descending stroke rate (events per 100 person-years). Reproduced with permission from Quinn et al.4 Copyright 2017 American Heart Association, Inc.

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Synopsis Prevention of stroke is important in patients with AF to maximize survival, health, and QOL. Selection of stroke risk reduction therapy should be guided by the patient’s risk of stroke, risks of bleeding with therapy, and their individual preferences. When considering stroke preven- tion therapy, the risk of stroke should inform the decision regardless of the pattern of AF (paroxysmal, persistent, long-standing persistent, or permanent). All decisions re- garding stroke prevention therapy should be periodically reassessed since a patient’s risk, eligibility, and prefer- ences can change over time.

Recommendation-Specific Supportive Text 1. Although the risk of stroke and systemic embolism

and all-cause mortality are increased in persons with more persistent forms of AF, selection of stroke pre- vention therapy should be based on the risk of stroke and not the pattern of AF. Treatment effects with oral anticoagulation are consistent across AF patterns (paroxysmal, persistent, long-standing persistent, or permanent) in trials of stroke prevention therapy.1–3

2. AF is a lifelong condition and, thus, patient char- acteristics, risk factors, and net clinical benefit can and often will change over time.4 In long-term follow-up, stroke risk increases due to age and

accumulation of other risk factors.6 Physiologic factors that impact stroke prevention therapy also change over time and can have important impli- cations for proper medication dosing and patient safety.5 Typically, periodic assessment should be performed once a year but might need to be per- formed more frequently in the context of changes in clinical status, such as reduction in renal function or development of additional risk factors.

6.3. Oral Anticoagulants Vitamin K Antagonists Since the 1950s, warfarin was used as a first-line ther- apy until DOACs came into practice. A narrow thera- peutic window based on international normalized ratios (INRs), frequent monitoring, more frequent drug inter- actions (mainly through CYP2C9), dietary restrictions, and low clinical safety profile affected the routine use of warfarin in practice. Because of affordability issues of DOACs for some patients with AF, warfa- rin is still an appropriate OAC due to its lower cost for patients who cannot afford DOACs. About 21% of patients with nonvalvular AF were still receiving war- farin, while the rest received DOACs in the first quar- ter of 2017.1 Warfarin remains the first-line therapy in

Table 9. Some Best Known Published Clinical Scores With Potential Advantages

Year of Publication, Score Name Score Components Potential Advantages

No. of Validation Studies19

Hyperlink to Online Score Calculator, if Available

2001 CHADS2

CHF, hypertension, age (≥65 y is 1 point, ≥75 y is 2 points), diabetes, stroke/TIA (2 points)

CHADS2 was superior to existing risk classification schemes AFI scheme: C-statistic, 0.68 (0.65–0.71) SPAF-III scheme: C-statistic, 0.74 (0.71–0.76) CHADS2 score: C-statistic, 0.82 (0.80–0.84)

46 https://www.mdcalc.com/calc/40/ chads2-score-atrial-fibrillation- stroke-risk

2010 CHA2DS2-VASc2

CHF, hypertension, age ≥75 y, diabetes, stroke or TIA, vascular disease, age 65–74 y, female sex

Most commonly used and studied, superior to CHADS2 score. C-statistic, 0.606 (0.513–0.699) for CHA2DS2-VASc score vs 0.561 (0.450–0.672) for CHADS2 score Improved compared with original CHADS2 score

82 https://www.mdcalc.com/ calc/801/cha2ds2-vasc-score- atrial-fibrillation-stroke-risk#next- steps

2013 ATRIA1

Age (65–74 y is 3 points, 75–84 y is 5 points, ≥85 y is 6 points), hypertension, diabetes, CHF, proteinuria, GFR <45 mL/ min/1.73 m2, sex

Includes more age categories, renal function, and proteinuria More patients were classified as low or high risk but not as well tested in general.

11 https://www.mdcalc.com/ calc/1842/atria-stroke-risk-score

2017 GARFIELD-AF3

Web-based, uses routinely collected clinical data, and includes a total of 16 questions

Web-based tool for predicting stroke and mortality, includes the effect of the different anticoagulants, bleeding risk and mortality to facilitate shared decision-making on the potential benefits/risks of anticoagulation

4 https://af.garfieldregistry.org/ garfield-af-risk-calculator

2016 MCHA2DS2-VASc26

Expanded lower threshold for age to 50 y (1 point for age 50–74 y)

Validated in Asian cohort Can further identify Asian AF patients who may derive benefits from stroke prevention. In 1 study, MCHA2DS2-VASc was superior to CHA2DS2-VASc C-statistics = 0.708 (0.703–0.712) vs 0.689 (0.684–0.694)

ATRIA indicates Anticoagulation and Risk Factors in Atrial Fibrillation: anemia, renal disease, elderly (age ≥75 y), any previous bleeding, hypertension; CHADS2, congestive heart failure, hypertension, age >75 y, diabetes, stroke/transient ischemia attack/thromboembolism; CHA2DS2-VASc, indicates congestive heart failure, hy- pertension, age ≥75 y (doubled), diabetes mellitus, prior stroke or transient ischemic attack or thromboembolism (doubled), vascular disease, age 65 to 74 y, sex category; CHF, congestive heart failure; GARFIELD-AF, Global Anticoagulant Registry in the Field-Atrial Fibrillation; GFR, glomerular filtration rate; SPAF-III, stroke prevention atrial fibrillation, and TIA, transient ischemic attack.

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patients with AF and moderate-severe rheumatic mi- tral stenosis or mechanical heart valves. Clinical stud- ies show that the target INR is between 2 and 3, and risk of bleeding becomes mostly apparent when INR exceeds 4. OAC use in special populations will be dis- cussed in separate sections.

Direct oral anticoagulants DOACs were developed to address the disadvantages of warfarin and are currently recommended as the first-line therapy over warfarin in patients with AF (except moderate to severe mitral stenosis or mechanical heart valve recipi- ents) in this guideline. All 4 pivotal clinical trials compar- ing individual DOACs (apixaban, dabigatran, edoxaban, and rivaroxaban) with warfarin showed superiority or noninfe- riority to warfarin for the prevention of stroke or systemic embolism in patients with AF except for moderate to se- vere mitral stenosis or mechanical heart valve.2–5 They also showed significantly lower risks of major bleeding in the apixaban, dabigatran 110 mg twice daily group, and edoxa- ban 30 mg or 60 mg daily dose groups compared with the warfarin group or nonsignificant differences in major bleed- ing between dabigatran 150 mg twice daily group or the rivaroxaban group and warfarin. All DOAC groups showed significantly lower risks of intracranial hemorrhage (ICH) compared with warfarin. Gastrointestinal bleeding risks were significantly higher in the dabigatran 150 mg twice daily, edoxaban 60 mg once daily, and rivaroxaban groups compared with the warfarin group. However, the apixaban group did not significantly increase the risk of gastrointes- tinal bleeding compared with the warfarin group.

6.3.1. Antithrombotic Therapy Recommendations for Antithrombotic Therapy Referenced studies that support the recommendations are summarized in the Online Data Supplement.

COR LOE Recommendations

1 A

1. For patients with AF and an estimated annual thromboembolic risk of ≥2% per year (eg, CHA2DS2-VASc score of ≥2 in men and ≥3 in women), anticoagulation is recommended to prevent stroke and systemic thromboembolism.1–7

1 A

2. In patients with AF who do not have a history of moderate to severe rheumatic mitral stenosis or a mechanical heart valve, and who are candidates for anticoagulation, DOACs are recommended over warfarin to reduce the risk of mortality, stroke, systemic embolism, and ICH.1–7

2a A

3. For patients with AF and an estimated annual thromboembolic risk of ≥1% but <2% per year (equivalent to CHA2DS2-VASc score of 1 in men and 2 in women), anticoagulation is reasonable to prevent stroke and systemic thromboembolism.1,3

3: Harm

B-R

4. In patients with AF who are candidates for antico- agulation and without an indication for antiplatelet therapy, aspirin either alone or in combination with clopidogrel as an alternative to anticoagulation is not recommended to reduce stroke risk.8,9

3: No Benefit

B-NR 5. In patients with AF without risk factors for stroke,

aspirin monotherapy for prevention of thromboem- bolic events is of no benefit.10,11

Synopsis A high risk for stroke or systemic embolism is about 2% per year, and all the DOAC trials (Re-LY [Random- ized Evaluation of Long-Term Anticoagulation Thera- py]; ROCKET AF [Rivaroxaban Once Daily Oral Direct

Table 10. Risk Factor Definitions for CHA2DS2-VASc Score as in the Original Article2

C Heart Failure The presence of signs and symptoms of either right (elevated central venous pres- sure, hepatomegaly, dependent edema) or left ventricular failure (exertional dyspnea, cough, fatigue, orthopnea, paroxysmal noc- turnal dyspnea, cardiac enlargement, rales, gallop rhythm, pulmonary venous conges- tion) or both, confirmed by noninvasive or invasive measurements demonstrating ob- jective evidence of cardiac dysfunction

H Hypertension A resting blood pressure >140 mm Hg systolic and/or >90 mm Hg diastolic on at least 2 occasions or current antihyperten- sive pharmacological treatment

A2 Age, additional risk/ point

Age ≥75 y

D Diabetes Fasting plasma glucose level ≥7.0 mmol/L (126 mg/dL) or treatment with hypoglycemic agent and/or insulin

S2 Thromboembolism Either an ischemic stroke, transient isch- emic attack, peripheral embolism, or pul- monary embolism

V Vascular Disease Coronary artery disease (prior myocardial infarction, angina pectoris, percutaneous coronary intervention, or coronary artery bypass surgery) or peripheral vascular disease (the presence of any of the fol- lowing: intermittent claudication, previous surgery or percutaneous intervention on the abdominal aorta or the lower extremity vessels, abdominal or thoracic vascular surgery, arterial and venous thrombosis)

A Age standard risk/ weight

Age 65–74 y

Sc Sex Category Female sex

Table 11. Additional Risk Factors That Increase Risk of Stroke Not Included in CHA2DS2-VASc

Higher AF burden/Long duration

Persistent/permanent AF versus paroxysmal

Obesity (BMI, ≥30 kg/m2)

HCM

Poorly controlled hypertension

eGFR (<45 mL/h)

Proteinuria (>150 mg/24 h or equivalent)

Enlarged LA volume (≥73 mL) or diameter (≥4.7 cm)

AF indicates atrial fibrillation; BMI, body mass index; eGFR, estimated glomeru- lar filtration rate; HCM, hypertrophic cardiomyopathy; and LA, left atrium.

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Factor Xa Inhibition Compared with Vitamin K Antag- onism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation]; ARISTOTLE; and ENGAGE AF-TIMI 48 [Effective Anticoagulation with Factor Xa Next Gen- eration in Atrial Fibrillation – Thrombolysis in Myocar- dial Infarction 48]) included patients with this level of risk.1–4 Patients at intermediate risk (1%-2%/y) can also benefit from anticoagulation, and the RE-LY1 and ARISTOTLE3 trials included this population. Stroke risk scores applied to cohorts give different stroke rates, and therefore any score should be viewed as only an estimate of true risk; in addition some scores used stroke, while others used thromboembolic events. Nonetheless, it is practical to use a validated risk score, such as CHA2DS2-VASc, ATRIA, or GARFIELD-AF. Fu- ture research may yield improved risk scores that refine how to incorporate risk modifiers, such as female sex12 and other parameters such as AF burden. Anticoagula- tion has also been shown to be superior to antiplatelet therapy to reduce stroke risk.8,9 Recommendations for

antithrombotic selection in valvular heart disease (VHD) are provided in Section 6.8.5 (“AF in VHD”) and for AFL in Section 6.8.6 (Figure 10).

Recommendation-Specific Supportive Text 1. Randomized trials published in the 1990s estab-

lished the superiority of anticoagulation, at that time limited to warfarin, to reduce stroke.11 Since that time, management has advanced considerably, and the randomized trials that compared DOACs with warfarin1–4 are more relevant to current anti- thrombotic management. In these trials1–4 and metanalyses,5–7 DOACs were favored for lower risk of stroke, systemic embolism, and ICH.1–7 These trials reported the CHADS2 score. The recently studied ATRIA and Swedish cohorts13,14 reported lower stroke rates, by CHADS2 score, compared with that previously reported.15 A CHADS2 score of 1 gave a stroke rate of 1.20 in ATRIA14 and 2.4 in a Swedish cohort.13 A CHADS2 score of 2

Table 12. Thromboembolic Event Rates by Point Score for ATRIA, CHADS2, and CHA2DS2-VASc Risk Scores*

ATRIA CHADS2† CHA2DS2-VASc‡

Points Events Person-Years Rate per 100 Person-Years Events Person-Years

Rate per 100 Person-Years Events Person-Years

Rate per 100 Person-Years

0 2 2652 0.08 22 6126 0.36 1 2493 0.04

1 12 2819 0.43 121 10 084 1.20 21 3806 0.55

2 14 1419 0.99 253 9757 2.59 46 5560 0.83

3 13 1780 0.73 178 4782 3.72 121 7305 1.66

4 19 2960 0.64 81 1309 6.19 193 6898 2.80

5 36 3614 0.99 19 450 4.23 175 4057 4.31

6 83 4346 1.91 11 101 10.84 85 1783 4.77

7 119 4768 2.50 — — — 24 498 4.82

8 151 3913 3.86 — — — 14 179 7.82

9 104 2400 4.33 — — — 5 30 16.62

10 75 1181 6.35 — — — — — —

11 31 501 6.18 — — — — — —

12 20 183 10.95 — — — — — —

13 4 53 7.52 — — — — — —

14 2 12 16.36 — — — — — —

15 0 7 0 — — — — — —

All 685 32 609 2.10 — — — — — —

Reproduced with permission from Singer et al.1 Copyright 2013 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley-Blackwell. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

*Black lines identify thresholds for low-, moderate-, and high-risk categories for the 3 stroke risk point scores using published cut points.8,9

†The CHADS2 score assigns points as follows: 1 point each for the presence of congestive heart failure, hypertension, age ≥75 y, and diabetes mellitus and 2 points for history of stroke/transient ischemic attack.

‡The CHA2DS2-VASc score assigns points as follows: 1 point each for congestive heart failure/left ventricular dysfunction, hypertension, diabetes mellitus, vascular disease, age 65 to 74 y, and female sex, and 2 points each for age ≥75 y and stroke/transient ischemic attack/thromboembolism.

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gave a stroke rate of 2.59 in ATRIA14 and 3.5 in the Swedish cohort.13 Therefore, the stroke risk of patients in the rivaroxaban2 and edoxaban4 trials was likely >2% given a required minimum CHADS2 score of 2, and lower in the apixaban3 and dabigatran1 trials that included scores of 0 and 1. A Markov state transition decision model16 concluded that anticoagulation was preferred for a stroke rate of 1.7%. Therefore, a stroke and sys- temic embolism risk threshold of 2% is likely to yield a benefit that far exceeds risk. In some con- ditions, such as hypertrophic cardiomyopathy, the risk of stroke is high enough independent of risk score to indicate anticoagulation.17

2. In the randomized DOAC trials, all DOACs achieved noninferiority1–4 and in 2 trials (for dabi- gatran, RE-LY, and for apixaban, ARISTOTLE) were superior to warfarin. With warfarin, regular assessment of the INR is necessary to maintain a therapeutic value. In the RCTs, the mean time in therapeutic range was only 55% in ROCKET AF2 and highest at 66% in ARISTOTLE.3 In a meta- analysis,6 DOACs, compared with warfarin, had a relative risk of stroke of 0.81 (95% CI, 0.73-0.91; P<0.0001), a relative risk of mortality of 0.90 (95% CI, 0.85-0.95; P=0.0003), relative risk of ICH of 0.48 (95% CI, 0.39-0.59; P<0.0001), and increased relative risk of bleeding of 1.25 (95% CI, 1.01-1.55; P=0.043). Although patients with moderate to severe mitral stenosis or mechani- cal valve were excluded from DOAC trials (and

subsequently shown they may have worse out- comes with DOACS), other forms of VHD were allowed, such as aortic stenosis or regurgitation or mitral regurgitation. Bioprosthetic valves and valve repair were allowed in the edoxaban (ENGAGE AF) and apixaban (ARISTOTLE) trials, and valve repair in the rivaroxaban (ROCKET AF) trial. A sys- tematic review18 of patients with VHD (other than mitral stenosis or mechanical valve) concluded that DOACs were safe.

3. As the DOAC trials1–4 demonstrated improved safety compared with warfarin, the threshold of using a DOAC might be different than for warfarin.16 A Markov decision model found the tipping point for warfarin to be at 1.7%/year stroke risk.16 Considering the improved ICH and mortality risk of DOACs compared with warfa- rin in meta-analyses of the DOAC trials,5–7 it is appropriate to designate a lower stroke risk threshold if a DOAC is utilized. The dabigatran1 and apixaban3 trials included lower risk patients and about one-third of patients had a CHADS2 score of 0 or 1. This likely corresponds to an estimated annual stroke risk of about 1%, con- sidering more recent cohorts.13,14 This is further supported by meta-analyses that showed a con- sistent benefit of DOACs across a broad range of vulnerable patients, including as classified by CHADS2 scores.6,7

4. A meta-analysis of AF trials from the 1990s and early 2000s found that while antiplatelet ther- apy (APT), most commonly aspirin, reduced stroke and systemic embolism compared with placebo, APT was inferior to warfarin in patients with AF.11 Aspirin was studied compared to apixaban in the AVERROES trial (Apixaban Versus ASA to Prevent Stroke In AF Patients Who Have Failed or Are Unsuitable for Vitamin K Antagonist Treatment)9 for patients unsuit- able for VKAs; this trial was stopped early due to the benefit of apixaban over aspirin to pre- vent stroke or systemic embolism, while major bleeding was similar between the 2 arms. The combination of clopidogrel and aspirin was com- pared to VKAs in ACTIVEW (Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events),8 and this trial was stopped prematurely due to the superiority of anticoagu- lation with VKAs to prevent stroke, non–central nervous system systemic embolus, MI, or vas- cular death. Unless there is an indication for antiplatelet therapy, such as coronary artery dis- ease (CAD) or vascular disease, patients with AF should not be prescribed antiplatelet therapy to reduce stroke risk.

Figure 10. Antithrombotic Options in Patients With AF. Colors correspond to Table 2. AF indicates atrial fibrillation; and DOAC, direct oral anticoagulant.

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5. Aspirin therapy was compared with no treatment in patients with low stroke risk in a multicenter RCT in Japan, the Japan Atrial Fibrillation Stroke Trial.10 This trial was stopped early when an interim analysis showed that aspirin gave a marginally higher risk of major bleeding and was unlikely to prevent primary or secondary endpoints. The primary endpoint was noncardiovascular death, ICH, major bleeding, and peripheral embolization. A meta-analysis of 7 trials that studied aspirin versus placebo found that aspirin reduced stroke by 19%, which did not reach statisti- cal significance with a CI that included 0 (–1% to 35%). Four of these were primary prevention trials and showed an absolute risk reduction with aspirin of 0.8% per year, with a number needed to treat of 125.11 Although aspirin has not been studied in patients without any risk factors for stroke, patients without stroke risk may derive no benefit from aspi- rin therapy. In fact, 1 study that analyzed stroke mechanisms in the SPAF (Stroke Prevention in Atrial Fibrillation) I-III trials demonstrated that aspirin did not decrease the rate of cardioembolic stroke and that AF patients at highest risk for stroke are those with the highest rates of cardioembolic stroke and have the greatest reduction in stroke with anticoagu- lants.19 Thus, modest reduction in stroke observed in some trials may have been related to noncardioem- bolic stroke in patients with additional risk factors.

6.3.1.1. Considerations in Managing Anticoagulants Recommendations for Considerations in Managing Anticoagulants Referenced studies that support the recommendations are summarized in the Online Data Supplement.

COR LOE Recommendations

1 C-LD

1. For patients with AF receiving DOACs, optimal man- agement of drug interactions is recommended for those receiving concomitant therapy with interacting drugs, especially CYP3A4 and/or p-glycoprotein inhibitors or inducers (Table 13).1–7

1 B-R

2. For patients with AF receiving warfarin,* a target INR between 2 and 3 is recommended, as well as optimal management of drug-drug interactions, consistency in vitamin K dietary intake, and routine INR monitoring to improve time in therapeutic range and to minimize risks of preventable thromboembolism or major bleed- ing.8–10

3: Harm

B-NR

3. For patients with AF, nonevidence-based doses of DOACs should be avoided to minimize risks of pre- ventable thromboembolism or major bleeding and to improve survival.11,12

*Excludes patients with mechanical valves.

Synopsis Multiple factors need to be considered to select an optimal OAC in patients with AF. Efficacy, safety, in- surance coverage, renal/hepatic function, drug inter- action screening, medication adherence, and patient preferences are the major factors for consideration.

Dosing of DOACs in patients with AF should be se- lected based on age, renal function, weight, and con- comitant medications. The hepatic function also needs to be evaluated for the appropriateness of DOACs. Characteristics and dosing of OACs are summarized in Table 13. Although DOAC drug interactions occur in practice less frequently than with warfarin, clinically significant drug interactions through CYP3A4 and/or p-glycoprotein should be carefully evaluated. Strong CYP3A4 and/or p-glycoprotein inhibitors such as ke- toconazole, itraconazole, and ritonavir may significantly increase DOAC plasma levels and the risk of bleeding, while strong CYP3A4 and/or p-glycoprotein inducers such as rifampin, phenytoin, phenobarbital, primidone, carbamazepine, or St. John’s wort may lower DOAC plasma levels and increase the risks of stroke or sys- temic embolism. The routine measurement of DOAC plasma concentrations is not indicated in practice due to the lack of well-established therapeutic ranges in the literature. DOAC levels may be indicated when cli- nicians assess DOAC adherence for potentially non- compliant patients, quantify residual anticoagulation levels before emergency invasive procedures/surger- ies, or evaluate the absorption of DOAC after bariatric surgery. Regular monitoring is recommended to opti- mize indications, ensure appropriate dosing, and avoid adverse effects. Suggested laboratory monitoring is summarized in Figure 11.

If warfarin is selected over DOACs, achievement of higher time in therapeutic range (eg, ≥70%), and thor- ough consideration of drug-drug interactions, vitamin K food intake advice, and patient education on adherence to dosing instructions are important to reduce adverse effects.

Recommendation-Specific Supportive Text 1. Rivaroxaban is contraindicated for patients receiving

ketoconazole or ritonavir, because ketoconazole or ritonavir coadministration significantly increased riva- roxaban plasma levels by 158% or 153%, respec- tively.1 Apixaban also requires dose adjustment to 2.5 mg twice daily for patients receiving apixaban 5 mg twice daily when ketoconazole, itraconazole, or ritonavir is started.13 Apixaban plasma level was significantly increased by 99% when ketoconazole was coadministered in healthy subjects.2 The con- comitant therapy of dronedarone or ketoconazole for patients with creatinine clearance (CrCl) 30 to 50 mL/min receiving dabigatran requires dose adjustment to dabigatran 75 mg twice daily because it produced comparable dabigatran exposure in patients with CrCl 30 to 50 mL/min receiving the concomitant therapy to patients with CrCl 15 to 29 mL/min receiving only dabigatran.14 A retrospective study revealed that the probability of patients with

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(Continued )

Table 13. OACs Pharmacokinetic Characteristics and Dosing

Class VKA Direct Thrombin Inhibitor Factor Xa Inhibitor

Name Warfarin Dabigatran Rivaroxaban Apixaban Edoxaban

Metabolism S-isomer: CYP2C9 R-isomer: CYP1A2, CYP2C19, CYP3A4

Minimal CYP3A4/5 CYP3A4 Minimal CYP3A4

P-glycoprotein substrate No Yes Yes Yes Yes

Excretion 0% renal; very little warfarin excreted unchanged in urine

80% renal 66% renal, 28% feces 27% renal, 73% biliary and intestinal

50% renal, 50% liver and biliary/intestinal

Half-life 20-60 h 12-17 h 5-9 h 12 h 10-14 h

Renal dosing adjustment based on actual body weight

N/A CrCl >30 mL/min

150 mg twice daily

CrCl >50 mL/min

20 mg daily with the biggest meal*

5 mg twice daily

CrCl >50– ≤95 mL/ min

60 mg once daily

CrCl 15- 30 mL/ min

75 mg twice daily

CrCl 15-50 mL/ min

15 mg daily with the biggest meal*

If any 2 of the following: age ≥80y, body weight ≤60 kg, SCr ≥1.5 mg/dL

2.5 mg twice daily

CrCl 15- 50 mL/ min

30 mg once daily

Drug interaction management based on concomitant therapy of CYP3A4 inhibitors/ p-glycoprotein inhibitors

Adjust dose based on INR trends

CrCl 30-50 mL/min with concomitant use of dronedarone or systemic ketocon- azole: 75 mg twice daily CrCl <30 mL/min: avoid dabigatran use concomitantly with dronedarone or sys- temic ketoconazole

Avoid rivaroxaban use with concomitant therapy of combined p-glycoprotein and strong CYP3A4 in- hibitors (eg, systemic ketoconazole and ritonavir) No dose adjustment required with clarithro- mycin Avoid rivaroxaban use in patients with CrCl 15–<80 mL/min receiving combined p-glycoprotein and moderate CYP3A4 inhibitors (eg, erythro- mycin)

In patients receiv- ing apixaban 5 mg twice daily, reduce dose to 2.5 mg twice daily when combined p-glycoprotein and strong CYP3A4 inhibitors (eg, itra- conazole, systemic ketoconazole, rito- navir) are used con- comitantly If patients already receiving apixaban 2.5 mg twice daily, avoid apixaban use if combined p-glyco- protein and strong CYP3A4 inhibitors are concomitantly used

No dose adjustment is required

Drug interaction management based on concomitant therapy of p-glycoprotein/ CYP3A4 inducers (eg, carbamazepine, phenytoin, rifampin, St. John’s wort)

Adjust dose based on INR trends

Avoid use Avoid use Avoid use Avoid use with rifampin. No study evaluated the effect of other p-glycopro- tein/CYP3A4 induc- ers on edoxaban drug levels

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subreference DOAC levels was significantly higher in patients receiving antiepileptic drugs compared to those not receiving any CYP3A4 inducers.4 The claim-based retrospective cohort study showed that CYP-inducing antiepileptic drug use was sig- nificantly associated with an 86% increase in throm- boembolic and ischemic adverse events in patients receiving DOACs.6 A prospective multicenter cohort study corroborated that the patients receiving con- comitant therapy of DOACs and antiepileptic drugs developed a higher rate of stroke/TIA/systemic embolism (5.7% patient-year).7

2. Warfarin remains the preferred agent in patients with AF receiving CYP3A4/p-glycoprotein–induc- ing agents, or moderate-severe mitral stenosis or mechanical heart valve. Also, warfarin may be selected over DOACs in patients with AF due to higher cost or intolerances of DOACs. The optimal INR control, with a therapeutic INR goal of 2 to 3, needs to be achieved through the appropriate drug-drug interaction man- agement, vitamin K dietary education, and routine INR monitoring. A systematic review of 47 studies found that time in therapeutic INR range showed negative correlation with risks of thromboembolism (R, –0.59; P=0.01) and major bleeding (R, –0.59; P=0.002).8 An RCT revealed that a weekly vitamin K dietary modification significantly achieved a therapeutic INR more frequently than a conventional group (74 ver- sus 58%; P=0.04) at 90 days after randomization.9 A meta-analysis of 11 RCTs and 61 observational studies for warfarin drug interactions found that the concomitant use of APT (odds ratio [OR], 1.74 [95% CI, 1.56-1.94]), nonsteroidal anti-inflammatory drugs (OR, 1.83 [95% CI, 1.29-2.59]), selective serotonin reuptake inhibitors (OR, 1.62 [95% CI, 1.42-1.85]), or antimicrobial agents (OR, 1.63 [95% CI, 1.45-1.83]) was significantly associated with higher risks of clini- cally relevant bleeding.10

3. A significant number of patients with nonvalvu- lar AF are receiving DOAC off-label doses not compliant with labeling.15–18 A meta-analysis of cohort studies showed that inappropriately lower DOAC doses are significantly associated with higher stroke or systemic embolism risks com- pared with the standard labeled doses (OR, 1.21 [95% CI, 1.02-1.43]; P=0.03), but no significant differences in bleeding risks were observed (OR, 1.03 [95% CI, 0.92-1.15]; P=0.62).11 Of note, 9 of 16 included studies were performed in Asia, while 4 studies in the United States, 2 studies in Europe, and 1 worldwide study were included. Another meta-analysis of observational studies found that inappropriately higher DOAC doses were significantly associated with higher risks of ischemic stroke/systemic embolism (hazard ratio [HR], 1.26 [95% CI, 1.11-1.43]; P=0.003) or major bleeding (HR, 1.30 [95% CI, 1.04-1.62]; P=0.025) compared with the standard doses.12 In this study, underdosing was also associated with a higher risk of net clinical outcome (HR, 1.19 [95% CI, 1.04-1.40]; P=0.04) and all-cause death (HR, 1.24 [95% CI, 1.04-1.48]; P=0.02). Off-label dos- ing should be avoided to optimize the efficacy and safety of DOACs.

6.4. Silent AF and Stroke of Undetermined Cause

Recommendation for Silent AF and Stroke of Undetermined Cause Referenced studies that support the recommendation are summarized in the Online Data Supplement.

COR LOE Recommendation

2a B-R

1. In patients with stroke or TIA of undetermined cause, initial cardiac monitoring and, if needed, extended monitoring with an implantable loop recorder are reasonable to improve detection of AF.1

Table 13. Continued

Class VKA Direct Thrombin Inhibitor Factor Xa Inhibitor

Name Warfarin Dabigatran Rivaroxaban Apixaban Edoxaban

Appropriate use based on liver function (Child-Pugh score)† Child-Pugh A (mild)

Not mentioned in the labeling

No dose adjustment needed

Child-Pugh B (moderate) Use with caution Avoid use Use with caution Use with caution

Child-Pugh C (severe) Avoid use Avoid use Avoid use Avoid use

*The effect of food (high-fat, high-calorie meal) on bioavailability for 10- and 20-mg tablet was evaluated in 24 subjects under fed and fasting conditions. After a single oral 20-mg dose, area under the curve was increased by 39%, and Cmax was increased by 76% under fed condition, but area under the curve and Cmax were similar between fasting and fed conditions.19

†Child-Pugh scoring: the severity of liver disease, primarily cirrhosis. Child-Pugh A (mild): 5 to 6 points; Child-Pugh B (moderate): 7 to 9 points; Child-Pugh C (severe): 10 to 15 points. The score is based on the 5 variables: encephalopathy (none=1 point, grade 1 and 2=2 points, grade 3 and 4=3 points); ascites (none=1 point, slight=2 points, moderate=3 points); total bilirubin (<2 mg/mL=1 point, 2-3 mg/mL=2 points, >3 mg/mL=3 points); albumin (>3.5 mg/mL=1 point, 2.8-3.5 mg/mL=2 points, <2.8 mg/mL=3 points); INR (<1.7=1 point, 1.7-2.2=2 points, >2.2=3 points).

CrCl indicates creatinine clearance; INR, international normalized ratio; OAC, oral anticoagulant; Scr, serum creatinine; and VKA, vitamin K antagonist.

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Figure 11. DOAC Laboratory Monitoring. *HAS-BLED scoring (low risk=score 0, moderate risk=score 1-2, high risk=score ≥3): uncontrolled hypertension (systolic blood pressure >160 mm Hg)=1 point; abnormal renal (serum creatinine >2.26 mg/dL, dialysis, or kidney transplant) or hepatic function (bilirubin >2 times upper limit normal, alanine aminotransferase/aspartate aminotransferase/alkaline phosphatase >3 times upper limit normal, or cirrhosis)=1 or 2 points; stroke (hemorrhagic or ischemic)=1 point; bleeding history or predisposition=1 point; labile INR (time in therapeutic range <60%)=1 point; elderly age ≥65 years=1 point; drugs (antiplatelet agents or nonsteroidal anti-inflammatory drugs) or excessive alcohol intake (8 units/week)=1 or 2 points. †Child-Pugh scoring: the severity of liver disease, primarily cirrhosis in patients with documented liver disease. Child-Pugh A (mild): 5 to 6 points; Child-Pugh B (moderate): 7 to 9 points; Child-Pugh C (severe): 10 to 15 points. The score is based on the 5 variables: encephalopathy (none=1 point, grade 1 and 2=2 points, grade 3 and 4=3 points); ascites (none=1 point, slight=2 points, moderate=3 points); total bilirubin (<2 mg/mL=1 point, 2-3 mg/mL=2 points, >3 mg/mL=3 points); albumin (>3.5 mg/mL=1 point, 2.8-3.5 mg/mL=2 points, <2.8 mg/mL=3 points); INR (<1.7=1 point, 1.7-2.2=2 points, >2.2=3 points). Original figure created by the 2023 Atrial Fibrillation Guideline Writing Committee. CrCL indicates creatinine clearance based on actual body weight; DOAC, direct oral anticoagulant; and INR, international normalized ratio.

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Synopsis Approximately 25% to 30% of ischemic strokes re- main cryptogenic after standard stroke evaluation.2,3 A large proportion of these events are presumed to be related to occult AF, particularly those of embolic appearance.4,5 APT is the recommended treatment of choice for patients with cryptogenic stroke, including embolic stroke of undetermined source.6,7 For patients with AF in general, however, anticoagulation has been shown to be superior to APT for stroke risk reduction.8 Thus, detection of occult AF after stroke may have significant therapeutic implications. Randomized tri- als have shown longer durations of cardiac monitoring result in higher rates of AF detection after stroke.1,9,10 However, data are limited regarding the effects of extended monitoring on risk reduction of recurrent stroke or poststroke mortality. For recommendations on anticoagulation and risk factors, refer to Section 6.4.1 (“Oral Anticoagulants”).

Recommendation-Specific Supportive Text 1. Growing evidence supports the use of extended

cardiac monitoring for the identification of occult AF in patients with cryptogenic stroke.11,12 In the EMBRACE (30 Day Event Monitoring Belt for Recording Atrial Fibrillation After a Cerebral Ischemic Event) trial, which randomized 572 patients ≥55 years of age with recent crypto- genic stroke or TIA to either 30-day external loop recorder or conventional 24-hour Holter monitoring, extended monitoring was associ- ated with higher rates of AF detection at 90 days.1The CRYSTAL-AF (Cryptogenic Stroke and Underlying AF) trial randomized 441 patients ≥40 years of age with recent cryptogenic stroke or TIA to cardiac monitoring with either insertable loop recorder or conventional follow-up ECGs. Implantable recorder was superior in detecting AF at 6 months (8.9% versus 1.4%), 12 months (12.4% versus 2.0%), and 3 years (30% versus 3%).9 In FIND-AF (Future Innovations in Novel Detection of Atrial Fibrillation), which compared repeated sets of 10-day Holter monitoring (at baseline, 3-month, and 6-month timepoints) to conventional 24-Holter in patients ≥60 years of age with recent stroke, higher rates of detection were associated with repeated monitoring (14% versus 5%; absolute difference, 9.0% [95% CI, 3.4-14.5]; P=0.002).10 Finally, the PER DIEM (Post-Embolic Rhythm Detection with Implantable vs External Monitoring) RCT also showed a sig- nificantly greater proportion of patients with AF detected at 1 year with prolonged monitor- ing.13 Additional studies are needed, however, to determine whether extended cardiac monitoring improves long-term poststroke outcomes.

6.4.1. Oral Anticoagulation for Device-Detected Atrial High-Rate Episodes Among Patients Without a Previous Diagnosis of AF

Recommendations for Oral Anticoagulation for Device-Detected Atrial High-Rate Episodes Among Patients Without a Previous Diagnosis of AF Referenced studies that support the recommendations are summarized in the Online Data Supplement.

COR LOE Recommendations

2a B-NR

1. For patients with a device-detected atrial high-rate episode (AHRE) lasting ≥24 hours1 and with a CHA2DS2-VASc score ≥2 or equivalent stroke risk,2 it is reasonable to initiate oral anticoagulation3 within a SDM framework that considers episode duration and individual patient risk.

2b B-NR

2. For patients with a device-detected AHRE last- ing between 5 minutes and 24 hours and with a CHA2DS2-VASc score ≥3 or equivalent stroke risk,2 it may be reasonable to initiate anticoagulation within a SDM framework that considers episode duration and individual patient risk.

3: No Benefit

B-NR

3. Patients with a device-detected AHRE lasting <5 minutes and without another indication for oral anticoagulation should not receive oral anticoagulation.4,5

Synopsis AHREs detected by a cardiovascular implantable elec- tronic device are associated with a stroke risk lower than that of clinical AF6 that varies according to the episode duration1 and CHA2DS2-VASc score.2 Clinician confir- mation of the duration and nature of the longest atrial high-rate episode is recommended.1 Episodes lasting ≥24 hours are associated with a significant risk of stroke or systemic embolism1,7 that may be reduced with oral anticoagulation.3 By contrast, short episodes, commonly defined as <5 minutes, are not associated with clinical events.4,5 Patients with episodes of intermediate duration and with an elevated stroke risk may benefit from oral anticoagulation.2 There is an interaction between AHRE duration and CHA2DS2-VASc score,2 suggesting both may be used to guide oral anticoagulation candidacy (Figure 12). Of note, the threshold for anticoagulation is higher as in device-detected AF the risk of stroke may be lower than in clinical AF.

Recommendation-Specific Supportive Text 1. AHREs lasting ≥24 hours are associated with

an elevated risk of stroke that varies accord- ing to CHA2DS2-VASc score. AHRE burden is most commonly defined according to the dura- tion of the longest-detected episode, though cumulative duration has also been examined. In a secondary analysis of the ASSERT (Atrial Fibrillation Reduction Atrial Pacing Trial), adju- dicated AHREs >24 hours was associated with an increased risk of subsequent stroke or sys- temic embolism (adjusted HR, 3.24 [95% CI, 1.51-6.95]; P=0.003).1 Similar findings are seen in observational studies in which most AHREs

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were not adjudicated,7 though clinician confirma- tion is preferred. In an observational study linking administrative claims data2 to a device database in which continuous rhythm monitoring data were available but not adjudicated, the risk of stroke among patents with subclinical AF >23.5 hours and a sex-modified CHA2DS2-VASc score ≥2 not taking anticoagulation exceeded 1% per year, a threshold that may be appropriate for use of non- VKAs, with a still higher stroke risk with increas- ing CHA2DS2-VASc score ≥3.8 In a retrospective

cohort study of patients with subclinical AF >24 hours with an average CHA2DS2-VASc score of 4.2±1.4, treatment of subclinical AF >24 hours with OAC was associated with a reduced stroke risk (HR, 0.28 [95% CI, 0.10-0.81]; P=0.02).2,3

2. Although the risk of stroke among patients with an AHRE of intermediate duration is lower than that among patients with an AHRE ≥24 hours, the precise stroke risk is uncertain and may vary according to the CHA2DS2-VASc score. In ASSERT, AHREs lasting >6 minutes to 24 hours

Figure 12. Consideration of Oral Anticoagulation for Device-Detected AHREs According to Patient Stroke Risk by CHA2DS2-VASc Score and Episode Duration. A potential approach to patients with SCAF could consider both patient risk (as gauged by the CHA2DS2-VASc score) and SCAF burden/duration. Circle A indicates patients at low risk or with short and infrequent AHREs do not require anticoagulation; Circle B, patients with intermediate risk and AHREs lasting >6 min to 24 h are an uncertain population but are currently under study in 2 prospective randomized controlled trials; and Circle C, patients at high risk with longer episodes could be considered reasonable candidates for anticoagulation, although the precise threshold for SCAF duration remains uncertain. Reproduced with permission from Noseworthy et al.13 Copyright 2019 American Heart Association, Inc. Modified from Freedman et al.14 Copyright 2017 Springer Nature Limited. AF indicates atrial fibrillation; AHRE, atrial high-rate episode; ARTESiA, Apixaban for the Reduction of Thrombo-Embolism in Patients With Device-Detected Subclinical Atrial Fibrillation trial; COMMANDER HF, A Study to Assess the Effectiveness and Safety of Rivaroxaban in Reducing the Risk of Death, Myocardial Infarction, or Stroke in Participants With Heart Failure and Coronary Artery Disease Following an Episode of Decompensated Heart Failure; COMPASS, Cardiovascular Outcomes for People Using Anticoagulation Strategies; ECG, electrocardiogram; NOAH, Non–Vitamin K Antagonist Oral Anticoagulants in Patients With Atrial High Rate Episodes Trial; OAC, oral anticoagulation; and SCAF, subclinical atrial fibrillation. Female sex is treated as a modifier in the computation of the CHA2DS2-VASc score.

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were not associated with stroke or systemic embo- lism compared with patients without AHREs.1 The CHA2DS2-VASc score of this subpopulation was 2.2±1.0 (mean±SD). In the aforementioned study linking administrative claims data to a device data- base in which continuous rhythm monitoring data were available, the risk of stroke and systemic embolism off anticoagulation exceeded 1% among patients with a sex-modified CHA2DS2-VASc score of 3 to 4 and exceeded 2% among patients with a sex-modified CHA2DS2-VASc score ≥5.2

3. Brief episodes of subclinical AF are at low risk of clin- ical events. In RATE (Registry of Atrial Tachycardia and Atrial Fibrillation), patients with clinical events such as hospitalization, death, or stroke were more likely than those without to have AHREs with either onset or offset of an adjudicated, single ECG (31.9% versus 22.1% among patients with pacemakers and 28.7% and 20.2% among patients with implantable cardioverter-defibrillators [ICDs]).4 AHREs >5 min- utes are highly correlated with AF and AFL, whereas shorter episodes often represent other tachyar- rhythmias.9 To remove most episodes of oversens- ing, AHREs lasting ≤5 minutes were excluded from analysis of MOST (Mode Selection Trial).10 A similar threshold was used in several subsequent key stud- ies to exclude spurious events.1,3,5,11,12

6.5. Nonpharmacological Stroke Prevention Although oral anticoagulation is the standard of care to reduce the risk of ischemic stroke in patients with AF, it is contraindicated in some patients due to an excess risk of major bleeding. Surgical and percutaneous techniques to occlude the LAA have been developed to reduce the risk of ischemic stroke. These techniques have the po- tential to obviate the need for or supplement long-term oral anticoagulation in select patients. Surgical LAAO is a particularly important consideration in patients with AF who undergo cardiac surgery.

6.5.1. Percutaneous Approaches to Occlude the LAA Recommendations for Percutaneous Approaches to Occlude the LAA Referenced studies that support the recommendations are summarized in the Online Data Supplement.

COR LOE Recommendations

2a B-NR

1. In patients with AF, a moderate to high risk of stroke (CHA2DS2-VASc score ≥2), and a contraindication (Table 14) to long-term oral anticoagulation due to a nonreversible cause, percutaneous LAAO (pLAAO) is reasonable.1–4

2b B-R

2. In patients with AF and a moderate to high risk of stroke and a high risk of major bleeding on oral anti- coagulation, pLAAO may be a reasonable alternative to oral anticoagulation based on patient preference, with careful consideration of procedural risk and with the understanding that the evidence for oral antico- agulation is more extensive.1–3,5,6

Synopsis A large body of evidence supports the use of OACs to reduce the risk of ischemic stroke in patients with AF; however, OACs may be contraindicated in some patients (Table 14). pLAAO devices are designed to prevent embolization of LAA thrombi and potentially obviate the need for OAC for stroke risk reduction. RCTs have demonstrated pLAAO to be noninferior to warfarin and DOACs for stroke and systemic embolism with a reduced risk of major bleeding.1–4 A prospective nonrandomized study has shown that patients deemed unsuitable for OAC who undergo pLAAO implant have a lower-than-expected risk of ischemic stroke.5 Pro- spective registries of pLAAO device implant in pa- tients who are not on long-term OAC have shown a high rate of procedural success, a low risk of major procedure-related complications, and a low rate of ischemic stroke in follow-up.6,7 Based on these find- ings, pLAAO is reasonable in patients with nonvalvular AF who have a contraindication to long-term OAC due to a nonreversible cause. Additionally, pLAAO may be reasonable as an alternative to OAC based on patient preference after careful consideration of procedural risk and with the understanding that there is a much greater body of evidence supporting OAC in this popu- lation in general.

Recommendation-Specific Supportive Text 1. pLAAO has been evaluated in patients with AF

and a contraindication to OAC. The ASAP (ASA Plavix Feasibility Study With Watchman Left Atrial Appendage Closure Technology) study was a non- randomized trial evaluating the performance of the Watchman device in 150 patients with AF who were deemed ineligible for OAC with warfarin.5 The rate of ischemic stroke was lower in patients who received the Watchman device than would be expected based on the CHADS2 scores of the cohort (2.3% versus 7.3%). The EWOLUTION (Evaluating Real-Life Clinical Outcomes in Atrial Fibrillation Patients Receiving the WATCHMAN Left Atrial Appendage Closure Technology) pro- spective registry showed a high rate of Watchman device procedural success (98.5%) with a low ischemic stroke risk (1.1%). This low ischemic stroke was demonstrated despite most of the patients (73%) not using oral anticoagulation peri- procedurally.6 The PINNACLE FLX (Protection Against Embolism for Nonvalvular AF Patients: Investigational Device Evaluation of the Watchman FLX LAA Closure Technology) prospective regis- try of the next-generation Watchman FLX device showed a high rate of procedural success (98.8%) and a low rate (0.5%) of the primary safety end- point (death, ischemic stroke, systemic embolism, procedure-related events requiring open cardiac

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surgery or major endovascular intervention).7 Registry data have shown substantial variation in postprocedure antithrombotic regimens in real- world practice compared with protocols in the pivotal RCTs; the effect this has on long-term out- comes has not been clearly established.8 ASAP- TOO (Assessment of the Watchman Device in Patients Unsuitable for Oral Anticoagulation) is an ongoing RCT evaluating the safety and efficacy of LAAO in patients with AF who are deemed ineli- gible for oral anticoagulation.9

2. PROTECT AF (Watchman Left Atrial Appendage System for Embolic Protection in Patients With Atrial Fibrillation) was a noninferiority RCT com- paring pLAAO with the Watchman device with warfarin in patients with AF at an increased risk for stroke. pLAAO was noninferior to warfarin for both primary composite efficacy (stroke, sys- temic embolism, and cardiovascular/unexplained death) and safety (procedure-related events and major bleeding) endpoints.1 pLAAO was superior to warfarin in terms of cardiovascular mortality (HR, 0.40, 95% CI, 0.21-0.75; P=0.005) and all- cause mortality (HR, 0.66, 95% CI, 0.45-0.98; P=0.004). The PREVAIL (Watchman Left Atrial Appendage Closure Device in Patients With Atrial Fibrillation Versus Long Term Warfarin Therapy) study was a follow-up RCT that compared the Watchman device with warfarin in a similar patient population.2 pLAAO did not achieve noninferiority for the first primary composite efficacy endpoint (stroke, systemic embolism, and cardiovascular/ unexplained death) but was limited in statistical power because of unexpectedly low event rates. pLAAO was statistically noninferior to warfarin for nonprocedure-related strokes. Higher implant success and lower procedure-related safety event rates were observed in PREVAIL than PROTECT AF. A 5-year patient-level meta-anal- ysis of these trials demonstrated similar efficacy of pLAAO for stroke prevention and reduced

rates of major bleeding compared with warfarin.3 PRAGUE-17 (Left Atrial Appendage Closure vs Novel Anticoagulation Agents in Atrial Fibrillation) was an RCT that compared pLAAO with DOACs in patients with nonvalvular AF.4 pLAAO was non- inferior to DOACs for the combined safety and efficacy composite endpoint (stroke, TIA, sys- temic embolism, cardiovascular death, major or nonmajor clinically relevant bleeding, or proce- dure-/device-related complications).

6.5.2. Cardiac Surgery—LAA Exclusion/Excision Recommendations for Cardiac Surgery—LAA Exclusion/Excision Referenced studies that support the recommendations are summarized in the Online Data Supplement.

COR LOE Recommendations

1 A

1. In patients with AF undergoing cardiac surgery with a CHA2DS2-VASc score ≥2 or equivalent stroke risk, surgical LAA exclusion, in addition to continued anti- coagulation, is indicated to reduce the risk of stroke and systemic embolism.1–3

1 A

2. In patients with AF undergoing cardiac surgery and LAA exclusion, a surgical technique resulting in absence of flow across the suture line and a stump of <1 cm as determined by intraoperative trans- esophageal echocardiography should be used.1,4,5

2b A

3. In patients with AF undergoing cardiac surgery with CHA2DS2-VASc score ≥2 or equivalent stroke risk, the benefit of surgical LAA exclusion in the absence of continued anticoagulation to reduce the risk of stroke and systemic embolism is uncertain.1–3

Synopsis Surgical left atrial appendage occlusion (S-LAAO) for reduction in the risk of recurrent arterial thromboemboli was first reported in 1949.6 After decades of relative clinical equipoise,7,8 accumulating evidence,2,8–10 culmi- nating in the large RCT LAAOS III (Left Atrial Append- age Occlusion Study),1 supports a benefit of S-LAAO in patients with AF who undergo2,9 coronary artery by- pass graft surgery (CABG) or valve surgeries. A 2019 meta-analysis before the publication of LAAOS III re- viewed 22 studies, including 280 585 patients of whom 36 686 underwent S-LAAO during cardiac surgery. S- LAAO showed an association with a 29% lower risk of stroke or thromboembolism. The all-cause mortality rate at 2 years was lower in patients who underwent S- LAAO. No benefit was found in the subgroup of studies that included patients without preoperative AF.9 These favorable findings were validated by the 4770-subject LAAOS III, which confirmed S-LAAO in addition to OAC provides a 33% reduction in risk of stroke and systemic embolism.1

LAAOS III enrolled only patients with preexisting AF; evidence of the effectiveness of S-LAAO in patients without AF is inconsistent and suggests the benefit of

Table 14. Situations in Which Long-Term Anticoagulation Is Contraindicated and Situations When It Remains Reasonable

Long-Term Anticoagulation Contraindicated

Long-Term Anticoagulation Is Still Reasonable

Severe bleeding due to a nonreversible cause involving the gastrointestinal, pulmonary, or genitourinary systems

Spontaneous intracranial/ intraspinal bleeding due to a nonreversible cause

Serious bleeding related to recurrent falls when cause of falls is not felt to be treatable

Bleeding involving the gastrointesti- nal, pulmonary, or genitourinary sys- tems that is treatable

Bleeding related to isolated trauma

Bleeding related to procedural complications

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adjunctive S-LAAO is unclear in patients without preop- erative AF.7,9 The results of ongoing RCTs in this popula- tion are awaited.

Recommendation-Specific Supportive Text 1. LAAOS III was performed with 4770 patients with

AF and a CHA2DS2-VASc score ≥2 undergoing cardiac surgery randomized to S-LAAO or no S-LAAO. Intraoperative transesophageal echo- cardiogram (TEE) was recommended to assess successful closure using an endorsed technique. Oral anticoagulation was continued postopera- tively. After a mean follow-up of 3.8 years, the primary endpoint of stroke or systemic embolism occurred in 4.8% of the S-LAAO group and 7.0% of the no S-LAAO group (HR, 0.67 [95% CI, 0.53-0.85]; P=0.001). Mortality rate, cross-clamp and bypass time, chest tube output, and bleed- ing were not different between groups. More than 75% of subjects in both groups received OAC. These data indicate S-LAAO provides additional benefit to oral anticoagulation without increasing risk of adverse events.

These findings cannot be extrapolated to patients without AF or patients who are not can- didates for OAC. Most subjects underwent CABG or valve surgery, and the mean CHA2DS2-VASc score was 4.2. Surgical AF ablation was performed in one-third of both groups. Patients undergoing mechanical valve surgery, transplant, off-pump bypass, left ventricular assistive device surgery, and congenital heart disease (CHD) cases were excluded.A subsequent meta-analysis of 5 RCTs and 22 observational studies including 540 111 patients showed a significant decrease in stroke and thromboembolism with S-LAAO.11 The postop- erative mortality rate did not differ but, in follow-up, was reduced in the S-LAAO group after 2 years. No difference in major bleeding, all-cause rehospi- talizations, or cross-clamp time was observed.11

2. Substantial heterogeneity in S-LAAO methods exists in the literature, and not all techniques effectively exclude the LAA.4 An increased risk of stroke and thromboembolism is associated with incomplete S-LAAO5,12; however, many stud- ies do not report assessment of occlusion suc- cess.9 This inconsistency has likely contributed to the variability in outcome.7,9 LAAOS III permit- ted 4 techniques: amputation and closure (which was promoted as the preferred technique), used in 56%; stapler closure, used in 11%; double- layer linear closure (if confirmed by TEE), used in 14%; or an approved LAAO device, used in 15%. Other techniques were approved on a case- by-case basis (4%). Intraoperative TEE was rec- ommended to assess successful closure, defined

as absence of flow across the suture line and a stump of <1 cm. If the initial closure was unsuc- cessful, additional suturing was performed for repair. Contemporary data show closure success of >95% using a surgical clip device.13 In the LAAOS series, the mean cross-clamp and bypass times were similar, and perioperative bleeding was not increased in the S-LAAO group.1,4 These data support the importance of complete S-LAAO in achieving beneficial outcomes.

3. In LAAOS III, S-LAAO reduced stroke and throm- boembolism by 33% in addition to OAC. LAAOS III was not designed to resolve whether oral anti- coagulation can be safely stopped after S-LAAO; at hospital discharge, >80% of subjects in both groups were receiving OAC, with >75% on OAC at the 3-year visit.1 A systematic review and meta- analysis focusing on the effects of anticoagula- tion found no statistically significant difference in stroke rates of S-LAAO/no S-LAAO subjects on OAC versus off OAC, with high heterogene- ity noted for both ischemic events and mortal- ity,14 and findings are subject to confounding by indication and the potentially beneficial effects of surgical AF ablation. The LAACS (Left Atrial Appendage Closure with Surgery) study of 187 subjects undergoing CABG, valve surgery, or both who were randomized to S-LAAO versus no S-LAAO showed a reduction in the risk of stroke in the S-LAAO group, independent of anticoagu- lation status.15 These results must be interpreted with caution, however, because the study was not powered to demonstrate a reduction in stroke, and substantial crossover occurred.

6.6. Active Bleeding on Anticoagulant Therapy and Reversal Drugs

Recommendations for Active Bleeding on Anticoagulant Therapy and Reversal Drugs Referenced studies that support the recommendations are summarized in the Online Data Supplement.

COR LOE Recommendations

1 B-NR

1. In patients with AF receiving dabigatran who develop life-threatening bleeding, treatment with idarucizumab is recommended to rapidly reverse dabigatran’s anticoagulation effect.1–3

2a C-LD

2. In patients with AF receiving dabigatran who develop life-threatening bleeding, treatment with activated prothrombin complex concentrate (PCC) is reason- able to reverse dabigatran’s anticoagulation effect if idarucizumab is unavailable.4,5

B-NR* 3. In patients with AF receiving factor Xa inhibitors

who develop life-threatening bleeding, treatment with either andexanet alfa (apixaban or rivaroxaban,* edoxaban†) or 4-factor prothrombin complex concen- trate† is recommended to rapidly reverse factor Xa inhibitor’s anticoagulation effect.6,7

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1 A

4. In patients with AF receiving warfarin who develop life-threatening bleeding, treatment with 4-factor prothrombin complex concentrate (if available) in addition to intravenous vitamin K is recommended to rapidly achieve INR correction over fresh frozen plasma and intravenous vitamin K treatment.8–10

2b B-NR

5. In patients with AF who develop major gastrointestinal bleeding, resumption of oral anticoagulation therapy may be reasonable after correction of reversible causes of bleeding and reassessment of its long-term benefits and risks with a multidisciplinary team approach during SDM with patients.11,12

*B-NR LOE applies to data on apixaban or rivaroxaban. †C-LD LOE applies to data on edoxaban.

Synopsis About 2% to 4% of patients who receive OACs expe- rience major bleeding and require intervention.13 Acti- vated charcoal may be administered up to 6 to 8 hours after the last dose of an OAC.14,15 Hemodialysis may be also considered to eliminate dabigatran but may be challenging and impractical due to coagulopathy and hemodynamic instability.16 The proportion of emergency department visits for bleeding from OACs due to DO- ACs increased from 2.3% in 2011 to 37.9% in 2017 because of the increased use of DOACs over the past decade.17 Some patients may require reversal agents to achieve rapid hemostasis. Failure to achieve effec- tive hemostasis is associated with a >3 times higher risk of death.18 Idarucizumab for dabigatran-induced major bleeding and andexanet alfa for apixaban or ri- varoxaban associated major bleeding are US Food and Drug Administration (FDA) approved. Four-factor PCC for DOAC-induced major bleeding was compared with andexanet alfa in retrospective cohort studies, but the comparison has never been investigated in clinical tri- als.7 For VKA, if life-threatening bleeding cannot be managed with supportive measures, the rapid reversal treatment with 4-factor PCC is preferred over fresh fro- zen plasma.8–10 Table 15 summarizes reversal agents for OACs. Table 16 describes bleeding events attributable to DOACs in pivotal clinical trials.

Recommendation-Supportive Text 1. The RE-VERSE AD (Reversal of Dabigatran

Anticoagulant Effect With Idarucizumab) study was a multicenter, prospective cohort study evaluat- ing the use of idarucizumab in patients receiving dabigatran for the management of uncontrolled or life-threatening bleeding or in patients requiring urgent surgery or invasive procedure.1 In patients with uncontrolled or life-threatening bleeding, ida- rucizumab reversed the dabigatran anticoagulation effect in 100% of patients, and 67.7% had bleed- ing cessation. Thrombosis events after the reversal agent use was 4.7% within 30 days. However, this

study did not have a control group. The post hoc analysis of the RE-VERSE AD study in patients with gastrointestinal bleeding found that 97.5% of patients achieved complete reversal of dabiga- tran, and bleeding cessation occurred in 76.2% of patients.2 Another post hoc analysis of the same study showed that idarucizumab was effective at reversing dabigatran’s anticoagulation effect, regardless of baseline renal function.3

2. Compared with idarucizumab, the data on PCC for dabigatran-associated bleeding are very limited. A prospective multicenter cohort study compared the use of activated PCC in 14 patients with dabiga- tran-associated major bleeding compared with his- torical matched cases.4 The study was prematurely stopped due to the availability of idarucizumab in the market. The effectiveness of activated PCC was assessed based on the assessment guide rat- ing from good, moderate, and poor. Nine patients (64%) were rated as good, 5 patients (36%) as moderate, and none as poor. No thromboem- bolic events were found. A randomized, placebo- controlled crossover trial in 12 healthy subjects evaluated the reversal effect of 4-factor PCC on rivaroxaban or dabigatran’s effect.5 It showed 4-factor PCC completely reversed rivaroxaban’s effect based the prothrombin time, but it did not reverse dabigatran’s effect based on the coagula- tion tests (aPTT, ecarin clotting time, and thrombin time). Four-factor PCC may not be appropriate for dabigatran-associated major bleeding manage- ment until further investigation is performed in prospective studies.

3. The ANNEXA 4 (Andexanet Alfa, a Novel Antidote to the Anticoagulation Effects of Factor Xa Inhibitors) trial evaluated the use of andexanet alfa in adult patients with acute major bleeding (safety population, n=254; efficacy population, n=254) receiving factor Xa inhibitors (apixa- ban 55%, rivaroxaban 36%, edoxaban 3%, and enoxaparin 6%).6 It found that after the bolus administration, the median anti-factor Xa activity decreased by 89%. Twelve hours after the andex- anet infusion, clinical hemostasis was adjudicated as excellent or good in 37 of 47 patients in the efficacy analysis (79% [95% CI, 64%-89%]); however, thrombotic events occurred in 12 of 67 patients (18%) during the 30-day follow-up. Currently, andexanet alfa is FDA-approved for only apixaban- or rivaroxaban-associated life- threatening or uncontrolled bleeding, because only limited data are available for other factor Xa inhibitors. For 4-factor PCC, a meta-analysis of 22 observational studies compared andexanet alfa (n=438) with PCC (n=1278) in patients with acute bleeding associated with oral factor Xa

Recommendations for Active Bleeding on Anticoagulant Therapy and Reversal Drugs (Continued )

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inhibitors.7 It showed that mean hemostatic effec- tiveness for andexanet alfa was 82% at 12 hours and 71% at 24 hours versus 88% at 12 hours and 76% at 24 hours for PCC. Mean 30-day venous thromboembolism rate was 5.0% in the andex- anet alfa group versus 1.9% in the PCC group. However, the meta-analysis had more significant methodological issues than the ANNEXA 4 trial. Thus, the level of evidence for the 4-factor PCC use was downgraded.

4. A meta-analysis of 13 studies (5 randomized trials and 8 observational studies) compared 4-factor PCC with fresh frozen plasma for warfarin-associated bleeding or urgent surgery/procedure.8 Four-factor PCC use was significantly associated with lower risk of all-cause mortality (25.1% versus 28.8%; OR, 0.56 [95% CI, 0.37-0.84]), higher probability to achieve INR correction (60.6% versus 12.8%; OR, 10.8 [95% CI, 6.12-19.07]), shortened time to INR correction (–6.5 h [95% CI, –9.75 h to –3.24 h]),

Table 15. Reversal Agents for Oral Anticoagulants

Idarucizumab Andexanet alfa 4-Factor PCC Activated PCC

Class Humanized monoclonal antibody fragment binding to dabigatran and neutralizing anticoagulation effects

A recombinant modified human factor Xa protein bind- ing and sequestering the factor Xa inhibitors

PCC: coagulation factors II, VII, IX, and X Anticoagulation proteins C and S

Nonactivated factors II, IX, and X Activated VII

FDA indications Reversal of dabigatran effects For emergency surgery/

urgent procedures Life-threatening or

uncontrolled bleeding

Reversal of apixaban or rivaroxaban For life-threatening or

uncontrolled bleeding

The urgent reversal for acute major bleeding or need for an urgent surgery/invasive procedure in patients receiving VKAs

Control and prevention of bleeding episodes, periopera- tive management, prophylaxis to prevent or reduce bleeding frequency in patients with hemophilia A and B

Off-label indications N/A Edoxaban-associated life-threatening bleeding

Reversal of factor Xa inhibitors in patients requiring urgent procedure or with life-threatening bleeding

Dabigatran-associated life-threatening bleeding

Dosing 5-g (2 separate vials of 2.5 g/ vial) intravenous infusion over 5 min. Additional 5 g may be given if reappearance of bleeding with elevated coag- ulation parameters have been observed or patients require second emergency surgery/ procedure and elevated co- agulation parameters

Low-dose regimen: 400-mg bolus at a target rate of 30 mg/min followed by 4 mg/min for up to 120 min High-dose regimen: 800-mg bolus at a target rate of 30 mg/min followed by 8 mg/min for up to 120 min The recommended dosing is based on apixaban or rivar- oxaban, dose, and time since the patient’s last dose of apixaban or rivaroxaban

Warfarin reversal based on pretreatment INR (units of factor IX): 1. INR 2–<4: 25 units/kg

|(up to 2500 units) 2. INR 4–6: 35 units/kg

(up to 3500 units) 3. INR >6: 50 units/kg

(up to 5000 units) Oral factor Xa inhibitors: 2000 units once or 25 to 50 units/kg

Dabigatran-associated life-threatening bleeding: 50 units/kg once

Onset Within 5 min Within 2 min Within 10 min Within 30 min

Duration 12-24 h 2 h 8 h 12 h

Monitoring Coagulation parameters (aPTT, diluted thrombin time, or ecarin clotting time) be- tween 12 and 24 h to assess redistribution of dabigatran from peripheral to plasma

Current commercial anti-Xa activity assays are unsuitable for measuring factor Xa activi- ties after andexanet alfa use

Warfarin reversal: Repeat INR within 30 min after the administration

N/A

Others Risk of serious reactions (hypoglycemia, hypophospha- temia, metabolic acidosis, in- crease in uric acid, acute liver failure) in patients with he- reditary fructose intolerance (due to sorbitol excipient 4 g in each 5 g of idarucizumab) No procoagulant effect based on endogenous thrombin potential

No FDA indication for other factor Xa inhibitors other than apixaban or rivaroxaban Andexanet alfa may interfere with the anticoagulation ef- fect of heparin US black box warning: Seri- ous and life-threatening adverse events (arterial and venous thromboembolism, myocardial infarction, isch- emic stroke, cardiac arrest, sudden deaths)

May not be indicated for patients with thromboembolic events in the previous 3 mo It includes heparin Administer intravenous vita- min K 10 mg over 10-20 min in addition to 4-factor PCC

It does not include heparin Coagulation parameters do not correlate with the drug’s efficacy Not effective to reverse factor Xa inhibitors

Information in table was obtained from manufacturer package inserts. aPTT indicates activated partial thromboplastin time; FDA, US Food and Drug Administration; PCC, prothrombin complex concentrate; and VKA, vitamin K antagonists.

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and lower risk of volume overload (2.1% versus 8.8%; OR, 0.27 [95% CI, 0.13-0.58]) compared with fresh frozen plasma. No significant difference in thromboembolic events (4.2% versus 4.8%; OR, 0.91 [95% CI, 0.44-1.89]; P=0.81) was found.

5. A meta-analysis of 10 cohort studies compared anticoagulation resumption (n=2080) versus discontinuation (n=2296) after gastrointesti- nal bleeding in patients receiving OACs for AF, venous thromboembolism, or prosthetic valve.11 Restarting anticoagulation was significantly asso- ciated with higher risks of recurrent gastrointes- tinal bleeding (10.1% versus 5.3%) but also with lower risks of thromboembolic events (6.3% ver- sus 10.6% ) and a reduction in all-cause mortal- ity (21.3% versus 31%). Another meta-analysis of 7 observational studies in patients with AF found no significant difference in stroke rates between resumption and discontinuation groups (9.1% versus 8.3%; OR, 0.75 [95% CI, 0.37- 1.51]).12 Resumption of anticoagulation therapy was associated with significant reduction in any thromboembolic events (8.0% versus 12.2%; OR, 0.54 [95% CI, 0.43-0.68]) and all-cause mortality (10.8% absolute risk reduction; OR, 0.38 [95% CI, 0.24-0.60]), at the expense of recurrent major bleeding (10.2% versus 5.0%). One study found the optimal timing of resuming a VKA after upper

gastrointestinal bleeding was between 3 and 6 weeks, while other studies revealed that resuming a VKA 1 week after gastrointestinal bleeding is the optimal timing.19–21 There is a paucity of data evaluating the timing of DOACs after gastrointes- tinal bleeding.

6.6.1. Management of Patients With AF and ICH Recommendations for Management of Patients With AF and ICH Referenced studies that support the recommendations are summarized in the Online Data Supplement.

COR LOE Recommendations

2a C-LD

1. In patients with AF and conditions associated with very high risk of thromboembolic events (>5%/year), such as rheumatic heart disease or a mechanical heart valve, early (1-2 weeks) resumption of antico- agulation after ICH is reasonable to reduce the risk of thromboembolic events.1

2b C-LD

2. In patients with AF and ICH, delayed (4-8 weeks) resumption of anticoagulation may be considered to balance the risks of thromboembolic and hemorrhagic complications after careful risk benefit assessment.2–5

2b B-NR

3. In patients with AF and conditions associated with high risk of recurrent ICH (eg, cerebral amyloid angiopathy) anticoagulation-sparing strategies (eg, LAAO) may be considered to reduce the risk of recurrent hemorrhage.6,7

Synopsis ICH is a term that refers to bleeding within any of the com- partments of the cranial vault, including intraparenchymal

Table 16. Bleeding Events (Percentage Per Year) in DOAC Pivotal Clinical Trials

Bleeding Event RE-LY (n=18 113) ARISTOTLE (n=18 201) ENGAGE AF-TIMI 48 (n=21 105) ROCKET AF (n=14 264)

Major bleeding Dabigatran 150 mg 3.11% (RR, 0.93 [95% CI, 0.81– 1.07]; P=0.31) Dabigatran 110 mg 2.71% (RR, 0.80 [95% CI, 0.69– 0.93]; P=0.003) Warfarin 3.36%

Apixaban 2.13% (HR, 0.69 [95% CI, 0.60–0.80]; P<0.001) Warfarin 3.09%

Edoxaban 60 mg 2.75% vs warfarin 3.43% (HR, 0.80 [95% CI, 0.71–0.91]; P<0.001) Edoxaban 30 mg 1.61% vs warfarin 3.43% (HR, 0.47 [95% CI, 0.41–0.55]; P<0.001)

Rivaroxaban 3.6% vs warfarin 3.4% (HR, 1.04 [95% CI, 0.90–1.20]; P=0.58)

Gastrointestinal bleeding Dabigatran 150 mg 1.51% vs warfarin 1.02% (RR, 1.50 [95% CI, 1.19–1.89]; P<0.001) Dabigatran 110 mg 1.12% vs warfarin 1.02% (RR, 1.10 [95% CI, 0.86–1.41]; P=0.43)

Apixaban 0.76% (HR, 0.89 [95% CI, 0.70–1.15]; P=0.37) Warfarin 0.86%

Edoxaban 60 mg 1.51% (HR, 1.23 [95% CI, 1.02–1.50] ; P=0.03) Edoxaban 30 mg 0.82% (HR, 0.67 [95% CI, 0.53–0.83]; P<0.001) Warfarin 1.23%

Rivaroxaban 3.2% (HR not reported; P<0.001) Warfarin 2.2%

Intracranial bleeding Dabigatran 150 mg 0.30% (RR, 0.40 [95% CI, 0.27– 0.60]; P<0.001) Dabigatran 110 mg 0.23% (RR, 0.31 [95% CI, 0.20– 0.47]; P<0.001) Warfarin 0.74%

Apixaban 0.33% (HR, 0.42 [95% CI, 0.30–0.58]; P<0.001) Warfarin 0.80%

Edoxaban 60 mg 0.39% (HR, 0.47 [95% CI, 0.34–0.63]; P<0.001) Edoxaban 30 mg 0.26% (HR, 0.30 [95% CI, 0.21–0.43]; P<0.001) Warfarin 0.85%

Rivaroxaban 0.80% (HR, 0.67 [95% CI, 0.47–0.93]; P=0.02) Warfarin 1.20%

Adapted with permission from Kido et al.22 Copyright 2021 American College of Clinical Pharmacy. ARISTOTLE indicates Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation; DOAC, direct anticoagulant; ENGAGE AF-TIMI 48,

Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation – Thrombolysis in Myocardial Infarction 48; HR indicates hazard ratio; RE-LY, Random- ized Evaluation of Long-Term Anticoagulation Therapy; ROCKET AF, Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation; and RR, relative risk.

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(or intracerebral), subarachnoid, subdural, and epidural hemorrhage. In clinical practice, the different forms of ICH are often classified by mechanism and most broadly as traumatic and nontraumatic or spontaneous ICHs (Figure 14). In patients with AF and conditions associated with high-risk for thromboembolic compli- cations (eg, mechanical valve, rheumatic valvular dis- ease), anticoagulation is often resumed early after ICH, regardless of mechanism. For other patients with AF, decisions regarding if (and when) to resume antico- agulation after ICH requires more careful risk-benefit assessment of patient-specific clinical factors. Patients with traumatic etiologies generally have lower long- term risk of recurrent hemorrhage, and anticoagulation is generally considered safe to resume. Nontraumatic/ spontaneous etiologies (eg, hypertensive parenchymal hemorrhage, hemorrhagic transformation after isch-

emic stroke, cerebral amyloid angiopathy-associated hemorrhage, chronic subdural hemorrhage) are gener- ally associated with higher risk of recurrence. Clinical decision-making regarding the appropriateness of re- sumption in these patients is based largely on individual risk-benefit calculations given the lack of randomized data assessing safety and long-term outcomes. For pa- tients with ICH deemed at high risk of recurrence, LAA closure may be a viable alternative to anticoagulation, although data on efficacy and safety are lacking in the ICH population.

Recommendation-Specific Supportive Text 1. Rheumatic valvular disease is associated with a

>5% per year risk of embolic events.8 In patients with mechanical heart valves, the rate can range from 4% to 23% per year depending on the type

Figure 13. Active Bleeding Associated With Oral Anticoagulant. Colors correspond to Table 2. PCC indicates prothrombin complex concentrate.

Figure 14. Forms of ICH, Classified by Mechanism. ICH indicates intracranial hemorrhage.

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and position of the prosthetic.9–11 These rates are even higher in patients with concurrent AF but are significantly reduced with the use of VKAs. Data are limited that explore the safety and timing of anticoagulation resumption in patients with ICH and high-risk valvular disease. In 1 observational analysis of 137 patients with ICH and mechani- cal heart valves, resuming anticoagulation within 2 weeks from index ICH was associated with increased hemorrhagic complications (HR, 7.06 [95% CI, 2.33-21.37]).1 However, in balancing the risk of hemorrhagic with thrombotic complications, the optimal window of resumption was found to be between 1 and 2 weeks post-ICH after weighing individual patient factors (Table 17).

2. Anticoagulation is associated with up to 25% of ICHs and is associated with worse functional out- comes and higher mortality.12–15 After ICH, anti- coagulation is generally held in the acute setting. Decisions regarding the appropriateness and timing of resumption are complex given the lim- ited amount of randomized data addressing risks and benefits in this population. Previous obser- vational reports evaluating risk of recurrent ICH, thromboembolism, and mortality in patients with nonvalvular AF have suggested possible reduc- tion in thromboembolic risk and mortality with resumption of anticoagulation but are limited by discordant patient populations and study designs, predominant use of VKAs, and potential selection

biases.16–22 In a meta-analysis of 2452 patients with AF and ICH, resumption of OACs was asso- ciated with lower risk of ischemic stroke (RR, 0.46 [95% CI, 0.29-0.72]) and no difference in risk of recurrent ICH compared with patients in whom anticoagulation was not resumed2 (Table 17). However, data are limited on the optimal timing for resumption. In an analysis of 2619 ICH survivors with AF, a composite net benefit minimizing risk of bleeding and thromboembolic complications occurred when anticoagulation was resumed at 7 to 8 weeks after ICH.3 In a retrospective study that included 1752 patients with OAC-related ICH across 3 Danish registries, anticoagulation resumed a median of 34 days was associated with an adjusted HR of ischemic stroke, systemic embolism, and all-cause mortal- ity of 0.55 (95% CI, 0.39-0.78) compared with no anticoagulation.4 In another meta-analysis of 8 observational studies, resuming OAC was associ- ated with reduced risk of ischemic stroke without increased risk of recurrent ICH at a median time to resumption of 10 to 39 days5 (Table 17). Of note, DOACs have been associated with lower rates of major bleeding complications compared with VKAs.23

3. Anticoagulation is used for stroke risk reduction in patients with AF at risk of thromboembolism. For some patients, however, risk of recurrent ICH may be prohibitively high with anticoagulation. Cerebral amyloid angiopathy is the most common cause of lobar hemorrhage in older adults and is associated with annual ICH recurrence risk that ranges from 5% in patients with isolated microhe- morrhages to 26.9% in patients with associated cortical superficial siderosis.24 Thus, in patients with AF and cerebral amyloid angiopathy-related ICH, alternative strategies for secondary stroke prevention are often pursued. The LAA is consid- ered the most common site for thrombus forma- tion in patients with AF.25,26 Two RCTs—PROTECT AF study and PREVAIL study—compared rates of stroke and mortality after LAA closure versus VKA in patients with AF.6,7 In a meta-analysis examining 5-year outcomes in the 2 RCTs, LAA closure was associated with significant reduc- tions in hemorrhagic stroke, disabling and fatal stroke, and all-cause mortality, with comparable rates of stroke and systemic embolism compared with warfarin.27 Of note, both studies excluded patients who were not candidates for antico- agulation. Additionally, newer treatment options such as epicardial LAA clipping are emerging for stroke prevention without need for postproce- dure APT.28,29

Table 17. Risk Factors for Thromboembolic Complications and Recurrent ICH

Factors Associated With High Risk of Thromboembolism

Factors Associated With High Risk of Recurrent ICH

Mechanical heart valve Suspected cerebral amyloid angiopathy

Rheumatic valve disease Lobar IPH

Previous history of stroke/ thromboembolism

Older age

Hypercoagulable state (eg, active malignancy, genetic thrombophilia)

>10 cerebral microbleeds on MRI

High CHA2DS2-VASc score (>5) Disseminated cortical superficial siderosis on MRI

Poorly controlled hypertension

Previous history of spontaneous ICH

Genetic/acquired coagulopathy

Untreated symptomatic vascular malformation or aneurysm

CHA2DS2-VASc indicates congestive heart failure, hypertension, age ≥75 y (doubled), diabetes mellitus, prior stroke or transient ischemic attack or throm- boembolism (doubled), vascular disease, age 65 to 74 y, sex category; ICH, in- tracranial hemorrhage; IPH, intraparenchymal hemorrhage; and MRI, magnetic resonance imaging.

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6.7. Periprocedural Management Recommendations for Periprocedural Management Referenced studies that support the recommendations are summarized in the Online Data Supplement.

COR LOE Recommendations

B-R* 1. In patients with AF (excluding those with recent

stroke or TIA, or a mechanical valve) and on oral anticoagulation with either warfarin* or DOAC† who are scheduled to undergo an invasive procedure or surgery, temporary cessation of oral anticoagulation without bridging anticoagulation is recommended.1–4

B-NR†

1 A

2. In patients with AF on warfarin anticoagulation and an annual predicted risk of thromboembolism of ≥5% undergoing pacemaker or defibrillator implantation or generator change, continued anticoagulation is rec- ommended in preference to interruption of warfarin and bridging anticoagulation with heparin to reduce the risk of pocket hematoma.5–7

2a A

3. In patients with AF with CHA2DS2-VASc score ≥2 or equivalent risk of stroke, on DOAC anticoagulation and undergoing pacemaker or defibrillator implanta- tion or generator change, either uninterrupted or interrupted DOAC is reasonable.8–10

1 B-NR

4. In patients with AF on DOAC and scheduled to undergo an invasive procedure or surgery that cannot be performed safely on uninterrupted antico- agulation, the timing of interruption of DOAC should be guided by the specific agent, renal function, and the bleeding risk of the procedure (Table 18).4,11,12

2a B-NR

5. In patients with AF on DOAC that has been inter- rupted for an invasive procedure or surgery, in gen- eral, resumption of anticoagulation the day after low bleeding risk surgery and between the evening of the second day and the evening of the third day after high bleeding risk surgery is reasonable, as long as hemostasis has been achieved and further bleeding is not anticipated.4

3: Harm

B-R

6. In patients with AF on warfarin anticoagulation, who are undergoing surgeries or procedures for which they are holding warfarin, except in patients with mechanical valve or recent stroke or TIA, bridging anticoagulation with low-molecular-weight heparin should not be administered.1,3,13–15

*B-R LOE applies to the data on warfarin. †B-NR LOE applies to the data on DOAC.

Synopsis Periprocedural anticoagulation management is driven by 2 competing aims: to hold the anticoagulant agent for the shortest possible time to minimize the risk of thrombo- embolism and to ensure coagulation parameters are as close to normal as possible at the time of the procedure to facilitate hemostasis and avoid intra- and postopera- tive bleeding. Considerations include the bleeding risk of the procedure, consequences of bleeding should it occur, patient-specific risk factors, and thrombotic risk while off anticoagulation. Invasive procedures and surgeries have been divided into high and low bleeding risks in several different classifications.16 Generally, endoscopic, dental extraction, many ophthalmologic procedures, and percu- taneous vascular access, such as cardiac catheterization, are considered to be of low bleeding risk. Higher bleeding risk surgeries include intra-abdominal, pelvic, orthopedic,

neurosurgical, cardiac, and transvenous lead extraction procedures. Very high bleeding risk procedures include neuraxial anesthesia and spinal surgery. Available data do not suggest high rates of bleeding from these pro- cedures, although bleeding could cause significant con- sequences.17 Patient-specific factors include abnormal liver and kidney function, bleeding or clotting disorders, concomitant antiplatelet or nonsteroidal anti-inflammato- ry use, alcohol, and anemia. Recent bleeding or throm- boembolism may increase the risk for recurrent events. To put thrombotic risk in perspective, the incidence of thromboembolism while anticoagulation was temporarily held has generally been <1%.3,18

Recommendation-Specific Supportive Text 1. To mitigate thromboembolic risk during inter-

ruption of warfarin therapy for a procedure or surgery, “bridging” anticoagulation can be adminis- tered. However, observational studies consistently showed an increased risk of bleeding without a dif- ference in thromboembolic risk with this strategy.3 The BRIDGE (Bridging Anticoagulation in Patients who Require Temporary Interruption of Warfarin Therapy for an Elective Invasive Procedure or Surgery) trial included patients with a mean CHADS2 score of 2.3 (range, 1-6); 61.7% of patients had a CHADS2 score <3.1 In this study, discussed in more depth below, interruption of war- farin without bridging anticoagulation was superior to bridging.1 In a meta-analysis of 6 observational studies reporting on patients not at high throm- boembolic risk receiving prophylactic dose or no bridging had an overall thromboembolic event

Table 18. Timing of Discontinuation of OACs in Patients With AF Scheduled to Undergo an Invasive Procedure or Surgery in Whom Anticoagulation Is to Be Interrupted

Anticoagulant Low Bleeding Risk Procedure

High Bleeding Risk Procedure

Apixaban (CrCl >25 mL/min)* 1 d† 2 d

Dabigatran (CrCl >50 mL/min) 1 d 2 d

Dabigatran (CrCl 30-50 mL/min) 2 d 4 d

Edoxaban (CrCl >15 mL/min) 1 d 2 d

Rivaroxaban (CrCl >30 mL/min) 1 d 2 d

Warfarin 5 d for a target INR <1.5 2-3 d for a target INR <2

5 d

*For patients on DOAC with creatinine clearance lower than the values in the table, few clinical data exist. Consider holding for an additional 1 to 3 days, espe- cially for high bleeding risk procedures.

†The number of days is the number of full days before the day of surgery in which the patient does not take any dose of anticoagulant. The drug is also not taken the day of surgery. For example, in the case of holding a twice daily drug for 1 day, if the drug is taken at 8 pm, and surgery is at 8 am, at the time of surgery, it will be 36 hours since the last dose was taken.

AF indicates atrial fibrillation; CrCl, creatinine clearance; DOAC, direct oral an- ticoagulation; INR, international normalized ratio; and OAC, oral anticoagulant.

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rate of 0.6% (11 of 1702). 3 A similar RCT has not been done in the DOAC era, given the ease of brief interruption of DOAC therapy; however, observational studies have shown similar results.2 The PAUSE (Perioperative Anticoagulation Use for Surgery Evaluation) cohort study, discussed below, enrolling patients with a mean CHADS2 score of 2.1 (range, 1-6) and CHA2DS2-VASc score of 3.5 (range, 1-9), found a low incidence of thromboem- bolic events when DOAC was briefly interrupted without bridging.4 This suggests that in patients at low-to-moderate thromboembolic risk, interruption of anticoagulation, without bridging, may provide a low risk of bleeding with an acceptable risk of stroke/TIA. Patients with mechanical valves, and recent stroke/TIA, or other high-risk markers, were not included in most studies and may still benefit from bridging anticoagulation: in these scenarios, management should be individualized.

2. Evidence has accrued that periprocedural unfrac- tionated or low-molecular-weight heparin bridg- ing has been associated with an increased risk of pocket hematoma after pacemaker or ICD procedures.19 BRUISE-CONTROL (Bridge or Continue Coumadin for Device Surgery Randomized Controlled Trial) randomized patients with AF (88%) or a mechanical valve with an estimated annual stroke risk of ≥5%, and undergoing elective device surgery, to continued

warfarin versus warfarin interruption with bridg- ing anticoagulation. The incidence of clinically significant pocket hematoma was >4 times higher in the bridging group.5 Several other pro- cedures have been performed on uninterrupted anticoagulation.20 Further study is needed to define which procedures, in which patients, can safely be performed with uninterrupted antico- agulation. Lead extraction procedures are gener- ally considered high bleeding risk and therefore should be treated as such (high bleeding risk procedures in Table 18) and warfarin interrupted, with occasional exceptions.

3. Two RCTs and several observational studies have shown little or no difference in the risk of pocket hematoma and thromboembolic events in patients with AF anticoagulated with DOACs and undergo- ing device surgery.8–10 Therefore, brief interruption of DOAC therapy (low bleeding risk procedures in Table 18 may be preferable for many, while uninter- rupted DOAC may be preferred for those at par- ticularly high thromboembolic risk. Lead extraction procedures are generally considered high bleeding risk and therefore should be treated as such (high bleeding risk procedures in Table 18) and DOAC interrupted, with occasional exceptions.

4. To achieve the goals of reducing or eliminating anticoagulant effect at the time of surgery, while also minimizing the time the patient spends without

Figure 15. Flowchart: Management of Periprocedural Anticoagulation in Patients With AF. Colors correspond to Table 2. AF indicates atrial fibrillation; CHA2DS2-VASc, congestive heart failure, hypertension, age ≥75 y (doubled), diabetes mellitus, prior stroke or transient ischemic attack or thromboembolism (doubled), vascular disease, age 65 to 74 y, sex category; DOAC, direct oral anticoagulant; ICD, implantable cardioverter-defibrillator; TE, thromboembolism; and TIA, transient ischemic attack.

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anticoagulation to prevent thromboembolism, the duration of cessation of anticoagulation should take into account both the pharmacokinetics and pharmacodynamics of the agent, the patient’s renal function, and the bleeding risk of the procedure. Direct measurement of DOAC levels is unavailable in clinical practice, but levels <30 ng/mL, which correspond to the expected plasma DOAC concen- tration reached after 3 half-lives, when most of the drug (87.5% of the Cmax) has been eliminated, is reached in two-thirds of patients 24 to 48 hours after the last drug intake.11 Similar results were observed for apixaban.12 A drug “hold” of 48 hours in clinical practice typically means 2 full days with- out drug intake, in addition to the day of the proce- dure, leading to a longer interval between last drug intake and procedure start longer than 48 hours, usually an additional 12 hours. Meta-analysis of the reports of periprocedural events from the piv- otal trials of each of the 4 available DOACs sug- gested similar outcomes in patients on DOAC or warfarin, with reduced major bleeding during an uninterrupted strategy with DOACs.21 The PAUSE protocol was studied in patients on apixaban, dabi- gatran, and rivaroxaban, and resulted in low rates of major bleeding (0.9%-1.85%) and thrombo- embolism (<1%). A high rate (>90%) of minimal anticoagulant level (<50 ng/mL) was achieved. Similar results have been observed with edoxa- ban in clinical practice.22 Different protocols have not been directly compared. Table 18 presents recommended DOAC interruption times based on agent, renal function, and the bleeding risk of the procedure.

5. The timing of resumption of interrupted antico- agulation after surgery is a complex decision that should integrate patient and surgical character- istics. Warfarin, which takes several days (usually 3-5) to become therapeutic, can often be restarted the evening of the procedure. Postoperative bridg- ing anticoagulation has not been shown to be gen- erally beneficial.1,13 In the PAUSE study, DOACs were started on the first postoperative day for low bleeding risk procedures and between the evening of the second and third postoperative days for high bleeding risk procedures. This resulted in a low risk of major bleeding.4 Input from the proceduralist should always be incorporated into decisions.

6. Several studies have compared a strategy of bridging anticoagulation with a comparator of no bridging in patients on anticoagulants who were scheduled to undergo an invasive procedure or sur- gery. The BRIDGE trial randomized 1 884 patients with AF or AFL to bridging anticoagulation before and after the procedure with dalteparin versus pla- cebo.1 Almost 90% of patients were undergoing

low bleeding risk procedures. No bridging was superior to bridging with respect to major bleeding and was noninferior with respect to thromboembo- lism, although the observed rate (0.4%) was lower than anticipated (1.0%). PERIOP2 (A Double Blind Randomized Control Trial of Post-Operative Low Molecular Weight Heparin Bridging Therapy Versus Placebo Bridging Therapy for Patients Who Are at High Risk for Arterial Thromboembolism) randomized patients, about two-thirds of whom were undergoing high bleeding risk procedures, and 79% of whom had AF, to postoperative bridg- ing with dalteparin or placebo until the INR was >1.9. All patients received preoperative bridging. Bleeding and thromboembolism outcomes were similar.13 These studies also excluded patients with recent bleeding or thromboembolism, and those undergoing spinal and neurological surgery, and in these cases, management should be individual- ized and may include bridging anticoagulation.1,13 A small randomized trial found that dental extractions could be performed on uninterrupted warfarin with- out bridging.14 A large multicenter registry also did not find a difference in thromboembolism, but an increase in bleeding, in bridged patients.15 Patients with mechanical valves should be managed as outlined in the “2020 ACC/AHA Guideline for the Management of Patients With Valvular Heart Disease.”23

6.8. Anticoagulation in Specific Populations 6.8.1. AF Complicating ACS or Percutaneous Coronary Intervention (PCI)

Recommendations for AF Complicating ACS or PCI Referenced studies that support the recommendations are summarized in the Online Data Supplement.

COR LOE Recommendations

1 A

1. In patients with AF and an increased risk for stroke who undergo PCI, DOACs are preferred over VKAs in combination with APT to reduce the risk of clinically relevant bleeding.1–5

1 A

2. In most patients with AF who take oral anticoagulation and undergo PCI, early discontinuation of aspirin (1-4 wk) and continuation of dual antithrombotic therapy with OAC and a P2Y12 inhibitor is preferred over triple therapy (OAC, P2Y12 inhibitor, and aspirin) to reduce the risk of clinically relevant bleeding.1–4,6

Synopsis Encountering a patient with AF at an increased risk for stroke who undergoes PCI for stable CAD or ACS is a common clinical scenario. The addition of APT to OAC after PCI introduces a risk for clinically significant bleed- ing. RCTs have compared the safety and efficacy of vari- ous antithrombotic regimens after PCI is performed in patients with AF. They have consistently shown that DO- ACs, when used in conjunction with APT, are associated

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with a lower risk of clinically relevant bleeding compared to VKAs.1–5 They have also shown that dual therapy with an OAC and single APT with a P2Y12 inhibitor signifi- cantly lowers the risk of clinically relevant bleeding com- pared with triple therapy (oral anticoagulation, P2Y12 inhibitor, and aspirin) without substantially increasing risk of major adverse cardiovascular events.1–4,6 Meta- analyses of these trials have shown a slightly increased risk of stent thrombosis with dual therapy compared to triple therapy.5 Thus, the risk of stent thrombosis must be weighed against the risk of bleeding in determining the antithrombotic regimen after PCI. This is particularly true in patients with a relatively high perceived risk of stent thrombosis (complex revascularization, multivessel PCI, previous history of stent thrombosis).

Recommendation-Specific Supportive Text 1. Post-PCI antithrombotic regimens comparing

DOACs with VKAs in combination with APT in patients with AF who do not have a specific indi- cation for VKAs (eg, mechanical valve) have con- sistently shown a reduction in clinically relevant bleeding.1,2,4 A meta-analysis of 3 RCTs com- paring DOACs with VKAs after PCI, PIONEER AF-PCI (Open-Label, Randomized, Controlled, Multicenter Study Exploring Two Treatment Strategies of Rivaroxaban and a Dose-Adjusted Oral Vitamin K Antagonist Treatment Strategy in Subjects with Atrial Fibrillation who Undergo Percutaneous Coronary Intervention) (rivaroxa- ban), RE-DUAL PCI trial (Randomized Evaluation of Dual Antithrombotic Therapy with Dabigatran versus Triple Therapy with Warfarin in Patients with Nonvalvular Atrial Fibrillation Undergoing Percutaneous Coronary Intervention) (dabigatran), and AUGUSTUS (Open-Label, 2×2 Factorial, Randomized, Controlled Clinical Trial to Evaluate the Safety of Apixaban vs Vitamin K Antagonist and Aspirin vs Aspirin Placebo in Patients With Atrial Fibrillation and Acute Coronary Syndrome and/or Percutaneous Coronary Intervention) (apixaban), showed a 42% relative risk reduc- tion for major bleeding in DOAC-based regimens compared with VKA-based regimens (OR, 0.577 [95% CI, 0.477-0.698]; P<0.001).5 There was no statistically significant difference in the risk of isch- emic events between groups. The ENTRUST-AF PCI (Edoxaban Treatment vs Vitamin K Antagonist in Patients With Atrial Fibrillation Undergoing Percutaneous Coronary Intervention) trial showed that edoxaban-based regimens were noninferior to VKA-based regimens in terms of clinically relevant bleeding after PCI.3 An important limitation of the aforementioned data is that most studies compared DOACs monotherapy against VKA plus aspirin, the only VKA-based dual antithrombotic therapy

(DAT) regimen was available in AUGUSTUS trial, thus providing limited information in comparison to DOAC-based DAT regimens available in all trials.5

2. RCTs have supported DAT with OAC and a P2Y12 inhibitor over triple therapy with OAC, P2Y12 inhibitor, and aspirin to reduce the risk of clinically relevant bleeding in patients with AF after PCI, including WOEST (What Is the Optimal Antiplatelet and Anticoagulant Therapy in Patients with Oral Anticoagulation and Coronary Stenting) (VKA), PIONEER AF-PCI (rivaroxaban), RE-DUAL (dabi- gatran), and AUGUSTUS (apixaban).1,2,4,6 A meta- analysis of PIONEER AF-PCI, RE-DUAL, and AUGUSTUS demonstrated a 40% relative risk reduction for International Society on Thrombosis and Haemostasis major bleeding in dual therapy regimens compared with triple therapy (OR, 0.598 [95% CI, 0.491-0.727]; P<0.001).5 Patients in the intervention group received varying dura- tion of triple therapy with aspirin after PCI up to 7 days. This meta-analysis showed that DAT with DOAC and P2Y12 inhibitor was associated with an increased risk of stent thrombosis (OR, 1.672 [95% CI, 1.022-2.733]; P=0.041) compared with triple therapy.5 This finding was mainly driven by outcomes in the 110-mg dosing group of dabiga- tran in the RE-DUAL trial. The number needed to treat for International Society on Thrombosis and Haemostasis major bleeding (n=42) was substan- tially lower than the number needed to harm for stent thrombosis (n=223) with DAT compared with triple therapy.5 Based on these findings, extended triple therapy up to 30 days after PCI is a consider- ation when the perceived risk of stent thrombosis is high (eg, complex revascularization, multivessel PCI, previous history of stent thrombosis).

6.8.2. Chronic Coronary Disease (CCD) Recommendation for CCD Referenced studies that support the recommendation are summarized in the Online Data Supplement.

COR LOE Recommendation

1 B-R

1. In patients with AF and CCD (beyond 1 year after revascularization or CAD not requiring coronary revascularization) without history of stent thrombosis, oral anticoagulation monotherapy is recommended over the combination therapy of OAC and single APT (aspirin or P2Y12 inhibitor) to decrease the risk of major bleeding.1–3

Synopsis APT is the first-line therapy to prevent recurrent cardiovas- cular events in patients with CAD, while anticoagulation therapy is recommended to prevent stroke or systemic embolism in patients with AF at increased risk of throm- boembolism. Minimal evidence was available until recently if a combination therapy of APT in addition to OAC ther- apy provides additional value to prevent cardiovascular

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events in patients with AF and concomitant CCD (at least 12 months after revascularization or CAD not re- quiring coronary revascularization) compared with oral anticoagulation monotherapy. A recent landmark clinical trial showed that rivaroxaban monotherapy significantly decreased the primary composite outcome (stroke, sys- temic embolism, MI, unstable angina requiring revascu- larization, or death from any cause) and decreased the risk of major bleeding compared with the combination therapy.1 The subgroup analysis of the previously men- tioned clinical trial in patients with AF only after coronary stenting and another clinical trial corroborated the main findings in a similar population.2,3

Recommendation-Specific Supportive Text 1. An RCT compared the rivaroxaban monotherapy

(n=1107) with the combination of rivaroxaban and a single APT (n=1108) in patients with AF and CCD or CAD not requiring revascularization.1 The primary efficacy outcome was the composite of stroke, systemic embolism, MI, unstable angina requiring revascularization, or death from any cause. Rivaroxaban monotherapy was noninferior to dual therapy for the primary outcome (4.14% versus 5.75%/patient-year; HR, 0.72 [95% CI, 0.55-0.95]) and was superior for primary safety endpoint of major bleeding (1.62% versus 2.76%/ patient-year; HR, 0.59 [95% CI, 0.39-0.89]) com- pared with combination therapy. Another clinical trial also showed the composite outcome of death from all causes, MI, stroke, or systemic embolism (15.7% versus 13.6%; HR, 1.16 [95% CI, 0.79- 1.72]; P=0.20 for noninferiority); the major bleed- ing risk in the oral anticoagulation monotherapy group was numerically lower than the combina- tion therapy group (7.8% versus 10.4%; HR, 0.73 [95% CI, 0.44-1.20]).2 However, this trial was ter- minated prematurely because of slow enrollment and did not have enough power for noninferiority; thus, it was inconclusive. Of note, both clinical trials excluded patients with history of stent thrombosis. Further investigation of oral anticoagulation ther- apy in patients with a history of stent thrombosis is needed.

6.8.3. Peripheral Artery Disease (PAD) Recommendation for PAD Referenced studies that support the recommendation are summarized in the Online Data Supplement.

COR LOE Recommendation

2a B-NR

1. In patients with AF and concomitant stable PAD, monotherapy oral anticoagulation is reasonable over dual therapy (anticoagulation plus aspirin or P2Y12 inhibitors) to reduce the risk of bleeding.1–5

Synopsis Antiplatelet monotherapy is the standard of care for pa- tients with symptomatic PAD and reasonable in asymp-

tomatic PAD with ankle-brachial index ≤0.90 to reduce the risk of MI, stroke, and vascular death.6 The 2016 AHA/ACC PAD guidelines recommend against antico- agulation for ischemic event risk reduction in the general PAD population (COR 3; LOE A) due to increased risk of bleeding without significant reduction in ischemic events compared with antiplatelet monotherapy,6,7 without mak- ing specific recommendations for patients with comorbid PAD and AF. Conversely, anticoagulation is recommend- ed for patients with AF at intermediate-to-high risk of stroke due to the inferiority of APT to prevent stroke and systemic thromboembolism in this population. Subgroup analysis of landmark DOAC clinical trials demonstrate comparable efficacy and safety of DOACs compared with warfarin among patients with AF with and without PAD.2–4 Clinical trial evidence is lacking to guide deci- sions regarding DAT in the setting of concomitant AF and PAD (whether stable PAD or after lower extremity revascularization). Observational studies of patients with concomitant AF and PAD treated with OAC monothera- py compared with dual therapy (OAC plus antiplatelet) found an increased risk of bleeding on dual therapy with- out reduction in major adverse cardiac events.5,8 How- ever, an important limitation of these studies was the lack of PAD-specific outcomes such as acute or critical limb ischemia, revascularization, or amputation as primary or secondary outcomes.5,8

Recommendation-Specific Supportive Text 1. In the WAVE (Warfarin Antiplatelet Vascular

Evaluation) trial of patients with PAD but without AF, dual therapy (antiplatelet plus warfarin) did not reduce the primary outcome of MI, stroke, cardiovascular death (RR, 0.92 [95% CI, 0.73- 1.16]; P=0.48) compared with monotherapy (antiplatelet alone), and dual therapy increased the risk of life-threatening bleeding (RR, 3.41 [95% CI, 1.84-6.35]; P<0.001).7 Meta-analysis of 3 RCT subgroup analyses (ENGAGE AF-TIMI 48, ARISTOTLE, ROCKET AF; total N=2 564) compared safety and efficacy outcomes between warfarin and DOACs in patients with concomitant AF and PAD.1–4 The meta-analysis demonstrated similar efficacy for DOACs compared with warfarin, including stroke and systemic embolism (RR, 0.93 [95% CI, 0.61-1.42]; P=0.73), all-cause death (RR, 0.91 [95% CI, 0.70-1.19]; P=0.50), and MI (RR, 1.10 [95% CI, 0.64-1.90]; P=0.74), without a sta- tistically significant difference in the risk of major bleeding (RR, 1.12 [95% CI, 0.70-1.81]; P=0.63) or ICH (RR, 0.54 [95% CI, 0.16-1.85]; P=0.33).1 In ORBIT-AF II (The Outcomes Registry for Better Informed Treatment of Atrial Fibrillation II),5 among AF patients with concomitant vascular disease (CAD or PAD), major adverse cardiac or neuro- logical events and bleeding events were compared

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between patients on OAC monotherapy versus dual therapy (OAC plus APT). Major adverse cardiac or neurological events (HR, 1.5 [95% CI, 1.00-2.25]) did not differ significantly between mono- and dual therapy, while dual therapy was associated with an increased risk of bleeding (HR, 2.27 [95% CI, 1.38-3.73]; P=0.001).5

6.8.4. Chronic Kidney Disease (CKD)/Kidney Failure Recommendations for CKD/Kidney Failure Referenced studies that support the recommendations are summarized in the Online Data Supplement.

COR LOE Recommendations

1 B-R

1. For patients with AF at elevated risk for stroke and CKD stage 3, treatment with warfarin or, preferably, evidence-based doses of direct thrombin or factor Xa inhibitors (Table 19) is recommended to reduce the risk of stroke.1–3

2a B-NR

2. For patients with AF at elevated risk for stroke and CKD stage 4, treatment with warfarin or labeled doses of DOACs is reasonable to reduce the risk of stroke.4,5

2b B-NR

3. For patients with AF at elevated risk for stroke and who have end-stage CKD (CrCl <15 mL/min) or are on dialysis, it might be reasonable to prescribe warfarin (INR 2.0-3.0) or an evidence-based dose of apixaban for oral anticoagulation to reduce the risk of stroke.6,7

Synopsis CKD is a risk factor for stroke in patients with AF, in- dependent of other risk factors.8 The prevalence of AF among patients with renal failure on dialysis is high, in- cluding asymptomatic AF.9 Despite compelling evidence in the general population, conflicting data exist as to whether AF is a risk factor for stroke in patients on di- alysis.10,11 Potential explanations for this discrepancy include competing risks of stroke and mortality, a high prevalence of undiagnosed AF in cohorts thought not to have AF, and the confounding effect of anticoagulation thrice weekly during hemodialysis.12 VKAs are limited by a markedly reduced time in therapeutic range in patients with severe CKD, including those on dialysis,13 and as- sociation with calciphylaxis.14 The pivotal DOAC trials excluded patients on dialysis, and recommendations for dosing are based on pharmacokinetic data only. Early ex- perience with dabigatran and rivaroxaban in this popula- tion suggested an increased risk of bleeding relative to warfarin, driven by the higher dose of each.15 Only dabi- gatran is substantially removed by dialysis.16 A small RCT and a retrospective population-based cohort study found a lower risk of thromboembolism with rivaroxaban ver- sus warfarin,17,18 but these findings await confirmation in larger studies. Limited data on LAAO exist in this group of patients, and prospective comparison to anticoagula- tion or no therapy is awaited.19

Recommendation-Specific Supportive Text 1. Early trials demonstrating the role of warfarin anti-

coagulation in preventing stroke did not enroll or

separately report outcomes in patients with CKD. An analysis of the SPAF III trial showed that dose- adjusted warfarin, compared with fixed low-dose warfarin plus aspirin, reduced the risk of stroke with a similar magnitude to patients with normal kidney function.3 In the AVERROES trial of apixa- ban versus aspirin in patients deemed unsuitable for warfarin, apixaban showed similar efficacy in patients with an estimated glomerular filtration rate (eGFR) of 25 to 50 mL/min as those with an eGFR >50 mL/min.20 Patients with CKD stage 3, which includes those with an eGFR of 30 to 60 mL/min, were enrolled in the pivotal trials of the DOACs and showed similar results compared with warfarin as seen in patients with normal kidney function.2

2. Evidence on the use of anticoagulation in patients with AF and stage 4 CKD (eGFR, 15-30 mL/ min/1.73 m2) is largely observational. A prospec- tive, multicenter cohort study of survivors of MI with AF found that warfarin prescription at discharge associated with a reduced risk of death, readmis- sion due to MI, ischemic stroke, and bleeding.5 An analysis of patients with CrCl 25 to 30 mL/min at the time of enrollment in the ARISTOTLE trial found numerically fewer stroke and major bleeding events with apixaban than warfarin.4 Because CrCl overes- timates eGFR, a proportion of the patients enrolled in the pivotal clinical trials of DOACs, which used CrCl cut-offs for enrollment, had CKD stage 4 as assessed by eGFR in current clinical practice.

3. The role of anticoagulation in patients with AF and severe CKD, including those on dialysis, is contro- versial.6,7,21,22 Pending the results of RCTs compar- ing warfarin with no treatment, and warfarin with DOACs, SDM incorporating risks of bleeding and thromboembolism is encouraged. The pivotal clinical trials of apixaban excluded patients with CrCl <25 mL/min.23,24 Subsequently, the FDA-approved label- ing was extended to include those with end-stage renal failure, including those on hemodialysis.25 A subsequent pharmacokinetic study found that drug levels with apixaban 2.5 mg twice daily approximate those seen with 5 mg twice daily in patients with normal renal function, suggesting 2.5 mg is a more appropriate dose in such patients.26 A large retro- spective cohort study of Medicare beneficiaries found no difference in thromboembolism, but less major bleeding, in patients treated with apixaban ver- sus warfarin.27 Another analysis found an increased risk of thromboembolism and of fatal or intracranial bleeding with apixaban 5 mg twice daily versus no anticoagulation but not with apixaban 2.5 mg twice daily.28 Two small trials of apixaban versus warfarin in patients with AF on hemodialysis could not show differences in safety or efficacy outcomes but sig- nificantly more bleeding than stroke events.29,30

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6.8.5. AF in VHD Recommendations for AF in VHD Referenced studies that support the recommendations are summarized in the Online Data Supplement.

COR LOE Recommendations

1 B-R

1. In patients with rheumatic mitral stenosis or mitral stenosis of moderate or greater severity and history of AF, long-term anticoagulation with warfarin is recommended over DOACs, independent of the CHA2DS2-VASc score to prevent cardiovascular events, including stroke or death.1

1 B-NR 2. In patients with AF and valve disease other than

moderate or greater mitral stenosis or a mechanical heart valve, DOACs are recommended over VKAs.2–8

Synopsis At least one-third of patients with AF have some degree of VHD. Patients with AF and VHD have a higher preva- lence of stroke and systemic thromboembolism than those patients with AF without VHD.9 Patients with VHD and AF should be evaluated for risk of thromboembolic events and treated with oral anticoagulation if they are at high risk or if they have significant mitral stenosis or a mechanical heart valve. VKAs are the anticoagulation drugs of choice for patients with rheumatic mitral steno- sis, mechanical heart valves, and new-onset AF within 3 months after mechanical aortic or mitral valve surgery.10

Recommendation-Specific Supportive Text 1. Historical data have reported that in patients

with mitral stenosis and AF, stroke risk was nearly 18-fold higher than an age-, sex-, and hypertension-matched population without AF.11 More recently, stroke or systemic embolism rates ranged between 0.4 and 4 per 100 patient-years among anticoagulated patients and were high- est in those with previous embolism. Warfarin is generally prescribed, but it has been questioned whether a DOAC may be an alternative. A ret- rospective cohort study from Korea examined 2230 individuals with mitral stenosis and AF who were prescribed either warfarin or a DOAC,

using propensity matching on 10 clinical vari- ables. Thromboembolic events in the DOAC group were 2.22% per year compared with 4.19% per year in the warfarin group (HR, 0.28 [95% CI, 0.18-0.45]).12 However, in the INVICTUS (The Investigation of Rheumatic AF Treatment Using VKAs, Rivaroxaban or Aspirin Studies) RCT,1 patients with AF, rheumatic heart disease, and mitral stenosis had a mean survival time to a pri- mary outcome event of stroke, systemic embolism, MI, or death from vascular or unknown cause of 1 675 days if treated with a VKA compared with 1 599 days if with rivaroxaban (difference, –76 days [95% CI, –121 to –31]; P<0.001).

2. Although patients with moderate to severe mitral stenosis or mechanical valve were excluded from DOAC trials, other forms of VHD were allowed, such as aortic stenosis or mitral regurgitation. Bioprosthetic valves and valve repair were allowed in the edoxaban (ENGAGE AF) and apixaban (ARISTOTLE) trials, and valve repair in the rivaroxa- ban (ROCKET AF) trial. A systematic review13 of patients with VHD (other than moderate to severe mitral stenosis or mechanical valve) concluded that DOACs were safe. A meta-analysis confirmed that DOACs decreased the risk of stroke/systemic embo- lism compared with warfarin in patients with (HR, 0.70 [95% CI, 0.58-0.86]) and without VHD (HR, 0.84 [95% CI, 0.75-0.95]).14 However, for patients with mechanical heart valves,15 the RE-ALIGN (Randomized, Phase II Study to Evaluate the Safety and Pharmacokinetics of Oral Dabigatran Etexilate in Patients After Heart Valve Replacement)10 trial was halted during phase II after enrolling 252 subjects due to increased thromboembolism and bleeding in the dabigatran arm. PROACT Xa (A Trial to Determine if Participants with an On-X Aortic Valve Can be Maintained Safely on Apixaban) was also terminated early due to higher thromboem- bolic events with apixaban in patients who were >3 months after mechanical On-X aortic valves.

Table 19. Recommended Doses of Currently Approved DOACs According to Renal Function

CrCl (mL/min)

DOAC >95 51-95 31-50 15-30 <15 or on dialysis

Apixaban 5 or 2.5 mg twice daily* 5 or 2.5 mg twice daily* 5 or 2.5 mg twice daily* 5 or 2.5 mg twice daily* 5 or 2.5 mg twice daily*

Dabigatran 150 mg twice daily 150 mg twice daily 150 mg twice daily 75 mg twice daily Contraindicated

Edoxaban Contraindicated 60 mg once daily 30 mg once daily 30 mg once daily Contraindicated

Rivaroxaban 20 mg once daily 20 mg once daily 15 mg once daily 15 mg once daily 15 mg once daily†

Note that other, nonrenal considerations such as drug interactions may also apply. The gray area indicates doses not studied in the pivotal clinical trials of these agents. *If at least 2 of the following are present: serum creatinine ≥1.5 mg/dL, age ≥80 y, or body weight ≤60 kg, the recommended dose is 2.5 mg twice daily. The ARIS-

TOTLE trial excluded patients with either a creatinine of >2.5 mg/dL or a calculated CrCl <25 mL/min. †Rivaroxaban is not recommended for other indications in patients with a CrCl <15 mL/min, but such a recommendation is not made for the AF indication. However,

pharmacokinetic data are limited. AF indicates atrial fibrillation; ARISTOTLE, Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation; CrCl, creatinine clearance; and

DOAC, direct oral anticoagulant.

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6.8.6. Anticoagulation of Typical AFL Recommendations for Anticoagulation of Typical AFL* Referenced studies that support the recommendations are summarized in Online Data Supplement.

COR LOE Recommendations

1 B-NR 1. For patients with AFL, anticoagulant therapy is

recommended according to the same risk profile used for AF.1–3

1 C-LD

2. In patients with AFL who undergo successful cardioversion or ablation resulting in restoration of sinus rhythm, anticoagulation should be continued for at least 4 weeks postprocedure.1–4

1 A

3. Patients with typical AFL who have undergone suc- cessful CTI ablation and have had AF previously detected before AFL ablation should receive ongoing oral anticoagulation postablation as indicated for AF.5,6

1 B-NR

4. Patients with typical AFL who have undergone suc- cessful CTI ablation and are deemed to be at high thromboembolic risk, without any known previous history of AF, should receive close follow-up and arrhythmia monitoring to detect silent AF if they are not receiving ongoing anticoagulation in view of significant risk of AF.7–9

2b B-NR

5. In patients with typical AFL who have undergone successful CTI ablation without any known previous history of AF who are at high risk for development of AF (eg, LA enlargement, inducible AF, chronic obstructive pulmonary disease [COPD], HF), it may be reasonable to prescribe long-term anticoagulation if thromboembolic risk assessment suggests high risk (>2% annual risk) for stroke.5,10–13

*This section refers to typical right-sided (CTI-dependent) AFL. Left-sided AFLs or atrial tachycardias (ATs) that develop after ablation of AF should be anticoagulated and managed in a manner similar to AF. “Typical” AFL is defined as either typical counterclockwise AFL when the macroreentrant circuit is de- pendent on the CTI using the isthmus from the patient’s right to left or typical clockwise AFL when the macroreentrant circuit is dependent on the CTI and uses this isthmus from the patient’s left to right. “Atypical” AFL is not dependent on the CTI and may arise from a macroreentrant circuit in the LA, such as perimitral or LA roof flutter or could be dependent on scar from previous ablation or surgery.

Synopsis AFL is a common atrial arrhythmia with a reported overall incidence of 88 per 100 000 person-years, and the inci- dence increases with age.14 AFL is 2.5 times more com- mon in men than in women, and it is significantly more likely to occur in patients with underlying HF or COPD.14

Because of the high success rate and low recurrence rate of typical AFL after CTI ablation, catheter ablation is often used as a first-line treatment. The high effective- ness of CTI ablation may decrease thromboembolic risk so that many physicians may elect to discontinue oral anticoagulation >1 month after ablation in the absence of previously detected AF. However, the high incidence of new onset AF at some time after CTI ablation places this practice in question. Because AF may be subclini- cal or asymptomatic, patients could be at significant risk of thromboembolic events after ablation of typical AFL depending on thromboembolic risk factors.

Catheter ablation of non–CTI-dependent AFL is technically more difficult, and “atypical” AFL or AT often occurs after AF ablation. These arrhythmias should be

anticoagulated and managed in a manner similar to AF. Recommendations in this section refer to treatment of “typical” AFL.

Recommendation-Specific Supportive Text 1. AFL is associated with increased thromboembolic

risk, but the exact risk and benefit of oral antico- agulation are difficult to ascertain as AFL and AF often coexist. In a population-based retrospective cohort study of patients with typical AFL and no history of AF, stroke occurred in 4.1% of patients with AFL compared with 1.2% of a general pop- ulation-matched cohort (P<0.001).1 However, no large, randomized trials specifically address throm- boembolic risks and benefits of anticoagulation in patients who have only AFL.

In patients referred for ablation of typical AFL without adequate previous appropriate anticoagu- lation, and no previous history of AF, TEE showed evidence for LA thrombus or dense spontaneous echocardiographic contrast in 3%.2 A systematic review identified thromboembolic event rates of 0% to 6% with cardioversion, with the highest inci- dence of thromboembolic events occurring 1 to 2 days postcardioversion of AFL.3 Echocardiographic studies reported LA thrombus in 0% to 38% and spontaneous echocardiographic contrast in 21% to 28% of cases.3 In 1 ablation study, thromboem- bolic events occurred in 13.9% of patients who did not receive anticoagulation.3 Observational studies report an elevated risk of stroke with AFL com- pared with a control group (RR, 1.4 [95% CI, 1.35- 1.46]) and elevated mortality risk (risk ratio, 1.9 [95% CI, 1.2-3.1]) with long-term follow-up.3

2. The incidence of embolism after cardioversion of AFL is similar to that of AF (0.72% versus 0.46%; P=not significant).4 Atrial stunning has been noted on TEE in patients undergoing cardioversion of AF, with partial atrial recovery 15 to 30 days and full recovery 30 to 90 days postcardioversion.15 LAA stunning also occurs in patients with AFL, although it appears to occur at a lesser degree than what is seen with AF.16 Although limited data are avail- able for AFL, 1 study demonstrated more force- ful mechanical LAA contraction and absence of spontaneous echocardiographic contrast 2 weeks after ablation of persistent AFL, suggesting ear- lier recovery.17 Because LA and LAA stunning are thought to contribute to thrombus formation and thromboembolic events after cardioversion, con- tinued anticoagulation is recommended early after conversion to sinus rhythm.

3. In a meta-analysis, the subsequent incidence of AF after ablation of CTI-dependent AFL was 34% over 14 months. However, the incidence of AF after flut- ter ablation is significantly higher in patients with

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a history of AF before ablation than those without AF before ablation (53% versus 23% after 16-18 months; P<0.05).5 The incidence of AF continues to increase over time in both patients with and without previous AF.5 Oral anticoagulation reduces risk of stroke or systemic thromboembolism in the setting of nonvalvular AF.6 Because AF is not nec- essarily reduced after ablation of AFL, continued anticoagulation is recommended based on throm- boembolic risk assessment.The acute success rate for catheter ablation typical AFL is reported to be 92% with a single procedure and 97% with multiple procedures in a meta-analysis.18 However, the sub- sequent incidence of AF occurring after ablation of CTI-dependent AFL is reported to be 16% to 82%,5,10,11 with a higher incidence in patients with a history of AF before ablation than those without (53% versus 23% after 16-18 months; P<0.05).5 In 1 study, 82% of patients who underwent typi- cal AFL ablation experienced new-onset AF during long-term follow-up (mean, 39 months).11

4. Because of the high rate of occurrence of new- onset AF after CTI ablation, close follow-up and monitoring are recommended. In patients undergo- ing AFL ablation, the detection of AF in patients without previous AF significantly increased with

more frequent monitoring and/or longer duration of follow-up.7 This is especially important in patients at high risk of stroke or thromboembolism (>2%/ year). Intermittent monitoring may be performed with ambulatory monitors or wearable devices. Alternatively, implantable devices can provide more prolonged and continuous monitoring. Implantable cardiac monitors have been used in multiple set- tings to detect AF, including after AF ablation or in patients with cryptogenic stroke. Implantable car- diac monitors have also been used for surveillance after AF ablation.9

5. Factors that predict AF after flutter ablation include LA enlargement,19–21 inducible AF at the time of flutter ablation,22,23 interatrial conduction time,24 prolonged HV interval,25 COPD,26 obstructive sleep apnea,20 and HATCH (hypertension, age ≥75 years, TIA or stroke, COPD, heart failure) score.21 One study that reported new-onset AF in 38% of patients after AFL ablation demonstrated a thromboembolic event rate of 10% during a mean follow-up of 5 years.12 In a Danish registry of patients undergoing flutter ablation, 5% of patients suffered a stroke, and 10% died during a mean follow-up of 4 years.13

Thus, patients who undergo successful flut- ter ablation are not free from thromboembolic

Figure 16. Anticoagulation for Typical (CTI-Dependent) AFL *Intraprocedural documentation of bidirectional block. †For example, left atrial enlargement, inducible AF, COPD, concomitant heart failure. Colors correspond to Table 2. AF indicates atrial fibrillation; AFL, atrial flutter; COPD, chronic obstructive pulmonary disease; and CTI, cavotricuspid isthmus.D

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complications during long-term follow-up, likely due to a high rate of development of new-onset AF.

7. RATE CONTROL 7.1. Broad Considerations for Rate Control

Recommendations for Broad Considerations for Rate Control Referenced studies that support the recommendations are summarized in the Online Data Supplement.

COR LOE Recommendations

1 B-NR

1. In patients with AF, SDM with the patient is recom- mended to discuss rhythm- versus rate-control strategies (taking into consideration clinical presen- tation, comorbidity burden, medication profile, and patient preferences), discuss therapeutic options, and for assessing long-term benefits.1–3

2a B-R

2. In patients with AF without HF who are candidates for select rate-control strategies, heart rate target should be guided by underlying patient symptoms, in general aiming at a resting heart rate of <100 to 110 bpm.2,4–6

Synopsis Rate control is a suitable strategy for many patients with AF.1,3 A solitary randomized trial has evaluated the optimal heart rate among patients with AF. In the RACE II study (Rate Control Efficacy in Permanent Atrial Fibrillation: A Comparison Between Lenient Ver- sus Strict Rate Control II), 614 patients with perma- nent AF were randomly assigned to either lenient rate control (resting heart rate <110 bpm) or strict rate control (heart rate, <80 bpm). A difference was not seen regarding either the primary composite outcome of death from cardiovascular causes, hospitalization for HF, stroke, systemic embolism, bleeding, and life- threatening arrhythmic events (absolute difference of –2.0 percentage points [90% CI, –7.6 to 3.5; P<0.001] for the noninferiority margin)2 or the secondary out- come of QOL7 at 3 years. These data suggest heart rate control intensity is not a central determinant of clinical outcomes. However, interpretation is limited by a difference of only 10 bpm between study groups attributable to the proportion of patients assigned to strict control who did not achieve target rate control (32.6%; n=98/301) and because 78% of lenient rate control participants having heart rate <100 bpm.8 In addition, because patients with HF were underrep- resented, whether the results can be extrapolated to those with HF is unknown. Nonrandomized data fo- cused on target heart rate among outpatients,4,9,10 as well as those with HF,5,11–16 are divergent.

Recommendation-Specific Supportive Text 1. Rate- and rhythm-control strategies have com-

parable clinical outcomes in many patients with AF. In the AFFIRM (Atrial Fibrillation Follow-up Investigation of Rhythm Management) study, rate control was comparable to cardioversion and

antiarrhythmic drugs regarding survival (HR, 1.15 [95% CI, 0.99-1.34]; P=0.08).1 In the HOT CAFE (How to Treat Chronic Atrial Fibrillation) trial, rate control was comparable to cardioversion and use of antiarrhythmic drugs with respect to a composite endpoint of all-cause mortality, number of thrombo- embolic events, or major bleeding (OR, 1.98 [95% CI, 0.28-22.3]; P>0.71).6 In a meta-analysis of ran- domized trials and observational studies comparing rhythm with rate control, management strategies were comparable with respect to all-cause (OR, 1.34 [95% CI, 0.89-2.02]) and cardiac mortality (OR, 0.96 [95% CI, 0.77-1.20]) as well as stroke (OR, 0.99 [95% CI, 0.76-1.30]).3 Although selec- tion of a rhythm-control therapy within a year of AF diagnosis may be considered to reduce the risk of adverse cardiovascular outcomes,17 early rate control may still be appropriate as a function of clinical presentation, comorbidity burden, medica- tion profile, and patient preferences. In this con- text, providers should partner with their patients to select a value-concordant approach within an SDM framework.

2. In RACE II, rate-control intensity (target resting heart rate, <110 bpm versus <80 bpm) did not influence cardiovascular morbidity or mortality.6,18 Rate control (AFFIRM: goal heart rate, ≤80 bpm at rest and ≤110 bpm during a 6-minute walk test; HOT CAFE: 70-90 bpm at rest and ≤140 bpm with moderate exercise) has been shown to be com- parable to rhythm control in a meta-analysis of 5 trials, yet some limitation of the studies include that most patients had well-tolerated persistent AF or high risk of recurrence, no long-term follow-up, and should not be extrapolated to patients with parox- ysmal AF, highly symptomatic, or patients with HF.1 Observational data among outpatients and those with HF are conflicting.4 In the ORBIT-AF trial, increasing heart rate was associated with higher all-cause mortality9 and incident HF.10 Whether a lenient rate-control strategy may be safely and effectively used in patients with heart failure with preserved ejection fraction (HFpEF)5,14 or reduced fraction11–13,15,16 has also shown conflicting results. Other populations that may benefit from a low heart rate goal include those with rate-related car- diac dysfunction,19 ICDs,20 cardiac resynchroniza- tion therapy,21 and tachycardia-bradycardia form of sick sinus syndrome22 (Table 20).

7.2. Specific Pharmacological Agents for Rate Control The overall goals for rate control in patients with both acute and chronic AF with a rapid ventricular response center on control of symptoms and the risk of developing

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LV systolic dysfunction. In general, nondihydropyridine calcium channel blockers (diltiazem and verapamil) and beta blockers are the standard of care in rate-control- ling AF. Nondihydropyridine calcium channel blockers slow conduction through the atrioventricular node and have negative inotropic and chronotropic effects. These agents are useful in ventricular rate control in the ab- sence of preexcitation. They provide reasonable rate control and also improve AF-related symptoms com- pared with beta blockers.1,2 Beta blockers also slow conduction through the atrioventricular node by block- ing beta-1 receptors. Digoxin is a time-honored medi- cation for patients with AF particularly among patients with HFrEF due to its positive inotropic and vagotonic effects. Limited data exist directly comparing rate-con- trol agents, especially in the setting of long-term rate control. Selection of specific agents should consider patient-specific characteristics and response. This sec- tion will outline the principles of treatment for acute and long-term rate control.

7.2.1. Acute Rate Control Recommendations for Acute Rate Control Referenced studies that support the recommendations are summarized in the Online Data Supplement.

COR LOE Recommendations

1 B-R

1. In patients with AF with rapid ventricular response who are hemodynamically stable, beta blockers or nondihydropyridine calcium channel blockers (vera- pamil, diltiazem; provided that EF >40%) are recom- mended for acute rate control (Figure 17).1–4

2a B-R

2. In patients with AF with rapid ventricular response in whom beta blockers and nondihydropyridine calcium channel blockers are ineffective or contraindicated, digoxin can be considered for acute rate control, either alone or in combination with the aforemen- tioned agents.5–9

2a A

3. In patients with AF with rapid ventricular response, the addition of intravenous magnesium to standard rate-control measures is reasonable to achieve and maintain rate control.10,11

2b B-NR

4. In patients with AF with rapid ventricular response who are critically ill and/or in decompensated HF in whom beta blockers and nondihydropyridine calcium channel blockers are ineffective or contraindicated, intravenous amiodarone may be considered for acute rate control.*12,13

3: Harm

B-NR

5. In patients with AF with rapid ventricular response and known moderate or severe LV systolic dysfunction with or without decompensated HF, intravenous nondihydropyridine calcium channel blockers should not be administered.14,15

*Consider the risk of cardioversion and stroke when using amiodarone as a rate-control agent.

Synopsis Controlling the ventricular rate in AF with a rapid ventric- ular response in the acute setting can vary effectiveness for control of symptoms. It can also present challenges, given some agents may or may not be preferable in the context of underlying comorbidities given the myriad of contributing factors. For patients requiring intravenous rate-control agents, hypotension and/or the presence of decompensated HF may limit use of otherwise effica- cious agents. In the acute setting, recognizing patients needing emergency cardioversion is important.

Recommendation-Specific Supportive Text 1. A randomized, double-blind, placebo-controlled trial

investigated the safety and efficacy of continuous intravenous diltiazem infusion for 24-hour heart rate control during AF and AFL. Seventeen of the 23 patients (74%) receiving diltiazem infusion and none of the 21 with placebo infusion maintained a therapeutic response for 24 hours. Over 24 hours, patients receiving diltiazem infusion lost response significantly more slowly than did those receiving placebo infusion. In another RCT, patients were ran- domly assigned in 1:1:1 ratio to receive intravenous diltiazem, digoxin, or amiodarone for ventricular rate control. At 24 hours, rate control was achieved in 119 of 150 patients (79%). The time to rate control was significantly shorter among patients in the dil- tiazem group, with the percentage of patients who achieved rate control being higher in the diltiazem group (90%) than the digoxin group (74%) and the amiodarone group (74%). A randomized, parallel, open-label study aimed to investigate esmolol ver- sus verapamil in the acute treatment of AF or AFL. The heart rate significantly declined with esmo- lol and verapamil. Fifty percent of esmolol-treated patients with new onset of arrhythmias converted to sinus rhythm, whereas only 12% of those who received verapamil converted. Mild hypotension was observed in both treatment groups.

2. The use of intravenous digoxin has been shown to be effective in controlling the rate of rapid AF compared

Table 20 Clinical Presentations and Objectives of Heart Rate Control

Presentation Objective

Symptomatic AF To reduce symptoms

Tachycardia-induced cardiomy- opathy

To improve heart function or reduce the risk of recurrent cardiomyopa- thy19

ICD use To reduce risk of inappropriate shock20

Cardiac resynchronization therapy use

To enhance biventricular pacing, likelihood of myocardial recovery, and/or preservation of function21

Tachycardia-bradycardia form of sick sinus syndrome among those with a pacemaker

To reduce the risk of hospitalization22

AF indicates atrial fibrillation; and ICD, implantable cardioverter-defibrillator.

Recommendations for Acute Rate Control (Continued)

COR LOE Recommendations

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with placebo in 1 multicenter RCT.5 However, other agents may be safer and more effective in achieving acute rate control. Intravenous diltiazem was more effective than intravenous digoxin in 2 small RCTs.6,7 One trial performed at an emergency department at an academic center randomized 150 patients with AF without major comorbidities and a ventricular rate >120 bpm in a 1:1:1 ratio to intravenous diltia- zem, digoxin, and amiodarone.6 The time to reduce the heart rate <90 bpm was significantly shorter in the diltiazem group compared with either digoxin or amiodarone, with fewer symptoms and shorter hos- pital lengths of stay. Another RCT of 30 patients randomized patients with AF and a rapid ventricular response to either intravenous diltiazem, digoxin, or a combination of both agents. Treatment with intra- venous diltiazem significantly decreased heart rate within 5 minutes versus 3 hours with intravenous digoxin.7 Intravenous diltiazem reduced heart rate

more rapidly than intravenous digoxin in a double- blinded RCT in 40 patients with rapid AF after CABG, with similar control at 12 to 24 hours. In another RCT of 84 patients in rapid AF who presented to the emergency department, intravenous amiodarone resulted in faster control of the ventricular response compared with intravenous digoxin.8 Finally, 52 patients with rapid AF were randomized to receive either an intravenous combination of diltiazem and digoxin or intravenous diltiazem alone, with a more rapid and durable response to the combination.9

3. In addition to atrioventricular nodal blockers and antiarrhythmics, intravenous magnesium has been investigated for rate controlling rapid AF. 10,11 The mechanism likely stems from blockade of slow inward calcium channels in the sinoatrial and atrio- ventricular node, thereby slowing the heart rate and prolonging atrioventricular conduction veloc- ity, respectively.16 Its low adverse effect profile

Table 21. Pharmacological Agents for Rate Control in Patients With AF

Intravenous Administration Oral Maintenance Dose Elimination Half-Life Notes

Beta blockers

Metoprolol tartrate 2.5-5 mg bolus over 2 min; up to 3 doses

25-200 mg, twice daily 3-4 h

Metoprolol succinate N/A 50-400 mg daily or twice daily in divided doses

3-7 h

Atenolol N/A 25-100 mg daily 6-7 h Renally eliminated

Bisoprolol N/A 2.5-10 mg daily 9-12 h

Carvedilol N/A 3.125-25 mg, twice daily 7-10 h

Esmolol 500 μg/kg bolus over 1 min; then 50-300 μg/kg/min

N/A 9 min

Nadolol N/A 10-240 mg daily 20-24 h

Propranolol 1 mg over 1 min; repeat as needed every 2 min; up to 3 doses

10-40 mg, 3-4 times daily IV: 2.4 h Oral: 3-6 h ER: 8-20 h

Nondihydropyridine calcium channel blockers

Diltiazem 0.25 mg/kg (actual body weight) IV over 2 min May repeat 0.35 mg/kg over 2 min; then 5-15 mg/h con- tinuous infusion

120-360 mg daily (ER) IV: 3-5 h Oral immediate release: 3-4.5 h ER: 4-9.5 h

Avoid in HFrEF

Verapamil 5-10 mg over ≥2 min (may repeat twice); then 5 mg/h continuous infusion (max 20 mg/h)

180-480 mg daily (ER) IV: 6-8 h Oral: 2-7 h ER: 12-17 h

Avoid in HFrEF

Digitalis glycoside

Digoxin 0.25-0.5 mg over several min; repeat doses of 0.25 mg every 6 h (maximum 1.5 mg/24 h)

0.0625-0.25 mg daily 1-2 d Renally eliminated Increased mortality at plasma concen- trations exceeding 1.2 ng/mL

Other

Amiodarone 150-300 mg IV over 1 h, then 10-50 mg/h over 24 h

100-200 mg daily (generally IV form used for rate control)

IV: 9-36 d Oral: 26-107 d

Loading dose 6-10 g ad- ministered over 2-4 wk; can combine IV and oral dosing to complete

AF indicates atrial fibrillation; ER, extended release; HFrEF, heart failure with reduced ejection fraction; IV, intravenous; and N/A, not applicable.

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and minimal toxicity make it a favorable option, often as an adjunct to conventional therapy (ie, atrioventricular nodal blockers). A meta-analysis including 6 RCTs (n=745 patients) investigated the effectiveness of intravenous magnesium in rate and rhythm control of rapid AF when admin- istered in combination with standard rate-control methods (including beta blockers, diltiazem, vera- pamil, digoxin), as well as placebo. In the pooled analysis, intravenous magnesium was superior in achieving rate control (63% versus 40%; OR, 2.49 [95% CI, 1.80-3.45]) and modestly effective in rhythm conversion to sinus (21% versus 14%; OR, 1.75 [95% CI, 1.08-2.84]) compared with standard rate-control methods. Subgroup analy- sis showed the superiority of a lower dose (≤5 g) (24% versus 13%; OR, 2.10 [95% CI, 1.22-3.61]) compared with the higher dose (>5 g) (16% ver- sus 13%; OR, 1.23 [95% CI, 0.65-2.32]) in rhythm control when compared with placebo.10

4. Intravenous amiodarone has been shown to be effective in controlling ventricular rates in patients who are critically ill. In a retrospective study of 38 patients admitted to the intensive care unit, intra- venous amiodarone was associated with a statis- tically significant decrease in heart rate without decrease in BP compared with intravenous dil- tiazem and digoxin.12 One study of 60 critically ill patients, predominantly with AF, with heart rate consistently >120 bpm randomized patients to 1 of 3 intravenous treatment regimens: diltiazem in a 25-mg bolus followed by a continuous infusion

of 20 mg/h for 24 hours; amiodarone in a 300- mg bolus; and amiodarone in a 300-mg bolus fol- lowed by 45 mg/h for 24 hours.13 A >30% rate reduction within 4 hours was not statistically dif- ferent in either treatment arm, with less effective control more frequently observed in those receiv- ing a bolus of amiodarone alone; thus overall, dil- tiazem allowed for significantly better heart rate control over 24 hours, but it also caused a signifi- cantly higher incidence of hypotension requiring discontinuation of the drug.

5. Limited data exist regarding the use of nondihydro- pyridine calcium channel blockers in patients with HFrEF, due to the presumed limitation of negative inotropic effects. Two retrospective analyses high- light potential for increased morbidity when admin- istered in this population. In a retrospective analysis of patients hospitalized with AF with rapid ven- tricular rate (RVR), diltiazem was associated with an increased risk of acute kidney injury within 48 hours of initiation of diltiazem in those patients with LVEF ≤50%, compared with those with normal EF (10% versus 3.6%; P=0.002).14 An additional ret- rospective analysis compared patients with HFrEF receiving either intravenous metoprolol or diltiazem. There was a higher incidence of worsening HF symptoms (increased oxygen requirement within 4 hours or initiation of inotropic support with 48 hours) in those patients receiving diltiazem (33% versus 15%; P=0.019). Neither analysis noted an increase in the in-hospital mortality rate, need for a higher level of care, or hypotension.

Figure 17. Acute Rate Control in AF With RVR. *Contraindicated in patients with moderate- severe LV dysfunction regardless of decompensated HF. Colors correspond to Table 2. AF indicates atrial fibrillation; AV, atrioventricular; HF, heart failure; LV, left ventricular; and RVR, rapid ventricular response.

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7.2.2. Long-Term Rate Control Recommendations for Long-Term Rate Control Referenced studies that support the recommendations are summarized in the Online Data Supplement.

COR LOE Recommendations

1 B-NR

1. In patients with AF, beta blockers or nondihydropyri- dine calcium channel blockers (diltiazem, verapamil) are recommended for long-term rate control with the choice of agent according to underlying substrate and comorbid conditions.1,2

2a B-NR 2. For patients with AF in whom measuring serum

digoxin levels is indicated, it is reasonable to target levels <1.2 ng/mL.3–6

2a B-R

3. In patients with AF and HF symptoms, digoxin is reasonable for long-term rate control in combination with other rate-controlling agents, or as monotherapy if other agents are not preferred, not tolerated, or contraindicated.7–9

3: Harm

C-LD

4. In patients with AF and LVEF <40%, nondihydro- pyridine calcium channel–blocking drugs should not be administered given their potential to exacerbate HF.10,11

3: Harm

B-R 5. In patients with permanent AF who have risk factors

for cardiovascular events, dronedarone should not be used for long-term rate control.12

Synopsis Both nondihydropyridine calcium channel blockers (vera- pamil and diltiazem) and beta blockers are effective for long-term rate control. These agents are useful in ventric- ular rate control in the absence of preexcitation. Digoxin may be useful in patients with limited tolerability to other agents, or as adjunct therapy in patients with a difficult to control ventricular rate. Limited data exist comparing various rate control agents, especially in the setting of chronic rate control. Selection of specific agents should consider patient-specific characteristics (ie, HFrEF, reac- tive airway disease) and response (Figure 18).

Recommendation-Specific Supportive Text 1. One prospective, randomized, investigator-blinded,

crossover study compared the effect of 4 rate- reducing once-daily drug regimens on the ventric- ular heart rate and arrhythmia-related symptoms in patients with permanent AF. The 24-hour mean heart rate was 96±12 bpm at baseline (no treat- ment), 75±10 bpm with diltiazem, 81±11 bpm with verapamil, 82±11 bpm with metoprolol, and 84±11 bpm with carvedilol. All drugs significantly reduced the heart rate compared with baseline.13 In a retrospective cohort study, investigators used a database from 2 urban emergency departments to identify consecutive patients with emergency department discharge diagnoses of AF. A total of 259 consecutive patients were enrolled, with 100 receiving calcium channel blockers and 159 receiv- ing beta blockers. Baseline demographics and comorbidities were similar. Twenty-seven percent of patients taking beta blockers were admitted,

31.0% of patients taking calcium channel blockers were admitted, and there were no significant dif- ferences in emergency department length of stay, adverse events, or 7- or 30-day emergency depart- ment revisits. A follow-up analysis of the AFFIRM study examined the difference in all hospitalization and all-cause mortality in participants treated with a single rate-control agent at baseline. No differ- ence was found among those participants receiv- ing beta blockers, nondihydropyridine calcium channel blockers, or digoxin.2

2. Seminal work investigating digoxin toxicity was based on a small series of patients, where toxic- ity was determined by electrocardiographic abnor- malities.14 Toxicity was seen when serum digoxin concentrations exceeded 2.0 ng/mL, and almost certainly at levels >3.0 ng/mL. Based on this small study, the narrow therapeutic range of digoxin is usually cited as 0.8 to 2.0 ng/mL, with substan- tial variation across institutional laboratories and published references.15,16 However, 3 post hoc analyses of the DIG (Digitalis Investigation Group) trial suggested that safe use of digoxin is seen at lower serum concentrations.4–6 Serum digoxin con- centrations of 0.5 to 0.9 ng/mL were associated with significantly lower all-cause mortality rates and hospitalizations compared with concentrations ≥1.0 ng/mL.3 Another analysis suggested that serum digoxin concentrations >1.2 ng/mL may be harmful, particularly in women.7 A post hoc analy- sis comparing patients with AF taking digoxin with propensity score-matched controls suggested that patients with serum digoxin concentrations <0.9 ng/mL had no increased risk of death, concen- trations of 0.9 to 1.1 ng/mL had a nonsignificant increased risk of death, and serum digoxin concen- trations ≥1.2 ng/mL were associated with a signifi- cant (56%) increased risk of death.4 Serum digoxin concentrations of 0.5 to 0.8 ng/mL seem safest in terms of benefit without adverse effects in patients with HFrEF.17

3. Digoxin may have added efficacy as rate control in conjunction with beta blockers in patients with AF. A small RCT of 47 patients with persistent AF and concomitant HFrEF compared the effects of digoxin alone, carvedilol alone, and their combina- tion.10 Combination therapy was significantly asso- ciated with better rate control and symptom relief than monotherapy with either agent. The RATE-AF trial randomized 160 patients with persistent AF and concomitant HFrEF to digoxin and bisopro- lol.11 No significant differences in the primary end- point of QOL were noted at 6 months with either agent. Several secondary outcomes, including N-terminal pro-brain natriuretic peptide level, were significantly lower in the digoxin group, without a

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significant difference in resting heart rate between the 2 groups at 12 months. Adverse effects were less common in the digoxin group. A large meta- analysis of 75 studies and approximately 620 000 patients found a significantly increased risk of death in digoxin users overall but, when limited to 7 RCTs (∼8400 patients), no difference in mortality rate was observed between digoxin or placebo— of note, these 7 RCTs in the subanalysis were in patients with concomitant HF.9 A post hoc sensi- tivity analysis assessing the impact of digoxin on mortality in patients with HF and concomitant AF found no impact on overall mortality in patients tak- ing digoxin, most with HFrEF.

4. MDPIT (Multicenter Diltiazem Postinfarction Trial) demonstrated an association of worsening HF in patients with a recent MI, with LV dysfunction ran- domized to diltiazem. Among those with a baseline EF of <40%, late HF appeared in significantly more patients receiving diltiazem compared with placebo (21% versus 12%; P=0.004). Life table analysis in patients with an EF of <40% confirmed significantly more frequent late HF in those tak- ing diltiazem. In addition, the diltiazem-associated rise in the frequency of late congestive heart failure (CHF) was progressively greater with increasingly severe decrements in baseline EF.10

5. The safety and efficacy of dronedarone, origi- nally designed as an antiarrhythmic to maintain sinus rhythm in patients with AF, was addressed in several seminal trials.18–20 PALLAS (Palbociclib Collaborative Adjuvant Study) was designed to investigate whether dronedarone would reduce major vascular events or hospitalizations in patients with permanent AF. The benefits of dronedarone in patients with permanent AF were initially sug- gested from the ERATO (Efficacy and Safety of Dronedarone for the Control of ventricular rate during atrial fibrillation) trial, which showed a

significant reduction in the ventricular response for patients with paroxysmal and permanent AF in the 24-hour setting, which were carried forward in a 6-month follow-up.12 PALLAS randomized approxi- mately 3200 patients with permanent AF at high risk for adverse events. The trial was terminated early, because of the strong signal for harm in 43 patients receiving dronedarone versus 19 receiv- ing placebo, namely death (13/21 due to arrhyth- mia), stroke, and hospitalization for HF.12

7.3. Atrioventricular Nodal Ablation (AVNA) Recommendations for AVNA Referenced studies that support the recommendations are summarized in the Online Data Supplement.

COR LOE Recommendations

1 C-LD

1. In patients with AF and a persistently rapid ventricular response who undergo AVNA, initial pacemaker lower rate programming should be 80 to 90 bpm to reduce the risk of sudden death.1,2

2a B-R

2. In patients with AF and uncontrolled rapid ventricular response refractory to rate-control medications (who are not candidates for or in whom rhythm control has been unsuccessful), AVNA can be useful to improve symptoms and QOL.3–6

1 B-NR

3. In patients with AF who are planned to undergo AVNA, implantation of a pacemaker before the ablation (ie, before or same day of ablation) is recommended to ensure adequacy of the pacing leads before performing ablation.7–9

2b C-LD 4. In patients with AF with normal EF undergoing AVNA,

conduction system pacing of the His bundle10–13 or left bundle area12,13 may be reasonable.

Synopsis AVNA provides ventricular rate control effectively and without medications yet creates dependence on pacing.3 Consideration of the consequences of lifelong pace- maker implantation, particularly with respect to age and comorbidities, is central to decision-making regarding benefit.

Figure 18. AF Long-Term Rate Control. Colors correspond to Table 2. AF indicates atrial fibrillation; LVEF, left ventricular ejection fraction; and NDCC, nondihydropyridine calcium channel blocker.

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Small RCTs of AVNA and right ventricular pacing (RVP) have shown improvements in symptoms and QOL compared with medical rate control alone but found no significant differences in EF or other measures of car- diac performance.3,14 Progression to persistent AF is described in many patients with previously paroxysmal AF after AVNA.15,16 Antiarrhythmic drugs reduce the transition to permanent AF but do not improve QOL or echocardiographic parameters, and patients treated with antiarrhythmic drugs have more episodes of HF and hos- pitalizations.17

Early concerns regarding AVNA included risks for device-related complications, sudden cardiac death, and worsened HF. Deaths due to malignant arrhythmias have been nearly eradicated by programming higher lower- rate pacing in the early postprocedure period.1,2,18 The risks of HF may be ameliorated by non-RVP strategies, but data are limited in patients who do not have HF before AVNA.19

Overall, long-term data on outcomes after AVNA are limited, and no evidence supports AVNA as first-line therapy.9

Recommendation-Specific Supportive Text 1. Early observational studies showed a concerning

incidence of sudden death after AVNA in 3% to 7% of patients.20,21 This immediate postprocedural risk results from ventricular fibrillation (VF) pre- dominantly due to bradycardia, QT prolongation, and heterogeneity of repolarization. Initiation of VF is often pause dependent or occurs during a rela- tively slow pacing rate.18 Deaths due to malignant arrhythmias have been minimized by current proto- cols specifying higher lower-rate pacing in patients after AVNA in the early postprocedure period.1,2,18 Subsequent lower rate adjustment is performed over the course of several weeks.

2. AVNA and pacemaker implantation provide safe and effective rate control in the fraction of patients with AF who cannot be effectively rate controlled with medical therapy3,4,22 and in whom sinus rhythm has failed or is not deemed to be effective. A meta-analysis of 6 small RCTs of studies compar- ing AVNA and pacemaker versus medical therapy or medical therapy with pacemaker including 323 subjects with paroxysmal or persistent AF showed improvement in symptoms and QOL in the AVNA group.6 No differences in survival, stroke, hospital- ization, EF, or exercise capacity were found. There was no effect of AVNA on all-cause mortality in a pooled analysis.6 Nonrandomized studies have shown improvement in a range of clinical out- comes5 in addition to data showing improved EF in patients with suspected tachycardia-related car- diomyopathy after AVNA.23 These favorable find- ings in nonrandomized studies are likely subject

to the placebo effect of device implantation. Early and late complication rates are not inconsequen- tial, specifically in young patients in view of the risk of pacemaker-mediated cardiomyopathy, and long- term follow-up data are scant.9

3. Although few studies concerning AVNA and pac- ing report complication rates for the pacemaker implant, the overall risk of lead dislodgement or failure is approximately 2%, and many operators perform both AVNA and pacemaker implant dur- ing the same procedure.9,13,24 Practice patterns vary, however, and a European survey indicated up to 80% of operators will choose to perform AVNA 1 to 3 months after pacemaker implantation to reduce risk of adverse outcome due to early lead dislodgement.25 In the prospective FOLLOWPACE registry from 23 centers in the Netherlands, lead dislodgment was the most frequent lead-related complication, occurring in 3.3% of patients within the first 2 months of implant.7 Relevant to the older age population usually undergoing AVNA, a pooled patient-level analysis of 4814 subjects from CTOPP (Canadian Trial of Physiologic Pacing), UKPACE (United Kingdom pacing and cardiovas- cular events), and Danish pacing trials—designed to compare pacemaker implantation complication rates in age <75 years versus age ≥75 years— found a higher risk of early complications in those age ≥75 years (5% versus 3%), driven by a higher rate of lead dislodgement (2%) and pneumothorax (1.6%).8 If AVNA and pacing are performed con- comitantly, ideally, leads should be placed first to ensure adequate lead function.

4. HF after AVNA is attributed to the deleterious effects of RVP,26 and risk is correlated with base- line cardiac function.9 The PAVE (Post AV Nodal Ablation Evaluation) trial compared outcomes in patient with persistent AF and uncontrolled rates undergoing AVNA and RVP with AVNA and biven- tricular pacing (BiVP) and found an improvement in 6-minute walk test and EF, but benefit was pre- dominantly seen in subjects with EF <45% or New York Heart Association (NYHA) class II to III HF at baseline.27 Not all patients appear to be at high risk of HF after AVNA and RVP.28 Because the benefit is less and the risk of complications is higher in BiVP compared with conventional pacing, RVP is advised in patients with preserved EF undergoing AVNA.19

Conduction system pacing of the His bundle or left bundle area offers promise to reduce the risk of RVP-induced cardiomyopathy and improve outcomes. Early studies have justifiably focused on patients with HF undergoing AVNA, and lim- ited data are available in patients with preserved EF and no HF diagnosis.27 His bundle pacing with

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AVNA has been shown to be feasible and associ- ated with improvements in EF in patients with EF <40%, and NYHA class, albeit with elevated pac- ing thresholds.10,11 Left bundle area pacing may deliver the advantages of His bundle pacing with reduced risk of elevated pacing thresholds or lead dislodgement.12 Early studies have shown stable EF with conduction system pacing and AVNA in follow-up, and improvement in patients with EF <50%.12,24

8. RHYTHM CONTROL 8.1. Goals of Therapy With Rhythm Control

Recommendations for Goals of Therapy With Rhythm Control Referenced studies that support the recommendations are summarized in the Online Data Supplement.

COR LOE Recommendations

1 B-R

1. In patients with reduced LV function and persistent (or high burden) AF, a trial of rhythm control should be recommended to evaluate whether AF is contributing to the reduced LV function.1–6

2a B-R 2. In patients with symptomatic AF, rhythm control can

be useful to improve symptoms.7–11

2a B-R 3. In patients with a recent diagnosis of AF (<1 year),

rhythm control can be useful to reduce hospitaliza- tions, stroke, and mortality.12–14

2a B-R

4. In patients with AF and HF, rhythm control can be useful for improving symptoms and improving out- comes, such as mortality and hospitalizations for HF and ischemia.15–19

2a B-NR 5. In patients with AF, rhythm-control strategies can be

useful to reduce the likelihood of AF progression.20–27

2b C-LD

6. In patients with AF where symptoms associated with AF are uncertain, a trial of rhythm control (eg, cardio- version or pharmacological therapy) may be useful to determine what if any symptoms are attributable to AF.28–32

2b B-NR

7. In patients with AF, rhythm-control strategies may be useful to reduce the likelihood of development of dementia or worsening cardiac structural abnormali- ties.33–45

Synopsis When caring for a patient with AF, deciding between rhythm and rate control is important but critical to ac- knowledge that the decision is nuanced, can evolve over time, and that the 2 strategies are necessarily not mu- tually exclusive depending on the definition used. For example, in EAST-AFNET 4 (Early Treatment of Atrial Fibrillation for Stroke Prevention Trial), which random- ized patients with recently identified AF to rhythm- or rate-control strategies, in those patients randomized to the rhythm control arm, initially 87% were treated with antiarrhythmic drugs and 8% with AF ablation; but, at 2 years, 35% were not on antiarrhythmic drugs or had re- ceived AF ablation.12 Similarly, although the decision on whether to use rhythm control is often based on symp- toms, in a post hoc analysis of the same trial, benefits

in the composite outcome of death, stroke, or cardiac hospitalization was observed in all patients regardless of whether symptoms were present or not.30 Data from EAST-AFNET 4 and large registries have consistently demonstrated the importance of monitoring patients for increased AF burden once AF has been identified and that rhythm-control therapies are more likely to be suc- cessful when implemented early when AF burden begins to increase.13,14,30,46,47 Finally, for all patients with AF, con- tinued long-term management of modifiable risk factors is essential.48

Recommendation-Specific Supportive Text 1. AF and reduced LV function are often recognized

in the same patient, with the combination being associated with worse prognosis when compared with patients with either HF or AF alone.1,49 Several studies have demonstrated improved LV func- tion in patients with AF after restoration of sinus rhythm.2–6 The incidence of AF or other atrial arrhythmias as an important contributor to reduced LVEF is unknown and likely dependent on arrhyth- mia burden, ventricular rates, and other factors.4–6 However, in patients who present with both AF and reduced LV function or develop reduced LV function after an initial diagnosis of AF, where no identifiable cause for the reduced LV function is observed, AF should initially be assumed as a very possible cause until proven otherwise. Although AF as a cause for reduced LV function is usually considered in the setting of rapid ventricular rates, improved LV function with rhythm control has been reported in the setting of AF with relatively well controlled heart rates.2,3

2. Rhythm and rate control can improve symptoms in AF.7,8,50,51 Multiple studies have shown improved QOL with rhythm control.7–9,50,51 Continued symp- toms due to AF are common with rate control. In the RACE II study, lenient rate control had similar primary outcomes (a combination of cardiovascu- lar death, hospitalization for HF, and several other endpoints) compared to strict rate control, but at the end of the follow-up period (>2 years), 46% of patients in both groups had continued symptoms associated with AF.10 Although a different popula- tion, symptoms due to recurrent AF were identified in 56 of 303 (18%) patients with newly identified AF undergoing rhythm control with either AADs or catheter ablation.11

3. EAST-AFNET 4 randomized 2733 patients with early onset AF (<1 year) and other risk factors for stroke to rhythm control or rate-control strat- egies.12 Rhythm control was associated with a 25% reduction in the combined endpoint of mor- tality rate, stroke, and hospitalizations due to HF or ACS. In 2 observational studies, 1 from claims

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data and another from a large national database, when compared with rate control, early initiation of rhythm control (<1 year) in patients with AF was associated with 15% and 19% reductions in the combined endpoint of cardiovascular death, ischemic stroke, or hospitalization for ischemia or HF, respectively.13,14 However, these recent find- ings must be balanced against studies that have reported increased emergency department visits and health care resource utilization associated with rhythm control.52–54

4. In the AF-CHF (Atrial Fibrillation and Congestive Heart Failure) trial, rhythm control did not affect cardiovascular mortality but was associated with improved QOL.15,55 Contemporary trials in patients with AF and HF, regardless of LV function, and often using catheter ablation as an important therapy, have reported trends or statistically significant improvement in clinical

outcomes associated with rhythm control when compared to rate control.16,17,49,56–58 In an analysis of patients with HF in EAST-AFNET 4, rhythm control was associated with a significant reduc- tion in the composite primary endpoint of car- diovascular death, stroke, or hospitalization due to HF or acute ischemic syndrome (HR, 0.74 [95% CI, 0.56-0.97]; P=0.03).16 Similarly, in the CABANA (Catheter Ablation vs Antiarrhythmic Drug Therapy for Atrial Fibrillation) trial, cath- eter ablation-based rhythm control was asso- ciated with a 46% reduction in the mortality rate in patients with HF compared with medi- cal therapy.19 Although catheter ablation is more effective in maintaining sinus rhythm than anti- arrhythmic drugs, maintenance of sinus rhythm was higher in the AF-CHF trial. In this study, amiodarone was the preferential strategy for rhythm control (82% of patients) compared

Figure 19. Patient and Clinical Considerations for Choosing Between Rhythm Control and Rate Control. Patient and clinical considerations for deciding between rhythm- and rate-control strategies in a patient with a high burden of AF. AF indicates atrial fibrillation; AV, atrioventricular; LA, left atrium; and LV, left ventricular.

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with the ablation-based CASTLE-AF (Catheter Ablation versus Standard Conventional Therapy in Patients with Left Ventricular Dysfunction and Atrial Fibrillation) trial (sinus rhythm at study completion: AF-CHF: 75% versus CASTLE-AF: 66%), and additionally the benefit of rhythm control in patients with HF is likely greatest in those patients with recently identified AF.15–18,49

5. AF commonly, but not always, progresses over time to higher burdens and becomes more sus- tained.20,59 Large registry studies have reported that AF progression is more commonly observed with a rate-control strategy compared to a rhythm-control strategy over a 1- to 2-year period, although the absolute magnitude and difference has varied. For example, in 2 registry studies, pro- gression to a more sustained form of AF burden was observed in 26% to 28% of patients under- going a rate-control strategy compared with 6% to 11% of patients treated with a rhythm-control strategy while, in an analysis of the ORBIT AF trial, although rhythm control was associated with a lower likelihood of progression, AF progression was much more common regardless of strategy (66% for rate control and 56% for rhythm control) likely due to older patients in this cohort.21–23 AF

progression is a complex process, and although the choice between rhythm-control and rate-con- trol strategy has an impact, many other factors such as age, presence or absence of HF or other comorbidities, LA size, heart rate, and modifiable risk factors are also important.21–27

6. The reported prevalence of asymptomatic AF var- ies from 10% to 40% depending on study cohort.28 Asymptomatic and symptomatic patients with AF have similar risks for death and stroke.28,29 In a post hoc analysis of EAST-AFNET 4, similar mag- nitudes of benefit were observed in symptomatic and asymptomatic patients for reducing the com- bined endpoint of cardiovascular death, stroke, and hospitalization for HF.30 Nevertheless, the evidence base for the benefits of a rhythm-control trial in asymptomatic patients with sinus rhythm is limited. Improved energy with return to sinus rhythm was noted in 1 observational study of 13 asymptomatic patients with persistent AF.31 In another study that included 18 asymptomatic patients, at 1-month fol- low-up, no patients had improvement in symptoms, although sinus rhythm was maintained in only 35% of patients.32 In 2 small studies that focused on the impact of catheter ablation in asymptomatic patients, maintenance of sinus rhythm was associated with

Figure 20. Flowchart for Treatment Choices When Required to Decrease AF Burden. *Younger with few comorbidities. Colors correspond to Table 2. AF indicates atrial fibrillation.

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improved QOL indices in all patients, but 24% to 34% of patients developed symptoms mainly due to AT after the ablation procedure.53,54

7. AF is associated with increased cognitive impair- ment, progressive increase in AF burden, and structural changes in the heart.33,34 Nonrandomized studies from registries or post hoc analyses of ran- domized trials have reported that rhythm control is associated with a reduction in the incidence of dementia and development of HF.36–38 Furthermore, AF can also be an etiologic reason for mitral regur- gitation or tricuspid regurgitation.39–45 In 1 study of 53 patients referred for AF ablation with moderate mitral regurgitation or worse, maintenance of sinus rhythm at follow-up was associated with signifi- cant decreases in LA size, mitral annular dilatation, and mitral regurgitation.39 In another study, 70% of patients undergoing ablation for AF who main- tained sinus rhythm at follow-up had improvement in mitral regurgitation.40 Similar results have been found in tricuspid valve function as assessed by echocardiography.42–45

8.2. Electrical and Pharmacological Cardioversion Cardioversion to restore sinus rhythm is a mode of acute rhythm control. Cardioversion can be achieved electrically or pharmacologically. Electrical cardioversion, given rapid- ity and efficacy, is the treatment of choice for patients with hemodynamic instability attributable to AF. Acute rhythm control with cardioversion should also be considered for patients with hemodynamically stable AF intolerant of atrioventricular dyssynchrony, loss of atrial kick, or unable to achieve adequate rate control. In patients with hemo- dynamically stable AF, both electrical cardioversion and pharmacological cardioversion are acceptable, safe, and efficacious methods for acute rhythm control.1–3 Electri- cal cardioversion is more effective than pharmacological cardioversion alone4,5 but involves the trade-off of anes- thesia or sedation.6 Thromboembolic risks and consider- ations for anticoagulation apply to both pharmacological cardioversion and electrical cardioversion.7,8

8.2.1. Prevention of Thromboembolism in the Setting of Cardioversion

Recommendations for Prevention of Thromboembolism in the Setting of Cardioversion Referenced studies that support the recommendations are summarized in the Online Data Supplement.

COR LOE Recommendations

1 B-R

1. In patients with AF duration of ≥48 hours, a 3-week duration of uninterrupted therapeutic anti- coagulation or imaging evaluation to exclude intra- cardiac thrombus is recommended before elective cardioversion.1

1 B-NR

2. In patients with AF undergoing cardioversion, thera- peutic anticoagulation should be established before cardioversion and continued for at least 4 weeks afterwards without interruption to prevent thromboembolism.2–7

1 C-LD

3. In patients with AF in whom cardioversion is deferred due to LAA thrombus detected on precardioversion imaging, therapeutic anticoagulation should be insti- tuted for at least 3 to 6 weeks, after which imaging should be repeated before cardioversion.1,8

2b B-NR

4. In patients with AF and previous LAAO who are not on anticoagulation, imaging evaluation to assess the adequacy of LAAO and exclude device-related throm- bosis before cardioversion may be reasonable.9–19

2b C-LD 5. In patients with AF and previous LAAO with residual

leak, pericardioversion anticoagulation may be considered and continued thereafter.9–11,20

2b C-LD

6. In patients with reported AF duration of <48 hours (not in the setting of cardiac surgery) and who are not on anticoagulation, precardioversion imaging to exclude intracardiac thrombus may be considered ins those who are at elevated thromboembolic risk (CHA2DS2-VASc score ≥2 or equivalent).21,22

2b C-LD

7. In patients with low thromboembolic risks (CHA2DS2-VASc 0-1 or equivalent) and AF duration of <12 hours, the benefit of precardioversion imaging or pericardioversion anticoagulation is uncertain given the low incidence of pericardioversion thromboembolic events in this population.21,22

Synopsis Thromboembolic risks and considerations of antico- agulation apply to both pharmacological cardioversion and electrical cardioversion.23,24 Thromboembolic risks in the setting of acute cardioversion relate to preexist- ing thrombus, change in atrial mechanical function with restoration of sinus rhythm, atrial stunning postcardio- version, and transient prothrombotic state.2,25 DOACs are alternatives to VKAs as thromboprophylaxis in the setting of cardioversion.26–29 Given additional favorable attributes of rapid time to therapeutic efficacy, reliabil- ity of maintenance of therapeutic efficacy, and ease of continuation, DOACs may be preferentially consid- ered over VKAs for patients with AF planned for car- dioversion barring contraindications to DOAC therapy. Precardioversion imaging is prudent for patients with AF who have previously undergone LAAO and are not on anticoagulation.9,10,14–16,19 Thromboembolic risks for patients with <48 hours of AF were not homogenous but, rather, varied by a patient’s risk profile for throm- boembolic complications (as defined by risk scores in specific studies) and duration of AF.21,22 More nuanced consideration of a patient’s thromboembolic risks in the setting of cardioversion for AF may integrate a patient’s substrate for atrial myopathy and risks for thromboem- bolism instead of strict dependence on the previously used 48-hour duration threshold.

Recommendations for Prevention of Thromboembolism in the Setting of Cardioversion (Continued )

COR LOE Recommendations

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Recommendation-Specific Supportive Text 1. Early experience with both pharmacological and then

electrical cardioversion of AF led to the observation that thromboembolism was less frequent in patients who were chronically anticoagulated than those who were not.30 This led to an empiric recommendation for 3 weeks of anticoagulation before cardioversion in the prospective, randomized, multicenter ACUTE (Assessment of Cardioversion Using Tranesophageal Echocardiography) study of patients with >2 days’ duration of AF.31 Precardioversion anticoagulation of at least 3 weeks may be accomplished via either ther- apeutic anticoagulation with VKAs or DOACs.26–28 Cardiac computed tomography, particularly with delayed contrast-enhanced image acquisition proto- col, has emerged as an alternate imaging modality to exclude intracardiac thrombus.32–34

2. Rationales for establishment of therapeutic anti- coagulation before cardioversion and continuation for the subsequent 4 weeks after cardioversion for AF are driven by elevated thromboembolic risks,6,7,35 high early recurrence of AF,36 and obser- vation of atrial dysfunction2–5 during this period. Thromboembolic risks are elevated around the time of cardioversion, especially within the 30 days after cardioversion.6,7 The observation of spontane- ous echocardiographic contrast in association with atrial dysfunction on TEE after cardioversion raised mechanistic concerns for atrial stunning in the set- ting of cardioversion,2,3 with recovery of mechanical atrial systole over the ensuing 1 month.4,5 Rapidity of recovery of mechanical atrial systole may be influenced by clinical variables,37 duration of the antecedent AF episode leading to cardioversion,5

Figure 21. Patients With Hemodynamically Stable AF Planned for Cardioversion. Colors correspond to Table 2. AC indicates anticoagulation; AF, atrial fibrillation; and LAAO, left atrial appendage occlusion.

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and the extent of comorbid conditions as risks fac- tors for atrial myopathy.38

3. In patients with AF, detection of intracardiac thrombus should prompt cancellation of planned cardioversion and institution of therapeutic anti- coagulation in anticoagulant-naïve patients. Detection of intracardiac thrombus in patients already on anticoagulation should prompt assessment of compliance, dosing appropriate- ness, drug absorption, and drug interactions. In patients with thrombus detected despite already being anticoagulated, potential reasons should be investigated, such as nonadherence and drug interaction, which may cause subtherapeu- tic levels. Switching to an alternate anticoagu- lant can be considered, although the benefit is uncertain. In anticoagulant-naïve patients, 61.2% had resolution of thrombus on follow-up TEE performed 3 to 12 weeks after initiation of VKA in the CLOT-AF (Retrospective Registry Providing Baseline Data on the Outcome of Left Atrial [LA] or LA Appendage [LAA] Thrombus in Patients With Nonvalvular Atrial Fibrillation [AF] or Atrial Flutter After Standard of Care [SoC] Anticoagulant Therapy) study, and 41.5% had resolution of thrombus on follow-up TEE performed 6 weeks after therapy with rivar- oxaban in the X-TRA (Exploring the Efficacy of Once Daily Oral Rivaroxaban for Treatment of Thrombus in Left Atrial/Left Atrial Appendage in Subjects With Nonvalvular Atrial Fibrillation or Atrial Flutter) study.8 Repeat imaging (TEE or computed tomography32–34) is generally pursued after at least 3 to 6 weeks of therapeutic antico- agulation to assess for resolution of intracardiac thrombus before reconsidering cardioversion.1,8

4. In the subset of patients who have undergone surgical or pLAAO procedures, inadequate occlu- sion may be seen acutely during the procedure or delayed after the procedure.9–14 Inadequate LAAO has been associated with elevated risks for thromboembolism.9–11 Device-related thrombosis, reported in patients with pLAAO devices,15–19 has also been associated with elevated stroke/sys- temic embolism.15–18 Imaging with TEE or cardiac computed tomography can assess adequacy of LAAO, residual leak, and device-related thrombo- sis.39–41 In the setting of transesophageal echocar- diographic imaging before electrical cardioversion, device-related thrombus was detected in 2.7% (4 of 148 patients) of a small multicenter retrospec- tive analysis of patients with Watchman LAAO device.20 These 4 patients were treated with oral anticoagulation and after 6 to 8 weeks, on con- firmation of thrombus resolution by repeat TEE, underwent successful electrical cardioversion.20

5. Data are limited to guide pericardioversion antico- agulation in patients with LAAO. In the broader (not limited to cardioversion) context, residual leak ≤5 mm by computed tomography after LAAO by sur- gical ligation has been associated with particularly elevated stroke/system embolism risks (especially in the absence of anticoagulation)9 and similarly for residual leak <5 mm by TEE post-Lariat.10 A large analysis that stratified National Cardiovascular Data Registry LAAO registry Watchman 2.5 device patients by transesophageal echocardiographic observation of residual leak (none, ≤5 mm, >5 mm) at 45 days, found ≤5 mm residual leak to be common (13 258 of 51 333 patients; 25.8%) and associated with modestly higher incidence of thromboembolic events over 1-year follow-up com- pared with no leak.11 OAC use was more frequent in patients with large (>5 mm) residual leak.11 Data specific to the setting of cardioversion are further limited. The largest to date is a retrospec- tive multicenter study of 148 Watchman LAAO device patients who underwent electrical cardio- version after precardioversion exclusion of intra- cardiac thrombus or large residual leak (≥5 mm in this study) by TEE.20 No thromboembolic events were observed within 6 weeks of cardioversion, in recipients or nonrecipients of pericardioversion anticoagulation.20 However, detection of thrombo- embolic events may be limited by study’s sample size. Pericardioversion antithrombotic regimen was at the discretion of the treating physicians,20 and the relationship of anticoagulation with presence/ absence of small residual leak was not reported. Considerations for anticoagulation may also vary based on specific surgical or pLAAO procedures and devices.

6. The safety of cardioversion without further assess- ment or previous anticoagulation in patients with AF duration of <48 hours has been challenged. In addition to concerns for underestimation of actual duration of episode and burden due to potential for asymptomatic occurrence of AF, emerging data demonstrate that thromboembolic risks in patients with <48 hours of AF were not homogenously low. Time to cardioversion >12 hours has been reported as an independent predictor for thrombo- embolic complications.21 A single-center observa- tional study of patients undergoing cardioversion for AF of <48 hours duration did not observe thromboembolic events in patients with CHA2DS2- VASc score of 0 or 1 or patients with postoperative AF but noted differential thromboembolic rates in CHA2DS2-VASc score ≥2.42 Larger studies simi- larly demonstrated that among patients with <48 hours of AF, postcardioversion thromboembolic risks increased with increasing CHA2DS2-VASc

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score,22,43 especially in those with CHA2DS2-VASc score ≥2 in the absence of anticoagulation.22

7. Retrospective observational data from the FinCV (Finnish CardioVersion) study noted low incidence of 30-day pericardioversion thromboembolic event rate of 0.4% in patients with AF with CHA2DS2- VASc of 0 to 122 or 0.3% in patients with duration of <12 hours of AF.21 Other retrospective studies have similarly demonstrated low pericardioversion throm- boembolic risks in patients with CHA2DS2-VASc score of 0 to 1.42 The combination of CHA2DS2- VASc of 0 to 1 in conjunction with duration of <12 hours of AF may identify a population at particularly low risk for pericardioversion thromboembolism.

8.2.2. Electrical Cardioversion Recommendations for Electrical Cardioversion Referenced studies that support the recommendations are summarized in the Online Data Supplement.

COR LOE Recommendations

1 C-LD 1. In patients with hemodynamic instability attributable

to AF, immediate electrical cardioversion should be performed to restore sinus rhythm.1

1 B-R

2. In patients with AF who are hemodynamically stable, electrical cardioversion can be performed as initial rhythm-control strategy or after unsuccessful pharmacological cardioversion.2

1 C-LD

3. In patients with AF undergoing electrical cardiover- sion, energy delivery should be confirmed to be syn- chronized to the QRS to reduce the risk of inducing VF.3

2a B-R

4. For patients with AF undergoing elective electrical cardioversion, the use of biphasic energy of at least 200 J as initial energy can be beneficial to improve success of initial electrical shock.4,5

2a B-NR

5. In patients with AF undergoing elective cardiover- sion, with longer duration of AF or unsuccessful initial shock, optimization of electrode vector, use of higher energy, and pretreatment with antiarrhythmic drugs can facilitate success of electrical cardioversion.5–9

2b C-LD

6. In patients with obesity and AF, use of manual pressure augmentation and/or further escalation of electrical energy may be beneficial to improve suc- cess of electrical cardioversion.10

Synopsis Electrical cardioversion is a strategy for acute rhythm control. Compared with pharmacological cardiover- sion alone, electrical cardioversion with synchronized direct current cardioversion is more rapid and effica- cious for restoring sinus rhythm from AF.1,11,12 Given rapidity and efficacy, electrical cardioversion is the treatment of choice for patients with hemodynami- cally unstable AF.

In hemodynamically stable patients with AF planned for acute rhythm control, electrical cardioversion can be performed as an initial strategy or after unsuccessful pharmacological cardioversion.2,6,13,14 Electrical cardio- version is favored over pharmacological cardioversion when the patient is able to tolerate sedation, desires

more immediate rhythm conversion, or has failed or not met candidacy for pharmacological cardioversion.

Although electrical cardioversion may achieve acute restoration of sinus rhythm, durability of sinus rhythm may be influenced by ongoing acute conditions, LA size, duration of the history of AF and/or specific episode, and comorbidities.14 In patients with a longer duration of AF, immediate recurrence of AF, a previous unsuc- cessful electrical cardioversion, or a desire to employ all reasonable efforts to avoid an AF recurrence, pretreat- ment antiarrhythmic drugs and subsequent continuation to facilitate success of acute cardioversion and promote maintenance of sinus rhythm postcardioversion6,8,9 may be pursued in the context of SDM with the patient. Opti- mization of energy delivery, electrode vector, and reduc- tion of transthoracic impedance with manual pressure augmentation may also improve success of electrical cardioversion.5–10

Recommendation-Specific Supportive Text 1. In patients with hemodynamically unstable AF,

immediate electrical cardioversion with synchro- nized direct current cardioversion is the treatment of choice. Direct data on emergency cardioversion of hemodynamically unstable patients is limited because of the emergency circumstances of the clinical context. Data on direct current cardiover- sion of AF in hemodynamically stable patients demonstrate high success rate of restoring sinus rhythm with direct current cardioversion.1,11,15–18 Electrical cardioversion is rapid. Electrical cardio- version alone is more effective than pharmacologi- cal cardioversion alone.1,11,12

2. Goals of rhythm control are summarized in Section 8.1 (“Goals of Therapy With Rhythm Control”). Real-world data support both electrical cardio- version and pharmacological cardioversion as acceptable, safe, and efficacious methods for acute rhythm control.6,13,14 Electrical cardioversion is more effective than pharmacological cardiover- sion alone1,11 but involves the trade-off of requiring sedation.19 In patients with hemodynamically stable AF of recent onset, the RAFF2 (Electrical versus pharmacological cardioversion for emergency department patients with acute atrial fibrillation) study demonstrated high success of restoration of sinus rhythm with either an upfront electrical car- dioversion strategy or a stepwise strategy with ini- tial pharmacological cardioversion and then direct current cardioversion if the pharmacological inter- vention did not restore sinus rhythm.2 In patients with unsuccessful pharmacological cardioversion, instead of switching to another antiarrhythmic drug (and with concerns for potentiation of adverse effects such as QT prolongation or bradycardia), electrical cardioversion should be pursued as next

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step for acute rhythm control. Therefore, in patients with hemodynamically stable AF, electrical cardio- version is favored over pharmacological cardiover- sion when the patient is able to tolerate sedation, desires more immediate rhythm conversion, or has failed or not met candidacy for pharmacological cardioversion. Monitoring and preparedness dur- ing and after electrical cardioversion include monitoring for rare chronotropic, hemodynamic, or thromboembolic complications, and the effects of anesthesia administered during electrical cardioversion.6,13,14,20–22

3. Unsynchronized or inappropriately synchronized cardioversion can induce VF if the shock energy is delivered during the vulnerable period, the inscrip- tion of the T wave.3,23–25 Therefore, electrical car- dioversion for AF should be synchronized with the QRS complex. The synchronization feature needs to be turned on or confirmed that it is on; in patients who require multiple shocks, the synchro- nization feature must be manually activated and/or confirmed before each shock attempt. Visual con- firmation of synchronization to QRS is important to detect inappropriate synchronization and ensure appropriate synchronization.

4. An earlier small, multicenter, prospective random- ized study demonstrated higher efficacy of initial electrical cardioversion with a biphasic waveform instead of monophasic waveform.4 A more contem- porary single-centered, randomized study of 279 patients who were randomized to synchronized direct current cardioversion with biphasic wave- form with either upfront maximum-fixed energy or strategy of low-escalating energy found higher first shock success with maximum-fixed energy (75% compared with 34% for low-escalating energy group).5 In the contemporary RAFF2 study of patients with hemodynamically stable AF of recent onset, the upfront electrical cardioversion group with initial biphasic 200 J shock (and up to 3 con- secutive shocks allowed, with higher energy per- mitted for subsequent shocks) had conversion to sinus rhythm in 176 of 192 (92%) patients in this upfront electrical cardioversion shock-only group.2

5. A previous study of patients with persistent AF (median AF duration, 5 months) undergoing direct current cardioversion with escalation of energy found the anterior-posterior orientation of the elec- trode vector more successful at restoring sinus rhythm than an anterior-lateral vector,7 while a sub- sequent study of patients with recently diagnosed AF (≥3 hours and <7 days) undergoing direct cur- rent cardioversion using biphasic upfront 200 J showed similar success rates with electrode vec- tors in either anterior-posterior or anterior-lateral orientation.2 Taken together, when energy output

is optimized as biphasic and maximal output and the AF is of recent onset, either vector orientation may be reasonable, but for patients with longer duration of AF, the anterior-posterior orientation of electrode vector may be favorable.2 Manual pres- sure augmentation26 or administration of antiar- rhythmic drugs as pretreatment (Section 8.2.3, “Pharmacological Cardioversion”)6,8,9 may also facilitate electrical cardioversion.

6. Increased body weight has been associated with reduced success of electrical cardioversion.27 In a small randomized clinical study, use of paddles, manual pressure augmentation (using electrically silent objects as insulator), and further escalation of electrical energy improved success of electri- cal cardioversion of obese patients with AF,10 and the benefits of these maneuvers may mechanisti- cally relate to overcoming increased transthoracic impedance. Other alternatives in refractory cases include the use of 2 defibrillators simultaneously, effectively doubling the delivered energy.

8.2.3. Pharmacological Cardioversion Recommendations for Pharmacological Cardioversion Referenced studies that support the recommendations are summarized in the Online Data Supplement.

COR LOE Recommendations

2a C-LD

1. For patients with AF, pharmacological cardioversion is reasonable as an alternative to electrical cardiover- sion for those who are hemodynamically stable or in situations when electrical cardioversion is preferred but cannot be performed.1

2a A 2. For patients with AF, ibutilide2,3 is reasonable for

pharmacological cardioversion for patients without depressed LV function (LVEF <40%).

2a A

3. For patients with AF, intravenous amiodarone is rea- sonable for pharmacological cardioversion, although time to conversion is generally longer than with other agents (8-12 hours).4–8

2a A

4. For patients with recurrent AF occurring outside the setting of a hospital, the “pill-in-the-pocket” (PITP) approach with a single oral dose of flecainide9–11 or propafenone,10–14 with a concomitant atrioventricular nodal blocking agent,15 is reasonable for pharmaco- logical cardioversion if previously tested in a moni- tored setting.16–18

2b B-R

5. For patients with AF, use of intravenous procainamide may be considered for pharmacological cardioversion when other intravenous agents are contraindicated or not preferred.19

Synopsis Pharmacological cardioversion is indicated for patients with new-onset or persistent AF that is hemodynamically stable, or in rare instances when electrical cardioversion is desired but contraindicated. Ibutilide works rapidly for pharmacological cardioversion of AF but is associ- ated with QT interval prolongation and torsades de pointes, particularly in patients with HFrEF.2,3,20,21 Data support intravenous amiodarone for pharmacological

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cardioversion,4–8 although intravenous amiodarone re- quires a longer time for AF conversion than ibutilide. Evidence from randomized studies support the efficacy of flecainide9–11 and propafenone10–14 for pharmaco- logical cardioversion, and these drugs are reasonable for administration via the PITP approach for AF occurring outside of the hospital.16–18 Intravenous procainamide is more effective than placebo for pharmacological conver- sion of AF19 but is less effective than ibutilide.22,23 Dofeti- lide,24,25 oral amiodarone,26–28 and oral sotalol27,28 have been shown to be effective for conversion of AF to sinus

rhythm but require several days for efficacy and there- fore are not practical choices for acute pharmacological cardioversion. Data do not support intravenous sotalol for pharmacological cardioversion of AF.29,30

Recommendation-Specific Supportive Text 1. No studies compare the efficacy of electrical car-

dioversion with that of pharmacological cardiover- sion in patients with AF who are hemodynamically unstable. However, in a retrospective, propensity score-matched analysis of 374 hemodynamically

Table 22. Drugs for Pharmacological Conversion of AF to Sinus Rhythm

Drug Route of Administration Loading Dose

Maintenance Dose

Approximate Time to Conversion to Sinus Rhythm

Primary Route(s) of Elimination

Elimination Half-Life Major Adverse Effects

Amiodarone IV 5-7 mg/kg or 300 mg*

1200-3000 mg via continuous infusion over 24 h

8-12 h Liver metabolism Biliary excretion

9-36 d Bradycardia Hypotension QT prolongation Phlebitis TdP

Flecainide Oral† 200 mg if <70 kg, 300 mg if >70 kg, single dose

N/A 3-8 h Liver (70%) Kidney (30%)‡

12-27 h Atrial flutter AV block Dizziness Dyspnea Exacerbation of HFrEF Headache Nausea QT prolongation VT Visual disturbances

Ibutilide IV ≥60 kg: 1 mg over 10 min <60 kg: 0.01 mg/ kg over 10 min If arrhythmia does not terminate within 10 min after the end of the first infu- sion, may adminis- ter a second dose, equal to the first dose.

N/A 30-90 min Liver 2-12 h Nonsustained VT QT prolongation TdP

Procainamide IV 1 g over 30 min 2 mg/min continuous infusion over 1 h

30-60 min Liver (16-33%) Kidney (50-65%)‡

3-4 h (parent) 7 h (NAPA)

Agranulocytosis AV block Exacerbation of HFrEF Hypotension Neutropenia QT prolongation Rash Thrombocytopenia TdP

Propafenone Oral 450 mg if <70 kg, 600 mg if >70 kg, single dose

N/A 3-8 h Liver 9 h Atrial flutter AV block Dizziness Dyspnea Exacerbation of HFrEF Nausea Taste disturbances VT Visual disturbances

*Some studies have administered intravenous amiodarone for 24 h followed by oral administration. †Flecainide is available in an intravenous dosage form in Europe. ‡Percentage of a dose excreted unchanged in urine. AV indicates atrioventricular; AF, atrial fibrillation; HFrEF, heart failure with reduced ejection fraction; IV, intravenous; N/A, not applicable; NAPA, N-acetylprocainamide;

TdP, torsades de pointes; and VT, ventricular tachycardia.

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stable patients with AF who presented to an emergency department, the incidence of success- ful cardioversion was higher in the direct current cardioversion group (78.2%) than in those who underwent pharmacological conversion (59.2%) or those for whom a “wait-and-watch” approach (37.9%) was used (P<0.001).1 Compared with the “wait-and-watch” strategy, the ORs for conversion to sinus rhythm for direct current cardioversion and pharmacological cardioversion were 6.00 (95% CI, 3.38-10.66) and 2.47 (1.45-4.20), respectively (P<0.001). Due to the potential greater efficacy of direct current cardioversion compared with that of pharmacological cardioversion, and due to the need for rapid successful conversion to sinus rhythm, immediate electrical cardioversion is gen- erally the favored option, yet some patients may not be candidates (eg, cannot undergo anesthesia), for whom pharmacological options are available.31

2. Randomized, double-blind placebo-controlled stud- ies have established the efficacy of ibutilide2,3 for conversion of AF to sinus rhythm, with AF con- version rates of about 30% (compared with 2% in placebo groups).2,3 The efficacy of ibutilide is greater for AFL (conversion rates, 38%-63%) than for AF.2,3 Ibutilide terminates AF rapidly, with most

patients converting to sinus rhythm within 30 to 90 minutes (Table 22). Ibutilide is associated with a risk of QT interval prolongation and torsades de pointes. The incidence of torsades de pointes associated with ibutilide is higher in patients with reduced LVEF than in those with normal LVEF,2,3 and the risk seems particularly high in patients with severely depressed LVEF.20 HFrEF is an indepen- dent risk factor for ibutilide-associated torsades de pointes.3,21 Therefore, ibutilide is best avoided in patients with LVEF ≤40%. Of note, studies have shown that a magnesium infusion immediately before administration of ibutilide may mitigate the risk of torsades de pointes and excessive QT prolongation.32,33

3. Multiple randomized studies have found intrave- nous amiodarone to be effective for conversion of AF to sinus rhythm.4–7 A meta-analysis of random- ized, placebo-controlled studies reported relative risks of sinus rhythm associated with intravenous amiodarone at 6 to 8 hours and at 24 hours of 1.23 (P=0.022) and 1.44 (P<0.001), respectively.8 However, pharmacological cardioversion of AF with intravenous amiodarone requires 8 to 12 hours, compared with a much shorter response time with ibutilide (Table 22).

Figure 22. Treatment Algorithm for Pharmacological Conversion of AF to Sinus Rhythm. *In the absence of preexcitation. †First dose administered in a facility that can provide continuous electrocardiographic monitoring and cardiac resuscitation because of the potential for proarrhythmia or postconversion bradycardia. ‡IV amiodarone requires several hours for efficacy; ibutilide is generally effective in 30 to 90 min but carries a higher risk of QT interval prolongation and torsades de pointes. §Recommend avoidance of IV procainamide for patients initially treated with amiodarone or ibutilide to avoid excessive QT interval prolongation and torsades de pointes. Rather, procainamide may be considered for patients for whom amiodarone and ibutilide are not considered optimal as first-line drugs. Colors correspond to Table 2. AF indicates atrial fibrillation; HFrEF, heart failure with reduced ejection fraction; IV, intravenous; LV, left ventricular; LVEF, left ventricular ejection fraction.D

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4. Single oral doses of flecainide9–11 and propafe- none10–14 are effective for conversion of AF to sinus rhythm, with 3- to 4-hour conversion rates of 58% to 68% for flecainide (compared with 18%-29% for placebo) and 45% to 57% for propafenone (compared with 17%-29% for placebo) (Table 22). A beta blocker or nondihy- dropyridine calcium channel blocker is generally administered at least 30 minutes before a dose of flecainide or propafenone to prevent 1:1 atrioven- tricular conduction during AFL.15 The PITP strat- egy was studied in 268 patients with stable AF of recent onset who presented to the emergency department.16 Patients received single-dose oral flecainide or propafenone, and those who were successfully treated (n=210) were discharged with a plan for the PITP approach. In the 15±5- month follow-up period, single-dose flecainide or propafenone was successful in 94% of episodes. However, the incidence of adverse effects is not insignificant (6%-17%).16–18 In view of this, and because in most studies, most patients received the first dose in the hospital before taking it as an outpatient, the PITP strategy should only be used for highly selected patients and after it first has been observed to be safe and effective in an inpatient setting.17,18,34

5. Intravenous procainamide was shown to be more effective than placebo for conversion of AF to sinus rhythm (conversion rates at 1 hour, 69% versus 38%; P=0.012) in a randomized, double- blind study of 114 patients.19 However, intrave- nous procainamide is less effective than ibutilide for conversion of AF to sinus rhythm (conversion rates, 14% versus 76%; P=0.001).22 The effi- cacy of procainamide for conversion of AF to sinus rhythm was similarly inferior to that of ibu- tilide in an analysis of pooled data.23 In addition, intravenous procainamide is associated with a relatively high incidence of clinically significant hypotension (5%-12%)19,23 and can exacerbate HFrEF.

8.3. Antiarrhythmic Drugs for Maintenance of Sinus Rhythm 8.3.1. Specific Drug Therapy for Long-Term Maintenance of Sinus Rhythm

Recommendations for Specific Drug Therapy for Long-Term Maintenance of Sinus Rhythm Referenced studies that support the recommendations are summarized in the Online Data Supplement.

COR LOE Recommendations

2a A* 1. For patients with AF and HFrEF (≤40%), therapy

with dofetilide*1 or amiodarone†2 is reasonable for long-term maintenance of sinus rhythm.B-NR†

2a A

2. For patients with AF and no previous MI, or known or suspected significant structural heart disease, or ven- tricular scar or fibrosis, use of flecainide3–5 or propafe- none5–12 is reasonable for long-term maintenance of sinus rhythm.

2a A

3. For patients with AF without recent decompensated HF or severe LV dysfunction, use of dronedarone5,13–15 is reasonable for long-term maintenance of sinus rhythm.

2a A

4. For patients with AF without significant baseline QT interval prolongation or uncorrected hypokalemia or hypomagnesemia, use of dofetilide1,5,16 5–7,10,17,18 is reasonable for long-term maintenance of sinus rhythm, with proper dose selection based on kidney function and close monitoring of the QT interval, serum potassium and magnesium concentrations, and kidney function.

2a A

5. For patients with AF and normal LV function, use of low-dose amiodarone (100-200 mg/d) is rea- sonable for long-term maintenance of sinus rhy thm2,5,17–22 but, in view of its adverse effect pro- file,5,23,24 should be reserved for patients in whom other rhythm control strategies are ineffective, not preferred, or contraindicated.

2b A

6. For patients with AF without significant baseline QT interval prolongation, hypokalemia, hypomag- nesemia, or bradycardia, use of sotalol5–7,10,17,18 may be considered for long-term maintenance of sinus rhythm, with proper dose selection based on kidney function and close monitoring of the QT interval, heart rate, serum potassium and magnesium con- centrations, and kidney function.

3: Harm

B-R

7. In patients with previous MI and/or significant struc- tural heart disease, including HFrEF (LVEF ≤40%), flecainide and propafenone25 should not be adminis- tered due to the risk of worsening HF, potential proarrhythmia, and increased mortality.26,27

3: Harm

B-R

8. For patients with AF, dronedarone should not be administered for maintenance of sinus rhythm to those with NYHA class III and IV HF or patients who have had an episode of decompensated HF in the past 4 weeks, due to the risk of increased early mortality associated with worsening HF.28

*A LOE applies to data on dofetilide. †B-NR LOE applies to data on amiodarone.

Synopsis Antiarrhythmic drugs are reasonable for long-term main- tenance of sinus rhythm for patients with AF who are not candidates for, or decline, catheter ablation or who prefer antiarrhythmic therapy. Flecainide3–5 and propafenone5–11 are options for maintenance of sinus rhythm in patients with no previous history of MI or significant structural heart disease.26,27 Dronedarone is an option for maintenance of sinus rhythm in patients without recent decompensated HF or severe LV dysfunction.5,13–15 Dofetilide1,5,16 and sota lol5–7,10,17,18 are effective for maintenance of sinus rhythm but are associated with torsades de pointes and require QT interval monitoring. Sotalol is best avoided in patients with HFrEF, because most patients are already taking a beta blocker, and the addition of sotalol is unlikely to

Recommendations for Specific Drug Therapy for Long-Term Maintenance of Sinus Rhythm (Continued )

COR LOE Recommendations

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be well-tolerated. A Cochrane database meta-analysis of randomized studies5 reported sotalol to be associated with an increase in all-cause mortality (RR, 2.23 [95% CI, 1.03-4.81]). Low-dose amiodarone is more effec- tive than sotalol and Class IC agents for maintenance of sinus rhythm; but, in view of its adverse effects and multiple drug interactions, is best reserved for patients for whom other antiarrhythmic drugsare ineffective, not preferred, or contraindicated. However, amiodarone and dofetilide are options for maintenance of sinus rhythm for patients with HFrEF, as they are effective,1,2 and most other drugs are contraindicated.

Recommendation-Specific Supportive Text 1. In subanalyses of randomized trials, dofetilide1 and

amiodarone2 have been shown to be effective for maintenance of sinus rhythm in patients with AF who have HF. Most antiarrhythmic agents, except amiodarone and dofetilide, are contraindicated in patients with HFrEF due to worsening of HF and/ or increased mortality. Sotalol is best avoided in most patients with HFrEF, because most patients with HFrEFare already taking a beta blocker for mortality reduction, and the addition of a second beta blocker (sotalol) is unlikely to be well-tolerated. Therefore, although amiodarone is associated with a wide range of adverse effects and many clinically important drug interactions, amiodarone is often used as a first-line agent for maintenance of sinus rhythm in patients with AF and HFrEF. Dofetilide is also an option for this indication. Patients undergo- ing initiation or reloading of dofetilide29,30 should be admitted for at least 3 days to a health care facility that can provide calculations of CrCl, continuous electrocardiographic monitoring, and availability of cardiac resuscitation.

2. Randomized, controlled studies and a comprehen- sive Cochrane database analysis have established the efficacy of flecainide3–5 and propafenone5–11 for maintenance of sinus rhythm in patients with AF. In the Flec-SL (Short-term versus long-term antiar- rhythmic drug treatment after cardioversion of atrial fibrillation) trial,4 flecainide prevented episodes of paroxysmal AF in 31% of patients over 4 months compared with 9% in the placebo group (0.013). Sustained-release propafenone 425, 325, and 225 mg twice daily extended the median time to the occur- rence of AF, AFL, or supraventricular tachycardia (SVT) compared with placebo (>300, 291, and 112 days versus 41 days, P<0.001, for all propafenone doses versus placebo).8 Patients with previous MI or significant structural heart disease (scar or fibrosis) should not take flecainide of propafenone,26,27 and individuals taking flecainide or propafenone should be concomitantly taking an atrioventricular nodal blocking agent to reduce the risk of 1:1 AFL.12

3. Randomized, controlled studies13–15 and a compre- hensive Cochrane database analysis5 have estab- lished the efficacy of dronedarone for maintenance of sinus rhythm in patients with AF. The combined analysis (n=1237) of EURIDIS (European Trial in Atrial Fibrillation or Flutter Patients Receiving Dronedarone for the Maintenance of Sinus Rhythm) and ADONIS (American-Australian-African Trial with Dronedarone in Atrial Fibrillation or Flutter Patients for the Maintenance of Sinus Rhythm) reported longer median times to AF recurrence in dronedarone groups versus placebo (EURIDIS: 96 versus 41 days; P=0.001; ADONIS 158 versus 59 days; P=0.002).14

4. Randomized, controlled studies and a compre- hensive Cochrane database analysis5 have estab- lished the efficacy of dofetilide for maintenance of sinus rhythm in patients with AF. In the SAFIRE-D (Symptomatic Atrial Fibrillation Investigative Research on Dofetilide) study,1,16 the probabil- ity of remaining in sinus rhythm at 1 year was higher in patients receiving dofetilide 500 μg twice daily compared with placebo (0.58 versus 0.25; P<0.001). Patients undergoing initiation or reload- ing of dofetilide29,30 should be admitted for at least 3 days to a health care facility that can provide cal- culations of CrCl, continuous electrocardiographic monitoring, and cardiac resuscitation.

5. Multiple randomized, controlled studies have established the efficacy of amiodarone for main- tenance of sinus rhythm in AF and have shown amiodarone to be superior to other antiarrhyth- mic agents. In SAFE-T (Sotalol Amiodarone Atrial Fibrillation Efficacy Trial), amiodarone was superior to sotalol and placebo with respect to median time to recurrence of AF (487 versus 74 versus 6 days, respectively; P<0.001, for amiodarone versus pla- cebo and amiodarone versus sotalol).17 In CTAF (Canadian Trial of Atrial Fibrillation), AF recurrence rates at 16 months were 35% in the amiodarone group and 63% in those randomized to combined propafenone or sotalol (P<0.001).19 However, the adverse effects profile of amiodarone is oner- ous. Amiodarone is associated with a wide range of adverse effects, including pulmonary fibrosis, hypo- or hyperthyroidism, elevated transaminases, and more rarely hepatotoxicity, photosensitivity, changes in skin pigmentation, peripheral neuropa- thy, sinus bradycardia, QT interval prolongation and torsades de pointes, corneal microdeposits, and rarely optic neuropathy.24 In addition, amiodarone is associated with many clinically relevant drug inter- actions.31 Therefore, amiodarone is best reserved for patients who do not respond to other recom- mended antiarrhythmic agents or for whom other antiarrhythmic drugs are contraindicated.

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6. Randomized, controlled studies and a comprehen- sive Cochrane database analysis5 have established the efficacy of sotalol6,7,10,17,18 for maintenance of sinus rhythm in patients with AF. In SAFE-T, the median time to AF recurrence was 74 days in the sotalol group, compared with 6 days for placebo (P<0.001).16 A Cochrane database meta-analysis of 5 randomized studies totaling 1882 patients with AF5 reported sotalol to be associated with an increase in all-cause mortality (RR, 2.23 [95% CI, 1.03-4.81]). However, this study included patients with advanced HF, and sotalol may still have a role in patients with preserved heart function. Patients undergoing initiation or reloading of oral sotalol should be admitted for at least 3 days to a health care facility that can provide calculations of CrCl, continuous electrocardiographic monitoring, and cardiac resuscitation. A recent FDA-approved intravenous sotalol formulation can be used to evaluate the drug safety and tolerability within 6 hours and thus may reduce cost and length of stay, although the data are limited to a small sample size and very selected population.32

7. In the randomized, double-blind, placebo-controlled CAST (Cardiac Arrhythmia Suppression Trial),26,27

the Vaughan Williams class IC antiarrhythmic agents flecainide and encainide were associated with an increased mortality rate in patients with recent MI; most patients also had LVEF <50%.26 In the con- tinuation of the study (CAST-II), the class IC agent moricizine also increased the mortality rate within the first 14 days of treatment.33 In CASH (Cardiac Arrest Study Hamburg),34 propafenone was associ- ated with worse outcomes and increased mortality in a population of cardiac arrest survivors, most of whom had structural heart disease. Thus, IC agents are best avoided in patients with AF who have a previous MI or significant structural heart disease, including HFrEF, due to the risk of worsening HF and increased mortality.

8. ANDROMEDA (Antiarrhythmic Trial with Dronedarone in Moderate to Severe CHF Evaluating Morbidity Decrease)28 was a random- ized, double-blind placebo-controlled study that tested the hypothesis that dronedarone would reduce the rate of hospitalization attributable to HF and possibly reduce mortality by reducing the incidence of arrhythmic death. The study enrolled patients who were hospitalized with new or wors- ening HF and who had at least 1 episode of NYHA

Figure 23. Treatment Algorithm for Drug Therapy for Maintenance of Sinus Rhythm. In each box, drugs are listed in alphabetical order. Significant structural heart disease with scar or fibrosis. Colors correspond to Table 2. HFrEF indicates heart failure with reduced ejection fraction; HF, heart failure; IV, intravenous; LV, left ventricular; LVEF, left ventricular ejection fraction; MI, myocardial infarction; and NYHA FC, New York Heart Association functional class.

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class III or IV HF (shortness of breath on minimal exertion or at rest). More than 40% of the patients had NYHA class II HF at baseline. The investigators reported that, contrary to the study’s hypothesis, the mortality rate was higher in the dronedarone group compared with that in the placebo group (8.1% versus 3.8%; HR, 2.13 [95% CI, 1.07-4.25]; P=0.03). The higher mortality rate was principally associated with worsening HF.

8.3.2. Inpatient Initiation of Antiarrhythmic Agents Recommendations for Inpatient Initiation of Antiarrhythmic Agents Referenced studies that support the recommendations are summarized in the Online Data Supplement.

COR LOE Recommendations

1 A

1. Patients with AF who are initiating, increasing the dose of, or reinitiating dofetilide therapy should be admitted for a minimum of 3 days to a facility that can provide continuous electrocardiographic monitoring, calculations of CrCl, and cardiac resuscitation, given the potential for proarrhythmia.1–7

2a B-R

2. In patients with AF, it is reasonable to initiate sotalol therapy in a facility that can provide continuous electrocardiographic monitoring, calculations of CrCl, and cardiac resuscitation, given the potential for proarrhythmia and bradycardia.4,8–10

2a B-NR

3. In patients with AF who are initiating PITP dosing of flecainide and propafenone with concomitant atrioventricular nodal blocking drugs, it is reasonable to receive the first dose in a facility that can provide continuous electrocardiographic monitoring, given the potential for proarrhythmia.9–13

Synopsis Pharmacological rhythm control is an alternative to cath- eter ablation in appropriately selected patients. However, many antiarrhythmic agents have a paradoxic risk of proarrhythmia and require close monitoring on initiation. Dofetilide and sotalol confer a relatively high risk of tor- sades de pointes given they prolong the QT interval, and this can occur early during initiation. As such, patients need to be admitted and closely monitored when start- ing or reinitiating dofetilide, as well as for increasing the dosage. Many practitioners choose to initiate sotalol in an inpatient setting given it can cause torsades de pointes; furthermore, unlike dofetilide, it can also cause bradyar- rhythmia. Amiodarone, flecainide, and propafenone can be started in the outpatient setting. Because PITP with class IC (with concomitant atrioventricular nodal block- ers) can cause brady- or tachyarrhythmias, the first at- tempt during an acute episode of AF may be performed in a monitored environment if a high dose is used.

Recommendation-Specific Supportive Text 1. Dofetilide, a class III antiarrhythmic drug, is a

selective IKr blocker that also blocks late Na+ cur- rent (INaL) and poses a high risk for torsades de pointes. The SAFIRE-D (Symptomatic Atrial Fibrillation Investigative Research on Dofetilide) study investigated dofetilide in cardioverting and

maintaining sinus rhythm in 325 patients with AF or AFL who underwent a minimum 3-day hospi- talization.1 Of 241 patients randomized to dofeti- lide, 10 patients had QTc prolongation within the first 3 days, with 2 episodes of torsades de pointes degenerating to VF. In a substudy of the AFFIRM trial, 1 of 12 patients on dofetilide experienced torsades de pointes.3 One retrospective cohort of 378 patients found no significant differences in the incidence of torsades de pointes during inpa- tient initiation of dofetilide and sotalol (1.3% versus 1.2%).4 One systematic review found a 1% to 10% incidence of torsades de pointes in patients tak- ing dofetilide, highest in patients with HFrEF and taking higher than recommended (or not renally adjusted) doses.14 In 2 randomized RCTs from the DIAMOND (Management of Hyperkalemia in Subjects Receiving Renin-angiotensin-aldosterone System Inhibitor Medications for Heart Failure with Reduced Ejection Fraction) population, in which all patients were hospitalized for at least 3 days after dofetilide was initiated, torsades de pointes occurred in 25 of 762 patients (3.3%)5 and 7 of 749 patients (0.9%),7 respectively, with most occurring within the first 3 days of dosing. In the DIAMOND AF substudy of these trials,6 torsades de pointes occurred in 4 dofetilide-treated patients with AF (1.6%).

2. Sotalol is a class III antiarrhythmic with beta-block- ing properties. Its action potential prolongation (due to the IKr-blocking properties of the d isomer in concert with INaL blockade) predisposes patients to torsades de pointes. One meta-analysis dem- onstrated that sotalol, compared with placebo or no treatment, was associated with a significantly higher all-cause mortality rate (RR, 2.23; 1882 patients in 5 RCTs) and proarrhythmia (RR, 3.55; 2989 patients in 12 RCTs).18 The SAFE-T trial randomized 665 patients to amiodarone, sotalol, or placebo, all initiated in the outpatient setting (sotalol at 80 mg twice daily for the first week and 160 mg twice daily subsequently).15 Fifteen deaths occurred in the sotalol group, 8 of which were sudden, with a nonsignificant mortality ratio of 1.8 compared with placebo. In 1 retrospective cohort of 120 patients undergoing sotalol initiation as an inpatient, 2 of 7 had torsades de pointes; 20 patients developed significant bradyarrhyth- mias necessitating dose reductions, and 3 patients required permanent pacing.8 Intravenous sotalol was introduced in the United States in 2015 and reaches therapeutic levels rapidly and with easier dose titration to QTc levels and clinical response. As such, it may be an option for more expedient inpatient initiation (obviating the need for a 3-day initiation period).16

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Table 23. Specific Drug Therapy for Maintenance of Sinus Rhythm in Patients With AF

Drug Loading Dose Maintenance Dose

Primary Route(s) of Elimination

Elimination Half-Life

Mechanism of Action Major Adverse Effects

Important Pharmacokinetic Drug Interactions

Amiodarone Total loading dose 6-10 g, given 400-800 mg daily in 2-4 divided doses for 1-4 wk

200 mg once daily

Liver metabolism Biliary excretion

14-59 d Inhibits IKr, IKs, INa, IKur, Ito, ICa-L, IKAch

Noncompetitive beta blocker

AV block Bradycardia Corneal microdeposits Elevation in transaminases Hepatotoxicity Hyperthyroidism Hypothyroidism Nausea QT prolongation Peripheral neuropathy Photosensitivity Pulmonary fibrosis Skin pigmentation (blue-gray) TdP

Moderate* inhibitor of CYP2C9, weak† inhibitor of CYP2D6 Some inhibition of CYP3A Increases plasma con- centrations of warfarin, lovastatin,‡ simvastatin,§ cyclosporine Inhibits p-gp Increases plasma concentrations of digoxin

Dofetilide N/A CrCl >60 mL/ min: 500 μg twice daily CrCl 40-60 mL/min: 250 μg twice daily CrCl 20-40 mL/min: 125 μg twice daily CrCl <20 mL/ min: Contrain- dicated

Kidney 10 h Inhibits IKr and augments late INa

QT prolongation TdP

Dofetilide is renally excreted via the renal cat- ion transport system. These drugs inhibit renal cation transport, increase plasma dofetilide concentrations, and are contraindicated in patients taking dofetilide: Cimetidine Dolutegravir Ketoconazole Megestrol Prochlorperazine Trimethoprim (alone or in

combination with sulfa- methoxazole)

Verapamil In addition, hydrochlorothia- zide (alone or in combination with triamterene) increases plasma dofetilide concentra- tions and should not be co- administered with dofetilide

Dronedarone N/A 400 mg twice daily

Liver metabo- lism

13-19 h Inhibits IKr IKs, INa, IKur, Ito, ICa-L, IKAch Noncom- petitive beta blocker

Abdominal pain Asthenia Bradycardia Diarrhea Nausea and vomiting QT prolongation Rash TdP

Dronedarone is a substrate for CYP3A and is a moderate inhibitor of CYP3A and CYP2D6 Dronedarone is also a substrate for, and inhibitor of, p-gp Dronedarone may increase plasma concentrations of: Dabigatran Digoxin Simvastatin‖ Sirolimus Tacrolimus Warfarin These drugs may increase plasma dronedarone concentrations: Grapefruit juice These drugs may decrease plasma dronedarone con- centrations: CYP3A inducers including St. John’s wort, rifampin, and phenytoin

(Continued )

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3. The PITP strategy—a high dose of a class IC agent (flecainide 200-300 mg or propafenone 450-600 mg, with an atrioventricular nodal blocker)—can be considered for patients who experience infrequent episodes of symptomatic AF and do not prefer chronic antiarrhythmic therapy. Class IC agents are generally administered with concomitantly atrioven- tricular nodal blocking agents to mitigate risk of rap- idly conducting AFL. Because of the risk of adverse effects and proarrhythmia with high-dose IC agents, inpatient initiation of PITP has been studied. In 1 trial evaluating the safety of outpatient PITP ther- apy after initiation as an inpatient, 58 of 268 (22%) patients experienced transient hypotension, 1:1 and 2:1 AFL, and symptomatic bradycardia.9 In a pro- spective study of 43 patients who presented to the emergency department for initiation of PITP,10 sinus

rhythm was restored in 30 patients; 13 patients remained in AF, and/or had symptomatic hypoten- sion, converted to rapid AFL requiring cardioversion, or experienced a syncopal conversion pause. In a retrospective cohort13 study of 273 patients initiat- ing PITP (62% inpatient), 7 patients experienced significant adverse events, including syncope, symp- tomatic bradycardia/hypotension, and organization to 1:1 AFL—2 of 7 of these patients initiated PITP as an inpatient, and 2 patients required permanent pacemakers for bradycardia.

8.3.3. Antiarrhythmic Drug Follow-Up Antiarrhythmic drugs are associated with important ad- verse effects, and monitoring is recommended to assess their efficacy for maintaining sinus rhythm and for pre- vention and/or early detection of adverse events.

Drug Loading Dose Maintenance Dose

Primary Route(s) of Elimination

Elimination Half-Life

Mechanism of Action Major Adverse Effects

Important Pharmacokinetic Drug Interactions

Flecainide N/A 50-300 mg/d PO divided q 8-12 h

Liver (70%) Kidney (30%)¶

12-27 h Inhibits INa Atrial flutter AV block Dizziness Dyspnea Exacerbation of HFrEF Headache Nausea QT prolongation VT Visual disturbances

Flecainide is a substrate for CYP2D6 These drugs may increase plasma flecainide concentrations: Amiodarone Duloxetine Fluoxetine Paroxetine

Propafenone N/A 150-300 mg PO q 8 h, ER 225-425 PO q 12 h

Liver 9 h Inhibits INa Atrial flutter Bradycardia AV block Dizziness Dyspnea Exacerbation of HFrEF Nausea Taste disturbances VT Visual disturbances

Propafenone is a substrate for CYP2D6 These drugs may increase plasma propafenone con- centrations: Fluoxetine Paroxetine Propafenone may increase plasma digoxin concentra- tions Propafenone may increase plasma warfarin concentrations

Sotalol CrCl >60 mL/ min: 40-80 mg twice daily for 3 d CrCl: 40-60 mL/min: 80 mg once daily for 3 d CrCl <40 mL/ min: Contrain- dicated

CrCl >60 mL/ min: 80-160 mg twice daily CrCl: 40-60 mL/min: 80- 160 mg once daily CrCl <40 mL/ min: Contrain- dicated

Kidney 12 h Inhibits IKr

Beta blocker d-Sotalol aug- ments late INa

AV block Bradycardia Bronchospasm Diarrhea Exacerbation of HFrEF Fatigue Nausea and vomiting QT prolongation TdP

None

*Moderate inhibitor: Causes a 2-fold to <5-fold increase in AUC or a 50% to 80% decrease in clearance. †Mild inhibitor: Causes a ≥1.25-fold but <2-fold increase in AUC or a 20% to 50% decrease in clearance. ‡Lovastatin doses should not exceed 40 mg daily in patients taking amiodarone. §Simvastatin doses should not exceed 20 mg daily in patients taking amiodarone. ‖Simvastatin doses should not exceed 10 mg daily in patients taking dronedarone. ¶Percentage of a dose excreted unchanged in urine. AF indicates atrial fibrillation; AUC, area under the plasma concentration versus time curve; AV, atrioventricular; CrCl, creatinine clearance; CYP, cytochrome P-450;

ER, extended release; HFrEF, heart failure with reduced ejection fraction; IV, intravenous; N/A, not applicable; NAPA, N-acetylprocainamide; p-gp, p-glycoprotein; PO, orally; TdP, torsades de pointes; and VT, ventricular tachycardia.

Table 23. Continued

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Amiodarone Recommendations for follow-up monitoring for patients taking oral amiodarone are provided in Table 24. Amio- darone contains 37% iodine by weight and is therefore associated with thyroid abnormalities in 2% to 24% of patients.1 In 1 study, the median time to onset of ami- odarone-induced hypothyroidism was 183 days, with a median onset of hyperthyroidism of 720 days.2 Oral ami- odarone may also provoke elevations in hepatic trans- aminases and, rarely, hepatotoxicity.3

Amiodarone may cause pulmonary toxicity, most com- monly in the form of interstitial lung disease or hypersen- sitivity syndrome,4 in 1% to 2% of patients and is fatal in approximately 10% of cases. Consequently, a chest x-ray is recommended at baseline and when there is a clinical sus- picion for pulmonary toxicity.4,5 Pulmonary function testing, including diffusing capacity for carbon monoxide, can reveal relatively early changes in pulmonary function that may be attributable to amiodarone-associated pulmonary toxicity; however, the sensitivity of the test for routine screening of drug-induced lung toxicity in general is uncertain.4–7

In patients who develop unexplained cough and dys- pnea while taking amiodarone, a chest CT scan can be helpful for diagnosis.5

Corneal microdeposits (epithelial keratopathy) are common, but visual abnormalities and light sensitivity are rare.8 Therefore, an ophthalmologic examination is rea- sonable only if visual abnormalities develop. Amiodarone has also been associated with neurological toxicity, par- ticularly peripheral neuropathy.

Although less common than class III antiarrhythmic agents, oral amiodarone may cause torsades de pointes9; 1 analysis estimated the incidence to be 0.7%.10

Other Antiarrhythmic Drugs Recommendations for follow-up of other antiarrhyth- mic agents used for management of AF are provided in Table 25.

Dofetilide Dofetilide is a potent inhibitor of IKr, augments INa-L, and is associated with torsades de pointes.9 The incidence of torsades de pointes associated with dofetilide ranges from 0.9% to 3.3%.11,12 However, the incidence can be substan- tially higher if the dofetilide dose is not properly adjusted for kidney function. Patients undergoing initiation or re- loading of dofetilide are generally admitted for at least 3 days to a health care facility that can provide calculations of CrCl, continuous electrocardiographic monitoring, and cardiac resuscitation. After discharge on a stable dose of these drugs, a 12-lead ECG, and levels for serum magne- sium, potassium, and creatinine are recommended every 3 to 6 months for assessment of QTc interval duration, elec- trolyte balance, and renal function, and more frequently for patients concomitantly taking other QT interval-prolonging drugs or with changing kidney function, to minimize the risk of drug-associated torsades de pointes.

Dronedarone Rare cases of severe liver injury have been reported in association with dronedarone. These cases have oc- curred 4.5 to 6 months after initiation of dronedarone therapy, although 1 case of hepatotoxicity was reported as early as 2 days after initiation of dronedarone (and was ultimately fatal a few days later),13 although a severe case of dronedarone-associated toxic hepatitis occurred 9 months after initiation of therapy.14

Ibutilide Ibutilide may prolong the QT interval and cause torsades de pointes15–22 and therefore continuous electrocardio- graphic monitoring is recommended during infusion and for 4 hours after completion of ibutilide infusion. Ibuti- lide is associated with nonsustained ventricular tachy- cardia (VT), QT interval prolongation, and torsades de pointes. The incidence of nonsustained VT has been re- ported to be as high as 8.3%.23 Torsades de pointes oc- curs in approximately 2% to 7% of patients,15–22 but the

Table 24. Recommended Monitoring for Patients Taking Oral Amiodarone

Adverse Effect Baseline Testing Initial Follow-Up Testing Additional Follow-Up Testing

Hypo- or hyperthyroidism TSH (T4 and T3 if TSH abnormal) 3-6 mo Every 6 mo

Hepatotoxicity AST, ALT 3-6 mo Every 6 mo

QT interval prolongation ECG Annually –

Interstitial lung disease Chest x-ray: Recommended CT chest: Not recommended

Chest x-ray: Unexplained cough or dyspnea or other signs/symptoms suspicious for interstitial lung disease

CT chest: As indicated to follow-up ongoing symptoms or chest x-ray findings

Corneal microdeposits (epithelial keratopathy)

Not recommended Development of visual abnormalities, which may indicate optic neuropathy

–

Dermatologic (blue-gray skin discoloration), photosensitivity

Not recommended Physical examination annually Development of skin discoloration, severe sunburn

Neurological Not recommended Physical examination annually Development of peripheral neuropa- thy or other neurological abnormalities

ALT indicates alanine transaminase; AST, aspartate transaminase; CT, computed tomography; ECG, electrocardiogram; TSH, thyroid-stimulating hormone; and TdP, torsades de pointes.

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incidence increases substantially in patients with de- pressed LVEF.22 Most reported cases of ibutilide-associated nonsustained VT and torsades de pointes have oc- curred within 30 minutes after the last dose; torsades de pointes has rarely been reported as late as 2.5 hours after an ibutilide infusion.22 QTc intervals generally return to baseline within 2 to 3 hours after a dose.

The risk of drug-induced torsades de pointes is higher in patients with hypokalemia and/or hypomag- nesemia. Hypokalemia has been reported to be present in 17% to 70% of patients who have developed drug- induced torsades de pointes.24–27 Similarly, hypomagne- semia has been reported to be a contributing factor to numerous published cases of drug-induced torsades de pointes.27–29 Therefore, maintenance of serum potassium and magnesium concentrations within the normal range is important before administration of ibutilide, and mag- nesium supplementation may mitigate the risk of tors- ades de pointes.

Procainamide Intravenous procainamide is associated with hypotension in 5% to 12% of patients when used for management of AF,30,31 and BP monitoring is recommended. Intravenous procainamide is also associated with widening of the

QRS complex and prolongation of the QT interval and may provoke proarrhythmia in the form of monomorphic VT32 and torsades de pointes.33

Sotalol Sotalol is a potent inhibitor of IKr, augments INa-L, and is as- sociated with torsades de pointes, with an incidence rang- ing from 0.4% to 2.3%.34,35 Patients undergoing initiation or dose escalation of sotalol are often admitted for at least 3 days to a health care facility that can provide calculations of CrCl, continuous electrocardiographic monitoring, and cardiac resuscitation. A new intravenous form of sotalol was recently FDA approved, which may obviate the need for 3-day admission. After discharge on a stable dose of these drugs, a 12-lead ECG, and levels of serum magne- sium, potassium, and creatinine are recommended every 3 to 6 months for assessment of QTc interval duration, elec- trolyte balance, and renal function, and more frequently for patients concomitantly taking other QT interval-prolonging drugs or with changing kidney function, to minimize the risk of drug-associated torsades de pointes.

8.3.4. Upstream Therapy Pharmacological treatments targeting upstream path- ways have included glucocorticoids, ACE inhibitors,

Table 25. Recommended Monitoring for Patients Taking Other Antiarrhythmic Drugs

Drug Baseline Testing Follow-Up Testing Additional Follow-Up Testing

Dofetilide 12-lead ECG* Continuous electrocardiographic monitoring during 3-d hospitalization for dofetilide initiation Serum potassium and magnesium concentration Serum creatinine for estimation of CrCl

In 3-6 mo: 12-lead ECG* Serum potassium and magnesium

concentration Serum creatinine for estimation of CrCl

Every 3-6 mo (more frequently for patients concomitantly taking other QT interval-prolonging drugs or with changing kidney function: 12-lead ECG* Serum potassium and magnesium

concentration Serum creatinine for estimation of CrCl

Dronedarone 12-lead ECG* AST† ALT†

Within first 6 mo: AST† ALT†

–

Ibutilide 12-lead ECG* Determination of serum potassium and magnesium concentrations and correction of hypokalemia and/or hypomagnesemia is recommended before initiation of the infusion

Continuous electrocardiographic monitoring for assessment of QTc interval duration is recommended for at least 4 h after infusion or until the QTc has returned to baseline to minimize the risk of ibutilide-associated TdP

–

Procainamide 12-lead ECG* BP

Electrocardiographic monitoring for assess- ment of rhythm, QRS width and QTc interval is recommended during the infusion to minimize the risk of procainamide-associated ventricular proarrhythmia, including TdP BP monitoring is recommended during the in- fusion to detect clinically relevant hypotension

–

Sotalol 12-lead ECG* Continuous electrocardiographic monitoring during 3-d hospitalization for sotalol initiation Serum potassium and magnesium concentration Serum creatinine for estimation of CrCl

In 3-6 mo: 12-lead ECG* Serum potassium and magnesium

concentration Serum creatinine for estimation of CrCl

Every 3-6 mo (more frequently for patients concomitantly taking other QT interval-prolonging drugs or with chang- ing kidney function: 12-lead ECG* Serum potassium and magnesium

concentration Serum creatinine for estimation of CrCl

*Assess rhythm and calculate QTc. †To facilitate early detection of potential dronedarone-associated hepatotoxicity. ALT indicates alanine transaminase; AST, aspartame transaminase; BP, blood pressure; ECG, electrocardiogram; CrCl, creatinine clearance; and TdP, torsades de pointes.

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ARBs, aldosterone antagonists, statins, omega-3 polyunsaturated fatty acids, antioxidants, and sodi- um-glucose cotransporter 2 inhibitors (see Section 5, “Lifestyle and Risk Factor Modification for AF Management”). Targeting inflammation, a random- ized study of glucocorticoids reduced recurrent AF after first occurrence of persistent AF, but adverse ef- fects inhibit long-term steroid use.1–9 Statins reduced postoperative AF in small RCTs.10–14 However, an ad- equately powered placebo-controlled trial of rosuvas- tatin did not reduce postoperative AF.15 Statins do not prevent AF in other cardiovascular settings.16 RCTs and a meta-analysis provide limited though consistent support for the antioxidant ascorbic acid for postoper- ative AF.17 Targeting fibrosis, small or secondary stud- ies of RCTs reported lower new AF with ACE inhibitors or ARBs.2–9 However, larger RCTs targeting AF failed to reduce recurrent AF.18–20 RCTs showed that MRAs reduced new-onset atrial arrhythmias in patients with HFrEF along with improvement of other cardiovascu- lar outcomes.21,22 In patients with type 2 diabetes, HF, or CKD, sodium-glucose cotransporter 2 inhibitors ap- pear to prevent new AF.23–25 In contrast, omega-3 fatty acids do not appear to reduce AF and, in 1 large study, was associated with higher occurrence of AF.26–31 With only limited or inconsistent data, no recommendations are made for use of these upstream therapies for pre- vention of AF.

8.4. AF Catheter Ablation Recommendations for AF Catheter Ablation Referenced studies that support the recommendations are summarized in the Online Data Supplement.

COR LOE Recommendations

1 A

1. In patients with symptomatic AF in whom anti- arrhythmic drugs have been ineffective, contra- indicated, not tolerated or not preferred, and continued rhythm control is desired, cath- eter ablation is useful to improve symptoms.1–10

1 A

2. In selected patients (generally younger with few comorbidities) with symptomatic parox- ysmal AF in whom rhythm control is desired, catheter ablation is useful as first-line therapy to improve symptoms and reduce progression to persistent AF.11–16

1 A 3. In patients with symptomatic or clinically

significant AFL, catheter ablation is useful for improving symptoms.17–19

2a B-NR

4. In patients who are undergoing ablation for AF, ablation of additional clinically significant supraventricular arrhythmias can be useful to reduce the likelihood of future arrhythmia.17,18,20–27

2a B-R

5. In patients (other than younger with few comorbidities) with symptomatic paroxysmal or persistent AF who are being managed with a rhythm-control strategy, catheter ablation as first-line therapy can be useful to improve symptoms.11–13,28

Cost Value

Statement: Intermediate

B-R

6. Catheter ablation for symptomatic AF provides intermediate economic value com- pared with antiarrhythmic drug therapy.29,30

2b B-NR

7. In selected* patients with asymptomatic or minimally symptomatic AF, catheter ablation may be useful for reducing progression of AF and its associated complications.31–39

*Younger patients with few comorbidities and a moderate to high burden of AF or persistent AF and AFL.

Synopsis Catheter ablation has become an established therapy for AF because of multiple RCTs and evidence from large registries and continues to evolve as new technologies are developed. Previous professional society documents have provided different recommendations for catheter ablation dependent on whether AF was persistent or paroxysmal.25,40 More recent information has shown that ablation for AF is more effective than antiarrhythmic drugs for both persistent and paroxysmal AF and that earlier implementation of rhythm control strategies is an important factor for improving AF ablation success rat es.4,35,41–44 As with all strategies for rhythm control of AF, impact on a patient’s goals of care and QOL should be the focus. For example, significantly reducing the fre- quency and duration of AF episodes but not eliminating all future episodes of AF may represent a clinically im- portant improvement. Although RCTs have mainly used younger patients (<70 years of age) who also experi- ence the largest benefits, observational studies have reported improvement in QOL with catheter ablation in older patients.3–6,8,45–47

Recommendation-Specific Supportive Text 1. In patients who have not responded to an antiar-

rhythmic drug due to a high burden of recurrent AF or adverse effects from the medication, RCTs have consistently demonstrated lower risk for recurrent symptomatic AF after ablation when compared with using another antiarrhythmic medication.1–10 As an example, in STOP-AF, patients who had failed ≥1 antiarrhythmic drug (approximately 70% and 30% for 1 or 2 failed drugs, respectively) were random- ized to either another antiarrhythmic drug or cath- eter ablation. At 1 year follow-up, catheter ablation was associated with a treatment success rate of 70% compared with 7% in the drug arm.10 Similarly, in the Thermo-cool (NAVISTAR THERMOCOOL Catheter for the Radiofrequency Ablation of Symptomatic Paroxysmal Atrial Fibrillation) trial, patients with paroxysmal AF who had failed 1 anti- arrhythmic medication were randomized to cath- eter ablation or another antiarrhythmic drug. After 9 months, 66% of patients in the catheter ablation

Recommendations for AF Catheter Ablation (Continued )

COR LOE Recommendations

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group were free from recurrent arrhythmia com- pared with 16% in the antiarrhythmic drug group.8 Finally, most recently, in the CABANA trial, 80% of patients were on an antiarrhythmic medication and thought to be candidates for AF ablation and were randomized to catheter ablation or continued anti- arrhythmic therapy. Catheter ablation was associ- ated with a nearly 50% reduction in recurrent AF (HR, 0.52 [95% CI, 0.45-0.60]; P<0.001).4,28

2. In selected patients with paroxysmal AF, ablation is a suitable first-line option. Several initial RCTs sug- gested a decrease in recurrent AF or AF burden with catheter ablation when compared with antiar- rhythmic drugs.16 More recent trials have shown a significant reduction in recurrent AF with catheter ablation compared with antiarrhythmic drugs. In a follow-up report of 1 study, after 3-year follow-up, catheter ablation continued to be associated with a significant decrease in recurrent atrial tachyarrhyth- mias when compared with antiarrhythmic drugs (HR, 0.51 [95% CI, 0.38-0.67]).14 More importantly, episodes of persistent AF developed in only 1.9% of patients randomized to catheter ablation com- pared with 7.4% of patients in the antiarrhythmic drug arm (HR, 0.25 [95% CI, 0.13-0.70]).14 All of the studies that have evaluated catheter ablation as an initial strategy for rhythm control in patients with paroxysmal AF, although fairly standard exclu- sion criteria were used, enrolled relatively young patients (average age approximately 60 years) who had relatively few comorbidities (if present, mainly hypertension).16

3. AFL is most commonly due to the critical isthmus formed by the inferior vena cava and the tricuspid valve. More rarely, in patients who have not under- gone previous ablation procedures atypical AFL or focal ATs can be observed. Catheter ablation of typical AFL is effective and relatively low risk.17–19 In an older meta-analysis of AFL ablation stud- ies, AFL ablation was associated with an acute success rate of 90% and a complication rate of 2.6%.18 The occurrence of AF after AFL ablation was 34%, with a recurrence rate of 23% in those patients without a history of AF compared with 53% in patients with a history of AF. By 5 years, AF developed in 60% to 70% of patients regard- less of whether the patient had a history of AF before the AFL ablation. Little evidence is avail- able in these studies for the clinical significance of AF after AFL ablation.

4. AF can be associated with other atrial arrhyth- mias, particularly AFL.20–22 During ablation for AF, ablation of previously documented or inducible sustained SVT or AFL is useful to reduce the likeli- hood of recurrent arrhythmias.22–25 Although abla- tion alone for AF in patients with both AF and AFL

will reduce the likelihood of AFL, and ablation tar- geting an inducible SVT in a patient with AF may reduce future AF, in both cases the likelihood of recurrent arrhythmias is high, although the actual recurrence rate will depend on the specific popu- lation.17,18,25–27,48,49 Conversely, prophylactic catheter ablation of the CTI in patients without documented or inducible AFL likely has minimal benefit.50 Alternatively, in 1 study, cryoballoon PVI as first-line treatment for AFL is equally effective compared with standard CTI ablation for preventing recur- rence of atrial arrhythmia and better at preventing new-onset AF.51

5. Several randomized trials have compared catheter ablation to AADs as first-line therapy for AF.11–13 In the MANTRA-AF study, ablation and antiar- rhythmic drugs as first-line therapy for paroxys- mal AF was evaluated. Although no differences in AF were identified during the first 18 months, at 24-month follow-up, ablation was associated with a lower AF burden (ablation, 9% versus anti- arrhythmic drugs, 18%; P=0.004).11 Subsequent studies have demonstrated similar results: In the EARLY-AF (Early Aggressive Invasive Intervention for Atrial Fibrillation) study, at 1-year follow-up, recurrent atrial arrhythmias were identified in 43% of the ablation group and 68% of the anti- arrhythmic drug group (P<0.001), and in the STOP AF First (Cryoballoon Catheter Ablation in an Antiarrhythmic Drug Naive Paroxysmal Atrial Fibrillation) study, recurrent atrial arrhythmias were identified in 25% of the ablation group and 55% of the antiarrhythmic drug group (P<0.001).12,13 Procedural complications were observed in 2% to 5% of patients in all 3 studies.11–13 Although AF burden was significantly reduced with abla- tion compared with antiarrhythmic drug therapy in EARLY-AF, AF burden was low with either strategy (percentage of time in AF: ablation, 0.6% versus antiarrhythmic drugs, 3.9%) and, in all 3 trials, the average age was ≤60 years.11–13 Although these trials enrolled patients with paroxysmal AF, recent studies have consistently found that catheter abla- tion is more commonly used and also effective in patients with persistent AF, particularly if of rela- tively recent onset (<1 year).28

6. Catheter ablation for AF is a costly procedure yet appears to provide value by improving the symp- toms of AF and patient QOL. Some of the initially higher costs of the ablation procedure may be offset by reductions in subsequent cardiovascular hospitalizations. Formal economic analyses have been performed alongside 2 randomized controlled clinical trials. Both trials showed higher costs and improved QOL during follow-up, with incremental cost-effectiveness ratios of $58 000 and €51 000

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per quality adjusted life-year added, values within the intermediate value range (between $50 000 and $150 000 per quality29,30,52–55 adjusted life-year added) by ACC/AHA criteria. Models of the cost- effectiveness of catheter ablation have reported more favorable results, but their results generally depended on assumptions that ablation reduced mortality, or ischemic stroke, or both, which have not been proven.

7. In most patients, continued untreated AF will lead to progression and higher AF burden associated with worse clinical outcomes.31–39 In patients with subclinical AF <24 hours, progression to overt AF or episodes >24 hours occurs at a rate of 8.8% per year, and those patients who develop AF are more likely to be hospitalized for HF.56 Several observational studies have reported AF progres- sion may be improved by using a catheter-based ablation rhythm-control strategy.33–35,37,38 As an example, in 1 randomized trial that was stopped prematurely, in 255 patients with paroxysmal AF randomized to catheter ablation or antiarrhyth- mic medication, freedom from persistent AF or AT was significantly higher with catheter ablation (ablation: 2.4%, versus antiarrhythmic medication, 17.5%, 1-sided P=0.0009).57 However, serious adverse events associated with the ablation were observed in 8% of patients.57 Despite the potential risks associated with catheter ablation, in a recent analysis of a large registry that specifically evalu- ated asymptomatic patients, rhythm control was associated with an improvement in the composite outcome of cardiac death, ischemic stroke, and hospitalization for HF.58 The impact was largest in those patients who underwent catheter ablation for rhythm control, particularly in those with paroxys- mal AF, LA diameters ≤50 mm,58 or higher stroke risk (CHA2DS2-VASc score ≥3). In a post hoc anal- ysis of EAST-AFNET 4, the magnitude of benefit from a rhythm-control strategy for reducing the pri- mary composite outcome of cardiovascular death, stroke, or hospitalizations for HF or ACS was inde- pendent of symptom status, and catheter ablation for rhythm control was used in approximately 20% of patients, whether symptomatic or not.59

8.4.1. Patient Selection Patient selection is the first step and a critically impor- tant step in deciding candidacy for catheter ablation.1–4 Younger patients are likely to derive greater long-term benefit, including delaying AF progression. However, clinical trials have demonstrated improved cardiovascular outcomes with rhythm control, even with median ages in the 70s.5 Patients with minimal atrial enlargement have the best outcomes,6 whereas increased myocardial fi- brosis7,8 and more persistent forms of AF are associated

with higher rates of recurrence after ablation. Time from diagnosis to ablation is also associated with improved outcomes after ablation.9,10 Although the likelihood of recurrence of AF is 1 factor that should be considered, it is difficult to predict,11 and certain patients may derive even greater benefits from catheter ablation, such as in patients with HFrEF, who have been shown to have im- proved functional status, LV function, and cardiovascular outcomes.12–14

In some patients, ablation should be avoided as it is unlikely to be successful due to overwhelming substrate or ongoing physiologic processes that either strongly perpetuate the risk of AF or make maintenance of sinus rhythm unlikely. These situations include but are not limited to advanced infiltrative cardiomyopathies like amyloid, severe mitral stenosis or regurgitation, and cor pulmonale.

8.4.2. Techniques and Technologies for AF Catheter Ablation

Recommendations for Techniques and Technologies for AF Catheter Ablation Referenced studies that support the recommendations are summarized in the Online Data Supplement.

COR LOE Recommendations

1 A 1. In patients undergoing ablation for AF, PVI is recom-

mended as the primary lesion set for all patients unless a different specific trigger is identified.1–7

2b B-R

2. In patients undergoing ablation for AF, the value of other endpoints beyond PVI such as noninducibility and ablation of additional anatomic ablation targets (eg, posterior wall sites, low voltage areas, complex fractionated electrograms, rotors) is uncertain.8–18

Synopsis Catheter ablation is now established as an effective op- tion for rhythm control in patients with AF and AFL.1–7,16 However, in patients with AF, additional ablation targets beyond isolation of PVI as a routine strategy have not reduced AF recurrence or burden in RCTs.8–18 Although achieving durable pulmonary vein ablation in patients with AF has been associated with less recurrent ar- rhythmias, other endpoints, such as termination of F and noninducibility, have not been associated with improved outcomes.19–28 Significant complications of AF ablation include stroke and TIAs, pericardial effusion, and vascu- lar complications.16 The most serious complication that occurs after the ablation procedure is development of an esophageal atrial fistula, although other complications, such as PV stenosis can occur.8–18

Recommendation-Specific Supportive Text 1. Multiple randomized studies have shown that PVI

is more effective than medical therapy for reduc- ing AF burden.1–7 A recent meta-analysis of 6 RCTs found that strategies that included PVI were asso- ciated with a 50% reduction in the development of recurrent AF when compared with strategies that did not include PVI.7

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2. Studies have evaluated the use of different end- points immediately after catheter ablation for pre- dicting durable PVI and the likelihood of future arrhythmias with mixed results.19–28 In the largest randomized study to date, techniques such as wait- ing for 30 minutes, using adenosine triphosphate to facilitate PV reconnection, or the combination of waiting and using adenosine were not supe- rior to no testing for predicting durable pulmonary vein isolation or reduction in future arrhythmias. Although noninducibility remains important in determining whether ablation for paroxysmal SVT has been successful, noninducibility after AF abla- tion or termination of AF with ablation have had mixed results for predicting the likelihood of future recurrence.19–29

Multiple ablation targets beyond PVI have been evaluated in randomized controlled and observa- tional trials, including the LAA, posterior wall, the ligament of Marshall, or atrial scar.8–18 Results have been mixed, and no strategy has emerged that is broadly applicable in all patients, likely because the individual mechanisms for AF vary from patient to patient.8–18 Targeting large areas of atrial tissue may have potential negative consequences, includ- ing a higher likelihood of complications such as atrioesophageal fistula, poor LA mechanics, atypi- cal flutters, and increased risk for stroke.30–35

8.4.3. Management of Recurrent AF After Catheter Ablation

Recommendations for Management of Recurrent AF After Catheter Ablation Referenced studies that support the recommendations are summarized in the Online Data Supplement.

COR LOE Recommendations

1 B-NR

1. In patients with recurrent symptomatic AF after catheter ablation, repeat catheter ablation or antiarrhythmic drug therapy is useful to improve symptoms and freedom from AF.1–11

2a A

2. In some patients who have undergone catheter ablation of AF, short-term antiarrhythmic drug therapy after ablation can be useful to reduce early recur- rences of atrial arrhythmia and hospitalization.12–16

Synopsis Recurrences of AF are common after a first ablation procedure, occurring in 30% to 40% of patients in con- temporary clinical trials.1,2 In general US practice, 11% of patients undergoing de novo ablation have a repeat ablation by 1 year.3 Patients often experience improved symptoms and QOL even when they experience recur- rence after catheter ablation.4 Nonetheless, recurrent atrial arrhythmia that leads to symptoms or LV dysfunc- tion requires treatment.

Recommendation-Specific Supportive Text 1. In general, successful suppression of AF improves

with additional or multiple ablation procedures.5–7

The absolute limit to the number of ablations a patient can undergo is unknown. For example, it is possible that a patient with previous PVI and repeat ablations with substrate modification may benefit from ablation of PV to LA reconnections, or ablation of additional triggers. However, repeat ablations carry increased risks of adverse effects. These risks are rare but include PV stenosis and stiff LA syndrome.8,9,17

Many of the randomized clinical trials, which have demonstrated superiority of catheter ablation over antiarrhythmic drug therapy, included repeat abla- tion procedures as part of their prospective study designs.1,10,11,18 Randomized data also suggest that repeat ablation is superior to antiarrhythmic drug therapy for the treatment of recurrent AF after first ablation.19 Although no large direct head-to-head trials are available of repeat catheter ablation ver- sus no repeat catheter ablation, the aggregate data from randomized trials suggest that repeat abla- tion improves arrhythmia suppression and symp- tom control. Limited numbers of randomized trials can guide the optimal approach to repeat catheter ablation (beyond reisolation of the PVs).12,13

Although randomized data suggest that repeat ablation is superior to antiarrhythmic drug therapy for the treatment of recurrent AF after first abla- tion,19 recurrences of AF after catheter ablation can also be successfully treated with antiarrhyth- mic drug therapy even when these same medica- tions may have been ineffective before ablation.3,14 Antiarrhythmic drugs have also been associated with decreased recurrent atrial arrhythmias in those who have undergone previous ablation.14 Other studies have shown that use of previously ineffective antiarrhythmic therapy can be effec- tive after ablation.15 Optimal rhythm control often requires a combined approach of catheter ablation and adjunctive antiarrhythmic drug therapy, espe- cially in patients with long-standing persistent AF or patients with advanced atrial myopathies.

2. Several clinical trials have demonstrated the efficacy and safety of short-term (3-6 months postablation) antiarrhythmic therapy to prevent recurrences of AF, symptoms, cardioversion, and hospitalization after ablation.16,20,21 Moreover, con- tinued use of antiarrhythmic drugs beyond the blanking period (3 months) may reduce the risk of recurrent atrial arrhythmias out to 1 year.15 Meta- analysis of randomized trials evaluating the use of short-term antiarrhythmic drug therapy have determined that it significantly decreases the risk of early, but not late, recurrence.22,23 Observational data from nationwide practice data also sug- gest that antiarrhythmic therapy after ablation can reduce hospital readmissions by 37% in the

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short term (90 days) after ablation.24 Although the evidence base for short-term antiarrhythmic drug therapy after ablation is robust, the decision to use short-term antiarrhythmic drug therapy should be based on the patient’s risk and informed by SDM.

8.4.4. Anticoagulation Therapy Before and After Catheter Ablation

Recommendations for Anticoagulation Therapy Before and After Catheter Ablation Referenced studies that support the recommendations are summarized in the Online Data Supplement.

COR LOE Recommendations

1 B-NR

1. In patients on warfarin who are undergoing catheter ablation of AF, catheter ablation should be performed on uninterrupted therapeutic anticoagula- tion with a goal INR of 2.0 to 3.0.1

1 A

2. In patients on a DOAC who are undergoing catheter ablation of AF, catheter ablation should be performed with either continuous or minimally interrupted oral anticoagulation.2–10

1 B-NR

3. In patients who have undergone catheter ablation of AF, oral anticoagulation should be continued for at least 3 months after the procedure with a longer duration determined by underlying risk.11

1 B-NR

4. In patients who have undergone catheter ablation of AF, continuation of longer-term oral anticoagulation should be dictated according to the patients’ stroke risk (eg, CHA2DS2-VASc score ≥2).11–17

Synopsis Catheter ablation has been demonstrated in randomized clinical trials to reduce arrhythmia burden improve QOL and, in select populations, it has been shown to improve cardiovascular outcomes. Complications after catheter ablation are infrequent, yet the risk of thromboembolic events is increased after ablation. The risk of stroke in the first 30 days after ablation is 0.8%.18 Thus, oral an- ticoagulation before, during, and after catheter ablation procedures is paramount.

Recommendation-Specific Supportive Text 1. All patients undergoing catheter ablation require

intraprocedural intravenous anticoagulation with heparin or direct thrombin inhibitors in those with heparin allergies. Management of oral anticoagu- lation during these procedures is also critically important. In those patients undergoing catheter ablation of AF who are taking warfarin for their oral anticoagulation, evidence from observational stud- ies and randomized trial data suggest that optimal efficacy and safety is achieved with uninterrupted warfarin. Patients undergoing catheter ablation of AF who have subtherapeutic INRs or interrupted warfarin have more evidence of silent cerebral isch- emic events on brain magnetic resonance imaging after the procedure.1 In the COMPARE (Role of Coumadin in Preventing Thromboembolism in Atrial Fibrillation [AF] Patients Undergoing Catheter Ablation) trial, interruption of warfarin was highly

associated with periprocedural thromboembolic events (OR, 13 [95% CI, 3.1-55.6]; P<0.001).1 Patients treated with uninterrupted warfarin had lower rates of thromboembolic events (5% versus 0.25%; P<0.001) and lower rates of periproce- dural bleeding compared with those in whom war- farin was stopped or interrupted.

2. Although uninterrupted warfarin is superior to interrupted warfarin among persons undergoing catheter ablation of AF, meta-analyses have dem- onstrated lower risks of major bleeding with unin- terrupted direct oral anticoagulation compared with uninterrupted vitamin K antagonism.2 Many ran- domized trials have been completed that compare uninterrupted DOACs versus uninterrupted VKAs, including trials of apixaban,3,4 dabigatran,5 edoxa- ban,6 and rivaroxaban.7 In aggregate, these trials have demonstrated the noninferiority of uninter- rupted direct-acting oral anticoagulation compared with uninterrupted vitamin K antagonism. Several randomized trials also compare minimally inter- rupted direct-acting oral anticoagulation versus uninterrupted direct-acting oral anticoagulation8 or uninterrupted vitamin K antagonism.9 These clinical trials and meta-analyses suggest that outcomes with minimally interrupted direct-acting oral antico- agulation are not different compared with continu- ous anticoagulation.10

3. The risk of thromboembolic and stroke events increases after ablation due to vascular and car- diac instrumentation, release of tissue factor, and myocardial injury. Most randomized clinical trials of catheter ablation that demonstrate a low risk of periprocedural stroke mandated oral anticoagula- tion for a minimum of 2 months after ablation to reduce the risk of stroke, regardless of CHA2DS2- VASc score.19

4. Greater burden or time in AF is associated with higher rates of stroke.12–14 Accordingly, reduc- ing exposure to AF via catheter ablation might be expected to reduce the risk of stroke. Although some observational studies have identified lower stroke risk after catheter ablation,15,16 randomized clinical trials of catheter ablation have not dem- onstrated reductions in stroke.11,17 Observational data regarding the risk of stroke after catheter ablation of AF are mixed and vary across study design and methods. For example, in an analysis of 4 050 patients undergoing catheter ablation with a CHA2DS2-VASc score ≥2 in Denmark, the risk after ablation was low and comparable in those who did (0.93/100 patient years) and did not (0.97/100 patient years) discontinue anticoagulation >3 months after ablation.20 In contrast, a study of 6 866 patients who underwent catheter ablation of AF in US clinical practice found that the risk of stroke was

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Table 26. Complications After AF Catheter Ablation

Complication Frequency of Complication1–4

Timing of Complication Signs and Symptoms Diagnosis Treatment

LA-esophageal fistula 0.2% 1-4 wk Chest pain, pain with swallowing, fever, stroke symptoms

CT scan of chest Surgery

Cardiac perforation with tamponade

0.4%-1.5% During procedure Hypotension Echocardiography Pericardiocentesis

CVA/TIA 0.1%-1.0% During procedure and up to 1 wk

Neurological findings MRI or CT scan Anticoagulate when safe

PV stenosis 0.1%-0.8% Months Dyspnea, hemoptysis MRI or CT scan Stent

Phrenic nerve paralysis 0.2%-0.4% During procedure Dyspnea Fluoroscopy Time

Vascular access complications

1%-7% During procedure and up to 1 mo

Pain, swelling at access site

Ultrasound or CT scan Observation

Vascular access complications requiring surgery

0.1%-0.3% During procedure and up to 1 mo

Pain and swelling at access site

Ultrasound or CT scan Surgery

Death 0.1%-0.4% During procedure

Pneumonia 0.4%-1.0% Days Cough, fever Chest x-ray Antibiotics

AF indicates atrial fibrillation; CT, computed tomography; CVA, cerebrovascular accident; LA, left atrial; PV, pulmonary vein; TIA, transient ischemic attack; and MRI, magnetic resonance imaging.

increased in patients with a CHA2DS2-VASc score ≥2 who discontinued oral anticoagulation after 3 months (HR, 2.48 [95% CI, 1.11-5.52]; P<0.05).21 In this same study, no increased risk was observed that was associated with discontinuation after 3 months in those with a CHA2DS2-VASc score of 0 to 1. Ongoing randomized trials are investigating whether oral anticoagulation can be safely discon- tinued in patients who have no significant arrhyth- mia recurrences after catheter ablation. Finally, the OPTION (Comparison of Anticoagulation With Left Atrial Appendage Closure After AF Ablation) trial (NCT03795298) will test whether LAAO is noninferior to continued oral anticoagulation after catheter ablation of AF.22 Given (1) the absence of randomized data that directly address this ques- tion, (2) the absence of consistent data demon- strating a lower risk of stroke after ablation, and (3) increased rates of stroke among persons with a CHA2DS2-VASc score ≥2 who discontinue oral anticoagulation after 3 months, persons who have undergone catheter ablation AF should continue guideline-directed oral anticoagulation beyond 3 months based on their stroke risk, such as those with moderate-high risk of stroke.

8.4.5. Complications After AF Catheter Ablation Complications of AF catheter ablation occur in ap- proximately 5% of patients, with most being vascular (Table 26).1–4 However, several life-threatening compli- cations may occur. Complications are more common with annual operator procedures <25 patients and hospital procedures <50 patients.1 Some studies dem- onstrate a higher incidence of complications in wom-

en,1 but the CABANA RCT did not.5 The most severe complication is an LA to esophageal fistula, which is often fatal but quite rare. Another life-threatening com- plication is pericardial tamponade, but this can usually be treated with prompt pericardiocentesis. Clinically significant strokes and TIAs are observed in <1% of patients.1–4 Deaths during ablations are typically from tamponade but may occur with strokes.1–4

Phrenic and vagal nerve paralysis are seen with cryo- ablation but are less common in radiofrequency ablation.2 Early reports of PV stenosis were largely due to ablation inside the veins; with antral ablation this is rarely seen. The most common complications include bruising and bleed- ing at the vascular access site. Less common vascular complications include damage to the arterial or venous system or an atrioventricular fistula requiring surgery.

8.5. Role of Pacemakers and ICDs for the Prevention and Treatment of AF

Recommendations for the Role of Pacemakers and ICDs for the Prevention and Treatment of AF Referenced studies that support the recommendations are summarized in the Online Data Supplement.

COR LOE Recommendations

1 A

1. In patients with bradycardia requiring cardiac- implanted electronic devices who have normal atrioventricular conduction, device selection and pro- gramming strategies to maintain atrioventricular syn- chrony and minimize ventricular pacing should be used to reduce the incidence and progression of AF. 1–6

2b B-NR

2. In selected patients with a pacemaker and symptomatic atrial tachyarrhythmias, antitachycar- dia atrial pacing and ventricular pacing minimiza- tion may be useful for reducing symptoms.7–13

(Continued )

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2b C-LD 3. In patients with AF who require significant

ventricular pacing, conduction system pacing may be useful to reduce progression of AF.14,15

3: No benefit

B-R

4. In patients with AF, specialized atrial pacing algorithms designed to suppress AF are not useful for reducing the incidence or slowing the progression of AF.12,16–18

Synopsis In patients with pacemakers, programming strategies to reduce RV pacing reduce the incidence of AF.1–6 Be- cause AF is observed in patients with symptomatic sinus node dysfunction who require permanent pacemakers- for rate support, pacing algorithms were designed 20 to 30 years ago to suppress atrial ectopy but, unfortu- nately, no algorithm was able to successfully reduce AF in RCTs.12,16–19 More recently, antitachycardia pacing al- gorithms have been designed to identify and terminate atrial arrhythmias and have been moderately effective in patients with arrhythmias associated with more orga- nized atrial activation due to reentry.7–13

Recommendation-Specific Supportive Text 1. Several randomized and nonrandomized stud-

ies have shown that in patients who require car- diac-implanted electronic devices for sinus node dysfunction who have intact atrioventricular con- duction, devices that maintain atrioventricular syn- chrony reduce the incidence and progression of AF.1–6 Although maintenance of atrioventricular synchrony is important, post hoc analysis of MOST and a meta-analysis have demonstrated that the amount of ventricular pacing is an important con- tributor to the development of AF.6,20 Algorithms designed specifically to reduce ventricular pacing reduced the incidence of AF in individual stud- ies, but meta-analyses of RCTs suggests that the benefit may extend only to those patients with very infrequent pacing (<10%).19,21–23 In the only ran- domized study that solely evaluated patients with atrioventricular block (and >70 years of age) who required permanent pacing, dual-chamber pacing did not reduce the incidence of AF when compared with single-chamber ventricular pacing.24

2. Several studies have reported that specialized antitachycardia pacing algorithms can terminate atrial tachyarrhythmias but have not reduced AF burden.7–9 However, in a post hoc analysis of a subset of patients who had high success rate of antitachycardia pacing (≥60%), antitachycardia pac- ing algorithms reduced the overall AF/AT burden from 2.5 hours/day to 0.68 hours/day (P<0.01).10 A more recent study (MINERVA [Minimize Right Ventricular Pacing to Prevent Atrial Fibrillation and

Heart Failure]) found a modestly effective pacing algorithm that monitors for periods of regularization of atrial activity to initiate pacing algorithms reduced progression to persistent AF.11,12 This algorithm may be more effective in patients who have undergone previous AF ablation.13

3. Early nonrandomized evidence suggests that His bundle and left bundle pacing may reduce AF inci- dence and progression when compared with RV pacing in patients with high burden ventricular pac- ing.14,15 In 1 study, left bundle branch area pacing reduced the incidence of new AF when compared with RV pacing, but this benefit was only evident in those patients with ventricular pacing >20%.14 However, a meta-analysis that has evaluated all published evidence has only demonstrated a trend toward reduced AF. In 1 study, His bundle pacing reduced the likelihood of development of persis- tent AF in patients with sinus node dysfunction and a PR interval >180 ms.25 There is indirect evidence for the potential benefit of the ventricular depolar- ization pattern for reducing AF because an algo- rithm that automatically adjusts pacing parameters based on intrinsic conduction has been associated with a decrease in longer AF episodes (>48 hours) when compared with conventional programming in a retrospective analysis.26–28

4. Several studies have evaluated atrial pacing algo- rithms to reduce AF.12,16–19 Pacing algorithms to minimize ventricular pacing in ATTEST (Atrial Therapy Efficacy and Safety Trial), a combination of algorithms designed to suppress AF and also pro- vide antitachycardia pacing did not suppress atrial arrhythmias in patients with paroxysmal AF (AF fre- quency 1.3 episodes/month when “on” compared with 1.2 episodes/month when “off”).8 Despite optimistic results in some studies,12 a meta-anal- ysis found no benefit with atrial pacing algorithms for reducing the incidence of AF.19

8.6. Surgical Ablation Recommendations for Surgical Ablation Referenced studies that support the recommendations are summarized in the Online Data Supplement.

COR LOE Recommendations

2a B-R 1. For patients with AF who are undergoing cardiac

surgery, concomitant surgical ablation can be beneficial to reduce the risk of recurrent AF.1–3

2a B-NR

2. In patients undergoing surgical ablation, anticoagulation therapy is reasonable for at least 3 months after the procedure to reduce the risk of stroke or systemic embolism.2–4

2b B-R

3. For patients with symptomatic, persistent AF refractory to antiarrhythmic drug therapy, a hybrid epi- cardial and endocardial ablation might be reasonable to reduce the risk of recurrent atrial arrhythmia.5–7

Recommendations for the Role of Pacemakers and ICDs for the Prevention and Treatment of AF (Continued )

COR LOE Recommendations

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Synopsis Among patients with AF or AFL, concomitant surgi- cal ablation at the time of cardiac surgery has been shown to reduce the risk of recurrent atrial arrhyth- mia. However, it is associated with an increased risk of renal dysfunction and pacemaker placement. Among patients with symptomatic, persistent AF, a hybrid procedure combining epicardial and endocar- dial ablation has been shown to reduce the burden of atrial arrhythmia.

Recommendation-Specific Supportive Text 1. The original atrial maze procedure consisted of a

biatrial lesion set derived from a “cut-and-sew” technical approach.8 Similar lesion sets delivered by cryoenergy or radiofrequency were subse- quently developed. Surgical ablation concomi- tant with cardiac surgery currently takes place in approximately 1 in 5 patients with previous AF, most commonly at the time of a mitral valve procedure but also during aortic and tricuspid procedures or CABG.9 In a Cochrane review of 22 clinical trials conducted between 1998 and 2013, there was evidence that surgical ablation is associated with increased freedom from AF, AFL, or AT (RR, 2.04 [95% CI, 1.63-2.55]). However, risk of pacemaker placement was increased (RR, 1.69 [95% CI, 1.12-2.54]).1,2 A subsequent trial of patients undergoing mitral valve surgery with AF similarly found that ablation leads to increased freedom from AF at 1 year (63.2% versus 29.4%; P<0.001) but with increased risk of pacemaker placement (21.5 versus 8.1 per 100 patient- years; P=0.01).3 Observational data suggest surgical ablation is associated with increased survival as well as risk of pacemaker placement and renal dysfunction.10–14

2. Two components of Virchow’s triad—endothelial injury and stasis of blood flow—can lead to a pro- thrombogenic milieu in the context of surgical ablation. The former is a consequence of suture lines or ablation lesions, whether they result from radiofrequency or cryoenergy. The latter can occur with postcardioversion atrial stunning and/or atrial manipulation and consequent loss of mechanical function. Accordingly, trial proto- cols for several key studies of surgical ablation include the use of oral anticoagulation for at least 3 months after intervention.2,3 Nonrandomized data suggest that stroke or systemic embolism in the first 3 months after catheter ablation is uncommon, but the risk increases with discon- tinuation of oral anticoagulation, especially in high-risk patients.4 Patients who undergo surgi- cal ablation may be at similar risk, and thus oral

anticoagulation, whether it be with warfarin or a DOAC15 because appropriate accounting for concomitant indications such as a mechanical heart valve or mitral stenosis, should be initiated regardless of stroke risk when adequate surgical hemostasis has been achieved.

3. In a randomized trial of 149 patients with symptom- atic and refractory AF, compared with catheter ablation, a hybrid procedure consisting of closed- chest, epicardial ablation combined with and fol- lowed by endocardial ablation led to increased freedom atrial arrhythmias, including AF, AFL, and AT at 12 months (67.7% versus 50.0%; P=0.036) at the expense of an increased risk of major adverse events such as stroke, bleeding, or peri- cardial effusion (0.0% versus 7.8%; P=0.0525).16 The ablation set of the hybrid procedure focused on surgical ablation of the LA posterior wall and PVI, while endocardial ablation completed PVI and addressed remaining gaps. Other observa- tional studies of hybrid procedures with limited sizes show comparable rates of AF-free survival and safety.5–7

9. MANAGEMENT OF PATIENTS WITH HF 9.1. General Considerations for AF and HF AF and HF frequently coexist, and either can predispose to the development of the other. Shared risk factors (eg, age, obesity, sedentary lifestyle, and hypertension) may contribute, as may atrial remodeling and diastolic dysfunction.1–3 The prevalence of AF is higher in pa- tients with heart failure with preserved ejection fraction compared with HFrEF.4 In a recent study of the Fram- ingham cohort, among individuals with new AF, more than one-third (37%) had HF.5 Conversely, among in- dividuals with new HF, more than half (57%) had AF. A meta-analysis, including 53 969 patients from 9 obser- vational and 7 randomized trials, concluded that after adjusting for confounding factors, AF was associated with an increased total mortality, irrespective of LV sys- tolic dysfunction, with an OR of 1.40 (95% CI, 1.32- 1.48) in randomized trials and an OR of 1.14 (95% CI, 1.03-1.26) in observational studies.6 The risk of mortal- ity is higher when AF is incident after a diagnosis of HF as compared with prevalent AF, and in patients with HFrEF compared with heart failure with preserved ejec- tion fraction.4,7–9

Special considerations for the management of patients with HF and AF are discussed in the next sec- tion on management of AF in HF, as well as in Section 7.2 (“Specific Pharmacological Agents for Rate Con- trol”) and Section 8.2 (“Electrical and Pharmacologi- cal Cardioversion”).

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9.2. Management of AF in Patients With HF Recommendations for Management of AF in Patients With HF* Referenced studies that support the recommendations are summarized in the Online Data Supplement.

COR LOE Recommendations

1 B-NR

1. In patients who present with a new diagnosis of HFrEF and AF, arrhythmia-induced cardiomyopathy should be suspected, and an early and aggressive approach to AF rhythm control is recommended.1,2

1 A

2. In appropriate patients with AF and HFrEF who are on GDMT, and with reasonable expectation of proce- dural benefit (Figure 24), catheter ablation is benefi- cial to improve symptoms, QOL, ventricular function, and cardiovascular outcomes.3–13

2a B-NR

3. In appropriate patients with symptomatic AF and HFpEF with reasonable expectation of benefit, catheter ablation can be useful to improve symptoms and improve QOL.14,15

2a B-R 4. In patients with AF and HF, digoxin is reasonable for rate

control, in combination with other rate-controlling agents or as monotherapy if other agents are not tolerated.16,17

2a B-NR

5. In patients with AF and HF with rapid ventricular rates in whom beta blockers or calcium channel blockers are contraindicated or ineffective, intravenous amiodarone is reasonable for acute rate control.†18,19

2a B-R

6. In patients with AF, HFrEF (LVEF <50%), and refractory rapid ventricular response who are not candidates for or in whom rhythm control has failed, AVNA and biventricular pacing therapy can be useful to improve symptoms, QOL, and EF.20–23

2a B-NR

7. In patients with AF, HF, and implanted biventricular pacing therapy in whom an effective pacing percentage cannot be achieved with pharmacological therapy, AVNA can be beneficial to improve functional class,24,25 reduce the risk of ICD shock,26 and improve survival.24,25

2a B-NR

8. In patients with AF-induced cardiomyopathy who have recovered LV function, long-term surveillance can be beneficial to detect recurrent AF in view of the high risk of recurrence of arrhythmia-induced cardiomyopathy.27,28

2b B-NR

9. In patients with suspected AF-induced cardiomyopathy or refractory HF symptoms undergoing pharmacological rate-control therapy for AF, a stricter rate-control strategy (target heart rate <80 bpm at rest and <110 bpm during moderate exercise) may be reasonable.29–31

2b C-LD

10. In patients with AF and HFrEF who undergo AVNA, conduction system pacing of the His bundle or left bundle branch area may be reasonable as an alterna- tive to biventricular pacing to improve symptoms, QOL, and LV function.32–35

3: Harm

B-R

11. In patients with AF and known LVEF <40%, nondihydropyridine calcium channel–blocking drugs should not be administered because of their potential to exacerbate HF.36

3: Harm

B-R

12. For patients with AF, dronedarone should not be administered for maintenance of sinus rhythm to those with NYHA class III and IV HF or patients who have had an episode of decompensated HF in the past 4 weeks, due to the risk of increased early mortality associated with worsening HF.37

*Please see other recommendations on anticoagulation in AF (Section 8.4.4, “Anticoagulation Therapy Before and After Catheter Ablation”), rate control in HF (Section 7, “Rate Control”), and agents for pharmacological cardioversion (Sec- tion 7.2, “Specific Pharmacological Agents for Rate Control”) and maintenance of sinus rhythm (Section 8.3.1, “Specific Drug Therapy for Long-Term Maintenance of Sinus Rhythm”). †Consider the risk of cardioversion and stroke when using amiodarone as a rate-control agent.

Synopsis AF is the most common cause of arrhythmia-induced cardiomyopathy,27,38 a condition where persistent AF, with or without rapid ventricular rates, can lead to LV dysfunction and HF that can be partially or completely reversed with adequate arrhythmia control.39 AF can either be the only reason for cardiomyopathy (AF-in- duced) or can exacerbate LV dysfunction and HF in a patient with concomitant structural heart disease (AF- mediated).38,39 Medical therapies for rate control (Sec- tion 7) or rhythm control (Section 8) of AF have special considerations in patients with HF based on differential safety. Routine pharmacological rhythm compared with rate control has not demonstrated benefit on clinical outcomes in patients with HFrEF,29,40 although a re- cent subgroup analysis of patients with HF (most heart failure with preserved ejection fraction) demonstrated benefit of early rhythm control compared to rate control on clinical outcomes.1 Several trials have compared AF catheter ablation with medical therapy in patients with HFrEF. Although earlier trials were small and focused on endpoints such as improvement in LVEF, QOL, and 6-minute walk, 2 of the largest trials have shown a ben- efit in reducing mortality rate and HF hospitalization.3–13 Patients with AF and HF may undergo AVNA for rate control refractory to medical therapy.20,21 Similar to find- ings in patients who undergo pacemaker implantation for conduction system disease, patients with HF appear to be more likely to develop or have worsened cardio- myopathy related to RV pacing dyssynchrony41,42 and have improved outcomes with biventricular or conduc- tion system pacing.23,32,33,35

Recommendation-Specific Supportive Text 1. It can be difficult to determine the extent of the

contribution of AF to cardiomyopathy and new onset HFrEF. Allowing AF to persist long term, regardless of reasonable rate control, may result in worsening HF and cardiomyopathy. An early and aggressive approach to rhythm control can reduce AF burden, resulting in favorable ventricu- lar remodeling and halting of any occult arrhyth- mia-induced cardiomyopathy. In a prespecified subanalysis of 798 HF patients (NYHA class II/ III or LVEF <50%) in EAST-AFNET (HFpEF, 442; midrange, 211; HFrEF [<40%], 132), early rhythm control significantly improved the compos- ite outcome of death, stroke, or hospitalization for worsening of HF or for ACS (early rhythm control, 94/396; 5.7/100 patient-years) versus usual care (130/402; 7.9/100 patient-years; HR, 0.74 [95% CI, 0.56-0.97]; P=0.03), and this was not altered by HF status. Safety outcomes in each group were comparable. However, only 17% of the HF popula- tion had LVEF <40%.1 In a post hoc analysis of the CASTLE-AF trial, an AF burden <50% at 6 months

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postcatheter ablation was associated with signifi- cant improvement in the mortality rate and HF hos- pitalization in patients with AF and HFrEF.2

2. Multiple RCTs in HFrEF have shown that in patients with symptoms due to AF, ablation improves symp- toms and QOL compared with a rate control or an antiarrhythmic drug strategy.3–13 In each of 3 meta- analyses, QOL was improved.3,10,13 Although in the past a trial of antiarrhythmic drugs was advised before pursuing catheter ablation, current data support ablation for AF as first-line therapy even before antiarrhythmic drugs; often patients require both. Data on LVEF, hospitalizations, and mortality rates are less robust, but nearly every larger RCT does show some benefit in these outcomes (Table 27). Characteristics that may identify patients with a higher likelihood of success or failure with AF catheter ablation are listed in Figure 24.43

3. Data for AF catheter ablation are far less robust for HFpEF. The largest analysis for this group of patients was a subanalysis of the CABANA trial of patients with HF; in this subgroup analysis, 778 patients (35% of the study population) enrolled in the study who had NYHA class II HF experienced improvement in survival, freedom from AF recur- rence, and improved QOL compared with the medi- cal therapy group.14 Most of these had HFpEF. In this subanalysis, catheter ablation was associated with a reduction in the mortality rate and HF. A meta-analysis on catheter ablation in patients with HFpEF that included 7 studies and 764 patients showed the ablation to be safe and effective and associated with lower hospitalizations and the mor- tality rate.15

4. A small RCT in patients with persistent AF and HF (most HFrEF) compared the effects of digoxin, carvedilol, and the combination.16 Combination therapy was associated with better rate con- trol and symptom relief than monotherapy. The RATE-AF trial randomized 160 patients (≥60 years of age) with persistent AF and HF (81% with LVEF ≥50%) to digoxin or bisoprolol.17 No significant difference was noted in the primary endpoint of QOL at 6 months. Secondary outcomes, including natriuretic peptide levels, were significantly lower in the digoxin group, without a significant differ- ence in resting heart rate at 12 months. Adverse effects were less common in the digoxin group. Observational and post hoc analyses have sug- gested an excess mortality with digoxin in patients with AF; however, residual confounding due to the use of digoxin in sicker patients may have a role.44 In patients with HF on digoxin chronically, post hoc analyses have suggested increased mortality rates and hospitalization with serum digoxin levels ≥1 ng/mL; levels <0.8 ng/mL in HF were associated

with the lowest mortality rate, although the study was for therapy of HF and not AF.45 In the DAAF (Digitalis in Acute Atrial Fibrillation) trial of 239 patients (12% with HF), intravenous digoxin led to a significant decrease in heart rate at 2 hours com- pared with placebo.

5. In trials of critically ill patients, some of which included a smaller proportion of patients with HF, intravenous amiodarone has been shown to be effective in controlling ventricular rates.18,19,46 In a randomized trial of 60 such patients (13 with HF), significant rate control was achieved with both intravenous diltiazem and intravenous amiodarone. However, intravenous diltiazem was associated with a significantly higher frequency of hypoten- sion requiring discontinuation.19 In another ret- rospective study of 38 patients admitted to the intensive care unit (9 with HF), intravenous amiod- arone was associated with a statistically significant decrease in ventricular rate without decrease in BP (and in some cases improved hemodynamics) compared with intravenous diltiazem and digoxin.18 Intravenous beta blockers may also cause hypo- tension and may not be tolerated in patients with HF and hemodynamic instability. Although less frequent, intravenous amiodarone can also be associated with hypotension, specifically with the intravenous bolus. The possibility of conversion to sinus rhythm with intravenous amiodarone and associated potential for thromboembolism, espe- cially in patients with longer-standing AF not on anticoagulation, should factor into the risk-benefit decision when intravenous amiodarone is chosen for rate control.

6. Small RCTs of patients with medically refractory AF and HF show that patients who undergo AVNA and conventional pacemaker implantation are less symptomatic and have improvements in QOL and exercise tolerance compared with subjects who are managed with medical rate control.20–22,47 A meta- analysis comparing outcomes with AVNA or medi- cations showed, in 2 studies analyzing patients with reduced EF, a modest, yet significant +4% increase in EF in patients undergoing AVNA and RV pacing, while patients with normal EF at base- line did not show a significant change.48 A meta- analysis of 93 studies including 11 343 patients who underwent AVNA with either RV pacing or biventricular pacing showed periprocedural compli- cations of arrhythmia, HF, and lead dislodgement in 2% to 2.5%,49 few long-term data, and worse outcomes in younger patients with reduced EF and RV pacing.49 Overall, these data showed improved mortality in patients with HF who are treated with cardiac resynchronization therapy (CRT), at the risk of increased device-related complications.49 The

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Table 27. Randomized Trials of Rhythm Control in HF

Study/ Author (y)

No. Pts. Inclusion Exclusion

Interven- tion

Primary Outcome

Death and Hospital- ization Death

Hospital- izations

Reduction in AF LVEF QOL 6MWT

Peak VO2 Max BNP

Roy

(2008)60

1376 LVEF <35%,

CHF

AAD

(primarily

amioda-

rone) vs

rate

control

Cardiovascu-

lar mortality

was no differ-

ent between

rhythm vs

rate control

No change No

difference

MacDonald

(2011)8

41 Persistent AF;

LVEF <35%,

CHF II-IV

PAF;

QRS

>150

RF to

medical

therapy

Similar

increase in

CMR LVEF

difference

Improved

with RF

Improved No

change

ARC-HF:

Jones

(2013)6

52 Persistent

AF; LVEF

<35%, CHF

RF to

medical

therapy

Improvement

in peak VO2

with RF

No change No

difference

change

Improved

with RF

change

Improved

CAMTAF

(2014)5

50 Persistent

AF; LVEF

<50%; CHF

RF to

medical

therapy

LVEF sig-

nificantly

improved

with RF

No change No

difference

Improved Improved

with RF

Improved

AATAC

(2016)4

203 Persistent AF;

LVEF <40%,

CHF II-III

RF to ami-

odarone

At 24 mo,

RF patients

more likely to

be in NSR

Improve-

ment with

Improved Improved Improved Improved

with

ablation

Improved

CAMERA

MRI

(2017)12

66 Persistent

AF; LVEF

<45%, CHF

II-III; idio-

pathic CM

RF to

medical

therapy

Improved

LVEF with

Improved No

change

Improved

CASTLE-AF

(2018)9

363 PAF or per-

sistent AF;

LVEF <36%,

CHF II-IV

and ICD

RF to

medical

therapy

Composite

of death and

hospitalization

lower with RF

Improve-

ment with

Improved Improved Improved

AMICA

(2019)7

140 Persistent

AF; LVEF

<36%

RF to

medical

therapy

No difference

in change in

LVEF

change

CABANA

substudy

(2021)14

778 Clinical HF

(largely HF-

pEF)

RF to

medical

therapy

Decrease in

composite of

MACE

Improved Improved

with RF

Improved

with RF

RAFT-AF

(2022)11

411 ≥4 PAF/y or

persistent AF,

NYHA class

II or III HF,

elevated pro-

BNP

RF to

medical

therapy

No difference

in change in

mortality/HF

No differ-

ence in

change in

mortality/

change

Improved

with RF

Improved

with RF

Improved

with RF

Improved

with RF

Improved

with RF

Meta-analy-

sis-Turagam

(2019)13

775 RF to

medical

therapy

Improved Reduced Improved Improved Improved Improved

Meta-anal-

ysis-Chen

(2020)3

1112 RF to

medical

therapy

Improved Reduced Improved

with RF

Improved Improved

Meta-anal-

ysis-Pan

(2021)10

775 RF to

medical

therapy

Improved Reduced Improved Improved Improved

AAD indicates antiarrhythmic drug; AATAC, Ablation vs Amiodarone for Treatment of Atrial Fibrillation in Patients With Congestive Heart Failure and an Implanted ICD/CRTD; AF, atrial fibrillation; AMICA, Atrial Fibrillation Management in Congestive Heart Failure With Ablation; ARC-HF, A Randomised Trial to Assess Catheter Ablation Versus Rate Control in the Management of Persistent Atrial Fibrillation in Chronic Heart Failure; BNP, brain natriuretic peptide; CABANA, Catheter Ablation vs Antiarrhythmic Drug Therapy for Atrial Fibrillation; CAMERA MRI, Catheter Ablation versus Medical Rate Control in Atrial Fibrillation and Systolic Dysfunction-an MRI-Guided Multi-centre Randomised Controlled Trial; CAMTAF, Catheter Ablation Versus Medical Treatment of AF in Heart Failure; CASTLE-AF, Catheter Ablation versus Standard Conventional Therapy in Patients with Left Ventricular Dysfunction and Atrial Fibrillation; CHF, congestive heart failure; CM, cardiomyopathy; CMR, cardiac magnetic resonance: HF, heart failure; HFpEF, heart failure with persistent ejection fraction; ICD, implantable cardioverter-defibrillator; LVEF, left ventricular ejection fraction; MACE, major adverse cardiovascular events; NSR, normal sinus rhythm; NYHA, New York Heart Association; PAF, paroxysmal atrial fibrillation; QOL, quality of life; RAFT-AF, Rhythm Control–Catheter Ablation With or Without Anti-arrhythmic Drug Control of Maintaining Sinus Rhythm Versus Rate Control With Medical Therapy and/or Atrio-ventricular Junction Ablation and Pacemaker Treatment for Atrial Fibrillation; RF, radiofrequency; VO2 max, maximal oxygen consumption; and 6MWT, 6-minute walk test.

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Figure 24. Management of Patients With HF and AF. Colors correspond to Table 2. AF indicates atrial fibrillation; AV, atrioventricular; CMP, cardiomyopathy; CMR, cardiac magnetic resonance; GDMT, guideline-directed medical therapy; HF, heart failure; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; IV, intravenous; LVEF, left ventricular ejection fraction; NDCC, nondihydropyridine calcium channel blocker; and NYHA, New York Heart Association.

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APAF-CRT (Ablate and Pace in Atrial Fibrillation plus Cardiac Resynchronization Therapy) mortal- ity trial of 133 subjects with AF, HF, and narrow QRS was stopped early due to a HR of 0.26 for all- cause mortality, also suggesting that when AVNA is performed in patients with HF, CRT is preferable to conventional RV pacing.23 Data are accumulat- ing regarding similarly improved outcomes with conduction system pacing compared with conven- tional RV pacing in this population.32–35

7. Conduction of AF may hinder delivery of biventricu- lar pacing therapy (CRT) and worsen outcomes.25 Initial clinical trials of CRT included low numbers of patients with AF,50 and observational analyses sug- gested a reduced benefit of CRT in patients with AF due to ineffective biventricular pacing.51,52 A systematic review to evaluate the impact of AVNA in patients with AF and CRT found AVNA was associated with significant reductions in all-cause mortality (RR, 0.42 [95% CI, 0.26-0.68]), cardio- vascular mortality (RR, 0.44 [95% CI, 0.24-0.81]), and improvement in NYHA class (RR, –0.52 [95% CI, –0.87 to –0.17]).24 Confirmatory evidence of the importance of adequate biventricular pacing per- centage is provided by an analysis of remote moni- toring data showing a strong association between increasing percentages of biventricular pacing and reduced mortality, with the greatest magni- tude reduction at >98% pacing.53 In a systematic review and meta-analysis of 31 studies in 83 571 individuals, CRT alone did not improve the mortality rate in patients with AF, but the all-cause mortality rate was lower in the AVNA group.25 Many patients with CRT devices also have combined defibrillator therapy. In a pooled analysis of 664 patients with AF and CRT in whom 282 underwent AVNA, a sig- nificant reduction in appropriate and inappropriate ICD shocks and a decrease in all-cause hospital- izations was associated with AVNA.26

8. In an observational study of 24 patients with AF-induced cardiomyopathy and NYHA class III/ IV HF, the median time from onset of arrhythmia to cardiomyopathy and HF was 4.2 years. Aggressive rate/rhythm control resulted in significant LVEF recovery in all patients within 6 months. Five of 24 patients had recurrent AF, and all had a rapid decline in LVEF within 6 months after arrhythmia recurrence.27 In an observational cohort of 69 patients with AF and LVEF <40% who underwent catheter ablation, patients who maintained sinus rhythm (65%) had complete LV function recovery and maintained normal LVEF over 28±11 months of follow-up, compared with those who had recur- rent AF/AT.28 Long-term surveillance to detect recurrent AF can be beneficial and can be accom- plished by various modalities, including wearable

devices, smart watches, random monitoring (Holter, event, mobile telemetry), and implantable loop recorders.

9. In patients with arrhythmia-induced cardiomyopa- thy and HFrEF, the ideal target heart rate for rate control remains uncertain. However, because of the potential negative impact of rapid ventricu- lar rates on HF and cardiomyopathy, a stricter rate-control strategy may be reasonable. In the AF-CHF trial, which compared rate control ver- sus rhythm control using antiarrhythmic therapy in AF and HFrEF, the target rate control was defined as ventricular rate <80 bpm during rest- ing 12-lead electrocardiography and <110 bpm during a 6-minute walk test.29 In the RACE II trial, 614 patients with permanent AF were random- ized to a heart rate <80 bpm at rest and <110 bpm during moderate exercise or lenient control (resting heart rate, <110 bpm), with results show- ing similar outcomes in each arm. However, RACE II trial patients were rate controlled at enrollment (baseline heart rate, 96 bpm), and only 15% of the study cohort had an LVEF <40%, plus very few patients had heart rates >100 bpm, even in the lenient rate control gorup.54 In a crossover study of 20 patients with persistent AF and LVEF <40%, patients were given escalating doses of metoprolol (average dose, 121 mg) to get tar- get heart rate <70 bpm. After 3 months, average resting heart rate decreased from 94±14 bpm to 85±12 bpm, but no significant differences in QOL on functional status were noted.31 Strict rate control is also advisable in patients with ICDs and CRT (See Table 20 in Section 7.1, “Broad Considerations for Rate Control”).55,56

10. In small observational series of patients undergo- ing AVNA and His bundle pacing, postprocedural increase in EF and improved functional class has been demonstrated, at the expense of increased pacing thresholds in some patients.32,35 A single- center study comparing outcomes after AVNA with His bundle pacing and left bundle area pacing in 105 patients showed a higher rate of recurrent AVN conduction in the His bundle pacing group and longer fluoroscopy time.33 Acute threshold rise, exit block, and elevated long-term thresholds were also seen in the His bundle pacing group but not in left bundle area pacingin follow-up limited to 10.5 months. Both strategies were associated with a significantly improved EF in patients with EF <50% at baseline (N=16; 37%±7.6% versus 46%±13%; P=0.02).33 An observational compara- tive study of patients undergoing AVNA, of whom 113 had RV (56) or BiV (57) pacing and 110 had conduction system pacing (84 His bundle pacing and 46 left bundle area pacing) showed increased

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EF in conduction system pacing compared with the mixed RV/BivP group (46.5%±14.2% to 51.9%±11.2%; P=0.02) in conduction sys- tem pacing and 36.4%±16.1% to 39.5%±16% (P=0.04) in RV/BiVP.34 A combined endpoint of time to death or HF hospitalization was reduced in the conduction system pacing group in >2 years of follow-up, but extrapolation is limited due to the observational and selected nature of the popula- tion and because the RV/BiVP group had lower EF and wider QRS at baseline.34

11. The nondihydropyridine calcium channel block- ers—diltiazem and verapamil—are negative inotro- pic agents and may not be tolerated in patients with HFrEF. In the acute setting, limited data from 2 retrospective analyses suggest the potential for increased morbidity with the use of diltiazem in patients with HFrEF, including worsening HF, need for inotropic support, or acute kidney injury.57,58 In the chronic setting, diltiazem had no impact on mortality in a trial of patients with nonischemic cardiomyopathy.59 However, in the multicenter ran- domized MDPIT of patients postacute MI, HF and cardiac events (cardiac death or nonfatal reinfarc- tion) were more frequent in the patients with LVEF <40% or pulmonary congestion who were ran- domized to diltiazem. Among those with a baseline EF of <40%, late HF appeared in 12% receiving placebo and 21% receiving diltiazem (P=0.004). Life table analysis in patients with an EF of <40% confirmed more frequent late HF in those taking diltiazem (P=0.0017). In addition, the diltiazem- associated increase in the frequency of late HF was progressively greater with decreasing base- line EF.36 This increase in late HF was not seen in patients with pulmonary congestion at baseline but an EF of ≥40%, suggesting the association of diltiazem-related late HF was present only in those with systolic LV dysfunction.

12. The ANDROMEDA37 study was a randomized, double-blind placebo-controlled study that tested the hypothesis that dronedarone would reduce the rate of hospitalization due to HF and pos- sibly reduce mortality by reducing the incidence of arrhythmic death. The study enrolled patients who were hospitalized with new or worsening HF and who had at least 1 episode of NYHA class III or IV HF (shortness of breath on minimal exertion or at rest). More than 40% of the patients had NYHA class II HF at baseline. The investigators reported that, contrary to the study’s hypothesis, mortality was higher in the dronedarone group compared to that in the placebo group (8.1% versus 3.8%; HR, 2.13 [95% CI, 1.07-4.25]; P=0.03). The excess mortality was principally associated with worsening HF.

10. AF AND SPECIFIC PATIENT GROUPS 10.1. Management of Early Onset AF, Including Genetic Testing

Recommendations for Management of Early Onset AF, Including Genetic Testing Referenced studies that support the recommendations are summarized in the Online Data Supplement.

COR LOE Recommendations

2b B-NR

1. In patients with an onset of unexplained AF before 30 years of age, electrophysiological study to evaluate and treat reentrant supraventricular tachyarrhythmias with a targeted ablation may be reasonable because of the high prevalence of reen- trant arrhythmias in this group.1–3

2b B-NR

2. In patents with an onset of AF before 45 years of age without obvious risk factors for AF, referral for genetic counseling, genetic testing for rare patho- genic variants, and surveillance for cardiomyopathy or arrhythmia syndromes may be reasonable.4,5

Synopsis Young patients are less likely to develop AF or associ- ated strokes compared with older populations. Consum- er-driven use of wearable devices is increasing and can lead to the diagnosis of AF at a young age.6 In those <30 years of age, reentrant SVTs (atrioventricular nod- al reentrant tachycardia and atrioventricular reentrant tachycardia) are found in about 25% of patients.1–3 Tar- geted ablation of the reentrant tachycardia is followed by resolution of AF episodes in most of these young patients. However, additional factors need to be taken into consideration in young patients who present with AF. Growing evidence suggests that, in addition to risk factors for AF present in older populations, young pa- tients who develop AF may also harbor susceptibility for inherited ion channel and cardiomyopathic disorders,4 even in those with normal echocardiograms.5 In addition to the standard workup for newly diagnosed AF, genetic testing for rare pathogenic variation, advanced imaging modalities, and surveillance screening could detect oth- erwise occult cardiomyopathy.

Recommendation-Specific Supportive Text 1. Two retrospective observational cohort studies

included patients with onset of AF before the age of 21 years2 and 30 years1 who underwent elec- trophysiological study to assess for reentrant SVTs. The former study found atrioventricular node reen- try tachycardia or atrioventricular reentry tachycar- dia in 39% of patients and the latter in 24%. In both studies, after targeted ablation of the reentry tachycardia, patients were observed for recurrence of AF for a median of about 1.5 years. The former study reported no recurrences of AF, and the lat- ter study reported that 86% remained free of atrial arrhythmias. In an additional prospective cohort study of patients referred for AF ablation who had inducible atrioventricular node reentry tachycardia,

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12 of 13 patients who underwent slow pathway ablation without PVI had no recurrence of AF after a mean follow-up of 21 months.3

2. A prospective observational cohort study in patients with AF diagnosed before the age of 66 years and who had sequencing of genes typically found in ion channelopathy and cardiomyopathy panels reported that among 1293 patients studied, 10% (131) were found to have a disease-associated variant, primarily in cardiomyopathy-related genes.4 In 1 study of 23 unrelated patients with onset of AF at <45 years of age who had a normal echo- cardiogram and no other readily identifiable causes of AF, 24% had a pathogenic or likely pathogenic variant identified. Most of these were also in car- diomyopathy-related genes.5

10.2. Athletes Recommendation for Athletes Referenced studies that support the recommendation are summarized in the Online Data Supplement.

COR LOE Recommendation

2a B-NR

1. In athletes who develop AF, catheter ablation with PVI is a reasonable strategy for rhythm control because of its effectiveness and low risk of detrimental effect on exercise capacity.1,2

Synopsis Engaging in moderate levels of exercise has several cardiovascular benefits and, in some studies, has been associated with a lower incidence of AF.3,4 However, high-volume endurance athleticism, defined here as exercise of >45 metabolic equivalent-hours per week, has been associated with a higher prevalence of AF,5 particularly in young athletes.6 The mechanisms behind this association are not well established but may be re- lated to atrial myopathy from exercise-induced stretch or perhaps inflamation.7,8 No studies have prospectively studied the effects of detraining on AF burden, but some have proposed that moderation of exercise may be con- sidered, although it is unclear whether changes are reversible.9 Nevertheless, athletes will often choose to continue sport participation, and aggressive rhythm con- trol strategies are often sought. Because many of these patients are young, medications are often not tolerated or preferred. PVI has been shown to be safe and effec- tive in this population without resulting in a significant reduction in exercise capacity1 and has been shown to significantly improve QOL.2

Recommendation-Specific Supportive Text 1. In a prospective cohort study of 144 athletes, AF

ablation with PVI, including multiple procedures, resulted in freedom from AF at 1 year in 86% of athletes with paroxysmal AF and 68% of ath- letes with persistent AF over a median follow-up of 3 years.1 Athletes underwent cardiopulmonary

exercise stress testing before and after ablation and, although the sinus rate increased on average 10 bpm after ablation (which may bother some ath- letes and thus should be discussed before the pro- cedure), no significant changes were observed in maximum metabolic equivalents on exercise tread- mill testing. In a retrospective cohort study of 133 competitive athletes who underwent catheter abla- tion for AF with 10-year follow-up, 83% of athletes did not have recurrent events and had significantly improved QOL scores.2

10.3. Management Considerations in Patients With AF and Obesity Obesity is a strong risk factor for AF.1 In the Framing- ham Study, overweight and obesity increased the risk of incident AF, with a 4% increase in AF risk per unit in- crease in BMI in men and women. Adjusted HRs for AF associated with obesity were 1.52 (95% CI, 1.09-2.13; P=0.02) and 1.46 (95% CI, 1.03-2.07; P=0.03) for men and women, respectively, compared with individuals with normal BMI. In that study, the excess risk of AF associ- ated with obesity appeared to be mediated through LA dilatation.2 Other studies suggest that the risk of AF with obesity is mediated through epicardial and abdominal fat, or structural changes in the atria.1,3 Obesity is also associated with other comorbidities, including hyperten- sion, HF, and sleep apnea, which themselves predispose to an increased incidence of AF. Further, higher BMI and obesity are associated with an increase in the burden of AF, including progression from paroxysmal to permanent AF, and an increased risk of AF recurrence after AF abla- tion.4 Special considerations for the management of AF in patients with obesity include the role of weight loss in the primary and secondary prevention of AF (Section 5, “Lifestyle and Risk Factor Modification for AF Man- agement”), as well as anticoagulation in patients with severe or class III obesity in this section and in Section 10.4 (“Anticoagulation Considerations in Patients With Class III Obesity”).

10.4. Anticoagulation Considerations in Patients With Class III Obesity

Recommendations for Anticoagulation Considerations in Patients With Class III Obesity Referenced studies that support the recommendations are summarized in the Online Data Supplement.

COR LOE Recommendations

2a B-NR 1. In patients with AF and class III obesity (BMI ≥

40 kg/m2), DOACs are reasonable to choose over warfarin for stroke risk reduction.1–5

2b C-LD

2. In patients with AF who have undergone bariatric surgery, warfarin may be reasonable to choose over DOACs for stroke risk reduction in view of concerns about DOAC drug absorption.6,7

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Synopsis Patients with class III obesity (BMI ≥40 kg/m2) are underrepresented in the major clinical trials evaluat- ing the efficacy and safety of DOACs in patients with AF. Post hoc analyses of major DOAC trials in AF and large observational studies have shown comparable efficacy and safety of DOACs compared with warfarin across weight groups, including patients with class III obesity.1–5 Thus, DOACs are preferred over warfarin for stroke risk prevention in patients with class III obesity and AF. Little evidence is available that evaluates the pharmacokinetics, efficacy, and safety of DOACs in pa- tients with AF who have undergone bariatric surgery. Thus, warfarin may be reasonable to choose over DO- ACs to reduce stroke risk in this population until further data become available.

Recommendation-Specific Supportive Text 1. Post hoc analyses of the ARISTOTLE (apixaban

versus warfarin), ROCKET AF (rivaroxaban versus warfarin), and ENGAGE AF-TIMI 48 (edoxaban versus warfarin) demonstrated consistent efficacy (stroke and systemic embolism) and safety (major bleeding) of DOACs compared with warfarin across weight groups in patients with AF.3–5 A meta-anal- ysis including these trials and RE-LY (dabigatran versus warfarin) again showed similar efficacy and safety of DOACs compared with warfarin, although the outcome differences were attenuated in obese patients.2 A large retrospective observational study including 36 094 patients compared risk of isch- emic stroke, significant bleeding, and mortality in patients receiving a DOAC or warfarin, stratified by BMI group.1 For all 3 endpoints, better outcomes were observed with DOACs across BMI groups. In patients with a BMI ≥40 kg/m2, a relative risk reduction of 25% for ischemic stroke (adjusted HR, 0.75 [95% CI, 0.64-0.87]; P<0.001), 57% for significant bleeding (adjusted HR, 0.43 [95% CI, 0.20-0.94]; P<0.001), and 34% for all-cause mortality (adjusted HR, 0.66 [95% CI, 0.56-0.77]; P<0.001) was observed with DOACs compared with warfarin.

2. Although case reports exist that demonstrate expected factor Xa trough levels in patients tak- ing a DOAC who undergo bariatric surgery, a meta- analysis of cohort studies, case series, and case reports has shown that 42% of patients who have undergone bariatric surgery had peak drug levels below the expected range.6,7 Patients who have undergone bariatric surgery are not well repre- sented in any of the major trials comparing DOACs with warfarin, and few observational data support DOAC use in this population. Warfarin’s therapeutic effect can be routinely monitored. Thus, in patients

with AF who have undergone bariatric surgery, warfarin may be a reasonable choice over DOACs for stroke risk reduction at this time.

10.5. AF and VHD VHD and AF commonly coexist. AF independently pre- dicts the risk of cerebrovascular events among patients with valve disease.1 This risk may be addressed with the use of oral anticoagulation, percutaneous and surgical LAAO, and surgical ablation as described in Sections 6.5.1 (“Percutaneous Approaches to Occlude the LAA”), 6.5.2 (“Cardiac Surgery—LAA Exclusion/Exci- sion”), and 6.8.5 (“AF in VHD”).

10.6. WPW and Preexcitation Syndromes Recommendations for WPW and Preexcitation Syndromes Referenced studies that support the recommendations are summarized in the Online Data Supplement.

COR LOE Recommendations

1 B-NR 1. Patients with AF with rapid anterograde conduction

(preexcited AF), and hemodynamic instability should be treated with electrical cardioversion.1,2

1 B-NR 2. For patients with AF with rapid anterograde

conduction (preexcited AF), catheter ablation of accessory pathways (APs) is recommended.3–7

1 C-LD

3. In patients with AF with rapid anterograde conduction (preexcited AF) and hemodynamic stability, pharmacological cardioversion with intravenous ibutilide or intravenous procainamide is recommended as an alternative to elective cardioversion.1,8,9

3: Harm

B-NR

4. For patients with AF with anterograde accessory pathway conduction (preexcited AF), pharmacologi- cal agents that block atrioventricular nodal con- duction (verapamil, diltiazem, amiodarone, digoxin, adenosine, or beta blockers) are contraindicated due to risk of precipitating VF or hemodynamic deterioration.10–14

Synopsis WPW and preexcitation syndromes refer to the pres- ence of extra-atrioventricular nodal connection(s) be- tween atrium and ventricle; such APs are comprised of atrial tissue.15 AF occurs in approximately 15% of per- sons with WPW and although the mechanism(s) remain unclear, the faster conduction properties of atrial tissue compared with the atrioventricular node allow for rapid rates in preexcited AF.15–17 The risk of preexcited AF is higher for those with multiple pathways and short ante- grade pathway refractory period (<250 ms), which allows rapid conduction and predisposes to VF and sudden death.1,18,19 Moreover, AF in young persons without evi- dence of comorbid conditions may be associated with an AP, and pathway ablation is definitive therapy for AF and SVT in these persons.1 For those who cannot undergo ablation, preventive pharmacological therapy is directed to slowing pathway conduction.20,21

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Recommendation-Specific Supportive Text 1. Preexcited AF can conduct rapidly over the path-

way and lead to VF. During an acute episode of preexcited AF with rapid ventricular response and hemodynamic instability, electrical cardioversion must be used to restore sinus rhythm.1,2

2. Pathway ablation has well-established efficacy and safety for those with preexcited AF for prevention of VF.1 Multiple large-patient series point to a high success rate (93%-95%) balanced with low risk of major short- and long-term complications.3–7 Electrophysiological study and AP ablation can be offered as first-line therapy.

3. Pharmacological treatments that increase the refractory period of atrial tissue (ie, ibutilide or pro- cainamide) can slow AP conduction and terminate AF. Hemodynamically stable patients presenting with preexcited AF with or without rapid ventricular rates can be pharmacologically managed with such agents.8,9 In 1 study involving 22 patients, ibutilide terminated AF in 21 patients and prolonged refrac- toriness of the atrioventricular node, His-Purkinje system, and AP.9

4. AP conduction can accelerate with atrioventricu- lar nodal block. Administration of pharmacological agents that block atrioventricular nodal conduc- tion can increase the risk of VF. The use of atrio- ventricular nodal blocking agents for patients with preexcited AF are potentially harmful due to the risk of accelerated pathway conduction and associated VF.1,10–12 One small series that reviewed intravenous amiodarone for this indica- tion raised significant concerns in view of several published reports on instances of VF precipitated by amiodarone.13 In 1 study of patients with WPW who received verapamil during electrophysi- ological study, verapamil decreased the shortest RR interval between preexcited ventricular com- plexes during AF, and 2 patients deteriorated and required cardioversion.14 Data are very limited and observational, but because other safer options are readily available, atrioventricular nodal agents are best avoided in this setting.

10.7. Hypertrophic Cardiomyopathy The “AHA/ACC Guideline for the Diagnosis and Treat- ment of Patients With Hypertrophic Cardiomyopathy” was published in December 2020, and this guideline included recommendations on AF.1 Data on AF in pa- tients with HCM published since the 2020 hypertrophic cardiomyopathy guideline were reviewed but did not result in any substantive changes in the recommenda- tions from 2020.2–6 AF is highly prevalent in HCM and increases the risk of stroke. The CHA2DS2-VASc score

should not apply to patients with HCM, because they have roughly an equivalent risk to a CHADs-VASc of 3. Data on the use of DOACs in patients with HCM suggest these to be acceptable alternatives to warfa- rin. When a rhythm-control strategy is needed, several antiarrhythmic drugs have been shown to be safe and effective, allowing for individualization according to underlying substrate and patient preference. Catheter ablation is also an important option, although more confirmatory studies have shown AF ablation is of low- er success compared with patients without HCM.7 For specifics, please see the “2020 AHA/ACC Guideline for the Diagnosis and Treatment of Patients With Hy- pertrophic Cardiomyopathy.”1

10.8. Adult Congenital Heart Disease (ACHD) Recommendations for ACHD Referenced studies that support the recommendations are summarized in the Online Data Supplement.

COR LOE Recommendations

1 B-NR

1. In adults with congenital heart disease and AF, it is recommended to evaluate for and treat precipitating factors and reversible causes of AF, recognizing that residual hemodynamic sequelae may contribute to the occurrence of the arrhythmia.1,2

1 C-LD

2. In adults with AF and moderate or complex congeni- tal heart disease, electrophysiological procedures should be performed by operators with expertise in ACHD procedures and in collaboration with an ACHD cardiologist, ideally in specialized centers, when available.3–5

1 C-LD

3. In adults with congenital heart disease and symp- tomatic or hemodynamically significant paroxysmal or persistent AF, an initial strategy of rhythm control is recommended regardless of lesion severity as AF in this population is often poorly tolerated.6

2a B-NR

4. In symptomatic patients with simple congenital heart disease with antiarrhythmic drug–refractory AF, it is reasonable to choose ablation over long-term antiar- rhythmic therapies.4,7

2b C-LD

5. In adults with congenital heart disease with AF undergoing PVI, it may be reasonable to include an ablative strategy in the right atrium directed at reentrant arrhythmia secondary to atriotomy scars and the CTI.8,9

2b C-LD

6. In adults with AF and moderate or severe forms of congenital heart disease, particularly those with low-flow states such as Fontan circulation, blind- ending cardiac chambers, and cyanosis, it may be reasonable to treat with anticoagulation independent of conventional risk score to reduce risk of thromboembolic events.10

Synopsis Atrial arrhythmias are a leading cause of morbidity in adults with congenital heart disease, and AF surpasses intra-atrial reentrant tachycardia in patients with CHD >50 years of age.11 Risk factors for development of AF in patients with ACHD are similar to those for the general population; however, the presence of an atrial

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septal defect is an independent risk factor. Adults may be classified as having simple, moderate, or complex forms of CHD, based on a classification proposed in the “2018 AHA/ACC Guideline for the Management of Adults With Congenital Heart Disease.”12 Choosing pharmacological therapy for treatment of patients with ACHD who have AF should consider factors such as coexisting sinus node dysfunction or atrioventricular block, as well as the ventricular function and other co- morbidities. Ablation strategies established in normal hearts can be applied to patients with simple forms of CHD; however, caution must be taken in those pa- tients with moderate or complex forms of ACHD.13 Knowledge of the underlying congenital anatomy is key, because access to the atrial chambers may re- quire specialized approaches. In those patients with moderate or complex forms of CHD, electrophysiolog- ical procedures should be performed by operators with expertise in CHD and in collaboration with an ACHD cardiologist.3

Recommendation-Specific Supportive Text 1. Adults with CHD often have hemodynamic sequelae

of childhood repair, and any new onset arrhythmia, including AF, should prompt an evaluation for treat- able and reversible causes. Studies have shown that AF is correlated with RA dilation, thus neces- sitating addressing the underlying substrate in addi- tion to treating the arrhythmia.1,2

2. Patients with ACHD who are undergoing inva- sive electrophysiological procedures in specialized ACHD centers generally have better outcomes, including survival, than those managed in other care settings.3–5 Special attention is required to ensure appropriate periprocedural care, including identification of procedure-related risk factors and availability of ancillary imaging.12

3. Adults with simple forms of CHD and AF are gen- erally managed according to standard published guidelines. In those patients with moderate or complex forms of CHD, choice of antiarrhythmic therapy should be individualized.6 Most antiar- rhythmic drugs are associated with proarrhyth- mic effects and increased mortality in ACHD patients.14 Rhythm control is generally preferred over rate control in patients with ACHD with moderate or complex disease who may toler- ate AF poorly. Class I antiarrhythmic drugs must be avoided in patients with ACHD with CAD or significant subpulmonary or systemic ventricular dysfunction.14–16 Amiodarone is an effective anti- arrhythmic agent for maintaining sinus rhythm in patients with ACHD; however, long-term therapy is limited by adverse effects, particularly amiod- arone-induced thyrotoxicosis, which is common

in women with CHD, cyanotic CHD, and those with Fontan physiology.17 Amiodarone should also be avoided in patients with ACHD who have a BMI <21 kg/m2 due to the increased incidence of thyrotoxicosis in these patients.18 Dofetilide may be a viable alternative to amiodarone in this complex population.19 Extrapolating data from noncongenital populations, dronedarone is best avoided in patients with ACHD who have mod- erate or complex disease or significant ventricu- lar dysfunction due to the increased risk of HF, stroke, and death.20,21

4. Data on ablative strategies for AF in patients with ACHD are limited; however, when performed by experienced centers, AF ablation in patients with simple forms of CHD is safe.4,13 Knowledge of the underlying congenital anatomy is key, as access to the atrial chambers may require differ- ent approaches, including transseptal puncture. Patients with ACHD who have persistent AF have lower success rates for ablation, and multiple pro- cedures may be required.22 There are insufficient data on the role, safety, and benefit of AF ablation in complex forms of CHD.

5. PVI has a lower success rate in patients with ACHD than in patients with structurally normal hearts. The operator should understand the vari- ations in systemic and pulmonary venous anat- omy, such as a left superior vena cava, which may be a trigger for AF.9 Due to related pathol- ogy in the right atrium of patients with repaired complex ACHD, additional ablative therapies directed at atriotomy scars and the CTI may be necessary. Cryoballoon ablation is a safe option for patients with simple or moderate forms of CHD and AF.23,24

6. All patients with CHD should be considered for some form of thromboembolic prophylaxis. Select groups of patients with CHD are at higher risks for thromboembolic events, such as cya- notic lesions, those with low-flow states (Fontan physiology), and those with blind-ending cardiac chambers. The prevalence of cerebrovascular accidents in patients with ACHD is estimated to be 10- to 100-fold higher than age-matched controls, and thromboembolic events account for at least 4% of all-cause mortality in patients with CHD.25 Increased complexity of CHD is associ- ated with thromboembolic events, but CHA2DS2 and CHA2DS2-VASc scores are not predictive of thromboembolic risk in patients with ACHD; there- fore, therapies must be individualized.10 Limited data are available for the use of DOACs in patients with ACHD, but in a survey, they appeared to be safe and effective.26

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10.9. Prevention and Treatment of AF After Cardiac Surgery 10.9.1. Prevention of AF After Cardiac Surgery

Recommendations for Prevention of AF After Cardiac Surgery Referenced studies that support the recommendations are summarized in the Online Data Supplement.

COR LOE Recommendations

2a B-R

1. In patients undergoing cardiac surgery who are at high risk for postoperative AF, it is reasonable to administer short-term prophylactic beta blockers or amiodarone to reduce the incidence of postoperative AF.1–5

2a B-R

2. In patients undergoing CABG, aortic valve, or ascend- ing aortic aneurysm operations, it is reasonable to perform concomitant posterior left pericardiotomy to reduce the incidence of postoperative AF.6,7

Synopsis New-onset AF after cardiac surgery is common and has been associated with increased risks of late mortality and stroke.8 Trials of prophylactic amiodarone and beta blockers have demonstrated effectiveness reducing the occurrence of new AF, but not in all studies. Building off previous studies, the PALACS (Effect of Posterior Pericardiotomy on the Incidence of Atrial Fibrillation Af- ter Cardiac Surgery) randomized trial studied the use of posterior left pericardiotomy7 and found significant reduction of AF in the treated group (17% versus 32% no intervention group; P=0.0007; OR, 0.44). Colchicine has shown uncertain benefit based on the results of more recent studies compared with earlier encourag- ing trials. Drug adverse effects result in frequent drug discontinuation.9–11

Recommendation-Specific Supportive Text 1. Preoperative prophylaxis with beta blockers or

amiodarone has shown mixed benefit, and stud- ies are difficult to compare because of variable medication combinations.1–5 One double-blind RCT of 601 patients listed for nonemergency CABG surgery and/or valve replacement/repair surgery showed a significant reduction of AF with amiodarone.

2. A meta-analysis and RCT showed that the inci- dence of postoperative AF was significantly lower in patients treated with posterior left pericardiot- omy during their cardiac procedure; however, the studies did not include patients undergoing mitral or tricuspid procedures.6,7

10.9.2. Treatment of AF After Cardiac Surgery Recommendations for Treatment of AF After Cardiac Surgery Referenced studies that support the recommendations are summarized in the Online Data Supplement.

COR LOE Recommendations

A* 1. In postoperative cardiac surgery patients, beta

blockers* are recommended to achieve rate control for AF1–4 unless contraindicated or ineffective in which case a nondihydropyridine calcium channel blocker† is recommended.5

B-R†

1 B-R

2. In hemodynamically stable cardiac surgery patients with postoperative AF, rate-control (target heart rate, <100 bpm) and/or rhythm-control medications are recommended as initial therapy, with the choice of strategy according to patient symptoms, hemody- namic consequences of the arrhythmia, and physician preference.5,6

1 B-R

3. In patients who develop poorly tolerated AF after cardiac surgery, direct current cardioversion in com- bination with antiarrhythmic drug therapy is recom- mended, with consideration of imaging to rule out left appendage thrombus before cardioversion in those patients in whom AF has been present >48 hours and who have not been on anticoagulation.5,6

2a B-NR

4. In patients who develop postoperative AF after cardiac surgery, it is reasonable to administer anti- coagulation when deemed safe in regard to surgical bleeding for 60 days after surgery unless complica- tions develop and to reevaluate the need for longer term anticoagulation at that time.5,7

2a C-LD

5. In patients who develop AF after cardiac surgery and who are treated with rate-control strategy, at 30- to 60-day follow-up it is reasonable to perform rhythm assessment and, if AF does not revert to sinus rhythm spontaneously, consider cardioversion after an adequate duration of anticoagulation.5,6

*A LOE applies to the data on beta blockers. †B-R LOE applies to the data on nondihydropyridine calcium channel blockers.

Synopsis For new-onset AF after cardiac surgery, rate control is typically managed with beta blockers, or calcium channel

Figure 25. Prevention of AF After Cardiac Surgery. Colors correspond to Table 2. AF indicates atrial fibrillation; and CABG, coronary artery bypass graft.

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blockers.1–4 A randomized trial showed no significant clinical differences comparing a strategy of rate-control versus rhythm-control medications for patients who are hemodynamically stable.5 For those with poorly controlled AF, cardioversion is reasonable, but for those with >48 hours of AF, imaging of the LAA (even if surgically closed) should be considered.5,6 The use of cardioversion and imaging in postoperative patients is a judgment call considering the patient’s clinical condition. For patients who develop postoperative AF, including during follow-up postdischarge, rhythm assessment, and possible cardio- version for the small number who are still in AF, should be considered.5,6 Colchicine had been shown to be effective, but more recent studies did not confirm this, and gastro- intestinal adverse effects may be significant.8–10

Recommendation-Specific Supportive Text 1. The use of beta blockers to control heart rate is

well documented.1–4 Calcium channel blockers are an option for rate control when beta blockers are ineffective.5

2. The use of rate control or rhythm control are both acceptable options in hemodynamically stable patients because neither has a distinct clinical advantage over the other based on a randomized study that included 529 patients. In this study, patients in the rhythm-control group received amiodarone.5,6

3. Cardioversion of patients with sustained post- operative AF is regularly performed, especially for those patients with hemodynamically poorly tolerated AF. Cardioversion is routinely com- bined with pharmacological therapy, especially amiodarone.5,6

4. A review of 8 observational studies that included 15 335 patients found a protective impact on the mortality rate at 5 years but no differences in thromboembolic events in patients with postop- erative AF treated with anticoagulants.7 In general, the duration of anticoagulation is a minimum of 60 days; in the randomized trial of rate control versus rhythm control, if patients remained in AF or had recurrent AF 48 hours after randomization, antico- agulation was recommended to be continued for 60 days, unless complications occurred. Patients should be evaluated before discontinuation to determine underlying rhythm, especially those at high risk for stroke.

5. The need for a rhythm-control strategy should be evaluated postdischarge. Patients who toler- ate rate control can be followed and often convert spontaneously after 6 to 8 weeks. A net advan- tage of rate control is earlier discharge in hemo- dynamically stable patients. Those who do not convert can be managed accordingly with rhythm- control strategy.5,6

Figure 26. Treatment of AF After Cardiac Surgery. Colors correspond to Table 2. AF indicates atrial fibrillation; and HR, heart rate.

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10.10. Acute Medical Illness or Surgery (Including AF in Critical Care)

Recommendations for Acute Medical Illness or Surgery (Including AF in Critical Care) Referenced studies that support the recommendations are summarized in the Online Data Supplement.

COR LOE Recommendations

1 B-NR

1. Patients with AF who are identified in the setting of acute medical illness or surgery should be coun- seled about the significant risk of recurrent AF after the acute illness is resolved.1–6

2a B-NR

2. In patients with AF who are identified in the setting of acute medical illness or surgery, outpatient follow- up for thromboembolic risk stratification and decision-making on OAC initiation or continuation, as well as AF surveillance, can be beneficial given a high risk of AF recurrence.4–9

2b B-NR

3. In patients with AF who are identified in the setting of critical illness due to sepsis, the benefits of anticoagulation during critical illness for stroke pre- vention are uncertain.10,11

Synopsis AF identified in the setting of hospitalization for acute noncardiac illness (acute AF), including patients who are critically ill, may represent new-onset AF that has been detected and treated for the first time. Incidence ranges from 1% to 46% in medical illness,1,12–14 with 6% to 22% in severe sepsis,15 and 3% to 16% after non- cardiac surgery.16 AF can be an incidental finding dur- ing low-risk procedures but can occur associated with a range of conditions, including critical illness or sepsis. A combination of underlying arrhythmogenic substrate and triggers related to the acute illness likely contribute to acute AF. Acute AF can be paroxysmal or persistent, with or without symptoms, and is associated with higher risk of AF recurrence.1–3 Acute AF is also associated with prolonged hospitalization13,14 as well as increased morbidity12,15 and mortality.13,15 Management of acute AF is directed toward detection and treatment of potential triggers, optimizing hemodynamics, rate and/or rhythm control, and reducing in-hospital and long-term risk of stroke. Rate- or rhythm-control strategy should be indi- vidualized, balancing the impact of rapid rates and atrio- ventricular dyssynchrony on hemodynamics with ability to tolerate treatment. Decisions regarding initiating anti- coagulation should be based on risk stratification of pa- tient substrate and comorbidities, and the timing should take into consideration bleeding risks and the complex- ity of the acute illness.

Recommendation-Specific Supportive Text 1. In patients who develop or are discovered to

have AF in the setting of acute medical illness and noncardiac surgery, recurrent AF was noted in 42% to 68%1,2 and 39%,3 respectively, during 5-year follow-up. Regardless of presence of an

initial precipitant, recurrent AF was associated with increased risks of HF (HR, 2.74 [95% CI, 2.39- 3.15]; P<0.001), stroke (HR, 1.57 [95% CI, 1.30- 1.90]; P<0.001), and mortality (HR, 2.96 [95% CI, 2.70-3.24]; P<0.001).2

2. In 10 723 patients with newly diagnosed AF (67.9±–9.9 years, 41% women) identified from a longitudinal database, 19% of patients had an acute AF precipitant, the most common being cardiac surgery (22%), pneumonia (20%), and noncardiac surgery (15%). AF recurrence at 5 years was 41% among those with a precipitant versus 52% in those without one (adjusted HR, 0.75 [95% CI, 0.69-0.81]; P<0.001) (Figure 27).3 Regardless of a precipitant, recurrent AF was associated with increased risk of HF (HR, 2.74 [95% CI, 2.39-3.15]; P<0.001), stroke (HR, 1.57 [95% CI, 1.30-1.90]; P<0.001), and death (HR, 2.96 [95% CI, 2.70-3.24]; P<0.001). In patients with acute AF after cardiac surgery, observational studies show that those who underwent continu- ous rhythm monitoring had a higher detection of AF.4–6 No randomized clinical trial has specifi- cally compared different monitoring strategies for outpatient follow-up of patients with acute AF. However, parallels could be drawn from stud- ies like the CRYSTAL-AF8 and SEARCH-AF (Post-Surgical Enhanced Monitoring for Cardiac Arrhythmias and Atrial Fibrillation)9 trials, which showed increased sensitivity for AF detection with long-term monitoring. Close outpatient fol- low-up with consideration of heart rhythm moni- toring and thromboembolic risk stratification is important considering the high risk of AF recur- rence in these patients, especially in those who underwent noncardiac surgery and with risk fac- tors for stroke in whom the AF is likely to recur (Figure 28). The optimal frequency, duration, and type of rhythm monitoring for patients with acute AF remain unclear and need further study.

3. In a retrospective cohort study of 38 582 patients with AF and sepsis admitted to US hospitals from July 1, 2010, to June 30, 2013, 13 611 patients (35.3%) received parenteral anticoagulation for AF. The CHA2DS2-VASc score was a poor pre- dictor of acute stroke risk, and parenteral anti- coagulation did not reduce stroke risk (1.3% versus 1.4%; RR, 0.94 [95% CI, 0.77-1.15]) and was associated with an increased risk of clinically significant bleeding (8.6% versus 7.2%; RR, 1.21 [95% CI, 1.10-1.32]). Risk of stroke did not dif- fer whether patients had preexisting AF and new onset AF.10 In a retrospective cohort study of 102 patients ≥65 years of age who were hospitalized with sepsis and with new-onset AF, 28% received

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a prescription for OACs within 30 days of admis- sion. Over 3-year follow-up, no significant asso- ciation was noted between anticoagulation and a lower incidence of ischemic stroke (OR, 1.98 [95% CI, 0.29-13.47]) or bleeding (OR, 0.96

[95% CI, 0.29-3.21]).11 Gaps in knowledge exist, and further research is needed to better under- stand the benefits and risks of acute and long- term anticoagulation in critically ill patients with acute AF.

Figure 27. Unadjusted Cumulative Risk of AF Recurrence. Unadjusted curves displaying cumulative risk of recurrent AF, generated using Kaplan-Meier method. (A) Overall risk of recurrent AF among individuals with and without acute precipitants. (B) Overall risk of recurrent AF among individuals with infection, cardiac surgery, and noncardiothoracic surgery compared with no precipitant. These 3 precipitants were selected for display because the risk of recurrent AF was significantly lower compared with the referent group without precipitants in multivariable adjusted models. Individuals with other AF precipitants were excluded from this plot for clarity. Reproduced with permission from Wang et al.3 Copyright 2020 American Heart Association, Inc. AF indicates atrial fibrillation; and CT, cardiothoracic.

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10.11. Hyperthyroidism

Recommendation for Hyperthyroidism Referenced studies that support the recommendation are summarized in the Online Data Supplement.

COR LOE Recommendation

1 B-NR

1. In patients with hyperthyroidism and AF who have an elevated risk of stroke based on a standard clinical risk score, anticoagulation is recommended until thyroid function has returned to normal and sinus rhythm can be maintained.1,2

Synopsis Hyperthyroidism, defined as elevated blood levels of thy- roid hormone with reduced levels of thyroid- stimulating hormone, is relatively common and may not lead to overt symptoms of thyrotoxicosis.3,4 Patients with hyperthyroid- ism are at increased risk of developing AF,5 which resolves in most cases after the restoration of the euthyroid state with effective antithyroid treatment.6,7 Excess thyroid hor- mone increases sensitivity to catecholamines,3,8 and beta blockers reduce symptoms and tachycardia in patients with hyperthyroidism.9–12 Nonselective beta blockers may reduce the systemic symptoms of hyperthyroidism a bit more than beta-1–selective agents do, and propranolol reduces the peripheral conversion of T4 to T3.10,13 Al- though it is uncertain whether hyperthyroidism is an inde- pendent risk factor for stroke, many patients have other risk factors that elevate stroke risk, and anticoagulation reduces risk of stroke to a similar extent among patients with and without hyperthyroidism.1,2,14 Restoration of si- nus rhythm is unlikely until a euthyroid state has been achieved15 and, in 1 study, spontaneous reversion to sinus rhythm occurred at a median of 1 to 3 weeks after thyroid hormone levels returned to normal.6

Recommendation-Specific Supportive Text 1. Patients with hyperthyroidism often have labora-

tory findings that suggest hypercoagulability,16 but it is uncertain whether this translates into a higher risk of stroke.1,17 Nevertheless, patients with hyperthyroidism are commonly at elevated risk of stroke due to other clinical factors, so anticoagu- lation should be considered using the framework in Section 6.3.1 (“Antithrombotic Therapy”). A Danish national registry study found that patients with thyrotoxicosis and AF had a lower overall risk of thromboembolic events but a similar reduction in the risk of thromboembolic events from antico- agulation compared with patients who did not have a secondary cause of AF.5 In a large, randomized trial of apixaban versus warfarin, patients with a history of hyperthyroidism or hypothyroidism had risk of stroke similar to that of patients with no history of thyroid disease, and the effectiveness of apixaban in reducing stroke was consistent across subgroups with and without a history of thyroid disease.16

10.12. Pulmonary Disease Recommendations for Pulmonary Disease Referenced studies that support the recommendations are summarized in the Online Data Supplement.

COR LOE Recommendations

2a B-R

1. In patients with AF and COPD, it is reasonable to use cardioselective beta blockers for rate control of AF, especially where other indications exist (eg, MI and HF).1–3

2a B-NR

2. In patients with pulmonary hypertension (PH) with pulmonary vascular disease and AF or AFL, a rhythm-control strategy is reasonable to improve functional status and potentially prolong survival.4–12

Synopsis Pulmonary disease is commonly associated with arrhyth- mias. AF is common in COPD and is associated with an increased risk of mortality and bleeding.13 The combina- tion of AF and asthma is less common, and beta blockers are generally avoided to prevent bronchospasm. A bidi- rectional relationship is seen between AF and pulmonary embolus (PE), although it is little studied. The risk of PE is increased in patients with AF.14 AF may also compli- cate acute PE, where it is a marker of increased risk of mortality.15 Whether AF in the setting of PE should influ- ence the intensity or duration of anticoagulation, or is as- sociated with future AF recurrence, is unknown. AF and other supraventricular arrhythmias are important causes of decompensation in patients with PH, which is espe- cially well described in World Health Organization groups 1 and 4. A successful rhythm-control strategy is associ- ated with better outcomes in these patients.

Recommendation-Specific Supportive Text 1. AF is common in patients with COPD, with a

prevalence of 11% in a large European registry.16 Furthermore, patients with COPD often have other concomitant heart disease. Because beta-2 ago- nists can be used for the treatment of COPD, there has been a reluctance to prescribe beta blockers in case these would antagonize beta-2 agonists or precipitate bronchospasm.17 However, a systematic review and meta-analysis of observational studies found that beta-blocker use, for diverse indications including HF and CAD, was associated with a sig- nificantly reduced risk of mortality in patients with COPD.1 Another meta-analysis of RCTs assess- ing the effect of cardioselective beta blockers on respiratory function and symptoms did not find any change in these parameters or in response to beta-2 agonists.2 An RCT of patients with advanced COPD at risk of severe exacerbation, but without an indi- cation for beta-blocker treatment, found no differ- ence in the time to first exacerbation but did find an increased risk of severe exacerbation.3 Therefore, although other agents can be used for rate control of AF (Section 7, “Rate Control”), beta blockers,

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especially cardioselective beta blockers, for treat- ment of AF need not be avoided when indicated, especially in patients with less than severe COPD. However, beta blockers can exacerbate reactive air- way disease and are generally avoided in that set- ting, such as in patients with asthma.

2. Atrial arrhythmias are common in PH with pulmonary vascular disease (PHPVD; hemodynamically defined as PH with increased pulmonary vascular resis- tance and normal left heart filling pressures, typical of World Health Organization group 1 but also of groups 3 and 4). Right atrial contraction accounts for a significantly greater proportion of total right heart function in patients with PHPVD than in nor- mal subjects,18 and the onset of atrial arrhythmia is frequently associated with clinical deterioration.4–12 Restoration of sinus rhythm results in improvement, whereas persistent arrhythmia or recurrence is asso- ciated with mortality.4,8,9 Pharmacological rhythm control and cardioversion have both been used, although negative inotropy may limit antiarrhythmic drug therapy. Catheter ablation of typical AFL has been well described in patients with PHPVD, with acceptable results and safety, as well as improve- ment in clinical and hemodynamic parameters.5,7,12 LA ablation has also been described, although the possibility of creating a right-to-left shunt should always be considered when planning transseptal puncture. Anesthetic management is also complex, and these patients are best cared for by centers with extensive clinical expertise in these conditions.

10.13. Pregnancy Recommendations for Pregnancy Referenced studies that support the recommendations are summarized in the Online Data Supplement.

COR LOE Recommendations

1 B-NR 1. In pregnant patients with AF, DCCV is safe to the

patient and fetus and should be performed in the same manner as in patients who are not pregnant.1

2b C-LD

2. In pregnant individuals with structurally normal hearts and hemodynamically stable AF, pharmacological cardioversion with agents with history of safe use in pregnancy, such as intravenous procainamide, may be considered.1,2

2a C-LD

3. In pregnant individuals with AF and without structural heart disease, antiarrhythmic agents with history of safe use in pregnancy (eg, flecainide and sotalol) are reasonable for maintenance of sinus rhythm.1,2

2a B-NR

4. In pregnant individuals with persistent AF, rate-control agents with a record of safety in pregnancy, such as beta blockers (eg, propranolol or metoprolol) and digoxin, either alone or in combination with beta blockers, are reasonable as first-line agents.1,2

2b C-LD

5. Pregnant individuals with AF and elevated risk of stroke may be considered for anticoagulation with the recognition that no anticoagulation strategy is completely safe for both the mother and fetus, and an SDM discussion should take place regarding risks to both mother and fetus (Table 28).3

Synopsis The incidence of atrial arrhythmias is rising in pregnancy, and data from the national inpatient sample suggest that this is largely driven by increasing incidence of AF, with a reported frequency of 27 per 100 000 hospitalizations.4 The incidence of AF/AFL in pregnant patients with heart disease is 1.3%, with a peak occurrence between 23 and 30 weeks gestation.5,6 Hospitalizations during pregnancy for arrhythmias are associated with an increased risk of maternal and fetal adverse outcomes. AF during preg- nancy is associated with increased maternal mortality (OR, 13.13 [95% CI, 7.77-22.21]; P<0.0001).9

Atrial arrhythmias may manifest for the first time dur- ing pregnancy; however, AF is usually associated with underlying structural or CHD. Factors associated with an increased incidence of AF in pregnant individuals include advanced maternal age,6 African American race, lower socioeconomic status, and left-sided obstructive lesions.4,5 Obesity is associated with the development of hypertensive disorders of pregnancy, which is also a known risk factor for AF.7 Another potential mechanism for development of AF in pregnancy is the cardiogastric interaction that occurs with elevated progesterone levels, leading to gastroesophageal reflux disease.8

In patients deemed to be at high risk of stroke, rec- ommendations for anticoagulation in pregnancy are extrapolated from experience in managing VHD. DOACs are contraindicated during pregnancy and during breast- feeding because of a lack of data to support their safety and efficacy in this patient population.

Recommendation-Specific Supportive Text 1. Rapid atrioventricular conduction may have serious

hemodynamic consequences for both mother and fetus.9 DCCV of AF in pregnant individuals is safe for both mother and fetus and should be performed within 48 hours of presentation to minimize risk of stroke.1 Appropriate sedation should be provided to the pregnant individuals before DCCV. Fetal monitor- ing is generally used during and directly after DCCV.

2. Antiarrhythmic drugs are used in pregnancy for both maternal and fetal conditions; therefore, their mechanisms and adverse effect profile must be tolerable to both mother and fetus. These medi- cations should be avoided if possible during the first trimester, and initiation of the drug should be attempted at the lowest dose with involvement of an electrophysiologist or cardiologist skilled in the management of arrhythmias in pregnancy.10 Intravenous ibutilide has been used effectively in pregnant women with refractory AF, although published reports included a very small number of patients. In a pregnant patient presenting with AF and manifest preexcitation, intravenous procain- amide is also an option.11

3. In pregnant individuals with structurally normal hearts and AF, rhythm-control strategies may include

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agents with a long record of safety (eg, flecainide and sotalol) with appropriate monitoring that includes surveillance ECGs.1,12 Amiodarone is generally avoided and reserved for life-threatening arrhythmias because of potential toxicities to the fetus, including goiter, neurodevelopmental abnormalities, bradycar- dia, delayed growth, and premature birth.10,12

4. In pregnant individuals with persistent AF, rate- control strategies may include beta blockers with long record of safety in pregnancy (propranolol, metoprolol) or digoxin. Atenolol is generally avoided in pregnancy due to concerns about intrauterine growth retardation. Serum digoxin levels may be unreliable in pregnancy as digoxin-like immunore- active substances are increased in pregnant indi- viduals and react with antibodies against digoxin, interfering with the radioassay used for detection of digoxin serum levels.13

5. Tools available to predict stroke risk in AF have not been validated in pregnancy. In the rare case of AF with no risk factors or signs of heart disease, antico- agulation may not be necessary.1,14 SDM should be used when considering anticoagulation during preg- nancy (Table 28). Some patients may be deemed at high risk for stroke, such as those with mitral steno- sis, for which recommendations for anticoagulation in pregnancy are extrapolated from experience in managing VHD. Warfarin may be administered in the first trimester providing the dose needed to achieve a therapeutic INR is ≤5 mg. If the dose of warfarin is >5 mg/day, low-molecular-weight heparin should be administered throughout the first trimester and then transitioned to warfarin for the remainder of the antenatal period until 36 hours before a planned delivery, at which time unfractionated heparin is

started.15 Vaginal delivery should be advised for most women, and VKAs are generally held to mitigate risk of bleeding compliciations.13 Use of novel DOACs is not recommended during pregnancy in view of lack of evidence about safety.16

10.14. Cardio-Oncology and Anticoagulation Considerations

Recommendations for Cardio-Oncology and Anticoagulation Considerations Referenced studies that support the recommendations are summarized in the Online Data Supplement.

COR LOE Recommendations

1 C-LD

1. In patients with cancer and AF, multidisciplinary com- munication including cardiology, oncology and other clinicians, and SDM with the patient is recommended to optimize cancer and AF treatment and to reduce the risk of drug-drug interactions, QTc prolongation, proarrhythmia, bleeding, and thromboembolism.1–3

2a C-LD

2. In patients who are to be initiated on cancer therapies associated with an increased risk of developing AF, increased vigilance for incident AF and treatment of contributing factors is reasonable to decrease morbidity.1,4–6

2a B-NR

3. In most patients with AF and cancer (remote history or receiving active cancer treatment), DOACs are reasonable to choose over VKAs for stroke risk reduction.7,8

Synopsis Patients with cancer have an increased risk of AF. A Dan- ish nationwide study observed an incident AF rate of 17.4 per 1000 person-years compared with 3.7 per 1000 person-years in patients without cancer.9 A meta-analysis of observational studies demonstrated the risk of AF to be ∼47% higher in patients with cancer compared with patients without cancer.5,10 The increased risk of AF is like- ly related to increased age, shared risk factors between cancer and CVD (eg, obesity and systemic inflammation), coexistent comorbidities (eg, hypertension and HF), car- diac involvement by the tumor, as well as certain medical therapeutics (Table 29), oncologic surgery, especially tho- racic, and thoracic radiation therapy.11,12 New-onset AF in patients with cancer is associated with a higher risk of HF, thromboembolism, bleeding, and mortality.13–15 Notably, Bruton’s tyrosine kinase (BTK) inhibitors, such as ibruti- nib, which are used to treat chronic lymphocytic leukemia and lymphoproliferative malignancies and often used for an extended period of time, are associated with a higher risk of AF due to off-target cardiac effects.16 In 1 meta- analysis, the risk of AF with use of ibrutinib was 4 times higher compared with that without use of ibrutinib.17

Although patients with cancer are underrepresented in the major trials comparing DOACs to VKAs, large observational studies and meta-analyses of studies of patients with cancer and AF have demonstrated similar or lower rates of ischemic stroke and bleeding in patients taking DOACs compared with warfarin.7,8 Patients with

Table 28. Anticoagulation Strategies During Pregnancy

Antenatal Options

Method 1 Method 2 Method 3 Alternative Method 4

First trimester Warfarin ≤5 mg

LMWH UFH LMWH

Second trimester Warfarin Warfarin Warfarin LMWH

Third trimester Warfarin Warfarin Warfarin LMWH

Delivery Planning

Method 1 Method 2

1 wk before Discontinue warfarin → continuous IV UFH

Dose-adjusted LMWH

36 h before Continuous IV UFH Switch to continuous IV UFH

4-6 h before Stop IV heparin Stop IV heparin

IV indicates intravenous; LMWH, low-molecular-weight heparin; and UFH, unfractionated heparin.

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AF and cancer are at an increased risk for major bleed- ing.18 They also are commonly on antineoplastic agents, which may have important drug interactions with OACs.19 Thus, these factors should be carefully considered in determining indication and choice of OAC.

Recommendation-Specific Supportive Text 1. In patients with cancer who develop AF in the pres-

ence of cancer therapeutics associated with an increased risk of incident AF (Table 29), the first approach usually consists of optimizing AF con- trol while continuing cancer therapy. However, if AF control cannot be achieved, decisions regard- ing dose reduction of the cancer therapy or even stoppage can only be made in concert with the oncology team and SDM with the patient. Drug- drug interactions between cancer, antiarrhythmic, rate-control, and anticoagulant therapies are com- mon and require close attention.1 For example, in the case of BTK inhibitors, CYP3A inhibitors such as amiodarone, dronedarone, verapamil, and diltia- zem are usually avoided, due to the associated risk of elevation in ibrutinib levels.1 Further, ibrutinib can raise levels of digoxin, a P-glycoprotein substrate.1 Therefore, beta blockers are considered the best

option for rate control in BTK inhibitor-associated AF. If additional agents are needed for AF control, any concomitant reduction in dose of ibrutinib is guided by oncology.1 Further, QTc prolongation, which is more common in patients with cancer due to several cancer therapies, antiemetics, antibiotics, and electrolyte derangements, can be further exac- erbated by QT-prolonging antiarrhythmic agents.3 Structured screening by pharmacists for potential drug-drug interactions could provide benefit.2

2. Certain medical cancer therapies can increase the risk of incident AF (Table 29). Patients with cancer and AF are older and have higher rates of hyperten- sion, MI, and HF compared with those who do not develop AF.13–15 The development of perioperative AF has been strongly associated with perioperative complications.20 In general, patients with cancer and CVD may be undertreated with GDMT or less often referred to specialists for cardiovascular care.21 Optimization of cardiovascular conditions such as hypertension and HF may decrease the risk of inci- dent AF, AF recurrence, and of major adverse car- diovascular events, including stroke.22–25 Therefore, in patients without a history of AF, or those with previous history of AF, who are to be started on

Table 29. Medical Cancer Therapy Associated With Increased Risk of AF (>1%)

Frequency Reported in Clinical Trials and Observational Studies

Cancer Therapy

Common: Incidence 1%-10%

Frequent: >10% Comments

Anthracyclines Doxorubicin, epirubicin, idarubicin, mitoxantrone

AF may be a secondary result of anthracycline cardiotoxicity; studies in different populations demonstrate variable risk of AF

Antimetabolites Clofarabine combined with cytarabine 5FU Cepecitabine Gemcitabine

X X X

Alkylating agents Cyclophosphamide Melphalan + stem cell transplantation

X X*

*Stem cell transplantation is associated with an increased risk of AF,28,29 and the risk may be higher with melphalan-associated regimens.

Immunomodulatory drugs Lenalidomide Interleukin-2

X X

Given rates reported from patients with multiple myeloma, AF due to underlying cardiac AL amyloid may contribute

TKIs Ibrutinib (BTKi) Acalbrutinib (second-generation BTKi) Zanubrutinib (second-generation BTKi) Ponatinib (BCR-ABL TKI) and other TKIs (eg, trametinib, osimertinib, nilotinib, ribociclib) VEGF inhibitor Sorafenib in combination with 5FU BRAF inhibitor Vemurafenib

X† X X X

X† †Reported AF rates with ibrutinib have varied across trials (4%-18%),6,30 partly related to varying duration of follow-up and patient factors. Second-generation BTKis have more selective BTK activity and are associated with a lower incidence of AF than ibrutinib.31

Based on FDA adverse event reporting system4

CAR T-cell therapy Tisagenlecleucel Axicabtagene ciloleucel

X X

Monoclonal antibodies Rituximab X

Table developed by 2023 Atrial Fibrillation Guideline Writing Committee. Data extracted from Buza et al32 and Fradley et al.33 AF indicates atrial fibrillation; BTKi, Bruton’s kinase inhibitor; CAR, chimeric antigen receptor; FDA, US Food and Drug Administration; 5FU, 5 fluorouracil; and TKI,

tyrosine kinase inhibitor.

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cancer therapies associated with a higher risk of AF, evaluation and optimization of cardiovascular risk factors or disease by a cardiologist could be beneficial in decreasing incident and recurrent AF and associated cardiovascular events, although no data are available specifically in patients with can- cer. Furthermore, elevated natriuretic peptides or a history of previous AF can identify patients at higher risk of AF after major thoracic cancer surgery.26,27

3. No large RCTs are available that compare DOACs to warfarin in patients with AF and cancer. A meta- analysis of post-hoc analyses of RCTs and ret- rospective observational studies that compared DOACs with warfarin in patients with AF and can- cer (n=229 221) demonstrated a lower risk of stroke or systemic embolism (RR, 0.65 [95% CI, 0.52-0.81]; P=0.001) and major bleeding (RR, 0.68 [95% CI, 0.50-0.92]; P=0.01) with DOACs.8 This meta-analysis included post hoc analyses of patients with cancer and AF from the ROCKET AF (rivaroxaban versus warfarin), ENGAGE TIMI-48 (edoxaban versus warfarin), and ARISTOTLE (apix- aban versus warfarin) trials. These findings were consistent in patients defined as having active can- cer, although definitions of active cancer varied by study. An additional large retrospective observation study comparing DOACs to warfarin in patients with active cancer demonstrated a lower risk of the composite endpoint of ischemic stroke/intracranial bleeding in patients taking DOACs compared with VKA (adjusted HR, 0.65 [95% CI, 0.48-0.88]).7 Although most of the data in this patient population came from retrospective observational studies that may be prone to selection bias, findings are largely consistent with post hoc analyses from RCTs and the major RCTs comparing DOACs with VKA in general. Special consideration should be given to patient bleeding risk and antineoplastic drug inter- actions in this patient population (Table 30).18,19

10.15. CKD and Kidney Failure CKD and kidney failure (formerly end-stage renal disease) share common risk factors with AF, such as hypertension and diabetes, and unsurprisingly, CKD and AF are associ- ated in a disproportionate manner. In population studies, baseline serum creatinine, eGFR, and proteinuria were strongly associated with incident of AF during follow- up.1,2 AF at baseline also predicted new renal dysfunction or proteinuria, suggesting a bidirectional relationship be- tween CKD and AF.2 In an insurance database of 206 229 adults with confirmed CKD, over a mean follow-up of 5 years, there was a 67% increased rate of kidney failure among patients with CKD who developed incident AF compared with those without AF, even after adjustment for baseline factors.3 Data on the management of AF in

patients with CKD is limited because the major trials of rate control, rhythm control, and catheter ablation have generally not reported eGFR or CKD as a baseline vari- able or excluded such patients. Antiarrhythmic drug doses are adjusted based on pharmacokinetic data and clinical experience, with amiodarone being the only drug that does not require dose adjustment in patients with CKD or those receiving dialysis. Catheter ablation is feasible, although particular attention must be paid to fluid balance when us- ing irrigated radiofrequency catheters. Anticoagulation in patients with CKD and AF is covered in Section 6.8.4 (“Chronic Kidney Disease [CKD]/Kidney Failure”).

10.16. Anticoagulation Use in Patients With Liver Disease

Recommendations for Anticoagulation Use in Patients With Liver Disease Referenced studies that support the recommendations are summarized in the Online Data Supplement.

COR LOE Recommendations

2a B-NR

1. For patients with AF who are at increased risk of systemic thromboembolism and mild or moderate liver disease (Child-Pugh* class A or B), OAC therapy is reasonable in the absence of clinically significant liver disease–induced coagulopathy or thrombocyto- penia.1–7

2a B-NR

2. For patients with AF who are at increased risk of systemic thromboembolism and mild or moderate liver disease (Child-Pugh class A or B) and who are deemed to be candidates for anticoagulation, it is reasonable to prescribe DOACs (Child-Pugh class A: any DOAC; Child-Pugh class B: apixaban, dabigatran, or edoxaban) over warfarin.1,7–11

3: Harm

C-LD

3. For patients with AF and moderate liver disease (Child-Pugh class B) at increased risk of systemic thromboembolism, rivaroxaban is contraindicated due to the potentially increased risk of bleeding.12

*Child-Pugh scoring: the severity of liver disease, primarily cirrhosis in patients with diagnosed liver disease. Child-Pugh A (mild): 5-6 points; Child-Pugh B (mod- erate): 7-9 points; Child-Pugh C (severe): 10-15 points. The score is based on the 5 variables: encephalopathy (none=1 point, grade 1 and 2=2 points, grade 3 and 4=3 points); ascites (none=1 point, slight=2 points, moderate=3 points); total bilirubin (<2 mg/mL=1 point, 2-3 mg/mL=2 points, >3 mg/mL=3 points); al- bumin (>3.5 mg/mL=1 point, 2.8-3.5 mg/mL=2 points, <2.8 mg/mL=3 points); INR (<1.7=1 point, INR 1.7-2.2=2 points, INR >2.2=3 points).

Table 30. Special Considerations for Anticoagulation in Patients With AF on Active Cancer Treatment

Increased bleeding risk High bleeding risk estimators (eg, HAS-BLED) Thrombocytopenia (platelet <50 000/uL) Intracranial malignancy Gastrointestinal malignancy History of major bleeding Severe kidney dysfunction (eGFR <30 mL/ min/1.73 m2)

Drug interactions P-glycoprotein inducers or inhibitors CYP3A4 inducers or inhibitors

AF indicates atrial fibrillation; eGFR, estimated glomerular filtration rate; and HAS-BLED, hypertension, abnormal renal/liver function, stroke, bleeding his- tory or predisposition, labile international normalized ratio (INR), elderly (age ≥65 years), drugs/alcohol concomitantly).

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Synopsis No RCT has evaluated the use of OACs in patients with AF and liver disease. Three observational studies and 1 meta-analysis of observational studies have compared OAC therapy with no OAC therapy in patients with AF and active liver disease or a history of liver disease.1–4 In addi- tion, 3 observational studies have compared OAC therapy in patients with liver disease to those without liver dis- ease.5–7 In general, anticoagulation has been associated with lower risks of ischemic stroke or thromboembolism but was also associated with a significantly higher risk of major bleeding or ICH compared with no oral antico- agulation therapy in patients with AF and liver disease. Oral factor Xa inhibitors undergo hepatic metabolism, and impaired liver function may increase their plasma concen- trations and the risk of bleeding. Pivotal clinical trials for DOACs excluded patients with active liver disease. Four postmarketing retrospective studies and 2 meta-analyses have evaluated the comparison between DOACs and VKAs in this population, and they showed DOACs were associated with a lower risk of major bleeding or ICH.1,7–11 Limited data exist on the safety of DOAC in severe liv- er disease. The uses of DOACs based on a Child-Pugh Score are summarized in Table 13 (Section 6.3.1.1. “Con- siderations in Managing Anticoagulation”).

Recommendation-Specific Supportive Text 1. A meta-analysis showed that VKA use was sig-

nificantly associated with lower risks of ischemic stroke or thromboembolism but was also associ- ated with significantly higher risks of major bleed- ing or ICH in patients with AF and liver disease compared with no oral anticoagulation therapy.7 A large-scale retrospective study also corrobo- rated that OAC use was significantly associated with a lower risk of stroke or all-cause mortality in patients with AF and cirrhosis.3 VKA use in the liver fibrosis group was associated with a higher risk of the composite cardiovascular events and major bleeding than in the nonliver fibrosis group.4 However, no significant difference in the composite cardiovascular events and major bleeding between the 2 groups receiving DOACs was found. The efficacy and safety of VKAs or DOACs were not affected by nonalcohol fatty liver disease status.5 The subgroup analysis of the meta-analysis found that the risk of major bleeding was not affected by the presence of esophageal varices.13

2. A meta-analysis found no significant difference in the risk of ischemic stroke and thromboembolism between DOACs and VKAs (OR, 0.82 [95% CI, 0.36- 1.88]; P=0.64) in patients with almost exclusively mild- to-moderate liver disease (Child-Pugh class A-B), but DOAC use was associated with lower risks of major bleeding (OR, 0.54 [95% CI, 0.38-0.75]; P=0.0003) and ICH (OR, 0.35 [95% CI, 0.23-0.53]; P<0.0001)

compared with the warfarin group.7 Another meta- analysis showed that, in patients with exclusively mild-to-moderate cirrhosis (Child-Pugh score A-B), DOAC use was associated with lower risks of isch- emic stroke (HR, 0.62 [95% CI, 0.10-0.90]), major bleeding (HR, 0.64 [95% CI, 0.57-0.72]), or ICH (HR, 0.49 [95% CI, 0.40-0.59]) compared with warfarin.11 DOACs are reasonable oral anticoagulation agents in patients with AF and mild-to-moderate liver disease (Child-Pugh class A-B). However, data on DOACs are lacking on patients with AF and severe liver disease (Child-Pugh class C).

3. Rivaroxaban is currently avoided in patients with mod- erate liver disease (Child-Pugh class B). Rivaroxaban AUC significantly increased by 2.27-fold after a sin- gle dose of rivaroxaban 10 mg in patients with mod- erate liver disease compared with healthy subjects.12 Although the FDA labeling recommends avoiding edoxaban in patients with moderate liver disease due to the concern of underlying coagulopathy, the edox- aban AUC was not significantly increased after a single dose of edoxaban 15 mg in patients with mod- erate liver disease compared with healthy subjects.14 Apixaban AUC was not significantly increased after a single dose of apixaban 5 mg in subjects with mild and moderate liver disease (Child-Pugh class A and B) compared with healthy subjects.15 Dabigatran AUC was also not significantly different after a single dose of dabigatran 150 mg in patients with moder- ate liver disease (Child-Pugh class B) compared with that in healthy subjects.16

11. FUTURE RESEARCH NEEDS Enormous progress and important advances have been made in recent years on the understanding of mecha- nisms and on the prevention and management of AF, in- cluding substantial progress since the 2014 guideline, as well as the 2019 focused update. Although the writ- ing committee has tried to make significant progress in this current guideline to address many of the gaps in the clinical management of AF, important gaps in knowledge remain and are listed below. 1. AF as a disease continuum: AF must be seen as

a disease continuum, yet historically the emphasis has been on rhythm management. More evidence is needed on how to best improve in other aspects of AF care, such as prevention, modification of risk factors, and how to incorporate holistic approaches to AF management into daily clinical practice.

2. Downstream consequences: The downstream consequences of AF over the long term must be better studied and defined. Most studies generally focus on short-term effects of therapy, usually 6 to 12 months. Many long-term consequences of AF

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remain poorly characterized, such as dementia and valvular insufficiency.

3. Better goal and outcome definition: Historically, ablation failure has been defined as having 30 seconds of AF identified during a follow-up period. However, that number might be too simplistic because AF burden may be a more important met- ric and because the 30-second metric might not reflect significant burden reduction that may be observed in many patients. Patient-oriented out- comes would also be more important, such as QOL.

4. Role of risk modifiers in AF stroke prevention: Great variation exists in risk of stroke depending on nonbinary or dynamic risk factors. Yet it is unclear how to best manage patients accordingly. For example, how should risk of stroke be assessed in a person with hypertension in whom the BP is very well controlled? Or, perhaps, how do we incorpo- rate AF burden on the risk calculation?

5. Individualization of AF and stroke risk: Although some studies have demonstrated an effective role of biomarkers in predicting AF and stroke, how to incorporate these findings into clinical practice remains elusive. Similarly, how to incorporate other clinical markers of atrial cardiopathy into clinical practice must be better defined, as well as clari- fication as to how these nontraditional risk factors help better stratify patient risk.

6. Incorporating other stroke risk scores: The ubiq- uitous nature and simplicity of the CHA2DS2-VASc score have diminished with consideration of other scores of potential utility, better c-statistics, and with potential advantages in particular populations. Additional studies are needed to better take advan- tage of scores for specific groups, scores that could potentially be incorporated into the electronic medi- cal record, and perhaps some with the potential ben- efit of better discriminating the true low-risk patients.

7. Surgical exclusion and LAAO: Increasingly avail- able evidence has demonstrated the benefit of sur- gical LAA exclusion for stroke prevention, but the most scientifically rigorous trials included patients who received concomitant anticoagulation. More evidence is needed on the magnitude of benefit of LAA exclusion in preventing stroke in patients who have contraindications to anticoagulation and how to best manage those patients around rhythm-con- trol interventions, such as cardioversion. Clinicians would also like to see additional data on pLAAO, particularly peri-implant stroke management and longer-term outcomes in patients in whom peripro- cedure anticoagulation is not possible.

8. Subclinical AF: What magnitude of AF burden mandates stroke prevention therapy in patients with subclinical AF must be better defined. Certainly, large general risk categories have been identified,

and general guidelines exist, but extensive practice variations remain, and more precise recommenda- tions for the community are needed. In addition, the role and impact on outcomes of AF screening in general and poststroke should be better defined.

9. Use and applicability of consumer-based wear- able heart monitoring devices: These devices are now widespread and are used to diagnose and monitor response to therapy in patients with AF. Validation on the accuracy of the most common available technologies is needed. How to best use these devices in practice, including for AF screen- ing, must be better defined.

10. Standardization of ablation procedures: Great practice variation exists on how AF ablation proce- dures are performed, either as first or repeat proce- dures. Large registries and more data are required to better define standards of care in this field. Many interventions, such as extra ablation lines, are still performed despite limited data demonstrating effi- cacy, whereas the best approaches to persistent AF and repeat ablation are poorly defined.

11. Candidates for ablation: We must better identify clinical markers to better identify when catheter ablation is unlikely to benefit patients and define specific criteria for candidacy for first time and repeat procedures.

12. Artificial intelligence for AF management: Artificial intelligence could potentially be used to better tailor therapy to the individual patient, taking into consideration numerous factors that may better select candidates for therapeutic approaches, such as anticoagulation versus LAAO, rhythm versus rate control, catheter abla- tion versus medical therapy, modification of risk factors, genetics, and others.

13. Strategies for anticoagulation: Ongoing clini- cal trials are assessing different strategies for oral anticoagulation in persons who have under- gone catheter ablation, including the OCEAN (Optimal AntiCoagulation for Enhanced-Risk Patients Post-Catheter Ablation for Atrial Fibrillation) trial (NCT02168829)1 and ODIn-AF (Prevention of Silent Cerebral Thromboembolism by Oral Anticoagulation With Dabigatran After Pulmonary Vein Isolation for Atrial Fibrillation) (NCT02067182)2 trial, because it is unclear in whom anticoagulation can be discontinued after successful ablation. Several studies also have investigated the use of intermittent or continu- ous rhythm monitoring to guide oral anticoagula- tion in persons with AF, including those who have undergone ablation.3,4 These so-called “PITP” or “electrocardiographic-guided” approaches are investigational. Ongoing clinical trials like REACT-AF (Rhythm Evaluation for Anticoagulation

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Therapy for Atrial Fibrillation) will help determine whether they are suitable for clinical practice. Also, anticoagulation/DOAC use in pregnancy needs to be investigated because it is currently contraindi- cated in view of lack of data on safety.

14. Sleep: Among patients with AF and SDB, the impact of treatment of SDB on maintenance of sinus rhythm and on general cardiovascular out- comes remains uncertain. Most studies have been observational, which introduces confounding fac- tors. Once diagnosed, the adherence to treatment for SDB is also suboptimal.

15. SDM and decision aids: Decision aids are per- ceived as important tools to better inform patients about options for AF management; yet, it is unclear if those tools improve clinical outcomes. Most deci- sion aids developed for AF focus on anticoagula- tion; there is a paucity of validated decision aids, including for AF rhythm management using antiar- rhythmic drugs or ablation.

16. Genetic testing: The use and applicability of consumer-based or targeted genetic testing for AF remains uncertain. Polygenic risk scores can indicate higher risk for AF, but the use of genetic testing to impact clinical surveillance, management, and clinical outcomes remains uncertain.

17. Race, ethnicity, gender, and sex differences: In sexual- and gender-diverse individuals, additional research is recommended to identify the inci- dence and outcomes of AF as well as the impact of gender-affirming therapies on arrhythmia inci- dence and outcomes. Additional data across racial and ethnic groups should also be encouraged.

18. Standardized measures: For patients with AF, a standardized measure might be useful to assess symptoms and/or QOL and impact of management strategies.

19. SDOH: The measurement and impact of SDOH in AF is underutilized and understudied.

PEER REVIEW COMMITTEE MEMBERS Andrew D. Krahn, MD, FHRS, Chair; Jason G. Andrade, MD, FHRS; Craig J. Beavers, PharmD, FACC, FAHA, FCCP, BCCP, BCPS (AQ-Cardiology), CACP; James M. Bischoff; T. Jared Bunch, MD, FACC, FHRS; Kristen Bova Campbell, PharmD, FACC; Lin Yee Chen, MD, MS, FAHA, FHRS; Robin Dharia, MD, FAHA; Michael P. Dorsch, PharmD, MS, FACC, FAHA; Edward P. Gerstenfeld, MD, MS, FACC, FHRS; Aubrey E. Jones, PharmD, MSCI; Stephanie Dwyer Kaluzna, PharmD; Luke Masha, MD, MPH; Isabelle Nault, MD; Peter A. Noseworthy, MD, FHRS; Cara N. Pellegrini, MD, FACC, FHRS; Stylianos E. Tzeis, MD; Annabelle Santos Volgman, MD, FACC, FAHA; Emily P. Zeitler, MD, MHS, FACC

ACC/AHA JOINT COMMITTEE ON CLINICAL PRACTICE GUIDELINES Joshua A. Beckman, MD, MS, FAHA, FACC, Chair; Catherine M. Otto, MD, FACC, FAHA, Chair-Elect; Anastasia L. Armbruster, PharmD, FACC; Leslie L. Davis, PhD, ANP-BC, FACC, FAHA; Lisa de las Fuentes, MD, MS, FAHA; Anita Deswal, MD, MPH, FACC, FAHA; Victor A. Ferrari, MD, FACC, FAHA; Adrian F. Hernandez, MD, FAHA; Heather M. Johnson, MD, MS, FAHA, FACC; W. Schuyler Jones, MD, FACC; Prateeti Khazanie, MD, MPH; Michelle M. Kittleson, MD, PhD, FACC; Debabrata Mukherjee, MD, FACC, FAHA; Latha Palaniappan, MD, MS, FAHA, FACC; Tanveer Rab, MD, FACC; Jacqueline E. Tamis-Holland, MD, FACC, FAHA; Y. Joseph Woo, MD, FACC, FAHA; Boback Ziaeian, MD, PhD, FAHA

PRESIDENTS AND STAFF American College of Cardiology B. Hadley Wilson, MD, FACC, President Cathleen C. Gates, Chief Executive Officer Richard J. Kovacs, MD, MACC, Chief Medical Officer Mindy J. Saraco, MHA, Director, Clinical Policy and

Guidelines Grace D. Ronan, Senior Production and Operations

Manager, Clinical Policy Publications Leah Patterson, Project Manager, Clinical Content

Development

American Heart Association/American College of Cardiology Thomas S.D. Getchius, National Senior Director,

Guidelines Abdul R. Abdullah, MD, Director, Guideline Science and

Methodology

American Heart Association Joseph C. Wu, MD, PhD, FAHA, President Nancy Brown, Chief Executive Officer Mariell Jessup, MD, FAHA, Chief Science and Medical

Officer Nicole Aiello Sapio, EdD, Executive Vice President, Office

of Science Strategies and Operations Radhika Rajgopal Singh, PhD, Senior Vice President,

Office of Science and Medicine Prashant Nedungadi, BPharm, PhD, Vice President,

Science and Medicine, Clinical Guidelines Anne Leonard, MPH, BSN, RN, FAHA, National Senior

Director, Science and Medicine Jody Hundley, Senior Production and Operations Man-

ager, Scientific Publications, Office of Science Operations

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ARTICLE INFORMATION This document was approved by the American College of Cardiology Clinical Policy Approval Committee and the American Heart Association Science Advi- sory and Coordinating Committee in July 2023, and the American College of Cardiology Science and Quality Committee and the American Heart Association Executive Committee in August 2023.

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This article has been copublished in the Journal of the American College of Cardiology.

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87. Scherer M, Dzemali O, Aybek T, et al. Impact of left atrial size reduc- tion on chronic atrial fibrillation in mitral valve surgery. J Heart Valve Dis. 2003;12:469–474.

88. Scherer M, Therapidis P, Wittlinger T, et al. Impact of left atrial size reduc- tion and endocardial radiofrequency ablation on continuous atrial fibrilla- tion in patients undergoing concomitant cardiac surgery: three-year results. J Heart Valve Dis. 2007;16:126–131.

89. Joshibayev S, Bolatbekov B. Early and long-term outcomes and qual- ity of life after concomitant mitral valve surgery, left atrial size reduction, and radiofrequency surgical ablation of atrial fibrillation. Anatol J Cardiol. 2016;16:797–803.

90. van de Vegte YJ, Siland JE, Rienstra M, et al. Atrial fibrillation and left atrial size and function: a Mendelian randomization study. Sci Rep. 2021;11:8431.

91. Mou L, Norby FL, Chen LY, et al. Lifetime risk of atrial fibrillation by race and socioeconomic status: ARIC study (Atherosclerosis Risk in Communities). Circ Arrhythm Electrophysiol. 2018;11:e006350.

92. Lunde ED, Joensen AM, Lundbye-Christensen S, et al. Socioeconomic position and risk of atrial fibrillation: a nationwide Danish cohort study. J Epidemiol Community Health. 2020;74:7–13.

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94. Bonaccio M, Di Castelnuovo A, Costanzo S, et al. Life course socioeco- nomic status and risk of hospitalization for heart failure or atrial fibrillation in the Moli-Sani study cohort. Am J Epidemiol. 2021;kwab046.

95. Chung SC, Sofat R, Acosta-Mena D, et al. Atrial fibrillation epidemiology, disparity and healthcare contacts: a population-wide study of 56 million individuals. Lancet Reg Health Eur. 2021;7:100157.

96. Lunde ED, Nielsen PB, Riahi S, et al. Associations between socioeconomic status, atrial fibrillation, and outcomes: a systematic review. Expert Rev Cardiovasc Ther. 2018;16:857–873.

97. Alzahrani Z, Ornelas-Loredo A, Darbar SD, et al. Association between fam- ily history and early-onset atrial fibrillation across racial and ethnic groups. JAMA Netw Open. 2018;1:e182497.

98. Arnar DO, Thorvaldsson S, Manolio TA, et al. Familial aggregation of atrial fibrillation in Iceland. Eur Heart J. 2006;27:708–712.

99. Lubitz SA, Yin X, Fontes JD, et al. Association between familial atrial fibrilla- tion and risk of new-onset atrial fibrillation. JAMA. 2010;304:2263–2269.

100. Roselli C, Chaffin MD, Weng LC, et al. Multi-ethnic genome-wide associa- tion study for atrial fibrillation. Nat Genet. 2018;50:1225–1233.

101. Nielsen JB, Thorolfsdottir RB, Fritsche LG, et al. Biobank-driven genom- ic discovery yields new insight into atrial fibrillation biology. Nat Genet. 2018;50:1234–1239.

2.2.2. Associated Arrhythmias 1. Saoudi N, Cosio F, Waldo A, et al. A classification of atrial flutter and

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2.3. Mechanisms and Pathophysiology 1. Haissaguerre M, Jais P, Shah DC, et al. Spontaneous initiation of atrial fibril-

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2. Allessie M, Ausma J, Schotten U. Electrical, contractile and structural re- modeling during atrial fibrillation. Cardiovasc Res. 2002;54:230–246.

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lation by ectopic beats originating in the pulmonary veins. N Engl J Med. 1998;339:659–666.

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4. Van Wagoner DR, Pond AL, McCarthy PM, et al. Outward K+ current densi- ties and Kv15 expression are reduced in chronic human atrial fibrillation. Circ Res. 1997;80:772–781.

5. Voigt N, Trausch A, Knaut M, et al. Left-to-right atrial inward rectifier po- tassium current gradients in patients with paroxysmal versus chronic atrial fibrillation. Circ Arrhythm Electrophysiol. 2010;3:472–480.

6. Gemel J, Levy AE, Simon AR, et al. Connexin40 abnormalities and atrial fibrillation in the human heart. J Mol Cell Cardiol. 2014;76:159–168.

7. Wirka RC, Gore S, Van Wagoner DR, et al. A common connexin-40 gene promoter variant affects connexin-40 expression in human atria and is as- sociated with atrial fibrillation. Circ Arrhythm Electrophysiol. 2011;4:87–93.

8. Lazzerini PE, Laghi-Pasini F, Acampa M, et al. Systemic Inflammation Rap- idly Induces Reversible Atrial Electrical Remodeling: The Role of Inter- leukin-6-Mediated Changes in Connexin Expression. J Am Heart Assoc. 2019;8:e011006.

9. Yan J, Kong W, Zhang Q, et al. c-Jun N-terminal kinase activation contrib- utes to reduced connexin43 and development of atrial arrhythmias. Cardio- vasc Res. 2013;97:589–597.

10. Iwasaki YK, Kato T, Xiong F, et al. Atrial fibrillation promotion with long- term repetitive obstructive sleep apnea in a rat model. J Am Coll Cardiol. 2014;64:2013–2023.

11. Landstrom AP, Dobrev D, Wehrens XHT. Calcium Signaling and Cardiac Arrhythmias. Circ Res. 2017;120:1969–1993.

12. Greer-Short A, Musa H, Alsina KM, et al. Calmodulin kinase II regulates atrial myocyte late sodium current, calcium handling, and atrial arrhythmia. Heart Rhythm. 2020;17:503–511.

13. Voigt N, Li N, Wang Q, et al. Enhanced sarcoplasmic reticulum Ca2+ leak and increased Na+-Ca2+ exchanger function underlie delayed af- terdepolarizations in patients with chronic atrial fibrillation. Circulation. 2012;125:2059–2070.

14. Wang X, Chen X, Dobrev D, et al. The crosstalk between cardiomyocyte calcium and inflammasome signaling pathways in atrial fibrillation. Pflugers Arch. 2021;473:389–405.

2.3.1.1. Triggers of AF 1. Haissaguerre M, Jais P, Shah DC, et al. Spontaneous initiation of atrial fibril-

lation by ectopic beats originating in the pulmonary veins. N Engl J Med. 1998;339:659–666.

2. Dewland TA, Vittinghoff E, Mandyam MC, et al. Atrial ectopy as a predictor of incident atrial fibrillation: a cohort study. Ann Intern Med. 2013;159:721– 728.

3. Heckbert SR, Jensen PN, Austin TR, et al. Associations of left atrial func- tion and structure with supraventricular ectopy: the Multi-Ethnic Study of Atherosclerosis. J Am Heart Assoc. 2021;10:e018093.

4. Howell SJ, Dukes JW, Vittinghoff E, et al. Premature atrial contrac- tion location and atrial fibrillation inducibility. Circ Arrhythm Electrophysiol. 2023;16:e011623.

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2.3.2. Atrial Structural Abnormalities, Remodeling, and Atrial Myopathy 1. Goette A, Kalman JM, Aguinaga L, et al. EHRA/HRS/APHRS/SOLAECE

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2. Rudolph V, Andrie RP, Rudolph TK, et al. Myeloperoxidase acts as a profi- brotic mediator of atrial fibrillation. Nat Med. 2010;16:470–474.

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2.3.2.1. Upstream Pathways 1. Purohit A, Rokita AG, Guan X, et al. Oxidized Ca(2+)/calmodulin-dependent

protein kinase II triggers atrial fibrillation. Circulation. 2013;128:1748–1757. 2. Mesubi OO, Rokita AG, Abrol N, et al. Oxidized CaMKII and O-GlcNAcyl-

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4. Yan J, Bare DJ, DeSantiago J, et al. JNK2, a newly-identified SERCA2 enhancer, augments an arrhythmic [Ca(2+)]SR leak-load relationship. Circ Res. 2021;128:455–470.

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6. Prinsen JK, Kannankeril PJ, Sidorova TN, et al. Highly reactive isolevuglan- dins promote atrial fibrillation caused by hypertension. JACC Basic Transl Sci. 2020;5:602–615.

7. Dobrev D, Dudley SC. Oxidative stress: a bystander or a causal contribu- tor to atrial remodelling and fibrillation? Cardiovasc Res. 2021;117:2291– 2293.

8. Watson T, Shantsila E, Lip GY. Mechanisms of thrombogenesis in atrial fibril- lation: Virchow's triad revisited. Lancet. 2009;373:155–166.

9. Chung MK. Cardiac surgery: postoperative arrhythmias. Crit Care Med. 2000;28:N136–N144.

10. Chung MK, Martin DO, Sprecher D, et al. C-reactive protein elevation in patients with atrial arrhythmias: inflammatory mechanisms and persistence of atrial fibrillation. Circulation. 2001;104:2886–2891.

11. Yao C, Veleva T, Scott L Jr, et al. Enhanced cardiomyocyte NLRP3 inflam- masome signaling promotes atrial fibrillation. Circulation. 2018;138:2227– 2242.

2.3.3. Role of the Autonomic Nervous System 1. Chen PS, Chen LS, Fishbein MC, et al. Role of the autonomic nervous system

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2. Linz D, Elliott AD, Hohl M, et al. Role of autonomic nervous system in atrial fibrillation. Int J Cardiol. 2019;287:181–188.

3. Malik V, Mishima R, A DE, et al. The “road” to atrial fibrillation: the role of the cardiac autonomic nervous system. J Atr Fibrillation. 2020;13:2400.

4. Lau DH, Schotten U, Mahajan R, et al. Novel mechanisms in the pathogen- esis of atrial fibrillation: practical applications. Eur Heart J. 2016;37:1573– 1581.

5. Schotten U, Verheule S, Kirchhof P, et al. Pathophysiological mechanisms of atrial fibrillation: a translational appraisal. Physiol Rev. 2011;91:265–325.

6. Iwasaki YK, Nishida K, Kato T, et al. Atrial fibrillation pathophysiology: impli- cations for management. Circulation. 2011;124:2264–2274.

7. Jayachandran JV, Sih HJ, Winkle W, et al. Atrial fibrillation produced by prolonged rapid atrial pacing is associated with heterogeneous changes in atrial sympathetic innervation. Circulation. 2000;101:1185–1191.

8. Chang CM, Wu TJ, Zhou S, et al. Nerve sprouting and sympathetic hyperin- nervation in a canine model of atrial fibrillation produced by prolonged right atrial pacing. Circulation. 2001;103:22–25.

9. Yu Y, Wei C, Liu L, et al. Atrial fibrillation increases sympathetic and para- sympathetic neurons in the intrinsic cardiac nervous system. Pacing Clin Electrophysiol. 2014;37:1462–1469.

10. Gussak G, Pfenniger A, Wren L, et al. Region-specific parasympathetic nerve remodeling in the left atrium contributes to creation of a vulnerable substrate for atrial fibrillation. JCI Insight. 2019;4:e130532.

11. Malik V, Elliott AD, Thomas G, et al. Autonomic afferent dysregulation in atrial fibrillation. JACC Clin Electrophysiol. 2022;8:152–164.

12. Malik V, McKitrick DJ, Lau DH, et al. Clinical evidence of autonomic dysfunc- tion due to atrial fibrillation: implications for rhythm control strategy. J Interv Card Electrophysiol. 2019;54:299–307.

13. Wasmund SL, Li JM, Page RL, et al. Effect of atrial fibrillation and an irregu- lar ventricular response on sympathetic nerve activity in human subjects. Circulation. 2003;107:2011–2015.

14. Mohanty PK, Arrowood JA, Ellenbogen KA, et al. Neurohumoral and hemo- dynamic effects of lower body negative pressure in patients with congestive heart failure. Am Heart J. 1989;118:78–85.

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2.4. Genetics 1. Lubitz SA, Yin X, Fontes JD, et al. Association between familial atrial fibrilla-

tion and risk of new-onset atrial fibrillation. JAMA. 2010;304:2263–2269. 2. Brugada R, Tapscott T, Czernuszewicz GZ, et al. Identification of a genetic

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4. Weng LC, Choi SH, Klarin D, et al. Heritability of atrial fibrillation. Circ Cardio- vasc Genet. 2017;10:e001838.

5. Roselli C, Chaffin MD, Weng LC, et al. Multi-ethnic genome-wide associa- tion study for atrial fibrillation. Nat Genet. 2018;50:1225–1233.

6. Low SK, Takahashi A, Ebana Y, et al. Identification of six new genetic loci associated with atrial fibrillation in the Japanese population. Nat Genet. 2017;49:953–958.

7. Lee JY, Kim TH, Yang PS, et al. Korean atrial fibrillation network genome- wide association study for early-onset atrial fibrillation identifies novel sus- ceptibility loci. Eur Heart J. 2017;38:2586–2594.

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9. Yoneda ZT, Anderson KC, Quintana JA, et al. Early-onset atrial fibrillation and the prevalence of rare variants in cardiomyopathy and arrhythmia genes. JAMA Cardiol. 2021;6:1371–1379.

10. Chalazan B, Mol D, Darbar FA, et al. Association of rare genetic variants and early-onset atrial fibrillation in ethnic minority individuals. JAMA Cardiol. 2021;6:811–819.

2.5. Addressing Health Inequities and Barriers to AF Management 1. Kim D, Yang PS, You SC, et al. Treatment timing and the effects of rhythm

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2. Tamirisa KP, Al-Khatib SM, Mohanty S, et al. Racial and ethnic differences in the management of atrial fibrillation. CJC Open. 2021;3:S137–S148.

3. Lunde ED, Nielsen PB, Riahi S, et al. Associations between socioeconomic status, atrial fibrillation, and outcomes: a systematic review. Expert Rev Car- diovasc Ther. 2018;16:857–873.

4. Hagengaard L, Andersen MP, Polcwiartek C, et al. Socioeconomic differ- ences in outcomes after hospital admission for atrial fibrillation or flutter. Eur Heart J Qual Care Clin Outcomes. 2021;7:295–303.

5. Harrington RA, Califf RM, Balamurugan A, et al. Call to action: rural health: a presidential advisory from the American Heart Association and American Stroke Association. Circulation. 2020;141:e615–e644.

6. Thompson LE, Maddox TM, Lei L, et al. Sex differences in the use of oral anticoagulants for atrial fibrillation: a report from the National Cardiovas- cular Data Registry (NCDR(®)) PINNACLE registry. J Am Heart Assoc. 2017;6:e005801.

7. Bhave PD, Lu X, Girotra S, et al. Race- and sex-related differences in care for patients newly diagnosed with atrial fibrillation. Heart Rhythm. 2015;12:1406–1412.

8. Avgil Tsadok M, Gagnon J, Joza J, et al. Temporal trends and sex differences in pulmonary vein isolation for patients with atrial fibrillation. Heart Rhythm. 2015;12:1979–1986.

9. Patel N, Deshmukh A, Thakkar B, et al. Gender, race, and health insurance status in patients undergoing catheter ablation for atrial fibrillation. Am J Cardiol. 2016;117:1117–1126.

10. Ugowe FE, Jackson LR 2nd, Thomas KL. Racial and ethnic differences in the prevalence, management, and outcomes in patients with atrial fibrilla- tion: a systematic review. Heart Rhythm. 2018;15:1337–1345.

11. Benjamin EJ, Thomas KL, Go AS, et al. Transforming atrial fibrillation re- search to integrate social determinants of health: a National Heart, Lung, and Blood Institute Workshop Report. JAMA Cardiol. 2023;8:182–191.

12. Gottlieb LM, Wing H, Adler NE. A systematic review of interventions on patients' social and economic needs. Am J Prev Med. 2017;53:719–729.

13. White-Williams C, Rossi LP, Bittner VA, et al. Addressing social determinants of health in the care of patients with heart failure: a scientific statement from the American Heart Association. Circulation. 2020;141:e841–e863.

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15. Davidson KW, Krist AH, Tseng CW, et al. Incorporation of social risk in US Preventive Services Task Force recommendations and identification of key challenges for primary care. JAMA. 2021;326:1410–1415.

16. Volgman AS, Benjamin EJ, Curtis AB, et al. Women and atrial fibrillation. J Cardiovasc Electrophysiol. 2021;32:2793–2807.

17. Russo AM, Zeitler EP, Giczewska A, et al. Association between sex and treatment outcomes of atrial fibrillation ablation versus drug therapy: results from the CABANA trial. Circulation. 2021;143:661–672.

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2. Wang PJ, Lu Y, Mahaffey KW, et al. A randomized clinical trial to evaluate an atrial fibrillation stroke prevention shared decision-making pathway. J Am Heart Assoc. 2022;12:e8009.

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9. Jones AE, McCarty MM, Brito JP, et al. Randomized evaluation of decision support interventions for atrial fibrillation: rationale and design of the RED- AF study. Am Heart J. 2022;248:42–52.

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11. Kunneman M, Branda ME, Hargraves IG, et al. Assessment of shared decision-making for stroke prevention in patients with atrial fibrillation: a randomized clinical trial. JAMA Intern Med. 2020;180:1215–1224.

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3. Li YG, Pastori D, Farcomeni A, et al. A simple clinical risk score (C2HEST) for predicting incident atrial fibrillation in asian subjects: derivation in 471 446 Chinese subjects, with internal validation and external application in 451 199 Korean subjects. Chest. 2019;155:510–518.

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5. Biersteker TE, Schalij MJ, Treskes RW. Impact of mobile health devices for the detection of atrial fibrillation: systematic review. JMIR Mhealth Uhealth. 2021;9:e26161.

6. Lin JY, Larson J, Schoenberg J, et al. Serial 7-day electrocardiogram patch screening for AF in high-risk older women by the CHARGE-AF score. JACC Clin Electrophysiol. 2022;8:1523–1534.

7. Noseworthy PA, Attia ZI, Behnken EM, et al. Artificial intelligence-guided screening for atrial fibrillation using electrocardiogram during sinus rhythm: a prospective non-randomised interventional trial. Lancet. 2022;400:1206– 1212.

8. Perez MV, Mahaffey KW, Hedlin H, et al. Large-scale assessment of a smart- watch to identify atrial fibrillation. N Engl J Med. 2019;381:1909–1917.

9. Hlatky MA, Greenland P, Arnett DK, et al. Criteria for evaluation of novel markers of cardiovascular risk: a scientific statement from the American Heart Association. Circulation. 2009;119:2408–2416.

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4.2.1. Basic Clinical Evaluation 1. Koyama J, Ray-Sequin PA, Falk RH. Longitudinal myocardial function as-

sessed by tissue velocity, strain, and strain rate tissue Doppler echocar- diography in patients with AL (primary) cardiac amyloidosis. Circulation. 2003;107:2446–2452.

2. Reddy YNV, Obokata M, Verbrugge FH, et al. Atrial dysfunction in patients with heart failure with preserved ejection fraction and atrial fibrillation. J Am Coll Cardiol. 2020;76:1051–1064.

3. Ma XX, Boldt LH, Zhang YL, et al. Clinical relevance of left atrial strain to predict recurrence of atrial fibrillation after catheter ablation: a meta- analysis. Echocardiogr. 2016;33:724–733.

4. Costa FM, Ferreira AM, Oliveira S, et al. Left atrial volume is more important than the type of atrial fibrillation in predicting the long-term success of cath- eter ablation. Int J Cardiol. 2015;184:56–61.

5. Shang W, Li L, Huang S, et al. Chronic kidney disease and the risk of new- onset atrial fibrillation: a meta-analysis of prospective cohort studies. PLoS One. 2016;11:e0155581.

6. Minhas AM, Usman MS, Khan MS, et al. Link between non-alcoholic fatty liver disease and atrial fibrillation: a systematic review and meta-analysis. Cureus. 2017;9:e1142.

7. Frost L, Vestergaard P, Mosekilde L. Hyperthyroidism and risk of atrial fibril- lation or flutter: a population-based study. Arch Intern Med. 2004;164:1675– 1678.

8. Askew JW, Miller TD, Hodge DO, et al. The value of myocardial perfusion single-photon emission computed tomography in screening asymptomatic patients with atrial fibrillation for coronary artery disease. J Am Coll Cardiol. 2007;50:1080–1085.

9. Cremer PC, Mentias A, Newton D, et al. Low yield of myocardial perfusion imaging in asymptomatic patients with atrial fibrillation. JAMA Intern Med. 2015;175:1854–1855.

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11. Delgado V, Di Biase L, Leung M, et al. Structure and function of the left atrium and left atrial appendage: AF and stroke implications. J Am Coll Car- diol. 2017;70:3157–3172.

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4.2.2. Rhythm Monitoring Tools and Methods 1. Yang TY, Huang L, Malwade S, et al. Diagnostic accuracy of ambulatory

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2. Prasitlumkum N, Cheungpasitporn W, Chokesuwattanaskul A, et al. Di- agnostic accuracy of smart gadgets/wearable devices in detecting atrial fibrillation: a systematic review and meta-analysis. Arch Cardiovasc Dis. 2021;114:4–16.

3. Wong KC, Klimis H, Lowres N, et al. Diagnostic accuracy of handheld elec- trocardiogram devices in detecting atrial fibrillation in adults in community versus hospital settings: a systematic review and meta-analysis. Heart. 2020;106:1211–1217.

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4. Kapa S, Epstein AE, Callans DJ, et al. Assessing arrhythmia burden after catheter ablation of atrial fibrillation using an implantable loop recorder: the ABACUS study. J Cardiovasc Electrophysiol. 2013;24:875–881.

5. Podd SJ, Sugihara C, Furniss SS, et al. Are implantable cardiac monitors the 'gold standard' for atrial fibrillation detection? A prospective randomized trial comparing atrial fibrillation monitoring using implantable cardiac moni- tors and DDDRP permanent pacemakers in post atrial fibrillation ablation patients. Europace. 2016;18:1000–1005.

6. de Voogt WG, van Hemel NM, van de Bos AA, et al. Verification of pace- maker automatic mode switching for the detection of atrial fibrillation and atrial tachycardia with Holter recording. Europace. 2006;8:950–961.

7. Eysenck W, Freemantle N, Sulke N. A randomized trial evaluating the ac- curacy of AF detection by four external ambulatory ECG monitors com- pared to permanent pacemaker AF detection. J Interv Card Electrophysiol. 2020;57:361–369.

8. Vitolo M, Imberti JF, Maisano A, et al. Device-detected atrial high rate episodes and the risk of stroke/thrombo-embolism and atrial fibrilla- tion incidence: a systematic review and meta-analysis. Eur J Intern Med. 2021;92:100–106.

9. Healey JS, Connolly SJ, Gold MR, et al. Subclinical atrial fibrillation and the risk of stroke. N Engl J Med. 2012;366:120–129.

10. Buck BH, Hill MD, Quinn FR, et al. Effect of implantable vs prolonged ex- ternal electrocardiographic monitoring on atrial fibrillation detection in pa- tients with ischemic stroke: the PER DIEM randomized clinical trial. JAMA. 2021;325:2160–2168.

11. Bernstein RA, Kamel H, Granger CB, et al. Effect of long-term continuous cardiac monitoring vs usual care on detection of atrial fibrillation in patients with stroke attributed to large- or small-vessel disease: the STROKE-AF randomized clinical trial. JAMA. 2021;325:2169–2177.

12. Hannun AY, Rajpurkar P, Haghpanahi M, et al. Cardiologist-level arrhythmia detection and classification in ambulatory electrocardiograms using a deep neural network. Nat Med. 2019;25:65–69.

13. Goldenthal IL, Sciacca RR, Riga T, et al. Recurrent atrial fibrillation/flutter detection after ablation or cardioversion using the AliveCor KardiaMobile device: iHEART results. J Cardiovasc Electrophysiol. 2019;30:2220–2228.

14. Gill S, Bunting KV, Sartini C, et al. Smartphone detection of atrial fibrillation using photoplethysmography: a systematic review and meta-analysis. Heart. 2022;108:1600–1607.

15. Tison GH, Sanchez JM, Ballinger B, et al. Passive detection of atrial fibrilla- tion using a commercially available smartwatch. JAMA Cardiol. 2018;3:409– 416.

16. Perez MV, Mahaffey KW, Hedlin H, et al. Large-scale assessment of a smart- watch to identify atrial fibrillation. N Engl J Med. 2019;381:1909–1917.

17. Guo Y, Wang H, Zhang H, et al. Mobile Photoplethysmographic technology to detect atrial fibrillation. J Am Coll Cardiol. 2019;74:2365–2375.

18. Avram R, Ramsis M, Cristal AD, et al. Validation of an algorithm for con- tinuous monitoring of atrial fibrillation using a consumer smartwatch. Heart Rhythm. 2021;18:1482–1490.

19. Dussault C, Toeg H, Nathan M, et al. Electrocardiographic monitoring for detecting atrial fibrillation after ischemic stroke or transient ischemic at- tack: systematic review and meta-analysis. Circ Arrhythm Electrophysiol. 2015;8:263–269.

20. Caceres BA, Hickey KT, Bakken SB, et al. Mobile electrocardiogram moni- toring and health-related quality of life in patients with atrial fibrillation: find- ings from the iPhone Helping Evaluate Atrial Fibrillation Rhythm Through Technology (iHEART) study. J Cardiovasc Nurs. 2020;35:327–336.

5.1. Primary Prevention 1. Tedrow UB, Conen D, Ridker PM, et al. The long- and short-term impact

of elevated body mass index on the risk of new atrial fibrillation the WHS (women's health study). J Am Coll Cardiol. 2010;55:2319–2327.

2. Elliott AD, Linz D, Mishima R, et al. Association between physical activity and risk of incident arrhythmias in 402 406 individuals: evidence from the UK Biobank cohort. Eur Heart J. 2020;41:1479–1486.

3. Gallagher C, Hendriks JML, Elliott AD, et al. Alcohol and incident atrial fibril- lation - a systematic review and meta-analysis. Int J Cardiol. 2017;246:46– 52.

4. Aune D, Schlesinger S, Norat T, et al. Tobacco smoking and the risk of atrial fibrillation: a systematic review and meta-analysis of prospective studies. Eur J Prev Cardiol. 2018;25:1437–1451.

5. Aune D, Feng T, Schlesinger S, et al. Diabetes mellitus, blood glucose and the risk of atrial fibrillation: a systematic review and meta-analysis of cohort studies. J Diabetes Complications. 2018;32:501–511.

6. Soliman EZ, Rahman AF, Zhang ZM, et al. Effect of intensive blood pressure lowering on the risk of atrial fibrillation. Hypertension. 2020;75:1491–1496.

7. Alonso A, Krijthe BP, Aspelund T, et al. Simple risk model predicts incidence of atrial fibrillation in a racially and geographically diverse population: the CHARGE-AF consortium. J Am Heart Assoc. 2013;2:e000102.

8. Himmelreich JCL, Veelers L, Lucassen WAM, et al. Prediction models for atrial fibrillation applicable in the community: a systematic review and meta- analysis. Europace. 2020;22:684–694.

9. Roselli C, Chaffin MD, Weng LC, et al. Multi-ethnic genome-wide associa- tion study for atrial fibrillation. Nat Genet. 2018;50:1225–1233.

10. Huxley RR, Lopez FL, Folsom AR, et al. Absolute and attributable risks of atrial fibrillation in relation to optimal and borderline risk factors: the Athero- sclerosis Risk in Communities (ARIC) study. Circulation. 2011;123:1501– 1508.

11. Garg PK, O'Neal WT, Ogunsua A, et al. Usefulness of the American Heart Association's Life Simple 7 to predict the risk of atrial fibrillation (from the REasons for Geographic And Racial Differences in Stroke [REGARDS] study). Am J Cardiol. 2018;121:199–204.

12. Di Benedetto L, Michels G, Luben R, et al. Individual and combined im- pact of lifestyle factors on atrial fibrillation in apparently healthy men and women: the EPIC-Norfolk prospective population study. Eur J Prev Cardiol. 2018;25:1374–1383.

13. Arnett DK, Blumenthal RS, Albert MA, et al. 2019 ACC/AHA guideline on the primary prevention of cardiovascular disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2019;140:e596–e646.

14. Lin AL, Nah G, Tang JJ, et al. Cannabis, cocaine, methamphetamine, and opiates increase the risk of incident atrial fibrillation. Eur Heart J. 2022;43:4933–4942.

15. Mishima RS, Verdicchio CV, Noubiap JJ, et al. Self-reported physical activ- ity and atrial fibrillation risk: a systematic review and meta-analysis. Heart Rhythm. 2021;18:520–528.

16. Jin MN, Yang PS, Song C, et al. Physical activity and risk of atrial fibrillation: a nationwide cohort study in general population. Sci Rep. 2019;9:13270.

17. Khurshid S, Weng LC, Al-Alusi MA, et al. Accelerometer-derived physical activity and risk of atrial fibrillation. Eur Heart J. 2021;42:2472–2483.

18. Tikkanen E, Gustafsson S, Ingelsson E. Associations of fitness, physical activity, strength, and genetic risk with cardiovascular disease: longitu- dinal analyses in the UK Biobank study. Circulation. 2018;137:2583– 2591.

19. Qureshi WT, Alirhayim Z, Blaha MJ, et al. Cardiorespiratory fitness and risk of incident atrial fibrillation results from the Henry Ford exercise testing (FIT) project. Circulation. 2015;131:1827–1834.

20. Khan H, Kella D, Rauramaa R, et al. Cardiorespiratory fitness and atrial fibril- lation: a population-based follow-up study. Heart Rhythm. 2015;12:1424– 1430.

21. Andersen K, Farahmand B, Ahlbom A, et al. Risk of arrhythmias in 52 755 long-distance cross-country skiers: a cohort study. Eur Heart J. 2013;34:3624–3631.

22. Baldesberger S, Bauersfeld U, Candinas R, et al. Sinus node disease and arrhythmias in the long-term follow-up of former professional cyclists. Eur Heart J. 2008;29:71–78.

23. Newman W, Parry-Williams G, Wiles J, et al. Risk of atrial fibrillation in athletes: a systematic review and meta-analysis. Br J Sports Med. 2021;55:1233–1238.

24. Morseth B, Graff-Iversen S, Jacobsen BK, et al. Physical activity, resting heart rate, and atrial fibrillation: the Tromsø study. Eur Heart J. 2016;37:2307– 2313.

25. Marcus GM, Vittinghoff E, Whitman IR, et al. Acute consumption of alco- hol and discrete atrial fibrillation events. Ann Intern Med. 2021;174:1503– 1509.

26. Voskoboinik A, McDonald C, Chieng D, et al. Acute electrical, autonomic and structural effects of binge drinking: insights into the 'holiday heart syn- drome'. Int J Cardiol. 2021;331:100–105.

27. Whitman IR, Agarwal V, Nah G, et al. Alcohol abuse and cardiac disease. J Am Coll Cardiol. 2017;69:13–24.

28. Csengeri D, Sprunker NA, Di Castelnuovo A, et al. Alcohol consumption, cardiac biomarkers, and risk of atrial fibrillation and adverse outcomes. Eur Heart J. 2021;42:1170–1177.

29. Tu SJ, Gallagher C, Elliott AD, et al. Risk Thresholds for total and beverage- specific alcohol consumption and incident atrial fibrillation. JACC Clin Elec- trophysiol. 2021;7:1561–1569.

30. Zuo H, Nygard O, Vollset SE, et al. Smoking, plasma cotinine and risk of atrial fibrillation: the Hordaland Health Study. J Intern Med. 2018;283:73–82.

31. Lu Y, Guo Y, Lin H, et al. Genetically determined tobacco and alcohol use and risk of atrial fibrillation. BMC Med Genomics. 2021;14:73.

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32. Larsson SC, Wallin A, Hakansson N, et al. Type 1 and type 2 diabetes mellitus and incidence of seven cardiovascular diseases. Int J Cardiol. 2018;262:66–70.

33. Qi W, Zhang N, Korantzopoulos P, et al. Serum glycated hemoglobin level as a predictor of atrial fibrillation: a systematic review with meta-analysis and meta-regression. PLoS One. 2017;12:e0170955.

5.2.1. Weight Loss in Individuals Who Are Overweight or Obese 1. Abed HS, Wittert GA, Leong DP, et al. Effect of weight reduction and

cardiometabolic risk factor management on symptom burden and se- verity in patients with atrial fibrillation: a randomized clinical trial. JAMA. 2013;310:2050–2060.

2. Pathak RK, Middeldorp ME, Meredith M, et al. Long-term effect of goal- directed weight management in an atrial fibrillation cohort: a long-term follow-up study (LEGACY). J Am Coll Cardiol. 2015;65:2159–2169.

3. Pathak RK, Middeldorp ME, Lau DH, et al. Aggressive risk factor reduction study for atrial fibrillation and implications for the outcome of ablation: the ARREST-AF cohort study. J Am Coll Cardiol. 2014;64:2222–2231.

4. 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;20:1929–1935.

5. Wong CX, Sullivan T, Sun MT, et al. Obesity and the risk of incident, post- operative, and post-ablation atrial fibrillation: a meta-analysis of 626 603 individuals in 51 studies. JACC: Clin Electrophysiol. 2015;1:139–152.

6. 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.

7. Mahajan R, Lau DH, Brooks AG, et al. Electrophysiological, electroanatomi- cal, and structural remodeling of the atria as consequences of sustained obesity. J Am Coll Cardiol. 2015;66:1–11.

8. Mahajan R, Lau DH, Brooks AG, et al. Atrial fibrillation and obesity: reverse remodeling of atrial substrate with weight reduction. JACC Clin Electrophysi- ol. 2021;7:630–641.

9. Grundvold I, Bodegard J, Nilsson PM, et al. Body weight and risk of atrial fibrillation in 7 169 patients with newly diagnosed type 2 diabetes; an ob- servational study. Cardiovasc Diabetol. 2015;14:5.

10. Di Benedetto L, Michels G, Luben R, et al. Individual and combined im- pact of lifestyle factors on atrial fibrillation in apparently healthy men and women: the EPIC-Norfolk prospective population study. Eur J Prev Cardiol. 2018;25:1374–1383.

11. Providência R, Adrag ão P, de Asmundis C, et al. Impact of body mass index on the outcomes of catheter ablation of atrial fibrillation: a European observational multicenter study. J Am Heart Assoc. 2019;8:e012253.

12. Glover BM, Hong KL, Dagres N, et al. Impact of body mass index on the outcome of catheter ablation of atrial fibrillation. Heart. 2019;105:244–250.

13. Donnellan E, Wazni O, Kanj M, et al. Outcomes of atrial fibrillation ablation in morbidly obese patients following bariatric surgery compared with a non- obese cohort. Circ Arrhythm Electrophysiol. 2019;12:e007598.

14. Donnellan E, Wazni OM, Kanj M, et al. Association between pre-ablation bariatric surgery and atrial fibrillation recurrence in morbidly obese patients undergoing atrial fibrillation ablation. Europace. 2019;21:1476–1483.

15. Donnellan E, Wazni OM, Elshazly M, et al. Impact of bariatric surgery on atrial fibrillation type. Circ Arrhythm Electrophysiol. 2020;13:e007626.

16. Donnellan E, Wazni OM, Kanj M, et al. Impact of risk-factor modification on arrhythmia recurrence among morbidly obese patients undergoing atrial fibrillation ablation. J Cardiovasc Electrophysiol. 2020;31:1979–1986.

17. Mohanty S, Mohanty P, Natale V, et al. Impact of weight loss on ablation outcome in obese patients with longstanding persistent atrial fibrillation. J Cardiovasc Electrophysiol. 2018;29:246–253.

5.2.2. Physical Fitness 1. Hegbom F, Stavem K, Sire S, et al. Effects of short-term exercise training

on symptoms and quality of life in patients with chronic atrial fibrillation. Int J Cardiol. 2007;116:86–92.

2. Malmo V, Nes BM, Amundsen BH, et al. Aerobic interval training reduces the burden of atrial fibrillation in the short term: a randomized trial. Circula- tion. 2016;133:466–473.

3. Elliott AD, Verdicchio CV, Mahajan R, et al. An exercise and physical activity program in patients with atrial fibrillation: the ACTIVE-AF randomized con- trolled trial. JACC Clin Electrophysiol. 2023;9:455–465.

4. Pathak RK, Elliott A, Middeldorp ME, et al. Impact of CARDIOrespiratory FITness on arrhythmia recurrence in obese individuals with atrial fibrillation: the CARDIO-FIT study. J Am Coll Cardiol. 2015;66:985–996.

5. Oesterle A, Giancaterino S, Van Noord MG, et al. Effects of supervised ex- ercise training on atrial fibrillation: a meta-analysis of randomized controlled trials. J Cardiopulm Rehabil Prev. 2022;42:258–265.

6. Osbak PS, Mourier M, Kjaer A, et al. A randomized study of the ef- fects of exercise training on patients with atrial fibrillation. Am Heart J. 2011;162:1080–1087.

7. Ahn HJ, Lee SR, Choi EK, et al. Association between exercise habits and stroke, heart failure, and mortality in Korean patients with incident atrial fibrillation: a nationwide population-based cohort study. PLoS Med. 2021;18:e1003659.

8. Skielboe AK, Bandholm TQ, Hakmann S, et al. Cardiovascular exercise and burden of arrhythmia in patients with atrial fibrillation - a randomized con- trolled trial. PLoS One. 2017;12:e0170060.

9. Abdulla J, Nielsen JR. Is the risk of atrial fibrillation higher in athletes than in the general population? A systematic review and meta-analysis. Europace. 2009;11:1156–1159.

10. Andersen K, Farahmand B, Ahlbom A, et al. Risk of arrhythmias in 52 755 long-distance cross-country skiers: a cohort study. Eur Heart J. 2013;34:3624–3631.

11. Smart NA, King N, Lambert JD, et al. Exercise-based cardiac rehabilitation improves exercise capacity and health-related quality of life in people with atrial fibrillation: a systematic review and meta-analysis of randomised and non-randomised trials. Open Heart. 2018;5:e000880.

12. Risom SS, Zwisler AD, Rasmussen TB, et al. Cardiac rehabilitation versus usual care for patients treated with catheter ablation for atrial fibrillation: re- sults of the randomized CopenHeartRFA trial. Am Heart J. 2016;181:120– 129.

13. Kato M, Ogano M, Mori Y, et al. Exercise-based cardiac rehabilitation for patients with catheter ablation for persistent atrial fibrillation: a randomized controlled clinical trial. Eur J Prev Cardiol. 2019;26:1931–1940.

14. Luo N, Merrill P, Parikh KS, et al. Exercise Training in patients with chronic heart failure and atrial fibrillation. J Am Coll Cardiol. 2017;69:1683–1691.

15. Buckley BJR, Harrison SL, Fazio-Eynullayeva E, et al. Exercise-based car- diac rehabilitation and all-cause mortality among patients with atrial fibrilla- tion. J Am Heart Assoc. 2021;10:e020804.

5.2.3. Smoking Cessation 1. Arnett DK, Blumenthal RS, Albert MA, et al. 2019 ACC/AHA guideline on

the primary prevention of cardiovascular disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2019;140:e596–e646.

2. Patnode CD, Henderson JT, Thompson JH, et al. Behavioral counseling and pharmacotherapy interventions for tobacco cessation in adults, including pregnant women: a review of reviews for the US Preventive Services Task Force. Ann Intern Med. 2015;163:608–621.

3. Choi S, Chang J, Kim K, et al. Association of smoking cessation after atrial fibrillation diagnosis on the risk of cardiovascular disease: a cohort study of South Korean men. BMC Public Health. 2020;20:168.

4. Benz AP, Healey JS, Chin A, et al. Stroke risk prediction in patients with atrial fibrillation with and without rheumatic heart disease. Cardiovasc Res. 2022;118:295–304.

5. Chatterjee NA, Chae CU, Kim E, et al. Modifiable risk factors for incident heart failure in atrial fibrillation. JACC Heart Fail. 2017;5:552–560.

6. Chamberlain AM, Alonso A, Gersh BJ, et al. Multimorbidity and the risk of hospitalization and death in atrial fibrillation: a population-based study. Am Heart J. 2017;185:74–84.

7. Sardana M, Tang Y, Magnani JW, et al. Provider-level variation in smoking cessation assistance provided in the cardiology clinics: insights from the NCDR PINNACLE registry. J Am Heart Assoc. 2019;8:e011412.

8. Huang Y, Britton J, Hubbard R, et al. Who receives prescriptions for smoking cessation medications? An association rule mining analysis using a large primary care database. Tob Control. 2013;22:274–279.

9. Stead LF, Buitrago D, Preciado N, et al. Physician advice for smoking cessa- tion. Cochrane Database Syst Rev. 2013;5:CD000165.

10. Hartmann-Boyce J, Livingstone-Banks J, Ordonez-Mena JM, et al. Behav- ioural interventions for smoking cessation: an overview and network meta- analysis. Cochrane Database Syst Rev. 2021;1:CD013229.

11. Suissa K, Lariviere J, Eisenberg MJ, et al. Efficacy and safety of smoking cessation interventions in patients with cardiovascular disease: a network meta-analysis of randomized controlled trials. Circ Cardiovasc Qual Out- comes. 2017;10:e002458.

12. Buiatti A, Kaess B, Reents T, et al. Catheter ablation for “lone” atrial fibril- lation: efficacy and predictors of recurrence. J Cardiovasc Electrophysiol. 2016;27:536–541.

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13. Cheng WH, Lo LW, Lin YJ, et al. Cigarette smoking causes a worse long- term outcome in persistent atrial fibrillation following catheter ablation. J Cardiovasc Electrophysiol. 2018;29:699–706.

14. Apostolakis S, Sullivan RM, Olshansky B, et al. Factors affecting quality of anticoagulation control among patients with atrial fibrillation on warfarin: the SAMe-TT(2)R(2) score. Chest. 2013;144:1555–1563.

15. Albertsen IE, Rasmussen LH, Lane DA, et al. The impact of smoking on thromboembolism and mortality in patients with incident atrial fibrilla- tion: insights from the Danish Diet, Cancer, and Health study. Chest. 2014;145:559–566.

16. Lee SR, Choi EK, Jung JH, et al. Smoking cessation after diagnosis of new-onset atrial fibrillation and the risk of stroke and death. J Clin Med. 2021;10:2238.

5.2.4. Alcohol Consumption 1. Voskoboinik A, Kalman JM, De Silva A, et al. Alcohol abstinence in drinkers

with atrial fibrillation. N Engl J Med. 2020;382:20–28. 2. Marcus GM, Dukes JW, Vittinghoff E, et al. A randomized, double-blind,

placebo-controlled trial of intravenous alcohol to assess changes in atrial electrophysiology. JACC Clin Electrophysiol. 2021;7:662–670.

3. Marcus GM, Modrow MF, Schmid CH, et al. Individualized studies of triggers of paroxysmal atrial fibrillation: the I-STOP-AFib randomized clinical trial. JAMA Cardiol. 2022;7:167–174.

4. Marcus GM, Vittinghoff E, Whitman IR, et al. Acute consumption of alco- hol and discrete atrial fibrillation events. Ann Intern Med. 2021;174:1503– 1509.

5. Abed HS, Wittert GA, Leong DP, et al. Effect of weight reduction and cardiometabolic risk factor management on symptom burden and se- verity in patients with atrial fibrillation: a randomized clinical trial. JAMA. 2013;310:2050–2060.

6. Pathak RK, Middeldorp ME, Lau DH, et al. Aggressive risk factor reduction study for atrial fibrillation and implications for the outcome of ablation: the ARREST-AF cohort study. J Am Coll Cardiol. 2014;64:2222–2231.

7. Pathak RK, Middeldorp ME, Meredith M, et al. Long-term effect of goal- directed weight management in an atrial fibrillation cohort: a long-term follow-up study (LEGACY). J Am Coll Cardiol. 2015;65:2159–2169.

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;20:1929–1935.

5.2.5. Caffeine Consumption 1. Lagier D, Nee L, Guieu R, et al. Peri-operative oral caffeine does not pre-

vent postoperative atrial fibrillation after heart valve surgery with cardiopul- monary bypass: a randomised controlled clinical trial. Eur J Anaesthesiol. 2018;35:911–918.

2. Marcus GM, Modrow MF, Schmid CH, et al. Individualized Studies of triggers of paroxysmal atrial fibrillation: the I-STOP-AFib randomized clinical trial. JAMA Cardiol. 2022;7:167–174.

3. Caldeira D, Martins C, Alves LB, et al. Caffeine does not increase the risk of atrial fibrillation: a systematic review and meta-analysis of observational studies. Heart. 2013;99:1383–1389.

4. Conen D, Chiuve SE, Everett BM, et al. Caffeine consumption and incident atrial fibrillation in women. Am J Clin Nutr. 2010;92:509–514.

5. Bazal P, Gea A, Navarro AM, et al. Caffeinated coffee consumption and risk of atrial fibrillation in two Spanish cohorts. Eur J Prev Cardiol. 2021;28:648– 657.

6. Larsson SC, Drca N, Jensen-Urstad M, et al. Coffee consumption is not as- sociated with increased risk of atrial fibrillation: results from two prospective cohorts and a meta-analysis. BMC Med. 2015;13:207.

7. Cheng M, Hu Z, Lu X, et al. Caffeine intake and atrial fibrillation incidence: dose response meta-analysis of prospective cohort studies. Can J Cardiol. 2014;30:448–454.

8. Kim EJ, Hoffmann TJ, Nah G, et al. Coffee consumption and incident tachyarrhythmias: reported behavior, Mendelian randomization, and their interactions. JAMA Intern Med. 2021;181:1185–1193.

9. Bodar V, Chen J, Gaziano JM, et al. Coffee consumption and risk of atrial fi- brillation in the physicians' health study. J Am Heart Assoc. 2019;8:e011346.

10. Groh CA, Faulkner M, Getabecha S, et al. Patient-reported triggers of parox- ysmal atrial fibrillation. Heart Rhythm. 2019;16:996–1002.

11. Yuan S, Larsson SC. No association between coffee consumption and risk of atrial fibrillation: a Mendelian randomization study. Nutr Metab Cardiovasc Dis. 2019;29:1185–1188.

12. Mattioli AV, Pennella S, Farinetti A, et al. Energy drinks and atrial fibrillation in young adults. Clin Nutr. 2018;37:1073–1074.

13. Di Rocco JR, During A, Morelli PJ, et al. Atrial fibrillation in healthy adoles- cents after highly caffeinated beverage consumption: two case reports. J Med Case Rep. 2011;5:18.

14. Mattioli AV, Bonatti S, Zennaro M, et al. Effect of coffee consumption, life- style and acute life stress in the development of acute lone atrial fibrillation. J Cardiovasc Med (Hagerstown). 2008;9:794–798.

5.2.6. Diet and Dietary Supplementation 1. Aleksova A, Masson S, Maggioni AP, et al. n-3 polyunsaturated fatty acids

and atrial fibrillation in patients with chronic heart failure: the GISSI-HF trial. Eur J Heart Fail. 2013;15:1289–1295.

2. Metcalf RG, Skuladottir GV, Indridason OS, et al. U-shaped relationship be- tween tissue docosahexaenoic acid and atrial fibrillation following cardiac surgery. Eur J Clin Nutr. 2014;68:114–118.

3. Gencer B, Djousse L, Al-Ramady OT, et al. Effect of long-term marine ome- ga-3 fatty acids supplementation on the risk of atrial fibrillation in random- ized controlled trials of cardiovascular outcomes: a systematic review and meta-analysis. Circulation. 2021;144:1981–1990.

4. Darghosian L, Free M, Li J, et al. Effect of omega-three polyunsaturated fatty acids on inflammation, oxidative stress, and recurrence of atrial fibrilla- tion. Am J Cardiol. 2015;115:196–201.

5. Kowey PR, Reiffel JA, Ellenbogen KA, et al. Efficacy and safety of prescrip- tion omega-3 fatty acids for the prevention of recurrent symptomatic atrial fibrillation: a randomized controlled trial. JAMA. 2010;304:2363–2372.

6. Nigam A, Talajic M, Roy D, et al. Fish oil for the reduction of atrial fibril- lation recurrence, inflammation, and oxidative stress. J Am Coll Cardiol. 2014;64:1441–1448.

7. Kumar S, Sutherland F, Stevenson I, et al. Effects of long-term ω-3 polyun- saturated fatty acid supplementation on paroxysmal atrial tachyarrhythmia burden in patients with implanted pacemakers: results from a prospective randomised study. Int J Cardiol. 2013;168:3812–3817.

8. Albert CM, Cook NR, Pester J, et al. Effect of marine omega-3 fatty acid and vitamin D supplementation on incident atrial fibrillation: a randomized clinical trial. JAMA. 2021;325:1061–1073.

9. Huang WL, Yang J, Yang J, et al. Vitamin D and new-onset atrial fibrilla- tion: a meta-analysis of randomized controlled trials. Hellenic J Cardiol. 2018;59:72–77.

10. Kara H, Yasim A. Effects of high-dose vitamin D supplementation on the occurrence of post-operative atrial fibrillation after coronary artery by- pass grafting: randomized controlled trial. Gen Thorac Cardiovasc Surg. 2020;68:477–484.

11. Shi R, Li ZH, Chen D, et al. Sole and combined vitamin C supplementation can prevent postoperative atrial fibrillation after cardiac surgery: a system- atic review and meta-analysis of randomized controlled trials. Clin Cardiol. 2018;41:871–878.

12. Abed HS, Wittert GA, Leong DP, et al. Effect of weight reduction and cardiometabolic risk factor management on symptom burden and se- verity in patients with atrial fibrillation: a randomized clinical trial. JAMA. 2013;310:2050–2060.

13. Pathak RK, Middeldorp ME, Meredith M, et al. Long-term effect of goal- directed weight management in an atrial fibrillation cohort: a long-term follow-up study (LEGACY). J Am Coll Cardiol. 2015;65:2159–2169.

14. Zhang S, Zhuang X, Lin X, et al. Low-carbohydrate diets and risk of in- cident atrial fibrillation: a prospective cohort study. J Am Heart Assoc. 2019;8:e011955.

5.2.7. Diabetes 1. Echouffo-Tcheugui JB, Shrader P, Thomas L, et al. Care patterns and out-

comes in atrial fibrillation patients with and without diabetes: ORBIT-AF registry. J Am Coll Cardiol. 2017;70:1325–1335.

2. Patti G, Di Gioia G, Cavallari I, et al. Safety and efficacy of nonvitamin K antagonist oral anticoagulants versus warfarin in diabetic patients with atrial fibrillation: a study-level meta-analysis of phase III randomized trials. Diabe- tes Metab Res Rev. 2017;33:e2876.

3. Donnellan E, Aagaard P, Kanj M, et al. Association between pre-ablation glycemic control and outcomes among patients with diabetes undergoing atrial fibrillation ablation. JACC Clin Electrophysiol. 2019;5:897–903.

5.2.8. Treatment of Hypertension 1. Neefs J, van den Berg NW, Limpens J, et al. Aldosterone pathway blockade

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5. Pinho-Gomes AC, Azevedo L, Copland E, et al. Blood pressure-lowering treatment for the prevention of cardiovascular events in patients with atrial fibrillation: an individual participant data meta-analysis. PLoS Med. 2021;18:e1003599.

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7. Rao MP, Halvorsen S, Wojdyla D, et al. Blood pressure control and risk of stroke or systemic embolism in patients with atrial fibrillation: results from the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial. J Am Heart Assoc. 2015;4:e002015.

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5.2.9. Sleep 1. Kadhim K, Middeldorp ME, Elliott AD, et al. Prevalence and assessment of

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3. Linz D, Brooks AG, Elliott AD, et al. Variability of sleep apnea severity and risk of atrial fibrillation: the VARIOSA-AF study. JACC Clin Electrophysiol. 2019;5:692–701.

4. Abumuamar AM, Dorian P, Newman D, et al. The prevalence of obstructive sleep apnea in patients with atrial fibrillation. Clin Cardiol. 2018;41:601– 607.

5. Platek AE, Szymanski FM, Filipiak KJ, et al. Stratification of cardiovascular risk in patients with atrial fibrillation and obstructive sleep apnea-validity of the 2MACE score. Sleep Breath. 2017;21:601–606.

6. Li X, Zhou X, Xu X, et al. Effects of continuous positive airway pressure treatment in obstructive sleep apnea patients with atrial fibrillation: a meta- analysis. Medicine (Baltim). 2021;100:e25438.

7. Yang Y, Ning Y, Wen W, et al. CPAP is associated with decreased risk of AF recurrence in patients with OSA, especially those younger and slimmer: a meta-analysis. J Interv Card Electrophysiol. 2020;58:369–379.

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22. Hunt TE, Traaen GM, Aakeroy L, et al. Effect of continuous positive airway pressure therapy on recurrence of atrial fibrillation after pulmonary vein iso- lation in patients with obstructive sleep apnea: a randomized controlled trial. Heart Rhythm. 2022;19:1433–1441.

5.2.10. Comprehensive Care 1. Voskoboinik A, Kalman JM, De Silva A, et al. Alcohol abstinence in drinkers

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3. Rienstra M, Hobbelt AH, Alings M, et al. Targeted therapy of underlying con- ditions improves sinus rhythm maintenance in patients with persistent atrial fibrillation: results of the RACE 3 trial. Eur Heart J. 2018;39:2987–2996.

4. Hendriks JM, de Wit R, Crijns HJ, et al. Nurse-led care vs usual care for pa- tients with atrial fibrillation: results of a randomized trial of integrated chronic care vs routine clinical care in ambulatory patients with atrial fibrillation. Eur Heart J. 2012;33:2692–2699.

5. Guo Y, Lane DA, Wang L, et al. Mobile health technology to improve care for patients with atrial fibrillation. J Am Coll Cardiol. 2020;75:1523–1534.

6. Karlsson LO, Nilsson S, Bång M, et al. A clinical decision support tool for improving adherence to guidelines on anticoagulant therapy in patients with atrial fibrillation at risk of stroke: a cluster-randomized trial in a Swedish primary care setting (the CDS-AF study). PLoS Med. 2018;15:e1002528.

7. Piccini JP Sr, Allred J, Bunch TJ, et al. Rationale, considerations, and goals for atrial fibrillation centers of excellence: a Heart Rhythm Society perspec- tive. Heart Rhythm. 2020;17:1804–1832.

8. Younis A, Shaviv E, Nof E, et al. The role and outcome of cardiac rehabilita- tion program in patients with atrial fibrillation. Clin Cardiol. 2018;41:1170– 1176.

9. Angaran P, Mariano Z, Dragan V, et al. The Atrial Fibrillation Therapies after ER visit: Outpatient Care for Patients with Acute AF - the AFTER3 study. J Atr Fibrillation. 2015;7:1187.

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11. van den Dries CJ, van Doorn S, Rutten FH, et al. Integrated management of atrial fibrillation in primary care: results of the ALL-IN cluster randomized trial. Eur Heart J. 2020;41:2836–2844.

12. Stewart S, Ball J, Horowitz JD, et al. Standard versus atrial fibrillation-spe- cific management strategy (SAFETY) to reduce recurrent admission and prolong survival: pragmatic, multicentre, randomised controlled trial. Lancet. 2015;385:775–784.

13. Willis TA, Collinson M, Glidewell L, et al. An adaptable implementation pack- age targeting evidence-based indicators in primary care: a pragmatic clus- ter-randomised evaluation. PLoS Med. 2020;17:e1003045.

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3. Fox KAA, Lucas JE, Pieper KS, et al. Improved risk stratification of patients with atrial fibrillation: an integrated GARFIELD-AF tool for the prediction of mortality, stroke and bleed in patients with and without anticoagulation. BMJ Open. 2017;7:e017157.

4. Quinn GR, Severdija ON, Chang Y, et al. Wide variation in reported rates of stroke across cohorts of patients with atrial fibrillation. Circulation. 2017;135:208–219.

5. 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 fibrilla- tion: the Euro Heart Survey. Chest. 2010;138:1093–1100.

6. Gage BF, Yan Y, Milligan PE, et al. Clinical classification schemes for pre- dicting hemorrhage: results from the National Registry of Atrial Fibrillation (NRAF). Am Heart J. 2006;151:713–719.

7. Fang MC, Go AS, Chang Y, et al. A new risk scheme to predict warfarin- associated hemorrhage: the ATRIA (Anticoagulation and Risk Factors in Atrial Fibrillation) Study. J Am Coll Cardiol. 2011;58:395–401.

8. Friberg L, Rosenqvist M, Lip GY. Net clinical benefit of warfarin in patients with atrial fibrillation: a report from the Swedish atrial fibrillation cohort study. Circulation. 2012;125:2298–2307.

9. Steinberg BA, Ballew NG, Greiner MA, et al. Ischemic and bleeding out- comes in patients with atrial fibrillation and contraindications to oral antico- agulation. JACC Clin Electrophysiol. 2019;5:1384–1392.

10. Chao TF, Lip GYH, Lin YJ, et al. Incident risk factors and major bleed- ing in patients with atrial fibrillation treated with oral anticoagulants: a comparison of baseline, follow-up and delta HAS-BLED scores with an approach focused on modifiable bleeding risk factors. Thromb Haemost. 2018;118:768–777.

11. Hlatky MA, Greenland P, Arnett DK, et al. Criteria for evaluation of novel markers of cardiovascular risk: a scientific statement from the American Heart Association. Circulation. 2009;119:2408–2416.

12. Alkhouli M, Friedman PA. Ischemic stroke risk in patients with nonval- vular atrial fibrillation: JACC review topic of the week. J Am Coll Cardiol. 2019;74:3050–3065.

13. Takabayashi K, Hamatani Y, Yamashita Y, et al. Incidence of stroke or sys- temic embolism in paroxysmal versus sustained atrial fibrillation: the Fushimi Atrial Fibrillation Registry. Stroke. 2015;46:3354–3361.

14. Steinberg BA, Hellkamp AS, Lokhnygina Y, et al. Higher risk of death and stroke in patients with persistent vs paroxysmal atrial fibrillation: results from the ROCKET-AF Trial. Eur Heart J. 2015;36:288–296.

15. Gao X, Cai X, Yang Y, et al. Diagnostic accuracy of the HAS-BLED bleeding score in VKA- or DOAC-treated patients with atrial fibrillation: a systematic review and meta-analysis. Front Cardiovasc Med. 2021;8:757087.

16. Zhu W, Fu L, Ding Y, et al. Meta-analysis of ATRIA versus CHA(2)DS(2)- VASc for predicting stroke and thromboembolism in patients with atrial fi- brillation. Int J Cardiol. 2017;227:436–442.

17. van den Ham HA, Klungel OH, Singer DE, et al. Comparative performance of ATRIA, CHADS2, and CHA2DS2-VASc risk scores predicting stroke in patients with atrial fibrillation: results from a national primary care database. J Am Coll Cardiol. 2015;66:1851–1859.

18. Dalgaard F, Pieper K, Verheugt F, et al. GARFIELD-AF model for prediction of stroke and major bleeding in atrial fibrillation: a Danish nationwide valida- tion study. BMJ Open. 2019;9:e033283.

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20. Chang G, Xie Q, Ma L, et al. Accuracy of HAS-BLED and other bleeding risk assessment tools in predicting major bleeding events in atrial fibrillation: a network meta-analysis. J Thromb Haemost. 2020;18:791–801.

21. Fauchier L, Chaize G, Gaudin AF, et al. Predictive ability of HAS-BLED, HEMORR2HAGES, and ATRIA bleeding risk scores in patients with atrial fibrillation A French nationwide cross-sectional study. Int J Cardiol. 2016;217:85–91.

22. Shah SJ, Eckman MH, Aspberg S, et al. Effect of variation in published stroke rates on the net clinical benefit of anticoagulation for atrial fibrillation. Ann Intern Med. 2018;169:517–527.

23. Go AS, Reynolds K, Yang J, et al. Association of burden of atrial fibrillation with risk of ischemic stroke in adults with paroxysmal atrial fibrillation: the KP-RHYTHM study. JAMA Cardiol. 2018;3:601–608.

24. Rao MP, Halvorsen S, Wojdyla D, et al. Blood pressure control and risk of stroke or systemic embolism in patients with atrial fibrillation: results from the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial. J Am Heart Assoc. 2015;4:e002015.

25. Gage BF, Waterman AD, Shannon W, et al. Validation of clinical classification schemes for predicting stroke: results from the National Registry of Atrial Fibrillation. JAMA. 2001;285:2864–2870.

26. Chao TF, Lip GY, Liu CJ, et al. Validation of a modified CHA2DS2-VASc score for stroke risk stratification in Asian patients with atrial fibrillation: a nationwide cohort study. Stroke. 2016;47:2462–2469.

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2. Link MS, Giugliano RP, Ruff CT, et al. Stroke and mortality risk in patients with various patterns of atrial fibrillation: results from the ENGAGE AF-TIMI 48 Trial (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48). Circ Arrhythm Electro- physiol. 2017;10:e004267.

3. Steinberg BA, Hellkamp AS, Lokhnygina Y, et al. Higher risk of death and stroke in patients with persistent vs paroxysmal atrial fibrillation: results from the ROCKET-AF Trial. Eur Heart J. 2015;36:288–296.

4. Chao TF, Lip GYH, Lin YJ, et al. Incident risk factors and major bleeding in pa- tients with atrial fibrillation treated with oral anticoagulants: a comparison of baseline, follow-up and delta HAS-BLED scores with an approach focused on modifiable bleeding risk factors. Thromb Haemost. 2018;118:768–777.

5. Minhas AS, Jiang Q, Gu X, et al. Renal function in atrial fibrillation patients switched from warfarin to a direct oral anticoagulant. J Thromb Thrombolysis. 2016;42:566–572.

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2. Granger CB, Alexander JH, McMurray JJ, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365:981–992.

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5. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in non- valvular atrial fibrillation. N Engl J Med. 2011;365:883–891.

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6. Ruff CT, Giugliano RP, Braunwald E, et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrilla- tion: a meta-analysis of randomised trials. Lancet. 2014;383:955–962.

7. Carnicelli AP, Hong H, Connolly SJ, et al. Direct oral anticoagulants versus warfarin in patients with atrial fibrillation: patient-level network meta-anal- yses of randomized clinical trials with interaction testing by age and sex. Circulation. 2022;145:242–255.

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2. 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– 1524.

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7. Khand AU, Rankin AC, Martin W, et al. Carvedilol alone or in combination with digoxin for the management of atrial fibrillation in patients with heart failure? J Am Coll Cardiol. 2003;42:1944–1951.

8. Kotecha D, Bunting KV, Gill SK, et al. Effect of digoxin vs bisoprolol for heart rate control in atrial fibrillation on patient-reported quality of life: the RATE- AF randomized clinical trial. JAMA. 2020;324:2497–2508.

9. Ziff OJ, Lane DA, Samra M, et al. Safety and efficacy of digoxin: systematic review and meta-analysis of observational and controlled trial data. BMJ. 2015;351:h4451.

10. Goldstein RE, Boccuzzi SJ, Cruess D, et al. Diltiazem increases late-onset congestive heart failure in postinfarction patients with early reduction in ejection fraction The Adverse Experience Committee; and the Multicenter Diltiazem Postinfarction Research Group. Circulation. 1991;83:52–60.

11. Multicenter Diltiazem Postinfarction Trial Research Group. The effect of dil- tiazem on mortality and reinfarction after myocardial infarction. N Engl J Med. 1988;319:385–392.

12. Connolly SJ, Camm AJ, Halperin JL, et al. Dronedarone in high-risk perma- nent atrial fibrillation. N Engl J Med. 2011;365:2268–2276.

13. Ulimoen SR, Enger S, Carlson J, et al. Comparison of four single-drug regi- mens on ventricular rate and arrhythmia-related symptoms in patients with permanent atrial fibrillation. Am J Cardiol. 2013;111:225–230.

14. Nikolaidou T, Channer KS. Chronic atrial fibrillation: a systematic review of medical heart rate control management. Postgrad Med J. 2009;85:303– 312.

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16. Hauptman PJ, McCann P, Romero JM, et al. Reference laboratory values for digoxin following publication of Digitalis Investigation Group (DIG) trial data. JAMA Intern Med. 2013;173:1552–1554.

17. Goldberger ZD, Goldberger AL. Therapeutic ranges of serum digoxin con- centrations in patients with heart failure. Am J Cardiol. 2012;109:1818– 1821.

18. Kober L, Torp-Pedersen C, McMurray JJ, et al. Increased mortal- ity after dronedarone therapy for severe heart failure. N Engl J Med. 2008;358:2678–2687.

19. Hohnloser S, Crijns H, van Eickels M, et al. Effect of dronedarone on cardio- vascular events in atrial fibrillation. Rev Port Cardiol. 2009;28:345–347.

20. Davy JM, Herold M, Hoglund C, et al. Dronedarone for the control of ven- tricular rate in permanent atrial fibrillation: the Efficacy and safety of dRone- dArone for the cOntrol of ventricular rate during atrial fibrillation (ERATO) study. Am Heart J. 2008;156:527.e521–527.e529.

7.3. Atrioventricular Nodal Ablation (AVNA) 1. Geelen P, Brugada J, Andries E, et al. Ventricular fibrillation and sudden

death after radiofrequency catheter ablation of the atrioventricular junction. Pacing Clin Electrophysiol. 1997;20:343–348.

2. Wang RX, Lee HC, Hodge DO, et al. Effect of pacing method on risk of sud- den death after atrioventricular node ablation and pacemaker implantation in patients with atrial fibrillation. Heart Rhythm. 2013;10:696–701.

3. Brignole M, Menozzi C, Gianfranchi L, et al. Assessment of atrioventricular junction ablation and VVIR pacemaker versus pharmacological treatment in patients with heart failure and chronic atrial fibrillation: a randomized, con- trolled study. Circulation. 1998;98:953–960.

4. Lim KT, Davis MJ, Powell A, et al. Ablate and pace strategy for atrial fibrilla- tion: long-term outcome of AIRCRAFT trial. Europace. 2007;9:498–505.

5. Wood MA, Brown-Mahoney C, Kay GN, et al. Clinical outcomes after ab- lation and pacing therapy for atrial fibrillation: a meta-analysis. Circulation. 2000;101:1138–1144.

6. Bradley DJ, Shen WK. Atrioventricular junction ablation combined with either right ventricular pacing or cardiac resynchronization therapy for atrial fibrillation: the need for large-scale randomized trials. Heart Rhythm. 2007;4:224–232.

7. Udo EO, Zuithoff NP, van Hemel NM, et al. Incidence and predictors of short- and long-term complications in pacemaker therapy: the FOLLOW- PACE study. Heart Rhythm. 2012;9:728–735.

8. Armaganijan LV, Toff WD, Nielsen JC, et al. Are elderly patients at increased risk of complications following pacemaker implantation? A meta-analysis of randomized trials. Pacing Clin Electrophysiol. 2012;35:131–134.

9. Baudo M, D'Ancona G, Trinca F, et al. Atrioventricular node ablation and pac- ing for atrial tachyarrhythmias: a meta-analysis of postoperative outcomes. Int J Cardiol. 2022;363:80–86.

10. Vijayaraman P, Subzposh FA, Naperkowski A. Atrioventricular node ablation and His bundle pacing. Europace. 2017;19:iv10–iv16.

11. Morina-Vazquez P, Moraleda-Salas MT, Arce-Leon A, et al. Effectiveness and safety of AV node ablation after His bundle pacing in patients with uncontrolled atrial arrhythmias. Pacing Clin Electrophysiol. 2021;44:1004– 1009.

12. Pillai A, Kolominsky J, Koneru JN, et al. Atrioventricular junction ablation in patients with conduction system pacing leads: a comparison of His-bundle

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vs left bundle branch area pacing leads. Heart Rhythm. 2022;19:1116– 1123.

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14. Brignole M, Gianfranchi L, Menozzi C, et al. Atrioventricular junction ablation and pacemaker therapy versus drug treatment in atrial fibrillation. Cardiol Rev. 1998;15:49–53.

15. Gillis AM, Connolly SJ, Lacombe P, et al. Randomized crossover comparison of DDDR versus VDD pacing after atrioventricular junction ablation for pre- vention of atrial fibrillation. Circulation. 2000;102:736–741.

16. D H, Novak P, O S. Survival of dual chamber pacing post atrioventricular nodal ablation in patients with atrial fibrillation. Heart Rhythm. 2009;6:S406– S407.

17. Brignole M, Menozzi C, Gasparini M, et al. An evaluation of the strategy of maintenance of sinus rhythm by antiarrhythmic drug therapy after ablation and pacing therapy in patients with paroxysmal atrial fibrillation. Eur Heart J. 2002;23:892–900.

18. Nowinski K, Gadler F, Jensen-Urstad M, et al. Transient proarrhythmic state following atrioventricular junctional radiofrequency ablation. Pacing Clin Electrophysiol. 2002;25:291–299.

19. Slotwiner DJ, Raitt MH, Del-Carpio Munoz F, et al. Impact of physiologic pacing versus right ventricular pacing among patients with left ventricular ejection fraction greater than 35%: a systematic review for the 2018 ACC/ AHA/HRS guideline on the evaluation and management of patients with bradycardia and cardiac conduction delay: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. Circulation. 2019;140:e483– e503.

20. Olgin JE, Scheinman MM. Comparison of high energy direct current and radiofrequency catheter ablation of the atrioventricular junction. J Am Coll Cardiol. 1993;21:557–564.

21. Kay GN, Ellenbogen KA, Giudici M, et al. The Ablate and Pace Trial: a prospective study of catheter ablation of the AV conduction system and permanent pacemaker implantation for treatment of atrial fibrillation APT Investigators. J Interv Card Electrophysiol. 1998;2:121–135.

22. Weerasooriya R, Davis M, Powell A, et al. The Australian Intervention Ran- domized Control of Rate in Atrial Fibrillation Trial (AIRCRAFT). J Am Coll Cardiol. 2003;41:1697–1702.

23. Redfield MM, Kay GN, Jenkins LS, et al. Tachycardia-related cardiomyopa- thy: a common cause of ventricular dysfunction in patients with atrial fibrilla- tion referred for atrioventricular ablation. Mayo Clin Proc. 2000;75:790–795.

24. Vijayaraman P, Hashimova N, Mathew AJ, et al. Simultaneous conduction system pacing and atrioventricular node ablation via axillary vs femoral ac- cess. Heart Rhythm. 2022;19:1019–1021.

25. Bongiorni MG, Proclemer A, Dobreanu D, et al. Preferred tools and tech- niques for implantation of cardiac electronic devices in Europe: results of the European Heart Rhythm Association survey. Europace. 2013;15:1664– 1668.

26. Vernooy K, Dijkman B, Cheriex EC, et al. Ventricular remodeling during long- term right ventricular pacing following His bundle ablation. Am J Cardiol. 2006;97:1223–1227.

27. Doshi RN, Daoud EG, Fellows C, et al. Left ventricular-based cardiac stimu- lation post AV nodal ablation evaluation (the PAVE study). J Cardiovasc Elec- trophysiol. 2005;16:1160–1165.

28. Chen L, Hodge D, Jahangir A, et al. Preserved left ventricular ejection frac- tion following atrioventricular junction ablation and pacing for atrial fibrilla- tion. J Cardiovasc Electrophysiol. 2008;19:19–27.

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2. Hsu LF, Jais P, Sanders P, et al. Catheter ablation for atrial fibrillation in congestive heart failure. N Engl J Med. 2004;351:2373–2383.

3. Prabhu S, Costello BT, Taylor AJ, et al. Regression of diffuse ventricular fibrosis following restoration of sinus rhythm with catheter ablation in pa- tients with atrial fibrillation and systolic dysfunction: a substudy of the CAM- ERA MRI trial. JACC Clin Electrophysiol. 2018;4:999–1007.

4. Stronati G, Guerra F, Urbinati A, et al. Tachycardiomyopathy in patients with- out underlying structural heart disease. J Clin Med. 2019;8:1411.

5. Jeong YH, Choi KJ, Song JM, et al. Diagnostic approach and treatment strategy in tachycardia-induced cardiomyopathy. Clin Cardiol. 2008;31:172– 178.

6. Marcusohn E, Postnikov M, Kobo O, et al. Factors associated with left ven- tricular function recovery in patients with atrial fibrillation related cardiomy- opathy. Isr Med Assoc J. 2022;24:101–106.

7. Cooper HA, Bloomfield DA, Bush DE, et al. Relation between achieved heart rate and outcomes in patients with atrial fibrillation (from the Atrial Fibrilla- tion Follow-up Investigation of Rhythm Management [AFFIRM] Study). Am J Cardiol. 2004;93:1247–1253.

8. Miura K, Ikemura N, Kimura T, et al. Treatment strategies and subsequent changes in the patient-reported quality-of-life among elderly patients with atrial fibrillation. Am Heart J. 2020;222:83–92.

9. Kosior DA, Szulc M, Rosiak M, et al. Functional status with rhythm- versus rate-control strategy for persistent atrial fibrillation. Pol Arch Intern Med. 2018;128:658–666.

10. Van Gelder IC, Groenveld HF, Crijns HJ, et al. Lenient versus strict rate control in patients with atrial fibrillation. N Engl J Med. 2010;362:1363– 1373.

11. Andrade JG, Wells GA, Deyell MW, et al. Cryoablation or drug therapy for initial treatment of atrial fibrillation. N Engl J Med. 2021;384:305– 315.

12. Kirchhof P, Camm AJ, Goette A, et al. Early rhythm-control therapy in pa- tients with atrial fibrillation. N Engl J Med. 2020;383:1305–1316.

13. Kim D, Yang PS, You SC, et al. Treatment timing and the effects of rhythm control strategy in patients with atrial fibrillation: nationwide cohort study. BMJ. 2021;373:n991.

14. Dickow J, Kirchhof P, Van Houten HK, et al. Generalizability of the EAST- AFNET 4 Trial: assessing outcomes of early rhythm-control therapy in pa- tients with atrial fibrillation. J Am Heart Assoc. 2022;11:1–11.

15. Roy D, Talajic M, Nattel S, et al. Rhythm control versus rate control for atrial fibrillation and heart failure. N Engl J Med. 2008;358:2667–2677.

16. Rillig A, Magnussen C, Ozga AK, et al. Early rhythm control therapy in pa- tients with atrial fibrillation and heart failure. Circulation. 2021;144:845– 858.

17. Marrouche NF, Brachmann J, Andresen D, et al. Catheter ablation for atrial fibrillation with heart failure. N Engl J Med. 2018;378:417–427.

18. Di Biase L, Mohanty P, Mohanty S, et al. Ablation versus amiodarone for treatment of persistent atrial fibrillation in patients with congestive heart failure and an implanted device: results from the AATAC multicenter ran- domized trial. Circulation. 2016;133:1637–1644.

19. Packer DL, Piccini JP, Monahan KH, et al. Ablation versus drug therapy for atrial fibrillation in heart failure: results from the CABANA trial. Circulation. 2021;143:1377–1390.

20. Veasey RA, Sugihara C, Sandhu K, et al. The natural history of atrial fibrilla- tion in patients with permanent pacemakers: is atrial fibrillation a progres- sive disease? J Interv Card Electrophysiol. 2015;44:23–30.

21. Holmqvist F, Kim S, Steinberg BA, et al. Heart rate is associated with pro- gression of atrial fibrillation, independent of rhythm. Heart. 2015;101:894– 899.

22. Zhang YY, Qiu C, Davis PJ, et al. Predictors of progression of recently diag- nosed atrial fibrillation in REgistry on Cardiac Rhythm DisORDers Assess- ing the Control of Atrial Fibrillation (RecordAF)-United States cohort. Am J Cardiol. 2013;112:79–84.

23. De Vos CB, Breithardt G, Camm AJ, et al. Progression of atrial fibrillation in the REgistry on Cardiac rhythm disORDers assessing the control of Atrial Fibrillation cohort: clinical correlates and the effect of rhythm-control thera- py. Am Heart J. 2012;163:887–893.

24. Blum S, Aeschbacher S, Meyre P, et al. Incidence and predictors of atrial fibrillation progression. J Am Heart Assoc. 2019;8:e012554.

25. Pathak RK, Middeldorp ME, Meredith M, et al. Long-term effect of goal- directed weight management in an atrial fibrillation cohort: a long-term follow-up study (LEGACY). J Am Coll Cardiol. 2015;65:2159–2169.

26. Koldenhof T, Wijtvliet PEPJ, Pluymaekers NAHA, et al. Rate control drugs differ in the prevention of progression of atrial fibrillation. EP: Europace. 2022;24:384–389.

27. Yang WY, Du X, Fawzy AM, et al. Associations of atrial fibrillation progression with clinical risk factors and clinical prognosis: a report from the Chinese Atrial Fibrillation Registry study. J Cardiovasc Electrophysiol. 2021;32:333– 341.

28. Kalman JM, Sanders P, Rosso R, et al. Should we perform catheter ablation for asymptomatic atrial fibrillation? Circulation. 2017;136:490–499.

29. Sgreccia D, Manicardi M, Malavasi VL, et al. Comparing outcomes in asymp- tomatic and symptomatic atrial fibrillation: a systematic review and meta- analysis of 81 462 patients. J Clin Med. 2021;10:3979.

30. Willems S, Borof K, Brandes A, et al. Systematic, early rhythm control strat- egy for atrial fibrillation in patients with or without symptoms: the EAST- AFNET 4 trial. Eur Heart J. 2022;43:1219–1230.

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32. Hermans ANL, Pluymaekers N, Lankveld TAR, et al. Clinical utility of rhythm control by electrical cardioversion to assess the association between self- reported symptoms and rhythm status in patients with persistent atrial fibril- lation. Int J Cardiol Heart Vasc. 2021;36:100870.

33. Senoo K, Suzuki S, Otsuka T, et al. Progression to the persistent form in asymptomatic paroxysmal atrial fibrillation. Circ J. 2014;78:1121–1126.

34. Disertori M, Lombardi F, Barlera S, et al. Clinical characteristics of patients with asymptomatic recurrences of atrial fibrillation in the Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico-Atrial Fibrillation (GISSI-AF) trial. Am Heart J. 2011;162:382–389.

35. Bodagh N, Yap R, Kotadia I, et al. Impact of catheter ablation versus medical therapy on cognitive function in atrial fibrillation: a systematic review. J Interv Card Electrophysiol. 2022;65:271–296.

36. Kim D, Yang PS, You SC, et al. Association of rhythm control with incident dementia among patients with atrial fibrillation: a nationwide population- based cohort study. Age Ageing. 2022;51:1–9.

37. Bunch TJ, Crandall BG, Weiss JP, et al. Patients treated with catheter abla- tion for atrial fibrillation have long-term rates of death, stroke, and demen- tia similar to patients without atrial fibrillation. J Cardiovasc Electrophysiol. 2011;22:839–845.

38. Slee A, Saksena S. Impact of initial heart failure emergence on clinical outcomes of atrial fibrillation patients in the AFFIRM trial. Am Heart J. 2020;220:1–11.

39. Gertz ZM, Raina A, Saghy L, et al. Evidence of atrial functional mitral regur- gitation due to atrial fibrillation: reversal with arrhythmia control. J Am Coll Cardiol. 2011;58:1474–1481.

40. Reddy ST, Belden W, Doyle M, et al. Mitral regurgitation recovery and atrial reverse remodeling following pulmonary vein isolation procedure in patients with atrial fibrillation: a clinical observation proof-of-concept cardiac MRI study. J Interv Card Electrophysiol. 2013;37:307–315.

41. Abe Y, Takahashi Y, Shibata T. Looking into the mechanistic link between mitral regurgitation and atrial fibrillation. Cardiol Clin. 2021;39:281–288.

42. Soulat-Dufour L, Lang S, Addetia K, et al. Restoring sinus rhythm reverses cardiac remodeling and reduces valvular regurgitation in patients with atrial fibrillation. J Am Coll Cardiol. 2022;79:951–961.

43. Markman TM, Plappert T, De Feria Alsina A, et al. Improvement in tricuspid regurgitation following catheter ablation of atrial fibrillation. J Cardiovasc Electrophysiol. 2020;31:2883–2888.

44. Pype L, Embrechts L, Cornez B, et al. Long-term effect of atrial fibrilla- tion on the evolution of mitral and tricuspid valve regurgitation. Acta Cardiol. 2020;75:639–647.

45. Wang J, Han J, Li Y, et al. Impact of Surgical ablation of atrial fibrillation on the progression of tricuspid regurgitation and right-sided heart remodeling after mitral-valve surgery: a propensity-score matching analysis. J Am Heart Assoc. 2016;5:e004213.

46. Lin PL, Huang CC, Wu YJ, et al. Relations between baseline burden, maximum duration, and relative reduction of atrial fibrillation: insights from continuous monitoring in rhythm control. J Cardiovasc Electrophysiol. 2019;30:178–182.

47. Chew DS, Jones KA, Loring Z, et al. Diagnosis-to-ablation time predicts recurrent atrial fibrillation and rehospitalization following catheter ablation. Heart Rhythm O2. 2022;3:23–31.

48. Chung MK, Eckhardt LL, Chen LY, et al. Lifestyle and risk factor modification for reduction of atrial fibrillation: a scientific statement from the American Heart Association. Circulation. 2020;141:e750–e772.

49. Gopinathannair R, Chen LY, Chung MK, et al. Managing atrial fibrillation in patients with heart failure and reduced ejection fraction: a scientific state- ment from the American Heart Association. Circ Arrhythm Electrophysiol. 2021;14:e000078.

50. Hagens VE, Ranchor AV, Van Sonderen E, et al. Effect of rate or rhythm control on quality of life in persistent atrial fibrillation. Results from the Rate Control Versus Electrical Cardioversion (RACE) Study. J Am Coll Cardiol. 2004;43:241–247.

51. Ha AC, Breithardt G, Camm AJ, et al. Health-related quality of life in patients with atrial fibrillation treated with rhythm control versus rate control: insights from a prospective international registry (Registry on Cardiac Rhythm Dis- orders Assessing the Control of Atrial Fibrillation: RECORD-AF). Circ Car- diovasc Qual Outcomes. 2014;7:896–904.

52. Govindapillai A, Cox JL, Thabane L, et al. Rhythm control vs rate control in a contemporary ambulatory atrial fibrillation cohort: post hoc analysis of the IMPACT-AF trial. CJC Open. 2022;4:551–557.

53. Wu L, Lu Y, Zheng L, et al. Comparison of radiofrequency catheter ablation between asymptomatic and symptomatic persistent atrial fibrillation: a pro- pensity score matched analysis. J Cardiovasc Electrophysiol. 2016;27:531– 535.

54. Mohanty S, Santangeli P, Mohanty P, et al. Catheter ablation of asymptom- atic longstanding persistent atrial fibrillation: impact on quality of life, ex- ercise performance, arrhythmia perception, and arrhythmia-free survival. J Cardiovasc Electrophysiol. 2014;25:1057–1064.

55. Suman-Horduna I, Roy D, Frasure-Smith N, et al. Quality of life and func- tional capacity in patients with atrial fibrillation and congestive heart failure. J Am Coll Cardiol. 2013;61:455–460.

56. Hsu LF, Jaïs P, Sanders P, et al. Catheter ablation for atrial fibrillation in congestive heart failure. N Engl J Med. 2004;351:2373–2383.

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2. Hernandez-Madrid A, Svendsen JH, Lip GY, et al. Cardioversion for atrial fibrillation in current European practice: results of the European Heart Rhythm Association survey. Europace. 2013;15:915–918.

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4. Stiell IG, Clement CM, Brison RJ, et al. Variation in management of recent- onset atrial fibrillation and flutter among academic hospital emergency de- partments. Ann Emerg Med. 2011;57:13–21.

5. Dankner R, Shahar A, Novikov I, et al. Treatment of stable atrial fibrillation in the emergency department: a population-based comparison of electrical direct-current versus pharmacological cardioversion or conservative man- agement. Cardiology. 2009;112:270–278.

6. Brandes A, Crijns H, Rienstra M, et al. Cardioversion of atrial fibrillation and atrial flutter revisited: current evidence and practical guidance for a common procedure. Europace. 2020;22:1149–1161.

7. Lip GY, Gitt AK, Le Heuzey JY, et al. Overtreatment and undertreatment with anticoagulation in relation to cardioversion of atrial fibrillation (the RHYTHM-AF study). Am J Cardiol. 2014;113:480–484.

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4. Manning WJ, Leeman DE, Gotch PJ, et al. Pulsed Doppler evaluation of atrial mechanical function after electrical cardioversion of atrial fibrillation. J Am Coll Cardiol. 1989;13:617–623.

5. Manning WJ, Silverman DI, Katz SE, et al. Impaired left atrial mechanical function after cardioversion: relation to the duration of atrial fibrillation. J Am Coll Cardiol. 1994;23:1535–1540.

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11. Alkhouli M, Du C, Killu A, et al. Clinical impact of residual leaks following left atrial appendage occlusion: insights from the NCDR LAAO registry. JACC Clin Electrophysiol. 2022;8:766–778.

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16. Alkhouli M, Busu T, Shah K, et al. Incidence and clinical impact of device- related thrombus following percutaneous left atrial appendage occlusion: a meta-analysis. JACC: Clinical Electrophysiology. 2018;4:1629–1637.

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54. Chew DS, Loring Z, Anand J, et al. Economic evaluation of catheter ablation of atrial fibrillation in patients with heart failure with reduced ejection frac- tion. Circ Cardiovasc Qual Outcomes. 2020;13:E007094.

55. Lau D, Sandhu RK, Andrade JG, et al. Cost-utility of catheter ablation for atrial fibrillation in patients with heart failure: an economic evaluation. J Am Heart Assoc. 2021;10:e019599.

56. Wong JA, Conen D, Van Gelder IC, et al. Progression of device-detected subclinical atrial fibrillation and the risk of heart failure. J Am Coll Cardiol. 2018;71:2603–2611.

57. Navarrete A, Conte F, Moran M, et al. Ablation of atrial fibrillation at the time of cavotricuspid isthmus ablation in patients with atrial flutter without documented atrial fibrillation derives a better long-term benefit. J Cardiovasc Electrophysiol. 2011;22:34–38.

58. Kim JY, Park HS, Park HW, et al. Clinical outcomes of rhythm control strate- gies for asymptomatic atrial fibrillation according to the quality-of-life score: the CODE-AF (Comparison Study of Drugs for Symptom Control and Complication Prevention of Atrial Fibrillation) registry. J Am Heart Assoc. 2022;11:e025956.

59. Willems S, Borof K, Brandes A, et al. Systematic, early rhythm control strat- egy for atrial fibrillation in patients with or without symptoms: the EAST- AFNET 4 trial. Eur Heart J. 2022;43:1219–1230.

8.4.1. Patient Selection 1. Packer DL, Mark DB, Robb RA, et al. Effect of catheter ablation vs anti-

arrhythmic drug therapy on mortality, stroke, bleeding, and cardiac arrest among patients with atrial fibrillation: the CABANA randomized clinical trial. JAMA. 2019;321:1261–1274.

2. Andrade JG, Turgeon RD, Macle L, et al. Cryoablation or drug therapy for initial treatment of atrial fibrillation. Eur Cardiol. 2022;17:e10.

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3. Calkins H, Reynolds MR, Spector P, et al. Treatment of atrial fibrillation with antiarrhythmic drugs or radiofrequency ablation: two systematic literature reviews and meta-analyses. Circ Arrhythm Electrophysiol. 2009;2:349–361.

4. Blomstrom-Lundqvist C, Gizurarson S, Schwieler J, et al. Effect of catheter ablation vs antiarrhythmic medication on quality of life in patients with atrial fibrillation: the CAPTAF randomized clinical trial. JAMA. 2019;321:1059– 1068.

5. Kirchhof P, Camm AJ, Goette A, et al. Early rhythm-control therapy in pa- tients with atrial fibrillation. N Engl J Med. 2020;383:1305–1316.

6. Njoku A, Kannabhiran M, Arora R, et al. Left atrial volume predicts atrial fibrillation recurrence after radiofrequency ablation: a meta-analysis. Euro- pace. 2018;20:33–42.

7. McLellan AJ, Ling LH, Azzopardi S, et al. Diffuse ventricular fibrosis mea- sured by T(1) mapping on cardiac MRI predicts success of catheter ablation for atrial fibrillation. Circ Arrhythm Electrophysiol. 2014;7:834–840.

8. Marrouche NF, Wilber D, Hindricks G, et al. Association of atrial tissue fibro- sis identified by delayed enhancement MRI and atrial fibrillation catheter ablation: the DECAAF study. JAMA. 2014;311:498–506.

9. Chew DS, Jones KA, Loring Z, et al. Diagnosis-to-ablation time predicts recurrent atrial fibrillation and rehospitalization following catheter ablation. Heart Rhythm O2. 2022;3:23–31.

10. Chew DS, Black-Maier E, Loring Z, et al. Diagnosis-to-ablation time and re- currence of atrial fibrillation following catheter ablation: a systematic review and meta-analysis of observational studies. Circ Arrhythm Electrophysiol. 2020;13:e008128.

11. Black-Maier E, Parish A, Steinberg BA, et al. Predicting atrial fibrilla- tion recurrence after ablation in patients with heart failure: validity of the APPLE and CAAP-AF risk scoring systems. Pacing Clin Electrophysiol. 2019;42:1440–1447.

12. Di Biase L, Mohanty P, Mohanty S, et al. Ablation versus amiodarone for treatment of persistent atrial fibrillation in patients with congestive heart failure and an implanted device: results from the AATAC multicenter ran- domized trial. Circulation. 2016;133:1637–1644.

13. Marrouche NF, Brachmann J, Andresen D, et al. Catheter ablation for atrial fibrillation with heart failure. N Engl J Med. 2018;378:417–427.

14. Turagam MK, Garg J, Whang W, et al. Catheter ablation of atrial fibrillation in patients with heart failure: a meta-analysis of randomized controlled trials. Ann Intern Med. 2019;170:41–50.

8.4.2. Techniques and Technologies for AF Catheter Abla- tion 1. Atienza F, Almendral J, Ormaetxe JM, et al. Comparison of radiofrequency

catheter ablation of drivers and circumferential pulmonary vein isolation in atrial fibrillation: a noninferiority randomized multicenter RADAR-AF trial. J Am Coll Cardiol. 2014;64:2455–2467.

2. Chen M, Yang B, Chen H, et al. Randomized comparison between pulmonary vein antral isolation versus complex fractionated electrogram ablation for paroxysmal atrial fibrillation. J Cardiovasc Electrophysiol. 2011;22:973–981.

3. Di Biase L, Elayi CS, Fahmy TS, et al. Atrial fibrillation ablation strategies for paroxysmal patients: randomized comparison between different techniques. Circ Arrhythm Electrophysiol. 2009;2:113–119.

4. Katritsis DG, Pokushalov E, Romanov A, et al. Autonomic denervation added to pulmonary vein isolation for paroxysmal atrial fibrillation: a randomized clinical trial. J Am Coll Cardiol. 2013;62:2318–2325.

5. Mamchur SE, Mamchur IN, Khomenko EA, et al. 'Electrical exclusion' of a critical myocardial mass by extended pulmonary vein antrum isolation for persistent atrial fibrillation treatment. Interv Med Appl Sci. 2014;6:31–39.

6. Verma A, Mantovan R, Macle L, et al. Substrate and Trigger Ablation for Reduction of Atrial Fibrillation (STAR AF): a randomized, multicentre, inter- national trial. Eur Heart J. 2010;31:1344–1356.

7. Sau A, Howard JP, Al-Aidarous S, et al. Meta-analysis of randomized con- trolled trials of atrial fibrillation ablation with pulmonary vein isolation versus without. JACC Clin Electrophysiol. 2019;5:968–976.

8. Marrouche NF, Wazni O, McGann C, et al. Effect of MRI-guided fibrosis ablation vs conventional catheter ablation on atrial arrhythmia recurrence in patients with persistent atrial fibrillation: the DECAAF II randomized clinical trial. JAMA. 2022;327:2296–2305.

9. Gianni C, Mohanty S, Di Biase L, et al. Acute and early outcomes of focal impulse and rotor modulation (FIRM)-guided rotors-only ablation in pa- tients with nonparoxysmal atrial fibrillation. Heart Rhythm. 2016;13:830– 835.

10. Narayan SM, Baykaner T, Clopton P, et al. Ablation of rotor and focal sources reduces late recurrence of atrial fibrillation compared with trigger ablation alone: extended follow-up of the CONFIRM trial (Conventional Ablation for

Atrial Fibrillation With or Without Focal Impulse and Rotor Modulation). J Am Coll Cardiol. 2014;63:1761–1768.

11. Tilz RR, Lenz C, Sommer P, et al. Focal impulse and rotor modulation abla- tion vs pulmonary vein isolation for the treatment of paroxysmal atrial fibril- lation: results from the FIRMAP AF study. Europace. 2021;23:722–730.

12. Sandler B, Kim MY, Sikkel MB, et al. Targeting the ectopy-triggering gangli- onated plexuses without pulmonary vein isolation prevents atrial fibrillation. J Cardiovasc Electrophysiol. 2021;32:235–244.

13. Kircher S, Arya A, Altmann D, et al. Individually tailored vs standardized sub- strate modification during radiofrequency catheter ablation for atrial fibrilla- tion: a randomized study. EP: Europace. 2018;20:1766–1775.

14. Lee KN, Roh SY, Baek YS, et al. Long-term clinical comparison of proce- dural end points after pulmonary vein isolation in paroxysmal atrial fibrilla- tion: elimination of nonpulmonary vein triggers versus noninducibility. Circ Arrhythm Electrophysiol. 2018;11:e005019.

15. Di Biase L, Burkhardt JD, Mohanty P, et al. Left atrial appendage: an under- recognized trigger site of atrial fibrillation. Circulation. 2010;122:109–118.

16. Calkins H, Hindricks G, Cappato R, et al. 2017 HRS/EHRA/ECAS/ APHRS/SOLAECE expert consensus statement on catheter and surgical ablation of atrial fibrillation. Heart Rhythm. 2017;14:e275–e444.

17. Kuo L, Frankel DS, Lin A, et al. PRECAF randomized controlled trial. Circ Arrhythm Electrophysiol. 2021;14:e008993.

18. Wang XH, Liu X, Sun YM, et al. Pulmonary vein isolation combined with superior vena cava isolation for atrial fibrillation ablation: a prospective ran- domized study. Europace. 2008;10:600–605.

19. Darma A, Daneschnejad SS, Gaspar T, et al. Role of inducibility and its dynamic change in the outcome of catheter ablation of atrial fibrillation: a single center prospective study. J Cardiovasc Electrophysiol. 2020;31:705– 711.

20. Fiala M, Bulkova V, Sknouril L, et al. Sinus rhythm restoration and arrhythmia noninducibility are major predictors of arrhythmia-free outcome after abla- tion for long-standing persistent atrial fibrillation: a prospective study. Heart Rhythm. 2015;12:687–698.

21. Santangeli P, Zado ES, Garcia FC, et al. Lack of prognostic value of atrial ar- rhythmia inducibility and change in inducibility status after catheter ablation of atrial fibrillation. Heart Rhythm. 2018;15:660–665.

22. Richter B, Gwechenberger M, Filzmoser P, et al. Is inducibility of atrial fibril- lation after radio frequency ablation really a relevant prognostic factor? Eur Heart J. 2006;27:2553–2559.

23. Tohoku S, Fukunaga M, Nagashima M, et al. Clinical impact of eliminating nonpulmonary vein triggers of atrial fibrillation and nonpulmonary vein pre- mature atrial contractions at initial ablation for persistent atrial fibrillation. J Cardiovasc Electrophysiol. 2021;32:224–234.

24. Jiang R, Chen M, Fan J, et al. Efficacy of ablation index-guided pulmonary vein isolation in patients with paroxysmal atrial fibrillation. Pacing Clin Elec- trophysiol. 2022;45:1186–1193.

25. Kawai S, Mukai Y, Inoue S, et al. Predictive value of the induction test with atrial burst pacing with regard to long-term recurrence after ablation in per- sistent atrial fibrillation. J Arrhythm. 2019;35:223–229.

26. Zeng LJ, Shi L, Tian Y, et al. Pace capture and adenosine triphosphate provocation are complementary rather than mutually exclusive methods to ensure durable pulmonary vein isolation. J Cardiovasc Electrophysiol. 2019;30:815–823.

27. Choi Y, Kim SH, Kim JY, et al. Utility of acute arrhythmia termination as an ablation endpoint for induced atrial tachyarrhythmia after complete pulmo- nary vein isolation during catheter ablation for persistent atrial fibrillation. J Interv Card Electrophysiol. 2019;54:25–34.

28. McLellan AJA, Prabhu S, Voskoboinik A, et al. Isolation of the posterior left atrium for patients with persistent atrial fibrillation: routine adenosine chal- lenge for dormant posterior left atrial conduction improves long-term out- come. Europace. 2017;19:1958–1966.

29. Page RL, Joglar JA, Caldwell MA, et al. 2015 ACC/AHA/HRS guideline for the management of adult patients with supraventricular tachycardia: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. Circulation. 2016;133:e506–e574.

30. Di Biase L, Mohanty S, Trivedi C, et al. Stroke risk in patients with atrial fibril- lation undergoing electrical isolation of the left atrial appendage. J Am Coll Cardiol. 2019;74:1019–1028.

31. Park JW, Yu HT, Kim TH, et al. Atrial fibrillation catheter ablation increases the left atrial pressure. Circ Arrhythm Electrophysiol. 2019;12:e007073.

32. Gibson DN, Di Biase L, Mohanty P, et al. Stiff left atrial syndrome after catheter ablation for atrial fibrillation: clinical characterization, prevalence, and predictors. Heart Rhythm. 2011;8:1364–1371.

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33. Kim YG, Shim J, Kim DH, et al. Characteristics of atrial fibrillation patients suffering atrioesophageal fistula after radiofrequency catheter ablation. J Cardiovasc Electrophysiol. 2018;29:1343–1351.

34. Muller P, Dietrich JW, Halbfass P, et al. Higher incidence of esophageal lesions after ablation of atrial fibrillation related to the use of esophageal temperature probes. Heart Rhythm. 2015;12:1464–1469.

35. Mohanty S, Trivedi C, Della Rocca DG, et al. Thromboembolic risk in atrial fi- brillation patients with left atrial scar post-extensive ablation: a single-center experience. JACC Clin Electrophysiol. 2021;7:308–318.

8.4.3. Management of Recurrent AF After Catheter Ablation 1. Packer DL, Mark DB, Robb RA, et al. Effect of catheter ablation vs anti-

arrhythmic drug therapy on mortality, stroke, bleeding, and cardiac arrest among patients with atrial fibrillation: the CABANA randomized clinical trial. JAMA. 2019;321:1261–1274.

2. Kuck KH, Fürnkranz A, Chun KR, et al. Cryoballoon or radiofrequency abla- tion for symptomatic paroxysmal atrial fibrillation: reintervention, rehospital- ization, and quality-of-life outcomes in the FIRE AND ICE trial. Eur Heart J. 2016;37:2858–2865.

3. Piccini JP, Sinner MF, Greiner MA, et al. Outcomes of Medicare ben- eficiaries undergoing catheter ablation for atrial fibrillation. Circulation. 2012;126:2200–2207.

4. Wokhlu A, Monahan KH, Hodge DO, et al. Long-term quality of life after ablation of atrial fibrillation the impact of recurrence, symptom relief, and placebo effect. J Am Coll Cardiol. 2010;55:2308–2316.

5. Calkins H, Reynolds MR, Spector P, et al. Treatment of atrial fibrillation with antiarrhythmic drugs or radiofrequency ablation: two systematic literature reviews and meta-analyses. Circ Arrhythm Electrophysiol. 2009;2:349–361.

6. Ganesan AN, Shipp NJ, Brooks AG, et al. Long-term outcomes of catheter ablation of atrial fibrillation: a systematic review and meta-analysis. J Am Heart Assoc. 2013;2:e004549.

7. Bhargava M, Di Biase L, Mohanty P, et al. Impact of type of atrial fibrillation and repeat catheter ablation on long-term freedom from atrial fibrillation: results from a multicenter study. Heart Rhythm. 2009;6:1403–1412.

8. Reddy YNV, El Sabbagh A, Packer D, et al. Evaluation of shortness of breath after atrial fibrillation ablation-is there a stiff left atrium? Heart Rhythm. 2018;15:930–935.

9. Szegedi N, Szeplaki G, Herczeg S, et al. Repeat procedure is a new inde- pendent predictor of complications of atrial fibrillation ablation. Europace. 2019;21:732–737.

10. Blomstrom-Lundqvist C, Gizurarson S, Schwieler J, et al. Effect of Catheter abla- tion vs antiarrhythmic medication on quality of life in patients with atrial fibrilla- tion: the CAPTAF randomized clinical trial. JAMA. 2019;321:1059–1068.

11. Packer DL, Kowal RC, Wheelan KR, et al. Cryoballoon ablation of pulmonary veins for paroxysmal atrial fibrillation: first results of the North American Arctic Front (STOP AF) pivotal trial. J Am Coll Cardiol. 2013;61:1713–1723.

12. Pokushalov E, Romanov A, Artyomenko S, et al. Cryoballoon versus radio- frequency for pulmonary vein re-isolation after a failed initial ablation proce- dure in patients with paroxysmal atrial fibrillation. J Cardiovasc Electrophysiol. 2013;24:274–279.

13. Kim D, Yu HT, Kim TH, et al. Electrical posterior box isolation in repeat abla- tion for atrial fibrillation: a prospective randomized clinical study. JACC Clin Electrophysiol. 2022;8:582–592.

14. Vamos M, Calkins H, Kowey PR, et al. Efficacy and safety of dronedarone in patients with a prior ablation for atrial fibrillation/flutter: insights from the ATHENA study. Clin Cardiol. 2020;43:291–297.

15. Duytschaever M, Demolder A, Phlips T, et al. PulmOnary vein isolation With vs without continued antiarrhythmic Drug trEatment in subjects with Recur- rent Atrial Fibrillation (POWDER AF): results from a multicentre randomized trial. Eur Heart J. 2018;39:1429–1437.

16. Leong-Sit P, Roux JF, Zado E, et al. Antiarrhythmics after ablation of atrial fi- brillation (5A Study): six-month follow-up study. Circ Arrhythm Electrophysiol. 2011;4:11–14.

17. Schoene K, Sepehri Shamloo A, Sommer P, et al. Natural course of acquired pulmonary vein stenosis after radiofrequency ablation for atrial fibrillation- is routine follow-up imaging indicated or not? J Cardiovasc Electrophysiol. 2019;30:1786–1791.

18. Jais P, Cauchemez B, Macle L, et al. Catheter ablation versus antiarrhythmic drugs for atrial fibrillation: the A4 study. Circulation. 2008;118:2498–2505.

19. Pokushalov E, Romanov A, De Melis M, et al. Progression of atrial fibrilla- tion after a failed initial ablation procedure in patients with paroxysmal atrial fibrillation: a randomized comparison of drug therapy versus reablation. Circ Arrhythm Electrophysiol. 2013;6:754–760.

20. Roux JF, Zado E, Callans DJ, et al. Antiarrhythmics after ablation of atrial fibrillation (5A study). Circulation. 2009;120:1036–1040.

21. Kaitani K, Inoue K, Kobori A, et al. Efficacy of antiarrhythmic drugs short- term use after catheter ablation for atrial fibrillation (EAST-AF) trial. Eur Heart J. 2016;37:610–618.

22. Chen W, Liu H, Ling Z, et al. Efficacy of short-term antiarrhythmic drugs use after catheter ablation of atrial fibrillation-a systematic review with meta- analyses and trial sequential analyses of randomized controlled trials. PLoS One. 2016;11:e0156121.

23. Xu B, Peng F, Tang W, et al. Short-term antiarrhythmic drugs after catheter ablation for atrial fibrillation: a meta-analysis of randomized controlled trials. Ann Pharmacother. 2016;50:697–705.

24. Noseworthy PA, Van Houten HK, Sangaralingham LR, et al. Effect of an- tiarrhythmic drug initiation on readmission after catheter ablation for atrial fibrillation. JACC Clin Electrophysiol. 2015;1:238–244.

8.4.4. Anticoagulation Therapy Before and After Catheter Ablation 1. Di Biase L, Gaita F, Toso E, et al. Does periprocedural anticoagulation man-

agement of atrial fibrillation affect the prevalence of silent thromboembolic lesion detected by diffusion cerebral magnetic resonance imaging in pa- tients undergoing radiofrequency atrial fibrillation ablation with open irrigat- ed catheters? Results from a prospective multicenter study. Heart Rhythm. 2014;11:791–798.

2. Cardoso R, Knijnik L, Bhonsale A, et al. An updated meta-analysis of novel oral anticoagulants versus vitamin K antagonists for uninterrupted antico- agulation in atrial fibrillation catheter ablation. Heart Rhythm. 2018;15:107– 115.

3. Kirchhof P, Haeusler KG, Blank B, et al. Apixaban in patients at risk of stroke undergoing atrial fibrillation ablation. Eur Heart J. 2018;39:2942–2955.

4. Kuwahara T, Abe M, Yamaki M, et al. Apixaban versus warfarin for the pre- vention of periprocedural cerebral thromboembolism in atrial fibrillation ablation: multicenter prospective randomized study. J Cardiovasc Electro- physiol. 2016;27:549–554.

5. Calkins H, Willems S, Gerstenfeld EP, et al. Uninterrupted dabigatran versus warfarin for ablation in atrial fibrillation. N Engl J Med. 2017;376:1627– 1636.

6. Hohnloser SH, Camm J, Cappato R, et al. Uninterrupted edoxaban vs vita- min K antagonists for ablation of atrial fibrillation: the ELIMINATE-AF trial. Eur Heart J. 2019;40:3013–3021.

7. Cappato R, Marchlinski FE, Hohnloser SH, et al. Uninterrupted rivaroxaban vs uninterrupted vitamin K antagonists for catheter ablation in non-valvular atrial fibrillation. Eur Heart J. 2015;36:1805–1811.

8. Reynolds MR, Allison JS, Natale A, et al. A prospective randomized trial of apixaban dosing during atrial fibrillation ablation: the AEIOU trial. JACC Clin Electrophysiol. 2018;4:580–588.

9. Nogami A, Harada T, Sekiguchi Y, et al. Safety and efficacy of minimally interrupted dabigatran vs uninterrupted warfarin therapy in adults undergo- ing atrial fibrillation catheter ablation: a randomized clinical trial. JAMA Netw Open. 2019;2:e191994.

10. van Vugt SPG, Westra SW, Volleberg R, et al. Meta-analysis of controlled studies on minimally interrupted vs continuous use of non-vitamin K antago- nist oral anticoagulants in catheter ablation for atrial fibrillation. Europace. 2021;23:1961–1969.

11. Packer DL, Mark DB, Robb RA, et al. Effect of catheter ablation vs anti- arrhythmic drug therapy on mortality, stroke, bleeding, and cardiac arrest among patients with atrial fibrillation: the CABANA randomized clinical trial. JAMA. 2019;321:1261–1274.

12. Steinberg BA, Hellkamp AS, Lokhnygina Y, et al. Higher risk of death and stroke in patients with persistent vs paroxysmal atrial fibrillation: results from the ROCKET-AF Trial. Eur Heart J. 2015;36:288–296.

13. Al-Khatib SM, Thomas L, Wallentin L, et al. Outcomes of apixaban vs war- farin by type and duration of atrial fibrillation: results from the ARISTOTLE trial. Eur Heart J. 2013;34:2464–2471.

14. Uittenbogaart SB, Lucassen WAM, van Etten-Jamaludin FS, et al. Burden of atrial high-rate episodes and risk of stroke: a systematic review. Europace. 2018;20:1420–1427.

15. Reynolds MR, Gunnarsson CL, Hunter TD, et al. Health outcomes with cath- eter ablation or antiarrhythmic drug therapy in atrial fibrillation: results of a propensity-matched analysis. Circ Cardiovasc Qual Outcomes. 2012;5:171– 181.

16. Friberg L, Tabrizi F, Englund A. Catheter ablation for atrial fibrillation is asso- ciated with lower incidence of stroke and death: data from Swedish health registries. Eur Heart J. 2016;37:2478–2487.

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17. Marrouche NF, Brachmann J, Andresen D, et al. Catheter ablation for atrial fibrillation with heart failure. N Engl J Med. 2018;378:417–427.

18. Piccini JP, Sinner MF, Greiner MA, et al. Outcomes of Medicare ben- eficiaries undergoing catheter ablation for atrial fibrillation. Circulation. 2012;126:2200–2207.

19. Calkins H, Hindricks G, Cappato R, et al. 2017 HRS/EHRA/ECAS/ APHRS/SOLAECE expert consensus statement on catheter and surgical ablation of atrial fibrillation. Heart Rhythm. 2017;14:e275–e444.

20. Karasoy D, Gislason GH, Hansen J, et al. Oral anticoagulation therapy after radiofrequency ablation of atrial fibrillation and the risk of thromboembolism and serious bleeding: long-term follow-up in nationwide cohort of Denmark. Eur Heart J. 2015;36:307–314a.

21. Noseworthy PA, Yao X, Deshmukh AJ, et al. Patterns of anticoagulation use and cardioembolic risk after catheter ablation for atrial fibrillation. J Am Heart Assoc. 2015;4:e002597.

22. Wazni OM, Boersma L, Healey JS, et al. Comparison of anticoagulation with left atrial appendage closure after atrial fibrillation ablation: rationale and design of the OPTION randomized trial. Am Heart J. 2022;251:35–42.

8.4.5. Complications After AF Catheter Ablation 1. Deshmukh A, Patel NJ, Pant S, et al. In-hospital complications associated

with catheter ablation of atrial fibrillation in the United States between 2000 and 2010: analysis of 93 801 procedures. Circulation. 2013;128:2104– 2112.

2. Steinbeck G, Sinner MF, Lutz M, et al. Incidence of complications related to catheter ablation of atrial fibrillation and atrial flutter: a nationwide in- hospital analysis of administrative data for Germany in 2014. Eur Heart J. 2018;39:4020–4029.

3. Loring Z, Holmes DN, Matsouaka RA, et al. Procedural patterns and safety of atrial fibrillation ablation: findings from Get With The Guidelines-Atrial Fibrillation. Circ Arrhythm Electrophysiol. 2020;13:e007944.

4. Campbell ML, Larson J, Farid T, et al. Sex-based differences in procedural complications associated with atrial fibrillation catheter ablation: a system- atic review and meta-analysis. J Cardiovasc Electrophysiol. 2020;31:3176– 3186.

5. Russo AM, Zeitler EP, Giczewska A, et al. Association between sex and treatment outcomes of atrial fibrillation ablation versus drug therapy: results from the CABANA trial. Circulation. 2021;143:661–672.

8.5. Role of Pacemakers and ICDs for the Prevention and Treatment of AF 1. Stambler BS, Ellenbogen KA, Orav EJ, et al. Predictors and clinical impact

of atrial fibrillation after pacemaker implantation in elderly patients treated with dual chamber versus ventricular pacing. Pacing Clin Electrophysiol. 2003;26:2000–2007.

2. Skanes AC, Krahn AD, Yee R, et al. Progression to chronic atrial fibrillation after pacing: the Canadian Trial of Physiologic Pacing. CTOPP Investigators. J Am Coll Cardiol. 2001;38:167–172.

3. Hesselson AB, Parsonnet V, Bernstein AD, et al. Deleterious effects of long-term single-chamber ventricular pacing in patients with sick sinus syndrome: the hidden benefits of dual-chamber pacing. J Am Coll Cardiol. 1992;19:1542–1549.

4. Andersen HR, Nielsen JC, Thomsen PE, et al. Long-term follow-up of pa- tients from a randomised trial of atrial versus ventricular pacing for sick- sinus syndrome. Lancet. 1997;350:1210–1216.

5. Lamas GA, Lee KL, Sweeney MO, et al. Ventricular pacing or dual-chamber pacing for sinus node dysfunction. N Engl J Med. 2002;346:1854–1862.

6. Elkayam LU, Koehler JL, Sheldon TJ, et al. The influence of atrial and ven- tricular pacing on the incidence of atrial fibrillation: a meta-analysis. Pacing Clin Electrophysiol. 2011;34:1593–1599.

7. Gillis AM, Unterberg-Buchwald C, Schmidinger H, et al. Safety and efficacy of advanced atrial pacing therapies for atrial tachyarrhythmias in patients with a new implantable dual chamber cardioverter-defibrillator. J Am Coll Cardiol. 2002;40:1653–1659.

8. Lee MA, Weachter R, Pollak S, et al. The effect of atrial pacing therapies on atrial tachyarrhythmia burden and frequency: results of a randomized trial in patients with bradycardia and atrial tachyarrhythmias. J Am Coll Cardiol. 2003;41:1926–1932.

9. Israel CW, Hügl B, Unterberg C, et al. Pace-termination and pacing for prevention of atrial tachyarrhythmias: results from a multicenter study with an implantable device for atrial therapy. J Cardiovasc Electrophysiol. 2001;12:1121–1128.

10. Gillis AM, Koehler J, Morck M, et al. High atrial antitachycardia pacing ther- apy efficacy is associated with a reduction in atrial tachyarrhythmia burden

in a subset of patients with sinus node dysfunction and paroxysmal atrial fibrillation. Heart Rhythm. 2005;2:791–796.

11. Padeletti L, Purerfellner H, Mont L, et al. New-generation atrial antitachy- cardia pacing (Reactive ATP) is associated with reduced risk of persistent or permanent atrial fibrillation in patients with bradycardia: results from the MINERVA randomized multicenter international trial. Heart Rhythm. 2015;12:1717–1725.

12. Boriani G, Tukkie R, Manolis AS, et al. Atrial antitachycardia pacing and man- aged ventricular pacing in bradycardia patients with paroxysmal or persistent atrial tachyarrhythmias: the MINERVA randomized multicentre international trial. Eur Heart J. 2014;35:2352–2362.

13. Nakagomi T, Inden Y, Yanagisawa S, et al. Characteristics of successful reactive atrial-based antitachycardia pacing in patients with cardiac im- plantable electronic devices: history of catheter ablation of atrial fibrilla- tion as a predictor of high treatment efficacy. J Cardiovasc Electrophysiol. 2022;33:1515–1528.

14. Zhu H, Li X, Wang Z, et al. New-onset atrial fibrillation following left bundle branch area pacing vs right ventricular pacing: a two-centre prospective co- hort study. Europace. 2022;25:121–125.

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16. Carlson MD, Ip J, Messenger J, et al. A new pacemaker algorithm for the treatment of atrial fibrillation: results of the Atrial Dynamic Overdrive Pacing Trial (ADOPT). J Am Coll Cardiol. 2003;42:627–633.

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23. Shurrab M, Healey JS, Haj-Yahia S, et al. Reduction in unnecessary ventricu- lar pacing fails to affect hard clinical outcomes in patients with preserved left ventricular function: a meta-analysis. Europace. 2017;19:282–288.

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26. Singh JP, Cha YM, Lunati M, et al. Real-world behavior of CRT pacing using the AdaptivCRT algorithm on patient outcomes: effect on mortality and atrial fibrillation incidence. J Cardiovasc Electrophysiol. 2020;31:825–833.

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28. Gasparini M, Birnie D, Lemke B, et al. Adaptive cardiac resynchronization therapy reduces atrial fibrillation incidence in heart failure patients with pro- longed AV conduction: the adaptive CRT randomized trial. Circ Arrhythm Electrophysiol. 2019;12:e007260.

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2. Huffman MD, Karmali KN, Berendsen MA, et al. Concomitant atrial fibrilla- tion surgery for people undergoing cardiac surgery. Cochrane Database Syst Rev. 2016;8:CD011814.

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5. Kress DC, Erickson L, Choudhuri I, et al. Comparative effectiveness of hy- brid ablation versus endocardial catheter ablation alone in patients with per- sistent atrial fibrillation. JACC Clin Electrophysiol. 2017;3:341–349.

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8. Cox JL, Schuessler RB, D'Agostino HJ Jr, et al. The surgical treatment of atrial fibrillation III Development of a definitive surgical procedure. J Thorac Cardiovasc Surg. 1991;101:569–583.

9. McCarthy PM, Davidson CJ, Kruse J, et al. Prevalence of atrial fibrillation before cardiac surgery and factors associated with concomitant ablation. J Thorac Cardiovasc Surg. 2020;159:2245–2253 e2215.

10. Musharbash FN, Schill MR, Sinn LA, et al. Performance of the Cox-maze IV procedure is associated with improved long-term survival in patients with atrial fibrillation undergoing cardiac surgery. J Thorac Cardiovasc Surg. 2018;155:159–170.

11. Iribarne A, DiScipio AW, McCullough JN, et al. Surgical atrial fibrillation abla- tion improves long-term survival: a multicenter analysis. Ann Thorac Surg. 2019;107:135–142.

12. Suwalski P, Kowalewski M, Jasinski M, et al. Survival after surgical ablation for atrial fibrillation in mitral valve surgery: analysis from the Polish National Registry of Cardiac Surgery Procedures (KROK). J Thorac Cardiovasc Surg. 2019;157:1007–1018.e1004.

13. Malaisrie SC, McCarthy PM, Kruse J, et al. Ablation of atrial fibrillation during coronary artery bypass grafting: late outcomes in a Medicare population. J Thorac Cardiovasc Surg. 2021;161:1251–1261 e1251.

14. Badhwar V, Rankin JS, Ad N, et al. Surgical ablation of atrial fibrillation in the United States: trends and propensity matched outcomes. Ann Thorac Surg. 2017;104:493–500.

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8. Kotecha D, Chudasama R, Lane DA, et al. Atrial fibrillation and heart failure due to reduced versus preserved ejection fraction: a systematic review and meta-analysis of death and adverse outcomes. Int J Cardiol. 2016;203:660– 666.

9. Zafrir B, Lund LH, Laroche C, et al. Prognostic implications of atrial fibrilla- tion in heart failure with reduced, mid-range, and preserved ejection fraction: a report from 14 964 patients in the European Society of Cardiology Heart Failure Long-Term Registry. Eur Heart J. 2018;39:4277–4284.

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tients with atrial fibrillation and heart failure. Circulation. 2021;144:845– 858.

2. Brachmann J, Sohns C, Andresen D, et al. Atrial fibrillation burden and clini- cal outcomes in heart failure: the CASTLE-AF trial. JACC Clin Electrophysiol. 2021;7:594–603.

3. Chen S, Pürerfellner H, Meyer C, et al. Rhythm control for patients with atrial fibrillation complicated with heart failure in the contemporary era of catheter ablation: a stratified pooled analysis of randomized data. Eur Heart J. 2020;41:2863–2873.

4. Di Biase L, Mohanty P, Mohanty S, et al. Ablation versus amiodarone for treatment of persistent atrial fibrillation in patients with congestive heart failure and an implanted device: results from the AATAC multicenter ran- domized trial. Circulation. 2016;133:1637–1644.

5. Hunter RJ, Berriman TJ, Diab I, et al. A randomized controlled trial of cath- eter ablation versus medical treatment of atrial fibrillation in heart failure (the CAMTAF trial). Circ Arrhythm Electrophysiol. 2014;7:31–38.

6. Jones DG, Haldar SK, Hussain W, et al. A randomized trial to assess cath- eter ablation versus rate control in the management of persistent atrial fibril- lation in heart failure. J Am Coll Cardiol. 2013;61:1894–1903.

7. Kuck KH, Merkely B, Zahn R, et al. Catheter ablation versus best medi- cal therapy in patients with persistent atrial fibrillation and congestive heart failure: the randomized AMICA trial. Circ Arrhythm Electrophysiol. 2019;12:e007731.

8. MacDonald MR, Connelly DT, Hawkins NM, et al. Radiofrequency ablation for persistent atrial fibrillation in patients with advanced heart failure and se- vere left ventricular systolic dysfunction: a randomised controlled trial. Heart. 2011;97:740–747.

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12. 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;70:1949–1961.

13. Turagam MK, Garg J, Whang W, et al. Catheter ablation of atrial fibrillation in patients with heart failure: a meta-analysis of randomized controlled trials. Ann Intern Med. 2019;170:41–50.

14. Packer DL, Piccini JP, Monahan KH, et al. Ablation versus drug therapy for atrial fibrillation in heart failure: results from the CABANA trial. Circulation. 2021;143:1377–1390.

15. Siddiqui MU, Junarta J, Riley JM, et al. Catheter ablation in patients with atrial fibrillation and heart failure with preserved ejection fraction: a system- atic review and meta-analysis. J Arrhythm. 2022;38:981–990.

16. Khand AU, Rankin AC, Martin W, et al. Carvedilol alone or in combination with digoxin for the management of atrial fibrillation in patients with heart failure? J Am Coll Cardiol. 2003;42:1944–1951.

17. Kotecha D, Bunting KV, Gill SK, et al. Effect of digoxin vs bisoprolol for heart rate control in atrial fibrillation on patient-reported quality of life: the RATE- AF randomized clinical trial. JAMA. 2020;324:2497–2508.

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20. Brignole M, Menozzi C, Gianfranchi L, et al. Assessment of atrioventricular junction ablation and VVIR pacemaker versus pharmacological treatment in patients with heart failure and chronic atrial fibrillation: a randomized, con- trolled study. Circulation. 1998;98:953–960.

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27. Nerheim P, Birger-Botkin S, Piracha L, et al. Heart failure and sudden death in patients with tachycardia-induced cardiomyopathy and recurrent tachy- cardia. Circulation. 2004;110:247–252.

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32. Morina-Vazquez P, Moraleda-Salas MT, Arce-Leon A, et al. Effectiveness and safety of AV node ablation after His bundle pacing in patients with uncontrolled atrial arrhythmias. Pacing Clin Electrophysiol. 2021;44:1004– 1009.

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37. Kober L, Torp-Pedersen C, McMurray JJ, et al. Increased mortal- ity after dronedarone therapy for severe heart failure. N Engl J Med. 2008;358:2678–2687.

38. Calo L, De Ruvo E, Sette A, et al. Tachycardia-induced cardiomyopathy: mechanisms of heart failure and clinical implications. J Cardiovasc Med (Hagerstown). 2007;8:138–143.

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6. Perez MV, Mahaffey KW, Hedlin H, et al. Large-scale assessment of a smart- watch to identify atrial fibrillation. N Engl J Med. 2019;381:1909–1917.

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10.6. WPW and Preexcitation Syndromes 1. Page RL, Joglar JA, Caldwell MA, et al. 2015 ACC/AHA/HRS guideline

for the management of adult patients with supraventricular tachycardia: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. Circulation. 2016;133:e506–e574.

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20. Higuchi S, Kabeya Y, Matsushita K, et al. Incidence and complications of perioperative atrial fibrillation after non-cardiac surgery for malignancy. PLoS One. 2019;14:e0216239.

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22. Chung MK, Eckhardt LL, Chen LY, et al. Lifestyle and risk factor modification for reduction of atrial fibrillation: a scientific statement from the American Heart Association. Circulation. 2020;141:e750–e772.

23. Rienstra M, Hobbelt AH, Alings M, et al. Targeted therapy of underlying con- ditions improves sinus rhythm maintenance in patients with persistent atrial fibrillation: results of the RACE 3 trial. Eur Heart J. 2018;39:2987–2996.

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26. Toufektzian L, Zisis C, Balaka C, et al. Effectiveness of brain natriuretic peptide in predicting postoperative atrial fibrillation in patients under- going non-cardiac thoracic surgery. Interact Cardiovasc Thorac Surg. 2015;20:654–657.

27. Amar D, Zhang H, Tan KS, et al. A brain natriuretic peptide-based prediction model for atrial fibrillation after thoracic surgery: development and internal validation. J Thorac Cardiovasc Surg. 2019;157:2493–2499 e2491.

28. Chang EK, Chanson D, Teh JB, et al. Atrial fibrillation in patients undergoing allogeneic hematopoietic cell transplantation. J Clin Oncol. 2021;39:902– 910.

29. Hemu M, Zimmerman A, Kalra D, et al. Pretransplant cardiac evaluation us- ing novel technology. J Clin Med. 2019;8:690.

30. Ganatra S, Sharma A, Shah S, et al. Ibrutinib-associated atrial fibrillation. JACC Clin Electrophysiol. 2018;4:1491–1500.

31. Abushukair H, Syaj S, Ababneh O, et al. First- versus second-generation Bruton tyrosine kinase inhibitors in Waldenstrom's macroglobulinemia: a systematic review and meta-analysis. Am J Hematol. 2022;97:942–950.

32. Buza V, Rajagopalan B, Curtis AB. Cancer treatment-induced arrhythmias: focus on chemotherapy and targeted therapies. Circ Arrhythm Electrophysiol. 2017;10:e005443.

33. Fradley MG, Beckie TM, Brown SA, et al. Recognition, prevention, and management of arrhythmias and autonomic disorders in cardio-oncology: a scientific statement from the American Heart Association. Circulation. 2021;144:e41–e55.

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ated with the incidence of atrial fibrillation: the Atherosclerosis Risk in Com- munities (ARIC) study. Circulation. 2011;123:2946–2953.

2. Watanabe H, Watanabe T, Sasaki S, et al. Close bidirectional relationship between chronic kidney disease and atrial fibrillation: the Niigata preventive medicine study. Am Heart J. 2009;158:629–636.

3. Bansal N, Fan D, Hsu CY, et al. Incident atrial fibrillation and risk of end- stage renal disease in adults with chronic kidney disease. Circulation. 2013;127:569–574.

10.16. Anticoagulation Use in Patients With Liver Disease 1. Qamar A, Antman EM, Ruff CT, et al. Edoxaban versus warfarin in pa-

tients with atrial fibrillation and history of liver disease. J Am Coll Cardiol. 2019;74:179–189.

2. Serper M, Weinberg EM, Cohen JB, et al. Mortality and hepatic decompen- sation in patients with cirrhosis and atrial fibrillation treated with anticoagu- lation. Hepatology. 2021;73:219–232.

3. Proietti M, Marzona I, Vannini T, et al. Impact of liver disease on oral antico- agulant prescription and major adverse events in patients with atrial fibrilla- tion: analysis from a population-based cohort study. Eur Heart J Cardiovasc Pharmacother. 2021;7:f84–f92.

4. Pastori D, Lip GYH, Farcomeni A, et al. Incidence of bleeding in patients with atrial fibrillation and advanced liver fibrosis on treatment with vitamin K or non-vitamin K antagonist oral anticoagulants. Int J Cardiol. 2018;264:58–63.

5. Pastori D, Sciacqua A, Marcucci R, et al. Prevalence and impact of nonalco- holic fatty liver disease in atrial fibrillation. Mayo Clin Proc. 2020;95:513– 520.

6. Kuo L, Chao TF, Liu CJ, et al. Liver cirrhosis in patients with atrial fibrillation: would oral anticoagulation have a net clinical benefit for stroke prevention? J Am Heart Assoc. 2017;6:e005307.

7. Chen S, Purerfellner H, Meyer C, et al. Anticoagulation in atrial fibrillation and liver disease: a pooled-analysis of >20 000 patients. Eur Heart J Car- diovasc Pharmacother. 2022;8:336–345.

8. Lee SR, Lee HJ, Choi EK, et al. Direct oral anticoagulants in patients with atrial fibrillation and liver disease. J Am Coll Cardiol. 2019;73:3295–3308.

9. Lee HF, Chan YH, Chang SH, et al. Effectiveness and safety of non-vitamin K antagonist oral anticoagulant and warfarin in cirrhotic patients with non- valvular atrial fibrillation. J Am Heart Assoc. 2019;8:e011112.

10. Wang CL, Wu VC, Kuo CF, et al. Efficacy and safety of non-vitamin K an- tagonist oral anticoagulants in atrial fibrillation patients with impaired liver function: a retrospective cohort study. J Am Heart Assoc. 2018;7:e009263.

11. Lee ZY, Suah BH, Teo YH, et al. Comparison of the efficacy and safety of direct oral anticoagulants and vitamin k antagonists in patients with atrial fibrillation and concomitant liver cirrhosis: a systematic review and meta- analysis. Am J Cardiovasc Drugs. 2022;22:157–165.

12. Kubitza D, Roth A, Becka M, et al. Effect of hepatic impairment on the phar- macokinetics and pharmacodynamics of a single dose of rivaroxaban, an oral, direct Factor Xa inhibitor. Br J Clin Pharmacol. 2013;76:89–98.

13. Menichelli D, Ronca V, Di Rocco A, et al. Direct oral anticoagulants and advanced liver disease: a systematic review and meta-analysis. Eur J Clin Invest. 2021;51:e13397.

14. Mendell J, Johnson L, Chen S. An open-label, phase 1 study to evaluate the effects of hepatic impairment on edoxaban pharmacokinetics and pharma- codynamics. J Clin Pharmacol. 2015;55:1395–1405.

15. Frost CE, Ly V, Garonzik SM. Apixaban Pharmacokinetics and pharmaco- dynamics in subjects with mild or moderate hepatic impairment. Drugs R D. 2021;21:375–384.

16. Stangier J, Stähle H, Rathgen K, et al. Pharmacokinetics and pharmacody- namics of dabigatran etexilate, an oral direct thrombin inhibitor, with coad- ministration of digoxin. J Clin Pharmacol. 2012;52:243–250.

11. Future Research Needs 1. Verma A, Ha ACT, Kirchhof P, et al. The Optimal Anti-Coagulation for En-

hanced-Risk Patients Post-Catheter Ablation for Atrial Fibrillation (OCEAN) trial. Am Heart J. 2018;197:124–132.

2. Schrickel JW, Linhart M, Bänsch D, et al. Rationale and design of the ODIn- AF Trial: randomized evaluation of the prevention of silent cerebral throm- boembolism by oral anticoagulation with dabigatran after pulmonary vein isolation for atrial fibrillation. Clin Res Cardiol. 2016;105:95–105.

3. Riley MP, Zado E, Hutchinson MD, et al. Risk of stroke or transient isch- emic attack after atrial fibrillation ablation with oral anticoagulant use guid- ed by ECG monitoring and pulse assessment. J Cardiovasc Electrophysiol. 2014;25:591–596.

4. Passman R, Leong-Sit P, Andrei AC, et al. Targeted anticoagulation for atrial fibrillation guided by continuous rhythm assessment with an insert- able cardiac monitor: the Rhythm Evaluation for Anticoagulation With Con- tinuous Monitoring (REACTCOM). Pilot Study. J Cardiovasc Electrophysiol. 2016;27:264–270.

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Appendix 1. Author Relationships With Industry and Other Entities—2023 ACC/AHA/ACCP/HRS Guideline for the Diagnosis and Management of Atrial Fibrillation

Committee Member Employment Consultant

Speakers Bureau

Ownership/ Partnership/ Principal

Personal Research

Institutional, Organizational, or Other Financial Benefit

Expert Witness

José A. Joglar, Chair

UT Southwestern Medical Center— Professor and Vice Chair for Clinical Affairs at Parkland, Department of Internal Medicine Elizabeth Thaxton and Ellis Batten Page Professorship in Cardiac Electrophysiology Research Director of Cardiac Electrophysiology Fellowship Program

None None None None None None

Mina K. Chung, Vice Chair

Cleveland Clinic, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University—Cardiac Pacing and Electrophysiology Department of Cardiovas- cular Medicine, Heart and Vascular Institute Department of Cardiovas- cular & Metabolic Sciences, Lerner Research Institute

NOT RELEVANT • ABIM* • Geisinger

Health Systems

None None NOT RELEVANT • AHA* • NIH*

NOT RELEVANT • Abbott‡ • AHA* • Biosense

Webster‡ • Boston

Scientific‡ • Elsevier • FNRA • Hamilton Health

Sciences/PHRI‡ • HRS† • Medtronic‡ • Myocardial

Solutions‡ • UptoDate

None

Anastasia L. Armbruster

St. Louis College of Phar- macy AT UHSP—Associate Professor, Pharmacy Practice

None RELEVANT • AstraZeneca

None None None None

Emelia J. Benjamin

Boston University Schools of Medicine and Public Health, The Framingham Heart Study—Associate Provost for Faculty Development, Boston University Medical Campus Vice Chair, Faculty Develop- ment and Diversity, Depart- ment of Medicine Cardiologist, Boston Medical Center, Boston University Medical Group

None None None NOT RELEVANT • AHA* • Cardia

(DSMB)† • NIH*

NOT RELEVANT • Circulation† • European Heart

Journal† • Nature Reviews

Cardiology†

None

Janice Y. Chyou

Icahn School of Medicine at Mount Sinai—Assistant Clini- cal Professor, Cardiac Elec- trophysiology, Cardiology Heart and Heart Rhythm Care

None None None None NOT RELEVANT • AHA† • HRS† • McGraw Hill

None

Edmond M. Cronin

Temple University Hospital— Main Campus—Temple Heart & Vascular Institute

RELEVANT • Medtronic

None None None NOT RELEVANT • Biosense

Webster§ • Janssen

Pharmaceuti- cals§

• Medtronic§

None

Anita Deswal The University of Texas MD Anderson Cancer Center—Chair, Department of Cardiology Ting Tsung and Wei Fong Chao Distinguished Chair Professor of Medicine

None None None None NOT RELEVANT • ACC* • CPRIT* • NIH

None

(Continued )

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Committee Member Employment Consultant

Speakers Bureau

Ownership/ Partnership/ Principal

Personal Research

Institutional, Organizational, or Other Financial Benefit

Expert Witness

Lee Eckhardt University of Wisconsin- Madison—Associate Professor of Medicine Gary and Marie Weiner Professor in Cardiovascular Medicine Research Cellular and Molecular Ar- rhythmia Research Program Division of Cardiovascular Medicine

None None None None None None

Zachary D. Goldberger

University of Wisconsin- Madison School of Medicine and Public Health Division of Cardiovascular Medicine/Electrophysiol- ogy—Associate Professor of Medicine Program Director, Cardiovascular Disease Fel- lowship Associate Program Director, Clinical Cardiac Electrophysi- ology Fellowship

None None None None None None

Rakesh Gopinathannair

University of Louisville— Associate Professor of Medicine (Adjunct) University of Missouri- Columbia—Cardiac EP Lab Director, Kansas City Heart Rhythm Institute EP Medical Director, Research Medical Center Professor of Medicine

RELEVANT • Abbott* • Biosense

Webster • Biotronik • Boston

Scientific* • Johnson &

Johnson • Pfizer* • Sanofi-Aventis • Zoll†

NOT RELEVANT • Academy for

Continued Healthcare Learning

RELEVANT • Pfizer† • Zoll†

None None NOT RELEVANT • AHA • Atricure • Geisinger

Health System • HRS • Janssen

Pharmaceuticals • Kowa

Pharmaceuticals • Medtronic • Methodist Health

System • Novartis • Pacemate† • Philips

None

Bulent Gorenek

Eskisehir Osmangazi University School of Medicine—Cardiovascular Diseases, Arrhythmias in Intensive Cardiac Care Unit. Professor in Cardiology Vice Director, Cardiology Department

RELEVANT • AstraZeneca • Bayer • Daiichi Sankyo • Roche

NOT RELEVANT • Sandoz

None None None None None

Paul L. Hess University of Colorado School of Medicine Seattle-Denver Center of Innovation Rocky Mountain Regional VA Medical Center—Associate Professor of Medicine

None None None None NOT RELEVANT • CPC Clinical

Research* • VA CSP

None

Mark Hlatky Stanford University School of Medicine—Professor of Health Policy, and of Medicine (Cardiovascular Medicine), and, by courtesy, of Epidemi- ology and Population Health

RELEVANT • Boehringer

Ingelheim

NOT RELEVANT • BCBS Center

for Effectiveness Evaluation*

None None None NOT RELEVANT • George Institute

None

Appendix 1. Continued

(Continued )

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Appendix 1. Continued

Committee Member Employment Consultant

Speakers Bureau

Ownership/ Partnership/ Principal

Personal Research

Institutional, Organizational, or Other Financial Benefit

Expert Witness

Gail Hogan Patient Representative None None None None NOT RELEVANT • Ohio State

University Wexner Medical Center

None

Chinwe Ibeh Columbia University CUIMC/ Neurological Institute of New York—Assistant Professor of Neurology Department of Neurology Division of Stroke and Cere- brovascular Disease

None None None None None None

Julia H. Indik University of Arizona College of Medicine—Professor of Medicine Director, Cardiovascular Disease Fellowship Program Division of Cardiology/Sarver Heart Center

None None None None None None

Kazuhiko Kido West Virginia University— Cardiology Pharmacy Special- ist, Advanced Heart Failure and Pulmonary Hypertension Clinical Assistant Professor of Clinical Pharmacy

None None None None None None

Fred Kusumoto

Mayo Clinic Jacksonville None None None NOT RELEVANT • EP Research

Foundation (TAP-CHF Trial)

NOT RELEVANT • Biotronik§

None

Mark S. Link UT Southwestern Medical Center, Dallas—Professor of Medicine. Director, Cardiac Electrophysiology. Laurence and Susan Hirsch/Centex Distinguished Chair in Heart Disease Department of Internal Medicine, Division of Cardiology

None None None None NOT RELEVANT • Circulation* • Journal Watch

Cardiology • UpToDate*

None

Kathleen T. Linta

Patient Representative None None None None None None

Gregory M. Marcus

University of California, San Francisco—Professor of Medicine in Residence Associate Chief of Cardiology for Research Endowed Professor of Atrial Fibrillation Research

NOT RELEVANT • InCarda*

RELEVANT • Johnson &

Johnson

None None NOT RELEVANT • Baylis*

NOT RELEVANT • InCarda*

None

Patrick M. McCarthy

Northwestern Medicine— Executive Director, Bluhm Cardiovascular Institute Vice President, Northwestern Medical Group Chief, Division of Cardiac Surgery Heller-Sacks Professor of Surgery

RELEVANT • Abbott • Atricure • Edwards

Lifesciences* • Medtronic

None None RELEVANT • Abbott†

NOT RELEVANT • Egnite • Siemens

RELEVANT • Edwards

Lifesciences*

None

Nimesh Patel UT Southwestern Medical Center— Assistant Professor of Medicine, Clinical Cardiac Electrophysiology

None None None None NOT RELEVANT • Abbvie§ • Novo Nordisk§

None

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Appendix 1. Continued

Committee Member Employment Consultant

Speakers Bureau

Ownership/ Partnership/ Principal

Personal Research

Institutional, Organizational, or Other Financial Benefit

Expert Witness

Kristen K. Patton

University of Washington—Professor of Medicine

None None None None NOT RELEVANT • ACGME† • AHA† • HRS† • JAMA • US FDA CDRH*

None

Marco V. Perez Stanford University— Associate Professor- University Med Line Department of Medicine, Med/Cardiovascular

RELEVANT • Biotronik* • Boehringer

Ingelheim* • Boston

Scientific* • Bristol Myers

Squibb • Johnson &

Johnson

None NOT RELEVANT • Feather

Health*

NOT RELEVANT • Apple* • NIH*

None NOT REL- EVANT Defen- dant, Digi- tal health tools case, 2021

Jonathan P. Piccini

Duke University School of Medicine— Department of Medicine

RELEVANT • Abbott* • Abbvie • ARCA

Biopharma • Biotronik • Bristol Myers

Squibb* • Electrophysiol-

ogy Frontiers* • Itamar Medical • Medtronic* • Milestone

Medical • Philips* • Recor • Sanofi-Aventis*

NOT RELEVANT • UpToDate*

None None RELEVANT • Abbott* • Bayer* • Boston

Scientific* • iRhythm* • Philips*

NOT RELEVANT • AAMI* • Acutus

Medical, Inc.§ • AHA* • Atricure§ • Element

Science (DSMB)*

• LivaNova (CEAC)*

• LSI Solutions§

NOT RELEVANT • LivaNova

(CEAC)*

None

Andrea M. Russo

Cooper University—Professor of Medicine Director, Elec- trophysiology and Arrhythmia Services Director of Research, Cooper Heart Institute Program Director, Clinical Cardiac Electrophysiology Fellowship

RELEVANT • Abbott • Atricure • Biosense

Webster • Biotonik • Boston

Scientific • Bristol Myers

Squibb • Medtronic • Pfizer • Sanofi

NOT RELEVANT • Medical Device

Business Services, Inc.

• Pacemate

None None None NOT RELEVANT • ABIM • Boston

Scientific‡ • Kestra‡ • MediLynx‡ • UpToDate

None

Prashanthan Sanders

The University of Adelaide Royal Adelaide Hospital— Director, Centre for Heart Rhythm Disorders Director, Cardiac Electrophysiology & Pacing NHMRC Practitioner Fellow

None None None RELEVANT • Abbott* • BD* • Boston

Scientific* • Medtronic*

RELEVANT • Abbott • Boston Scientific • CathRX • Medtronic

NOT RELEVANT • Pacemate

None

Megan M. Streur

University of Washington— Assistant Professor and En- dowed Faculty Fellow for Car- diovascular Disease Prevention Department of Biobehavioral Nursing and Health Informatics Adjunct Assistant Professor, Cardiac Electrophysiology Department of Medicine

None None None NOT RELEVANT • NIH/NINR*

None None

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Committee Member Employment Consultant

Speakers Bureau

Ownership/ Partnership/ Principal

Personal Research

Institutional, Organizational, or Other Financial Benefit

Expert Witness

Kevin L. Thomas

Duke University School of Medicine— Professor of Medicine Vice Dean for Diversity, Equity and Inclusion Member in the Duke Clinical Research Institute

RELEVANT • Biosense

Webster • Johnson &

Johnson

None None None NOT RELEVANT • Community

Health Coalition†

None

Sabrina Times§

American Heart Association/ American College of Cardiol- ogy Science and Health Advisor, Guidelines

None None None None None None

James E. Tisdale

Purdue University College of Pharmacy—Professor Indiana University School of Medicine—Adjunct Professor

None None None NOT RELEVANT • AHRQ* • AHA* • NIH*

NOT RELEVANT • American

Society for Health-Systems Pharmacists

• AZCert† • Crediblemeds.

org† • Nova Southeast-

ern University • Pharmacother-

apy Journal • Pharmacother-

apy Publications, Inc. †

None

Anne Marie Valente

Boston Children’s Hospital, Brigham and Women’s Hospital—Co-Director, Pregnancy and Cardiovascu- lar Disease Program Brigham and Women’s Hospital Associate Professor, Medicine and Pediatrics Harvard Medical School Section Chief, Boston Adult Congenital Heart Disease (BACH) and Pulmonary Hypertension Program

NOT RELEVANT • Elsevier*

None None None NOT RELEVANT • Elsevier* • Journal of the

ACC* • United

Therapeutics§

None

David R. Van Wagoner

Cleveland Clinic, ND-50— Department of Cardiovascular & Metabolic Sciences

None None None NOT RELEVANT • AHA* • NIH/NHLBI*

None None

This table represents all relationships of committee members with industry and other entities that were reported by authors, including those not deemed to be relevant to this document, at the time this document was under development. 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 ≥$5000 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 previ- ous 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. Please refer to https://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.

*Significant relationship. †No financial benefit. ‡This disclosure was entered under the Clinical Trial Enroller category in the ACC’s disclosure system. To appear in this category, the author acknowledges that there

is no direct or institutional relationship with the trial sponsor as defined in the (ACCF or AHA/ACC) Disclosure Policy for Writing Committees. §Sabrina Times is an AHA/ACC joint staff member and acts as the Science and Health Advisor for the “2023 ACC/AHA/ACCP/HRS Guideline for the Diagnosis

and Management of Atrial Fibrillation.” No relevant relationships to report. Nonvoting author on measures and not included/counted in the RWI balance for this writing committee.

AAMI indicates Association for the Advancement of Medical Instrumentation; ABIM, American Board of Internal Medicine; ACC, American College of Cardiology; ACGME, Accreditation Council for Graduate Medical Education; AHA, American Heart Association; AHRQ, Agency for Health Research and Quality; BCBS, Blue Cross Blue Shield; BD, Becton Dickinson; CDRH, Center for Devices and Radiological Health; CEAC, Clinical Event Adjudication Committee; CPRIT, Cancer Prevention and Research Institute of Texas; CUIMC, Columbia University Irving Medical Center; DSMB, data and safety monitoring board; EP, electrophysiology; FDA, US Food and Drug Administration; FNRA, French National Research Agency; HRS, Heart Rhythm Society; JAMA, Journal of the American Medical Association; NIH, National Institutes of Health; NINR, National Institute of Nursing Research; NHLBI, National Heart, Lung, and Blood Institute; NHMRC, National Health and Medical Research Council; PHRI, Population Health Research Institute; UHSP, University of Health Science and Pharmacy in St. Louis; UT, University of Texas; and VA CSP, Veterans Affairs Cooperative Studies Program.

Appendix 1. Continued

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CLINICAL STATEM ENTS

AND GUIDELINES

Circulation. 2024;149:e1–e156. DOI: 10.1161/CIR.0000000000001193 January 2, 2024 e155

Joglar et al 2023 Guideline for the Diagnosis and Management of Atrial Fibrillation

Appendix 2. Reviewer Relationships With Industry and Other Entities (Comprehensive)—2023 ACC/AHA/ACCP/HRS Guideline for the Diagnosis and Management of Atrial Fibrillation

Reviewer Representation Employment Consultant Speakers Bureau

Ownership/ Partnership/ Principal

Personal Research

Institutional, Organizational, or Other Financial Benefit

Expert Witness

Andrew D. Krahn

AHA/ACC Atrial Fibrillation Peer Review Committee Chair

University of British Columbia

None None • CCS* • HRS*

None None None

Jason G. Andrade

AHA/ACC Atrial Fibrilla- tion Peer Review Com- mittee

University of Montreal

• Biosense Webster

• Medtronic

• Bayer • Bristol Myers

Squibb/Pfizer Alliance

• Servier

None • Medtronic† None None

Craig J. Beavers

AHA/ACC Atrial Fibrillation Peer Review Committee, representing ACCP

University of Kentucky College of Pharmacy

None None None None None None

James M. Bischoff

AHA/ACC Atrial Fibrillation Peer Review Committee, Patient Representative

Superinten- dent, Retired

None None None None None None

T. Jared Bunch

AHA/ACC Atrial Fibrillation Peer Review Committee, representing HRS

University of Utah School of Medicine

None None None • Altathera† • Boehringer

Ingelheim†

• Abbott‡ • Altathera‡ • Cardiva‡ • St. Jude’s

Medical‡

None

Kristen Bova Campbell

AHA/ACC Atrial Fibrillation Peer Review Committee

Duke University

• Wolters Kluwer

None None None None None

Lin Yee Chen

AHA/ACC Atrial Fibrillation Peer Review Committee

University of Minnesota School of Medicine

None None None None • NIH† None

Robin Dharia

AHA/ACC Atrial Fibrillation Peer Review Committee

Thomas Jefferson University

None None None None • NIH‡ None

Michael P. Dorsch

AHA/ACC Atrial Fibrillation Peer Review Committee, representing JCPM

University of Michigan

None None None None None None

Edward P. Gerstenfeld

AHA/ACC Atrial Fibrillation Peer Review Committee

University of California San Francisco

• Biosense Webster†

• Medtronic • St. Jude

Medical

None None • Abbott (DSMB)†

• Adagio* • Boston

Scientific* • Thermedical

(DSMB)†

• Boston Scientific*

None

Aubrey E. Jones

AHA/ACC Atrial Fibrillation Peer Review Committee

University of Utah College of Pharmacy

None None None • AHRQ† • NIH-NHLBI†

None None

Stephanie Dwyer Kaluzna

AHA/ACC Atrial Fibrillation Peer Review Committee

University of Illinois Chicago College of Pharmacy

None None None None None None

Luke Masha AHA/ACC Atrial Fibrillation Peer Review Committee

Oregon Health & Science University

None None None None • Ancora‡ • Endotronix‡

None

Isabelle Nault

AHA/ACC Atrial Fibrillation Peer Review Committee

Quebec Heart and Lung Institute

• Bristol Myers Squibb

• Pfizer

• Bayer† • Biosense

Webster • Medtronic • Servier†

None None None None

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January 2, 2024 Circulation. 2024;149:e1–e156. DOI: 10.1161/CIR.0000000000001193e156

Joglar et al 2023 Guideline for the Diagnosis and Management of Atrial Fibrillation

Reviewer Representation Employment Consultant Speakers Bureau

Ownership/ Partnership/ Principal

Personal Research

Institutional, Organizational, or Other Financial Benefit

Expert Witness

Peter A. Noseworthy

AHA/ACC Atrial Fibrillation Peer Review Committee

Mayo Clinic None None None None • Anumana* • Milestone‡

None

Cara N. Pellegrini

AHA/ACC Atrial Fibrillation Peer Review Committee

University of California San Francisco

• Abbott • Biosense

Webster • Cook

Medical • Medtronic

None None None None None

Stylianos E. Tzeis

AHA/ACC Atrial Fibrillation Peer Review Committee

Mitera Hospital

• Pfizer None None None • Bayer‡ None

Annabelle Santos Volgman

AHA/ACC Atrial Fibrillation Peer Review Committee

Rush University Medical Center

• Bristol Myers Squibb Foundation DCICDP

• Janssen Pharmaceu- ticals

• Merck • Pfizer • Sanofi

Aventis†

None None • NIH† • Apple* • Novartis‡

None

Emily P. Zeitler

AHA/ACC Atrial Fibrillation Peer Review Committee

Dartmouth Hitchock Medical Center

• Abbott • Biosense

Webster • Medtronic

None None • Boston Scientific†

• Sanofi Aventis*

None None

This table represents all reviewers’ relationships 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. 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.

*No financial benefit. †Significant relationship. ‡This disclosure was entered under the Clinical Trial Enroller category in the ACC’s disclosure system. To appear in this category, the author acknowledges that there

is no direct or institutional relationship with the trial sponsor as defined in the (ACCF or AHA/ACC) Disclosure Policy for Writing Committees. ACC indicates American College of Cardiology; ACCF, American College of Cardiology Foundation; AACP, American Association of Colleges of Pharmacy; AHA,

American Heart Association; AHRQ, Agency for Healthcare Research and Quality; CCS, Canadian Cardiovascular Society; DCICDP, Diverse Clinical Investigator Career Development Program; DSMB; data and safety monitoring board; HRS, Heart Rhythm Society; JCPM, ACC/AHA Joint Committee on Performance Measures, NHLBI, National Heart, Lung, and Blood Institute; and NIH, National Institutes of Health.

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Table of Contents
Top 10 Take-Home Messages
Preamble

Intended Use
Clinical Implementation
Methodology and Modernization
Selection of Writing Committee Members
Relationships With Industry and Other Entities
Evidence Review and Evidence Review Committees
Guideline-Directed Management and Therapy

1. Introduction

1.1. Methodology and Evidence Review
1.2. Organization of the Writing Committee
1.3. Document Review and Approval
1.4. Scope of the Guideline
1.5. Class of Recommendations and Level of Evidence
1.6. Abbreviations

2. Background and Pathophysiology

2.1. Epidemiology
2.2. Atrial Arrhythmia Classiﬁcation and Definitions
2.3. Mechanisms and Pathophysiology
2.4. Genetics
2.5. Addressing Health Inequities and Barriers to AF Management

3. Shared Decision-Making (SDM) in AF Management
4. Clinical Evaluation

4.1. Risk Stratification and Population Screening
4.2. Basic Evaluation

5. Lifestyle and Risk Factor Modification (LRFM) for AF Management

5.1. Primary Prevention
5.2. Secondary Prevention: Management of Comorbidities and Risk Factors

6. Prevention of Thromboembolism

6.1. Risk Stratiﬁcation Schemes
6.2. Risk-Based Selection of Oral Anticoagulation: Balancing Risks and Benefits
6.3. Oral Anticoagulants
6.4. Silent AF and Stroke of Undetermined Cause
6.5. Nonpharmacological Stroke Prevention
6.6. Active Bleeding on Anticoagulant Therapy and Reversal Drugs
6.7. Periprocedural Management
6.8. Anticoagulation in Specific Populations

7. Rate Control

7.1. Broad Considerations for Rate Control
7.2. Speciﬁc Pharmacological Agents for Rate Control
7.3. Atrioventricular Nodal Ablation (AVNA)

8. Rhythm Control

8.1. Goals of Therapy With Rhythm Control
8.2. Electrical and Pharmacological Cardioversion
8.3. Antiarrhythmic Drugs for Maintenance of Sinus Rhythm
8.4. AF Catheter Ablation
8.5. Role of Pacemakers and ICDs for the Prevention and Treatment of AF
8.6. Surgical Ablation

9. Management of Patients With HF

9.1. General Considerations for AF and HF
9.2. Management of AF in Patients With HF

10. AF and Specific Patient Groups

10.1. Management of Early Onset AF, Including Genetic Testing
10.2. Athletes
10.3. Management Considerations in Patients With AF and Obesity
10.4. Anticoagulation Considerations in Patients With Class III Obesity
10.5. AF and VHD
10.6. WPW and Preexcitation Syndromes
10.7. Hypertrophic Cardiomyopathy
10.8. Adult Congenital Heart Disease (ACHD)
10.9. Prevention and Treatment of AF After Cardiac Surgery
10.10. Acute Medical Illness or Surgery (Including AF in Critical Care)
10.11. Hyperthyroidism
10.12. Pulmonary Disease
10.13. Pregnancy
10.14. Cardio-Oncology and Anticoagulation Considerations
10.15. CKD and Kidney Failure
10.16. Anticoagulation Use in Patients With Liver Disease

11. Future Research Needs
Peer Review Committee Members
ACC/AHA Joint Committee on Clinical Practice Guidelines
Presidents and Staff
Article Information