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Canadian Journal of Cardiology

The 2020 Canadian Cardiovascular Society/Canadian Heart Rhythm Society Comprehensive Guidelines for the Management of Atrial Fibrillation

Published:October 22, 2020DOI:https://doi.org/10.1016/j.cjca.2020.09.001

      Abstract

      The Canadian Cardiovascular Society (CCS) atrial fibrillation (AF) guidelines program was developed to aid clinicians in the management of these complex patients, as well as to provide direction to policy makers and health care systems regarding related issues. The most recent comprehensive CCS AF guidelines update was published in 2010. Since then, periodic updates were published dealing with rapidly changing areas. However, since 2010 a large number of developments had accumulated in a wide range of areas, motivating the committee to complete a thorough guideline review. The 2020 iteration of the CCS AF guidelines represents a comprehensive renewal that integrates, updates, and replaces the past decade of guidelines, recommendations, and practical tips. It is intended to be used by practicing clinicians across all disciplines who care for patients with AF. The Grading of Recommendations, Assessment, Development and Evaluations (GRADE) system was used to evaluate recommendation strength and the quality of evidence. Areas of focus include: AF classification and definitions, epidemiology, pathophysiology, clinical evaluation, screening and opportunistic AF detection, detection and management of modifiable risk factors, integrated approach to AF management, stroke prevention, arrhythmia management, sex differences, and AF in special populations. Extensive use is made of tables and figures to synthesize important material and present key concepts. This document should be an important aid for knowledge translation and a tool to help improve clinical management of this important and challenging arrhythmia.

      Résumé

      Le programme de lignes directrices de la Société canadienne de cardiologie (SCC) en matière de fibrillation auriculaire (FA) a été élaboré pour aider les cliniciens à prendre en charge ces patients complexes, ainsi que pour orienter les décideurs politiques et les systèmes de soins de santé sur des questions connexes. La dernière édition complète des lignes directrices de la SCC en matière de FA a été publiée en 2010. Depuis lors, des mises à jour périodiques ont été publiées, traitant de domaines en évolution rapide. Cependant, en 2020, un grand nombre de développements s'y étaient ajoutés, couvrant un large éventail de domaines, ce qui a motivé le comité à créer une refonte complète des lignes directrices. L'édition 2020 des lignes directrices de la SCC en matière de FA représente un renouvellement complet qui intègre, met à jour et remplace les lignes directrices, les recommandations et les conseils pratiques des dix dernières années. Elle est destinée à être utilisée par les cliniciens praticiens de toutes les disciplines qui s'occupent de patients souffrant de FA. L'approche GRADE (Gradation des Recommandations, de l’Appréciation, du Développement et des Évaluations) a été utilisée pour évaluer la pertinence des recommandations et la qualité des résultats. Les domaines d'intérêt incluent : la classification et les définitions de la FA, son épidémiologie, sa physiopathologie, l’évaluation clinique, le dépistage de la FA, la détection et la gestion des facteurs de risque modifiables, l’approche intégrée de la gestion de la FA, la prévention des accidents vasculaires cérébraux, la gestion de l'arythmie, les différences entre les sexes et la FA dans des populations particulières. Des tableaux et figures ont été largement utilisés pour synthétiser les éléments importants et présenter les concepts clés. Ce document devrait représenter une aide importante pour l’intégration des connaissances et un outil pour aider à améliorer la gestion clinique de cette arythmie importante et difficile à traiter.
      Atrial fibrillation (AF), the most common sustained cardiac arrhythmia, is associated with reduced quality of life (QOL), functional status, cardiac performance, and survival. The contemporary management of AF is centred on symptomatic improvement, diminution in morbidity and mortality (particularly the prevention of cardiomyopathy, and stroke/systemic embolism), and reduction in AF-related emergency department (ED) visits or hospitalizations (Fig. 1).
      Figure thumbnail gr1
      Figure 1General overview of the management of atrial fibrillation (AF). CHADS-65, Canadian Cardiovascular Society algorithm; ED, emergency department; OAC, oral anticoagulation; LV, left ventricular; QOL, quality of life.
      The Canadian Cardiovascular Society (CCS) AF guidelines program was developed to aid clinicians in the management of these complex patients, as well as to provide direction to policy makers and health systems regarding the management of patients with AF. Beginning with the 1994 CCS consensus conference on AF, the CCS AF guidelines program has provided comprehensive guideline updates in 2004 and 2010, with focused updates on the basis of emerging evidence in 2012, 2014, 2016, and 2018.
      Canadian Cardiovascular Society Consensus Conference on Atrial Fibrillation.
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      • Andrade J.G.
      • Verma A.
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      • et al.
      2018 Focused update of the Canadian Cardiovascular Society guidelines for the management of atrial fibrillation.
      The 2020 iteration of the CCS AF guidelines is a comprehensive renewal that integrates, updates, and replaces the past decade of guidelines, recommendations, and practical tips. It is intended to be used by practicing clinicians across all disciplines who care for patients with AF.
      The 2020 comprehensive AF guidelines address the following topics:
      • 1.
        Classification and Definitions
      • 2.
        Epidemiology
      • 3.
        Pathophysiology
      • 4.
        Clinical Evaluation
      • 5.
        Screening and Opportunistic AF Detection
      • 6.
        Detection and Management of Modifiable Risk Factors
      • 7.
        Integrated Approach to AF management
      • 8.
        Stroke Prevention
      • 9.
        Arrhythmia Management
      • 10.
        Sex Differences
      • 11.
        AF and Special Populations

      Preamble and Guideline Development Methodology

      This document was developed in accordance with CCS best practices and the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach.
      • Guyatt G.H.
      • Oxman A.D.
      • Vist G.E.
      • et al.
      GRADE: an emerging consensus on rating quality of evidence and strength of recommendations.
      The primary panelists developed the scope of the document, identified topics for review, performed the literature review, evaluated the quality of the evidence, and drafted the recommendations. A systematic search was performed to identify relevant studies within each topic, including systematic reviews and meta-analyses. Draft recommendations were presented, reviewed, and refined by the primary panel. Final review was performed by the primary and secondary panels, with each recommendation achieving more than 90% agreement.
      Strength of recommendations and quality of evidence were evaluated according to the GRADE approach. Evidence derived from randomized clinical trials (RCTs) was initially estimated as high-quality evidence, with observational evidence initially deemed low-quality evidence. These estimates were further refined through detailed appraisal into 4 categorical grades (“high,” “moderate,” “low,” and “very low”) after consideration of the risk of bias, confounding, consistency of results, directness of evidence, precision, publication bias, magnitude of effect, and dose-response gradient. After this evaluation, the strength of recommendation was determined by considering the balance between desirable and undesirable effects (ie, risk-benefit), confidence in the magnitude of effect (quality of evidence), patient values and preferences, as well as resource considerations. The strength of recommendation was graded as “strong” (the desirable effects outweigh the undesirable effects, and therefore, most individuals will be best served by the recommended course of action) or “weak” (the desirable effects probably outweigh the undesirable effects, indicating that there is a need to consider the individual patient’s clinical details, circumstances, values, and preferences).
      Peer review of the guideline document was provided by external content experts, patient partners, and the CCS Guidelines Committee (outlined in the Acknowledgements section). The final draft was presented and approved by the CCS Executive Committee. For the constitution and roles of the primary and secondary panels, systematic review strategy, methods for formulating the recommendations, and evidence see the Supplementary Material and www.ccs.ca.

      1. Classification and Definitions

      1.1 Classification on the basis of clinical pattern of AF

      AF pattern is defined on the basis of clinical assessment of episode persistence. These patterns have been used to characterize the severity of disease, define patient populations in clinical trials, and are used to form the basis of therapeutic recommendations regarding pharmacological and invasive arrhythmia management.
      • Andrade J.G.
      • Macle L.
      • Nattel S.
      • Verma A.
      • Cairns J.
      Contemporary atrial fibrillation management: a comparison of the current AHA/ACC/HRS, CCS, and ESC guidelines.
      Four main clinical patterns of AF have been described. Paroxysmal AF is defined as a continuous AF episode lasting longer than 30 seconds but terminating within 7 days of onset. Persistent AF is defined as a continuous AF episode lasting longer than 7 days but less than 1 year. “Longstanding” persistent AF is defined as continuous AF ≥ 1 year in duration, in patients in whom rhythm control management is being pursued. Permanent AF is defined as continuous AF for which a therapeutic decision has been made not to pursue sinus rhythm restoration. The mode of termination (spontaneous vs pharmacological/electrical cardioversion) does not influence the classification.
      In many patients, AF progresses from short episodes of self-terminating paroxysmal AF to more frequent exacerbations of longer-lasting persistent AF. In the event that both paroxysmal and persistent episodes are present, the classification should be defined on the basis of the predominant AF pattern.
      Although valuable, there are limitations to classifying AF patterns by clinical assessment. First, the distinction between paroxysmal and persistent AF is often inaccurate, because clinical assessment often underestimates the temporal persistence of AF/AF burden compared with long-term electrocardiogram (ECG) monitoring.
      • Charitos E.I.
      • Ziegler P.D.
      • Stierle U.
      • et al.
      Atrial fibrillation burden estimates derived from intermittent rhythm monitoring are unreliable estimates of the true atrial fibrillation burden.
      • Charitos E.I.
      • Purerfellner H.
      • Glotzer T.V.
      • Ziegler P.D.
      Clinical classifications of atrial fibrillation poorly reflect its temporal persistence: insights from 1,195 patients continuously monitored with implantable devices.
      • Andrade J.G.
      • Yao R.R.J.
      • Deyell M.W.
      • et al.
      Clinical assessment of AF pattern is poorly correlated with AF burden and post ablation outcomes: a CIRCA-DOSE sub-study.
      Second, although the AF patterns have been associated with adverse outcomes (eg, heart failure [HF], stroke, and death), there remains uncertainty regarding their independent role of these clinical patterns to predict response to therapy (eg, antiarrhythmic drugs or catheter ablation).
      • Andrade J.G.
      • Yao R.R.J.
      • Deyell M.W.
      • et al.
      Clinical assessment of AF pattern is poorly correlated with AF burden and post ablation outcomes: a CIRCA-DOSE sub-study.
      • Banerjee A.
      • Taillandier S.
      • Olesen J.B.
      • et al.
      Pattern of atrial fibrillation and risk of outcomes: the Loire Valley Atrial Fibrillation Project.
      • Vanassche T.
      • Lauw M.N.
      • Eikelboom J.W.
      • et al.
      Risk of ischaemic stroke according to pattern of atrial fibrillation: analysis of 6563 aspirin-treated patients in ACTIVE-A and AVERROES.
      • Atar D.
      • Berge E.
      • Le Heuzey J.Y.
      • et al.
      The association between patterns of atrial fibrillation, anticoagulation, and cardiovascular events.
      • Andrade J.G.
      • Deyell M.W.
      • Verma A.
      • et al.
      Association of atrial fibrillation episode duration with arrhythmia recurrence following ablation: a secondary analysis of a randomized clinical trial.

      1.2 Classification on the basis of pathophysiological pattern of AF

      The likelihood of developing AF varies across physiological and pathological states. Despite similar clinical patterns the mechanisms underpinning AF vary substantially between patients. Within this context AF may be considered “primary” if the AF represents an established pathophysiological process or “secondary” if caused by a self-limited or acutely reversible precipitant (Figs. 2 and 3A ).
      • Quon M.J.
      • Pilote L.
      Is secondary atrial fibrillation different? Or Is atrial fibrillation just atrial fibrillation?.
      “Primary AF” should not be considered analogous to the antiquated term, “lone AF,” which previously defined AF without known cause.
      • Wyse D.G.
      • Van Gelder I.C.
      • Ellinor P.T.
      • et al.
      Lone atrial fibrillation: does it exist?.
      Common causes of secondary AF include surgery, sepsis, acute myocardial infarction (MI), thyrotoxicosis, or acute pulmonary disease. Secondary AF can be further dichotomized on the basis of the underlying cardiac substrate and risk for AF recurrence into “reversible” or “provoked” AF.
      • Cheung C.C.
      • Andrade J.G.
      Reversible or provoked atrial fibrillation?: The devil in the details.
      Specifically, “reversible AF” defines AF that occurs solely secondary to an acute illness, with little to no abnormal underlying substrate and therefore limited future risk of AF. In contrast, “provoked AF” represents AF that is unmasked by the acute illness, occurring in patients with significant abnormal underlying substrate, and therefore ongoing risk for AF recurrence (Fig. 3, B and C). Examples of the former category include patients with hyperthyroidism or alcohol intoxication (“holiday heart”) in the absence of previous heart disease or risk factors, and the latter would include patients developing AF after mitral valve surgery or in the context of a chronic obstructive pulmonary disease (COPD) exacerbation. These concepts are explored in greater depth in section 8.3.6.
      Figure thumbnail gr2
      Figure 2A conceptual model of the life cycle of atrial fibrillation (AF). Early in its course AF is a disease of focal triggers that can be genetically determined. As patients grow older the contribution of abnormal substrate predominates, including nonmodifiable substrate related to age, sex, and genetically determined factors, modifiable substrate related to reversible risk factors (eg, hypertension), as well as substrate induced by the AF episodes themselves. In this model, control of the arrhythmia and therapies directed at cardiovascular risk reduction are complementary for control of the arrhythmia.
      Figure thumbnail gr3
      Figure 3Secondary atrial fibrillation (AF). (A) Components of AF susceptibility include the baseline modifiable substrate, nonmodifiable substrate, and substrate induced by AF triggers (as outlined in ), as well as new substrate/transient triggers induced by the reversible event (eg, cardiac surgery). A reversible event might only transiently induce substrate or lead to new permanent substrate. In this model, if the sum of the substrate allows the trigger to reach threshold then an AF event might occur. Whether or not the AF recurs is a function of the baseline substrate and any new permanent substrate added by the trigger event. (B) “Reversible AF” defines AF that occurs solely secondary to an acute illness, with little to no abnormal underlying substrate and, therefore, limited future risk of AF. (C) In contrast, “provoked AF” represents AF that is unmasked by the acute illness, occurring in patients with significant abnormal underlying substrate and, therefore, ongoing risk for AF recurrence. ANS, autonomic nervous system; HTN, hypertension; OSA, obstructive sleep apnea.

      1.3 Valvular and nonvalvular AF

      The term, “nonvalvular AF” (NVAF) dates back to the late 1970s and was used interchangeably with nonrheumatic AF. This early distinction was on the basis of the observation of the high risk of stroke/systemic embolism associated with severe mitral stenosis. More recently this distinction was used to define candidacy for participation in the landmark phase III trials in which non-vitamin K direct-acting oral anticoagulants (DOACs) were compared with vitamin K antagonists (VKAs) for stroke prevention in patients with NVAF.
      • Connolly S.J.
      • Ezekowitz M.D.
      • Yusuf S.
      • et al.
      Dabigatran versus warfarin in patients with atrial fibrillation.
      • Patel M.R.
      • Mahaffey K.W.
      • Garg J.
      • et al.
      Rivaroxaban versus warfarin in nonvalvular atrial fibrillation.
      • Granger C.B.
      • Alexander J.H.
      • McMurray J.J.
      • et al.
      Apixaban versus warfarin in patients with atrial fibrillation.
      • Connolly S.J.
      • Eikelboom J.
      • Joyner C.
      • et al.
      Apixaban in patients with atrial fibrillation.
      • Giugliano R.P.
      • Ruff C.T.
      • Braunwald E.
      • et al.
      Edoxaban versus warfarin in patients with atrial fibrillation.
      Although previous iterations of the CCS AF guidelines have considered rheumatic mitral stenosis, mitral valve repair, mechanical heart valves, and bioprosthetic heart valves to constitute valvular heart disease, the definition of “valvular AF” has continued to evolve on the basis of emerging evidence.
      • Verma A.
      • Cairns J.A.
      • Mitchell L.B.
      • et al.
      2014 focused update of the Canadian Cardiovascular Society Guidelines for the management of atrial fibrillation.
      ,
      • Macle L.
      • Cairns J.A.
      • Andrade J.G.
      • et al.
      The 2014 atrial fibrillation guidelines companion: a practical approach to the use of the Canadian Cardiovascular Society guidelines.
      • Noseworthy P.A.
      • Yao X.
      • Shah N.D.
      • Gersh B.J.
      Comparative effectiveness and safety of non-vitamin K antagonist oral anticoagulants versus warfarin in patients with atrial fibrillation and valvular heart disease.
      • Siontis K.C.
      • Yao X.
      • Gersh B.J.
      • Noseworthy P.A.
      Direct oral anticoagulants in patients with atrial fibrillation and valvular heart disease other than significant mitral stenosis and mechanical valves: a meta-analysis.
      ,
      • Guimarães H.P.
      • Lopes R.D.
      • de Barros E.
      • Silva P.G.M.
      • et al.
      RIVER Trial Investigators. Rivaroxaban in patients with atrial fibrillation and a bioprosthetic mitral valve.
      The current definition of “valvular AF” is limited to AF in the presence of any mechanical heart valve, or in the presence of moderate to severe mitral stenosis (rheumatic or nonrheumatic).

      2. Epidemiology

      2.1 Incidence and prevalence

      AF is the most common sustained arrhythmia encountered in clinical practice.
      • Andrade J.
      • Khairy P.
      • Dobrev D.
      • Nattel S.
      The clinical profile and pathophysiology of atrial fibrillation: relationships among clinical features, epidemiology, and mechanisms.
      Current evidence suggests that the prevalence of AF is 1%-2% in the general population, and increases significantly with age (< 1.0% up to 50 years of age, to 4% at 65 years, and 12% of those 80 years of age or older).
      • Andrade J.
      • Khairy P.
      • Dobrev D.
      • Nattel S.
      The clinical profile and pathophysiology of atrial fibrillation: relationships among clinical features, epidemiology, and mechanisms.
      ,
      • Kannel W.B.
      • Wolf P.A.
      • Benjamin E.J.
      • Levy D.
      Prevalence, incidence, prognosis, and predisposing conditions for atrial fibrillation: population-based estimates.
      Although the incidence has been relatively stable over time (approximately 28 per 1000 person-years), the overall prevalence of AF is increasing because of changing population demographics (eg, from 41 cases per 1000 in 1993 to 85 cases per 1000 in 2007).
      • Andrade J.
      • Khairy P.
      • Dobrev D.
      • Nattel S.
      The clinical profile and pathophysiology of atrial fibrillation: relationships among clinical features, epidemiology, and mechanisms.
      ,
      • Piccini J.P.
      • Hammill B.G.
      • Sinner M.F.
      • et al.
      Incidence and prevalence of atrial fibrillation and associated mortality among Medicare beneficiaries, 1993-2007.
      However, the true prevalence of AF is likely to be substantially higher than 1-2%, as these historical estimates were derived from populations with AF diagnosed using ECG, and did not routinely account for patients with paroxysmal AF (which is estimated to be approximately two-thirds of the AF population) or patients with silent AF.
      • Kannel W.B.
      • Abbott R.D.
      • Savage D.D.
      • McNamara P.M.
      Epidemiologic features of chronic atrial fibrillation: the Framingham study.
      • Furberg C.D.
      • Psaty B.M.
      • Manolio T.A.
      • et al.
      Prevalence of atrial fibrillation in elderly subjects (the Cardiovascular Health Study).
      • Rietbrock S.
      • Heeley E.
      • Plumb J.
      • van Staa T.
      Chronic atrial fibrillation: incidence, prevalence, and prediction of stroke using the Congestive heart failure, Hypertension, Age >75, Diabetes mellitus, and prior Stroke or transient ischemic attack (CHADS2) risk stratification scheme.
      • Chiang C.E.
      • Naditch-Brule L.
      • Murin J.
      • et al.
      Distribution and risk profile of paroxysmal, persistent, and permanent atrial fibrillation in routine clinical practice: insight from the real-life global survey evaluating patients with atrial fibrillation international registry.
      When factoring in patients with paroxysmal and silent AF, the prevalence of AF increases from 500,000 to nearly 1 million Canadians.
      • Go A.S.
      • Hylek E.M.
      • Phillips K.A.
      • et al.
      Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study.
      ,
      • Miyasaka Y.
      • Barnes M.E.
      • Gersh B.J.
      • et al.
      Secular trends in incidence of atrial fibrillation in Olmsted County, Minnesota, 1980 to 2000, and implications on the projections for future prevalence.

      2.2 Morbidity and mortality

      Although rarely acutely life-threatening, AF is associated with significant impairments in functional capacity and health-related quality of life (HRQOL), as well as with an increased morbidity and mortality. These impairments have been noted across multiple HRQOL domains, with a magnitude comparable or worse than that observed in patients with HF or who are on long-term hemodialysis.
      • Dorian P.
      • Jung W.
      • Newman D.
      • et al.
      The impairment of health-related quality of life in patients with intermittent atrial fibrillation: implications for the assessment of investigational therapy.
      • Savelieva I.
      • Paquette M.
      • Dorian P.
      • Luderitz B.
      • Camm A.J.
      Quality of life in patients with silent atrial fibrillation.
      • Singh S.N.
      • Tang X.C.
      • Singh B.N.
      • et al.
      Quality of life and exercise performance in patients in sinus rhythm versus persistent atrial fibrillation: a Veterans Affairs Cooperative Studies Program substudy.
      • Thrall G.
      • Lane D.
      • Carroll D.
      • Lip G.Y.
      Quality of life in patients with atrial fibrillation: a systematic review.
      • Kang Y.
      Relation of atrial arrhythmia-related symptoms to health-related quality of life in patients with newly diagnosed atrial fibrillation: a community hospital-based cohort.
      Even in the absence of perceived symptoms, AF patients objectively experience reduced global life satisfaction.
      • Dorian P.
      • Jung W.
      • Newman D.
      • et al.
      The impairment of health-related quality of life in patients with intermittent atrial fibrillation: implications for the assessment of investigational therapy.
      AF is independently associated with a 1.5- to 4-fold increased risk of mortality, which is predominantly due to increased risk of thromboembolic events and ventricular dysfunction.
      • Piccini J.P.
      • Hammill B.G.
      • Sinner M.F.
      • et al.
      Incidence and prevalence of atrial fibrillation and associated mortality among Medicare beneficiaries, 1993-2007.
      ,
      • Singh S.N.
      • Tang X.C.
      • Singh B.N.
      • et al.
      Quality of life and exercise performance in patients in sinus rhythm versus persistent atrial fibrillation: a Veterans Affairs Cooperative Studies Program substudy.
      ,
      • Wolf P.A.
      • Mitchell J.B.
      • Baker C.S.
      • Kannel W.B.
      • D’Agostino R.B.
      Impact of atrial fibrillation on mortality, stroke, and medical costs.
      • Andersson T.
      • Magnuson A.
      • Bryngelsson I.L.
      • et al.
      All-cause mortality in 272,186 patients hospitalized with incident atrial fibrillation 1995-2008: a Swedish nationwide long-term case-control study.
      • Benjamin E.J.
      • Virani S.S.
      • Callaway C.W.
      • et al.
      Heart disease and stroke statistics-2018 update: a report from the American Heart Association.
      • Lee E.
      • Choi E.K.
      • Han K.D.
      • et al.
      Mortality and causes of death in patients with atrial fibrillation: a nationwide population-based study.
      Nonanticoagulated patients with AF have a 3- to 5-fold increased risk of stroke, which are generally more severe (greater resource utilization, long-term disability, and mortality) and more recurrent than strokes unrelated to AF.
      • Wolf P.A.
      • Mitchell J.B.
      • Baker C.S.
      • Kannel W.B.
      • D’Agostino R.B.
      Impact of atrial fibrillation on mortality, stroke, and medical costs.
      ,
      • Petty G.W.
      • Brown Jr., R.D.
      • Whisnant J.P.
      • et al.
      Ischemic stroke subtypes: a population-based study of functional outcome, survival, and recurrence.
      • Bruggenjurgen B.
      • Rossnagel K.
      • Roll S.
      • et al.
      The impact of atrial fibrillation on the cost of stroke: the Berlin Acute Stroke study.
      • Gladstone D.J.
      • Bui E.
      • Fang J.
      • et al.
      Potentially preventable strokes in high-risk patients with atrial fibrillation who are not adequately anticoagulated.
      • Healey J.S.
      • Connolly S.J.
      • Gold M.R.
      • et al.
      Subclinical atrial fibrillation and the risk of stroke.
      To date, the only therapeutic intervention that has been consistently and definitively shown to improve survival in the AF population is the use of oral anticoagulation (OAC; see section 8).
      • Hart R.G.
      • Pearce L.A.
      • Aguilar M.I.
      Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation.
      ,
      • Ruff C.T.
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      • Braunwald E.
      • et al.
      Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials.
      Strategies targeting modifiable cardiovascular risk factors and relevant comorbid conditions offer potential opportunities to further improve survival (see sections 3 and 6).

      2.3 Health care resource utilization

      The economic burden of AF care is substantial. A significant proportion of AF health care expenses are attributed to the direct costs associated with hospitalization and the provision of acute care.
      • Andrade J.
      • Khairy P.
      • Dobrev D.
      • Nattel S.
      The clinical profile and pathophysiology of atrial fibrillation: relationships among clinical features, epidemiology, and mechanisms.
      ,
      • Stewart S.
      • Murphy N.F.
      • Walker A.
      • McGuire A.
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      Cost of an emerging epidemic: an economic analysis of atrial fibrillation in the UK.
      • Humphries K.H.
      • Jackevicius C.
      • Gong Y.
      • et al.
      Population rates of hospitalization for atrial fibrillation/flutter in Canada.
      • Wu E.Q.
      • Birnbaum H.G.
      • Mareva M.
      • et al.
      Economic burden and co-morbidities of atrial fibrillation in a privately insured population.
      • Lee W.C.
      • Lamas G.A.
      • Balu S.
      • et al.
      Direct treatment cost of atrial fibrillation in the elderly American population: a Medicare perspective.
      • Kim M.H.
      • Lin J.
      • Hussein M.
      • Kreilick C.
      • Battleman D.
      Cost of atrial fibrillation in United States managed care organizations.
      • O’Reilly D.J.
      • Hopkins R.B.
      • Healey J.S.
      • et al.
      The burden of atrial fibrillation on the hospital sector in Canada.
      • Meyre P.
      • Blum S.
      • Berger S.
      • et al.
      Risk of hospital admissions in patients with atrial fibrillation: a systematic review and meta-analysis.
      In Canada, AF resulted in 8815 same-day procedures, 76,964 ED visits, and 64,214 acute care admissions (25,892 with AF as the principal diagnosis and 38,222 with AF as a comorbid diagnosis) in the 2007-2008 fiscal year. The annual direct cost of AF care adjusted to 2020 Canadian dollars (CAD$) was $956 million: $66 million for ED visits with AF as the principal diagnosis and $20 million with comorbid AF; $204 million for hospitalization with AF as the principal diagnosis and $634 million with comorbid AF; and $32 million for AF-related day procedures.
      • O’Reilly D.J.
      • Hopkins R.B.
      • Healey J.S.
      • et al.
      The burden of atrial fibrillation on the hospital sector in Canada.
      On a per-patient basis, the excess annual direct cost of AF has been estimated to be $16,944-$19,529 (adjusted 2020 US dollars).
      • Wu E.Q.
      • Birnbaum H.G.
      • Mareva M.
      • et al.
      Economic burden and co-morbidities of atrial fibrillation in a privately insured population.
      ,
      • Lee W.C.
      • Lamas G.A.
      • Balu S.
      • et al.
      Direct treatment cost of atrial fibrillation in the elderly American population: a Medicare perspective.
      In addition to these direct costs, the annual indirect costs (eg, days of work missed because of illness) have been estimated to be $3082 higher for AF patients compared with those without AF.
      • Kim M.H.
      • Lin J.
      • Hussein M.
      • Kreilick C.
      • Battleman D.
      Cost of atrial fibrillation in United States managed care organizations.
      It is important to recognize that the cost of care is not uniform across the spectrum of AF. Specifically, the annual inpatient and outpatient direct costs are more than twice as high for patients with “primary AF” compared with patients with “secondary AF” (see section 1.2).
      • Kim M.H.
      • Lin J.
      • Hussein M.
      • Kreilick C.
      • Battleman D.
      Cost of atrial fibrillation in United States managed care organizations.

      3. Pathophysiology and Risk Factors

      AF is a complex and multifaceted condition ranging from an isolated electrophysiological disorder or, more commonly, a manifestation or consequence of other cardiac and noncardiac pathologies (Table 1, Fig. 2).
      • Wyse D.G.
      • Van Gelder I.C.
      • Ellinor P.T.
      • et al.
      Lone atrial fibrillation: does it exist?.
      AF generally results from a combination of focal ectopic activity and reentry.
      • Andrade J.
      • Khairy P.
      • Dobrev D.
      • Nattel S.
      The clinical profile and pathophysiology of atrial fibrillation: relationships among clinical features, epidemiology, and mechanisms.
      ,
      • Nattel S.
      New ideas about atrial fibrillation 50 years on.
      Ectopic atrial foci arise from perturbations that cause cells to spontaneously depolarize, either secondary to enhanced automaticity or, more frequently, to triggered activity from afterdepolarizations. Discrete abnormalities in Ca2+ handling have been identified as centrally involved in afterdepolarization generation in paroxysmal and persistent AF, as well as postoperative AF (POAF).
      • Voigt N.
      • Heijman J.
      • Wang Q.
      • et al.
      Cellular and molecular mechanisms of atrial arrhythmogenesis in patients with paroxysmal atrial fibrillation.
      ,
      • Voigt N.
      • Li N.
      • Wang Q.
      • et al.
      Enhanced sarcoplasmic reticulum Ca2+ leak and increased Na+-Ca2+ exchanger function underlie delayed afterdepolarizations in patients with chronic atrial fibrillation.
      There is emerging evidence that inflammatory signalling plays a key role in promoting afterdepolarization generation, as well as other components of AF pathophysiology.
      • Yao C.
      • Veleva T.
      • Scott Jr., L.
      • et al.
      Enhanced cardiomyocyte NLRP3 inflammasome signaling promotes atrial fibrillation.
      These repetitive rapid discharges predominantly originate from the pulmonary veins (PVs), which are a vulnerable region for triggered activity and micro reentry due to the shorter action potential duration, lower resting membrane potentials, and nonuniform myofibril arrangement.
      • Nishida K.
      • Datino T.
      • Macle L.
      • Nattel S.
      Atrial fibrillation ablation: translating basic mechanistic insights to the patient.
      When triggered, AF can be maintained by sustained rapid firing of focal impulses that disorganize into fibrillatory waves at their periphery or, in most cases, AF perpetuating reentry. Reentry requires specific conditions for initiation and maintenance. Although reentry is not sustained in the normal atrium, the presence of a vulnerable substrate can perpetuate AF through electrical heterogeneity (eg, regional differences in resting membrane potentials, refractory periods, action potential duration, and conduction velocities). In addition, conduction abnormalities can promote reentrant activity and stabilize reentrant circuits by creating functional barriers that allow recovery of tissue excitability. Structural abnormalities such as atrial fibrosis promote reentry through localized conduction slowing and structural conduction barriers, with atrial chamber dilatation promoting reentry through maintenance of the balance between rotor formation and rotor annihilation.
      Table 1Risk markers and comorbid conditions associated with AF
      Established risk factors
      • Advancing age
      • Male sex
      • Hypertension
      • HF with reduced ejection fraction
      • Valvular heart disease
      • Overt thyroid disease
      • Obstructive sleep apnea
      • Obesity
      • Excessive alcohol intake
      • Congenital heart disease (eg, early repair of atrial septal defect)
      Emerging risk factors
      • Prehypertension and increased pulse pressure
      • Chronic obstructive pulmonary disease
      • HF with preserved ejection fraction
      • Subclinical hyperthyroidism
      • Coronary artery disease
      • Morphometric (increased height, increased birth weight)
      Potential risk factors
      • Familial/genetic factors
      • Tobacco use
      • Left atrial dilatation
      • LV hypertrophy
      • Inflammation
      • Diabetes
      • Pericardial fat
      • Subclinical atherosclerosis
      • Chronic kidney disease
      • Excessive endurance exercise
      • Electrocardiographic (atrial conduction delay, PR interval prolongation)
      AF, atrial fibrillation; HF, heart failure; LV, left ventricular.
      Recently, there has been a renewed focus on the contribution of modifiable cardiovascular risk factors to the causation of AF, because an improved understanding of this relationship is key to providing effective personalized primary and secondary prevention measures.
      • Andrade J.
      • Khairy P.
      • Dobrev D.
      • Nattel S.
      The clinical profile and pathophysiology of atrial fibrillation: relationships among clinical features, epidemiology, and mechanisms.
      ,
      • Pathak R.K.
      • Middeldorp M.E.
      • Lau D.H.
      • et al.
      Aggressive risk factor reduction study for atrial fibrillation and implications for the outcome of ablation: the ARREST-AF cohort study.
      ,
      • Lau D.H.
      • Nattel S.
      • Kalman J.M.
      • Sanders P.
      Modifiable risk factors and atrial fibrillation.
      Although the precise mechanistic links between risk factors and AF occurrence remain somewhat uncertain, information available from the literature provides many potential insights.
      • Andrade J.
      • Khairy P.
      • Dobrev D.
      • Nattel S.
      The clinical profile and pathophysiology of atrial fibrillation: relationships among clinical features, epidemiology, and mechanisms.
      Hypertension, the most significant population-attributable modifiable risk factor for AF, causes activation of the sympathetic and renin-angiotensin-aldosterone systems as well as structural and electrophysiological atrial remodelling that enhances AF susceptibility. Diabetes mellitus promotes AF via structural and autonomic remodelling. Tobacco use promotes AF through a combination of the direct effects of nicotine on the atrium (eg, altered atrial conduction and refractoriness) along with structural remodelling, inflammation, and oxidative stress. Alcohol, when consumed in excess, promotes AF through the induction of arrhythmia triggers (increased sympathetic activity/impairment of vagal tone) as well as atrial fibrosis (from the direct toxic effects of alcohol metabolites). Obesity promotes AF through weight-related structural (changes in atrial dimensions and interstitial fibrosis) and electrophysiological remodelling (conduction slowing and shortening of the effective refractory period), autonomic dysfunction, and inflammation. Obstructive sleep apnea (OSA) promotes AF acutely through strongly negative intrathoracic pressures leading to increased venous return (AF-promoting left atrial [LA] volume loading) and hypoxia-induced pulmonary vasoconstriction. Chronic OSA induces electrical and structural remodelling of the atria, autonomic dysregulation, oxidative stress, and inflammation. Regular exercise protects against AF by combating risk factors like obesity and metabolic syndrome but sustained intense exercise might promote AF occurrence (see section 11.3).
      The relationship between key risk factors and AF are outlined in Table 2.
      Table 2The relationship between AF and modifiable and nonmodifiable risk factors
      Risk factorRole in AFMechanism
      HypertensionHypertension is a strong and independent predictor of incident AF
      • Kannel W.B.
      • Wolf P.A.
      • Benjamin E.J.
      • Levy D.
      Prevalence, incidence, prognosis, and predisposing conditions for atrial fibrillation: population-based estimates.


      AF incidence is linearly related to BP, with increased risk noted even in the prehypertensive range (adjusted HR, 1.3 for systolic BP 130-139 mm Hg vs < 120 mm Hg)
      • Mitchell G.F.
      • Vasan R.S.
      • Keyes M.J.
      • et al.
      Pulse pressure and risk of new-onset atrial fibrillation.
      ,
      • Conen D.
      • Tedrow U.B.
      • Koplan B.A.
      • et al.
      Influence of systolic and diastolic blood pressure on the risk of incident atrial fibrillation in women.


      Increased pulse pressure has been associated with an increased AF risk (adjusted HR, 1.25 per 20 mm Hg increase)
      • Mitchell G.F.
      • Vasan R.S.
      • Keyes M.J.
      • et al.
      Pulse pressure and risk of new-onset atrial fibrillation.
      Hypertension might induce AF through:
      • Neurohormonal activation (sympathetic nervous system and the renin-angiotensin-aldosterone system)
      • Structural remodelling (atrial fibrosis)
      • Electrical remodelling (conduction disturbances)
      DiabetesDiabetes has been associated with approximately a 1.5 times increased risk of AF
      • Watanabe H.
      • Tanabe N.
      • Watanabe T.
      • et al.
      Metabolic syndrome and risk of development of atrial fibrillation: the Niigata preventive medicine study.
      ,
      • Dublin S.
      • Glazer N.L.
      • Smith N.L.
      • et al.
      Diabetes mellitus, glycemic control, and risk of atrial fibrillation.


      AF risk is independently associated with a longer duration of treated diabetes (3% increased risk for each additional year of diabetes) and with worse glycemic control (13% increased risk with each 1% increase in HbA1c; and 33% increased risk with each 1 mmol/L increase in fasting glucose)
      • Dublin S.
      • Glazer N.L.
      • Smith N.L.
      • et al.
      Diabetes mellitus, glycemic control, and risk of atrial fibrillation.
      • Psaty B.M.
      • Manolio T.A.
      • Kuller L.H.
      • et al.
      Incidence of and risk factors for atrial fibrillation in older adults.
      • Huxley R.R.
      • Alonso A.
      • Lopez F.L.
      • et al.
      Type 2 diabetes, glucose homeostasis and incident atrial fibrillation: the Atherosclerosis Risk in Communities study.
      • Latini R.
      • Staszewsky L.
      • Sun J.L.
      • et al.
      Incidence of atrial fibrillation in a population with impaired glucose tolerance: the contribution of glucose metabolism and other risk factors. A post hoc analysis of the Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research trial.
      • Chang S.H.
      • Wu L.S.
      • Chiou M.J.
      • et al.
      Association of metformin with lower atrial fibrillation risk among patients with type 2 diabetes mellitus: a population-based dynamic cohort and in vitro studies.


      Coexistence of AF and diabetes portends a worsened prognosis, increasing all-cause mortality, cardiovascular death, and HF
      • Fatemi O.
      • Yuriditsky E.
      • Tsioufis C.
      • et al.
      Impact of intensive glycemic control on the incidence of atrial fibrillation and associated cardiovascular outcomes in patients with type 2 diabetes mellitus (from the Action to Control Cardiovascular Risk in Diabetes Study).
      Diabetes might induce AF through:
      • Structural remodelling (atrial fibrosis)
      • Electrical remodelling (conduction slowing)
      • Autonomic remodelling
      TobaccoTobacco use has been associated with increased risk
      • Kannel W.B.
      • Wolf P.A.
      • Benjamin E.J.
      • Levy D.
      Prevalence, incidence, prognosis, and predisposing conditions for atrial fibrillation: population-based estimates.
      ,
      • Heeringa J.
      • Kors J.A.
      • Hofman A.
      • van Rooij F.J.
      • Witteman J.C.
      Cigarette smoking and risk of atrial fibrillation: the Rotterdam Study.
      • Chamberlain A.M.
      • Agarwal S.K.
      • Folsom A.R.
      • et al.
      Smoking and incidence of atrial fibrillation: results from the Atherosclerosis Risk in Communities (ARIC) study.
      • Suzuki S.
      • Otsuka T.
      • Sagara K.
      • et al.
      Association between smoking habits and the first-time appearance of atrial fibrillation in Japanese patients: evidence from the Shinken Database.
      • Active smokers have a higher risk than former smokers
      • Risk is linked to cumulative exposure (greatest risk in the highest tertile, > 675 cigarette-years)
      Continued tobacco use is associated with worse outcomes after catheter ablation
      • Smit M.D.
      • Maass A.H.
      • De Jong A.M.
      • et al.
      Role of inflammation in early atrial fibrillation recurrence.


      Pooled analyses have not established a relationship between smokeless tobacco products and AF, and there are limited data regarding electronic cigarettes or secondhand smoke
      • Hergens M.P.
      • Galanti R.
      • Hansson J.
      • et al.
      Use of Scandinavian moist smokeless tobacco (snus) and the risk of atrial fibrillation.
      Tobacco use might induce AF through:
      • Electrical remodelling (altered atrial conduction and refractoriness [direct effects of nicotine])
      • Structural remodelling (atrial fibrosis)
      • Inflammation and oxidative stress
      AlcoholAcute paroxysms of AF have been reported after binge consumption (> 5 standard drinks on a single occasion; “holiday heart” syndrome)
      • Liang Y.
      • Mente A.
      • Yusuf S.
      • et al.
      Alcohol consumption and the risk of incident atrial fibrillation among people with cardiovascular disease.
      • Tonelo D.
      • Providencia R.
      • Goncalves L.
      Holiday heart syndrome revisited after 34 years.
      • Larsson S.C.
      • Drca N.
      • Wolk A.
      Alcohol consumption and risk of atrial fibrillation: a prospective study and dose-response meta-analysis.


      Heavy habitual consumption has been associated with risk of incident AF in a dose-dependent relationship (8% increase in incident AF with each additional drink per day)
      • Liang Y.
      • Mente A.
      • Yusuf S.
      • et al.
      Alcohol consumption and the risk of incident atrial fibrillation among people with cardiovascular disease.
      ,
      • Larsson S.C.
      • Drca N.
      • Wolk A.
      Alcohol consumption and risk of atrial fibrillation: a prospective study and dose-response meta-analysis.
      ,
      • Mukamal K.J.
      • Tolstrup J.S.
      • Friberg J.
      • Jensen G.
      • Gronbaek M.
      Alcohol consumption and risk of atrial fibrillation in men and women: the Copenhagen City Heart study.


      Patients with established AF who continue to consume alcohol have higher rates of progression (eg, paroxysmal to persistent AF), and experience more AF recurrences after cardioversion or ablation
      • Ruigomez A.
      • Johansson S.
      • Wallander M.A.
      • Garcia Rodriguez L.A.
      Predictors and prognosis of paroxysmal atrial fibrillation in general practice in the UK.
      Alcohol use might induce AF through:
      • Neurohormonal activation (increased sympathetic activity, impairment of vagal tone)
      • Electrical remodelling (increase in inter- and intra-atrial conduction time, shortening of atrial effective refractory period)
      • Structural remodelling (atrial fibrosis)
      Physical inactivityHabitual moderate-intensity exercise is inversely associated with risk of incident AF, with a graded inverse relationship shown between increasing fitness and AF (7% lower risk of incident AF with every additional metabolic equivalent achieved on exercise testing)
      • Ofman P.
      • Khawaja O.
      • Rahilly-Tierney C.R.
      • et al.
      Regular physical activity and risk of atrial fibrillation: a systematic review and meta-analysis.
      ,
      • Mozaffarian D.
      • Furberg C.D.
      • Psaty B.M.
      • Siscovick D.
      Physical activity and incidence of atrial fibrillation in older adults: the cardiovascular health study.
      ,
      • Everett B.M.
      • Conen D.
      • Buring J.E.
      • et al.
      Physical activity and the risk of incident atrial fibrillation in women.
      Exercise might protect against AF through:
      • Potentiation of parasympathetic tone
      • Improved cardiovascular risk factor profile (weight loss; improved BP, glucose, and lipids)
      • Improved endothelial function
      Intense exerciseIntense exercise practices have been associated with an increased incidence of AF, and a greater rate of AF recurrence after cardioversion or catheter ablation
      • Mozaffarian D.
      • Furberg C.D.
      • Psaty B.M.
      • Siscovick D.
      Physical activity and incidence of atrial fibrillation in older adults: the cardiovascular health study.
      ,
      • Heidbuchel H.
      • Anne W.
      • Willems R.
      • et al.
      Endurance sports is a risk factor for atrial fibrillation after ablation for atrial flutter.


      In this athletic population, AF paroxysms are more than 3 times as likely to occur in vagal contexts (postprandial, sleep, at rest) compared with healthy controls
      • Mont L.
      • Sambola A.
      • Brugada J.
      • et al.
      Long-lasting sport practice and lone atrial fibrillation.
      Vigorous activity might induce AF through:
      • Acute catecholamine fluxes
      • Parasympathetic enhancement (baroreflex enhancement and acetylcholine sensitization)
      • Long-term structural remodelling (atrial dilatation with associated atrial fibrosis)
      • Electrical remodelling (heterogenous refractoriness)
      ObesityCompared with people with a normal BMI (< 25), overweight (25-30) and obese (> 30) individuals are at increased risk for AF development, with a linear relationship between BMI and AF incidence (AF incidence increasing 3%-7% for each unit increase in BMI)
      • Dublin S.
      • French B.
      • Glazer N.L.
      • et al.
      Risk of new-onset atrial fibrillation in relation to body mass index.
      ,
      • Frost L.
      • Hune L.J.
      • Vestergaard P.
      Overweight and obesity as risk factors for atrial fibrillation or flutter: the Danish Diet, Cancer, and Health Study.


      Weight gain has been associated with AF risk independent of BMI (34% increased AF with a 16%-35% weight gain, and 61% increased AF with > 35% weight gain)
      • Rosengren A.
      • Hauptman P.J.
      • Lappas G.
      • et al.
      Big men and atrial fibrillation: effects of body size and weight gain on risk of atrial fibrillation in men.


      Coexistence of AF and obesity confers worsened prognosis, increasing all-cause mortality and thromboembolism
      • Overvad T.F.
      • Rasmussen L.H.
      • Skjoth F.
      • et al.
      Body mass index and adverse events in patients with incident atrial fibrillation.
      Obesity might induce AF through:
      • Structural remodelling (atrial dilatation and fibrosis)
      • Electrical remodelling (conduction slowing)
      • Autonomic dysfunction
      • Inflammation and epicardial fat infiltration
      • Left ventricular diastolic dysfunction
      Sleep apneaOSA is highly prevalent among those with AF, with a rate that is double that of the general population
      • Gami A.S.
      • Pressman G.
      • Caples S.M.
      • et al.
      Association of atrial fibrillation and obstructive sleep apnea.


      Patients with moderate to severe OSA have a three- to sixfold increased risk of developing AF
      • Mehra R.
      • Benjamin E.J.
      • Shahar E.
      • et al.
      Association of nocturnal arrhythmias with sleep-disordered breathing: the Sleep Heart Health study.


      CPAP reduces the risk of AF, supporting a causal role of OSA in AF pathogenesis
      • Fein A.S.
      • Shvilkin A.
      • Shah D.
      • et al.
      Treatment of obstructive sleep apnea reduces the risk of atrial fibrillation recurrence after catheter ablation.
      ,
      • Gami A.S.
      • Pressman G.
      • Caples S.M.
      • et al.
      Association of atrial fibrillation and obstructive sleep apnea.
      ,
      • Kanagala R.
      • Murali N.S.
      • Friedman P.A.
      • et al.
      Obstructive sleep apnea and the recurrence of atrial fibrillation.
      ,
      • Naruse Y.
      • Tada H.
      • Satoh M.
      • et al.
      Concomitant obstructive sleep apnea increases the recurrence of atrial fibrillation following radiofrequency catheter ablation of atrial fibrillation: clinical impact of continuous positive airway pressure therapy.


      Coexistence of AF and OSA confers worsened prognosis, with higher recurrence after cardioversion and ablation
      • Fein A.S.
      • Shvilkin A.
      • Shah D.
      • et al.
      Treatment of obstructive sleep apnea reduces the risk of atrial fibrillation recurrence after catheter ablation.
      ,
      • Kanagala R.
      • Murali N.S.
      • Friedman P.A.
      • et al.
      Obstructive sleep apnea and the recurrence of atrial fibrillation.
      ,
      • Naruse Y.
      • Tada H.
      • Satoh M.
      • et al.
      Concomitant obstructive sleep apnea increases the recurrence of atrial fibrillation following radiofrequency catheter ablation of atrial fibrillation: clinical impact of continuous positive airway pressure therapy.
      Acute OSA might induce AF through:
      • Left atrial volume loading
      • Hypoxia-induced pulmonary vasoconstriction
      • Long-term OSA might induce AF through:
      • Structural remodelling (atrial dilatation and fibrosis)
      • Electrical remodelling (conduction anisotropy)
      • Autonomic dysregulation
      • Oxidative stress and inflammation
      DyslipidemiaThe association between dyslipidemia and incident AF is unclear
      • Lopez F.L.
      • Agarwal S.K.
      • Maclehose R.F.
      • et al.
      Blood lipid levels, lipid-lowering medications, and the incidence of atrial fibrillation: the Atherosclerosis Risk in Communities study.
      ,
      • Alonso A.
      • Yin X.
      • Roetker N.S.
      • et al.
      Blood lipids and the incidence of atrial fibrillation: the Multi-Ethnic Study of Atherosclerosis and the Framingham Heart study.
      Unclear
      AgeAge is one the most powerful predictors of incident AF

      The lifetime risk of developing AF for individuals 40-55 years of age has been estimated to be 22%-26%
      • Go A.S.
      • Hylek E.M.
      • Phillips K.A.
      • et al.
      Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study.
      ,
      • Heeringa J.
      • van der Kuip D.A.
      • Hofman A.
      • et al.
      Prevalence, incidence and lifetime risk of atrial fibrillation: the Rotterdam study.
      Aging might induce AF through:
      • Structural remodelling
      • Electrical remodelling
      SexSex is one of most powerful predictors of incident AF

      After adjustment, male sex is associated with a 1.5-fold risk of developing AF
      • Piccini J.P.
      • Hammill B.G.
      • Sinner M.F.
      • et al.
      Incidence and prevalence of atrial fibrillation and associated mortality among Medicare beneficiaries, 1993-2007.
      • Kannel W.B.
      • Abbott R.D.
      • Savage D.D.
      • McNamara P.M.
      Epidemiologic features of chronic atrial fibrillation: the Framingham study.
      • Furberg C.D.
      • Psaty B.M.
      • Manolio T.A.
      • et al.
      Prevalence of atrial fibrillation in elderly subjects (the Cardiovascular Health Study).
      • Rietbrock S.
      • Heeley E.
      • Plumb J.
      • van Staa T.
      Chronic atrial fibrillation: incidence, prevalence, and prediction of stroke using the Congestive heart failure, Hypertension, Age >75, Diabetes mellitus, and prior Stroke or transient ischemic attack (CHADS2) risk stratification scheme.
      ,
      • Go A.S.
      • Hylek E.M.
      • Phillips K.A.
      • et al.
      Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study.
      ,
      • Heeringa J.
      • van der Kuip D.A.
      • Hofman A.
      • et al.
      Prevalence, incidence and lifetime risk of atrial fibrillation: the Rotterdam study.
      Male sex might predispose to AF through:
      • Electrical and structural differences (greater atrial dimensions)
      Valve diseaseValvular heart disease has been associated with a 1.8- to 3.4-fold increased risk for AF
      • Kannel W.B.
      • Wolf P.A.
      • Benjamin E.J.
      • Levy D.
      Prevalence, incidence, prognosis, and predisposing conditions for atrial fibrillation: population-based estimates.


      AF risk is greatest for stenotic left-sided valvular lesions, with the highest risk among those with severe stenosis
      • Stortecky S.
      • Buellesfeld L.
      • Wenaweser P.
      • et al.
      Atrial fibrillation and aortic stenosis: impact on clinical outcomes among patients undergoing transcatheter aortic valve implantation.


      AF risk is increased with complexity of rheumatic heart disease (15% isolated MR, 30% isolated MS, 50% mixed MR and MS, to 70% with mixed mitral and tricuspid valve disease)
      • Diker E.
      • Aydogdu S.
      • Ozdemir M.
      • et al.
      Prevalence and predictors of atrial fibrillation in rheumatic valvular heart disease.
      Valvular disease might induce AF through:
      • Structural remodelling
      CardiomyopathyAF increases with severity of HF symptomatology (< 5% in NYHA class I, 10%-25% in NYHA class II-III, and > 50% in NYHA class IV)
      • Maisel W.H.
      • Stevenson L.W.
      Atrial fibrillation in heart failure: epidemiology, pathophysiology, and rationale for therapy.


      Although AF prevalence increases with worsening systolic dysfunction, AF is more common in patients with HFpEF compared with those with HFrEF
      • Maisel W.H.
      • Stevenson L.W.
      Atrial fibrillation in heart failure: epidemiology, pathophysiology, and rationale for therapy.
      • Sartipy U.
      • Dahlstrom U.
      • Fu M.
      • Lund L.H.
      Atrial fibrillation in heart failure with preserved, mid-range, and reduced ejection fraction.
      • Pellicori P.
      • Urbinati A.
      • Kaur K.
      • et al.
      Prevalence and incidence of atrial fibrillation in ambulatory patients with heart failure.


      AF prevalence varies depending on the cause of cardiopathy
      • Noubiap J.J.
      • Bigna J.J.
      • Agbor V.N.
      • et al.
      Meta-analysis of atrial fibrillation in patients with various cardiomyopathies.
      :
      • Prevalence > 20% with nonischemic, ischemic, and restrictive cardiomyopathies
      • Prevalence 15%-20% with amyloid, hypertrophic, Keshan, and LV noncompaction
      • Prevalence < 15% with Takotsubo, Chagas, and arrhythmogenic RV cardiomyopathies
      HF might induce AF through:
      • Structural remodelling
      • Electrical remodelling (abnormal Ca2+-handling and increased triggered activity)
      • Neurohormonal activation (increased sympathetic activity, impairment of vagal tone)
      Thyroid dysfunctionAF increases with decreasing levels of thyroid stimulating hormone
      • Auer J.
      • Scheibner P.
      • Mische T.
      • et al.
      Subclinical hyperthyroidism as a risk factor for atrial fibrillation.
      ,
      • Selmer C.
      • Olesen J.B.
      • Hansen M.L.
      • et al.
      The spectrum of thyroid disease and risk of new onset atrial fibrillation: a large population cohort study.
      • RR, 1.1 with high-normal euthyroidism
      • RR, 1.2-4 with subclinical hyperthyroidism
      • RR, 3-6 with overt hyperthyroidism
      Hyperthyroidism might induce AF through:
      • Neurohormonal activation (increased sympathetic tone)
      • Structural remodelling
      • Electrical remodelling
      • Promotion of PV automaticity/triggered activity (thyroid hormone)
      Genetic factorsAF is more common in those with a family history of AF in a first-degree relative
      • Christophersen I.E.
      • Ravn L.S.
      • Budtz-Joergensen E.
      • et al.
      Familial aggregation of atrial fibrillation: a study in Danish twins.


      Monogenic and polygenic inheritance has been described, with multiple susceptibility signals identified at the chromosome 4q25 locus
      • Olson T.M.
      • Michels V.V.
      • Ballew J.D.
      • et al.
      Sodium channel mutations and susceptibility to heart failure and atrial fibrillation.
      • Chen Y.H.
      • Xu S.J.
      • Bendahhou S.
      • et al.
      KCNQ1 gain-of-function mutation in familial atrial fibrillation.
      • Gollob M.H.
      • Jones D.L.
      • Krahn A.D.
      • et al.
      Somatic mutations in the connexin 40 gene (GJA5) in atrial fibrillation.
      • Olson T.M.
      • Alekseev A.E.
      • Moreau C.
      • et al.
      KATP channel mutation confers risk for vein of Marshall adrenergic atrial fibrillation.
      • Lubitz S.A.
      • Sinner M.F.
      • Lunetta K.L.
      • et al.
      Independent susceptibility markers for atrial fibrillation on chromosome 4q25.
      • Chinchilla A.
      • Daimi H.
      • Lozano-Velasco E.
      • et al.
      PITX2 insufficiency leads to atrial electrical and structural remodeling linked to arrhythmogenesis.
      Genetic causes of AF typically result from cardiac ion channel alterations (promoting reentry or ectopic activity), alterations in cellular coupling, or increasing susceptibility to AF
      AF, atrial fibrillation; BMI, body mass index; BP, blood pressure; CPAP, continuous positive airway pressure; HbA1c, hemoglobin A1c; HF, heart failure; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; HR, hazard ratio; LV, left ventricular; MR, mitral regurgitation; MS, mitral stenosis; NYHA, New York Heart Association; OSA, obstructive sleep apnea; PV, pulmonary vein; RR, relative risk; RV, right ventricular.

      4. Clinical Evaluation

      The purpose of the initial evaluation of a patient with AF is to establish the magnitude and severity of symptoms attributable to AF, identify the underlying etiology and precipitants of AF, establish prognosis, and develop a therapeutic strategy for symptom relief and morbidity mitigation (Fig. 4).
      Figure thumbnail gr4
      Figure 4Evaluation of the atrial fibrillation (AF) patient. ED, emergency department.

      4.1 AF history

      A comprehensive AF history should include the date of first symptomatic attack as well as the date of first ECG documentation. For patients in AF at the time of assessment, the timing of onset for the current AF episode should be determined.
      The duration and frequency of episodes should be used to establish the predominant pattern of AF (paroxysmal vs persistent; see section 1). Of note, in some cases the symptom evaluation might be insufficient for the determination of AF pattern and additional monitoring might be required.
      • Charitos E.I.
      • Purerfellner H.
      • Glotzer T.V.
      • Ziegler P.D.
      Clinical classifications of atrial fibrillation poorly reflect its temporal persistence: insights from 1,195 patients continuously monitored with implantable devices.
      ,
      • Andrade J.G.
      • Yao R.R.J.
      • Deyell M.W.
      • et al.
      Clinical assessment of AF pattern is poorly correlated with AF burden and post ablation outcomes: a CIRCA-DOSE sub-study.
      The presence and nature of AF-related symptoms, their severity, and their effect on QOL should be determined (see section 4.3). Symptoms might be absent or manifest as palpitations, dyspnea, dizziness, weakness, fatigue, or chest pain.
      • Dorian P.
      • Guerra P.G.
      • Kerr C.R.
      • et al.
      Validation of a new simple scale to measure symptoms in atrial fibrillation: the Canadian Cardiovascular Society Severity in Atrial Fibrillation scale.
      In addition, it is important to elicit any history of regular palpitations because any supraventricular tachycardia (SVT) can lead to the development of AF, and ablation of the SVT might eliminate or substantially reduce the likelihood of recurrent AF (see section 11.7).
      • Haissaguerre M.
      • Fischer B.
      • Labbe T.
      • et al.
      Frequency of recurrent atrial fibrillation after catheter ablation of overt accessory pathways.
      ,
      • Brembilla-Perrot B.
      • Olivier A.
      • Villemin T.
      • et al.
      Prediction of atrial fibrillation in patients with supraventricular tachyarrhythmias treated with catheter ablation or not. Classical scores are not useful.
      Symptoms at the termination of AF episodes, such as presyncope or syncope, should be determined because significant sinus pauses might limit the use of rate- or rhythm-controlling medications and might require the use of permanent pacing or prompt early ablation.
      Precipitating factors (“triggers for AF episodes”), reversible causes, and coexisting cardiovascular risk conditions should be determined. These include modifiable cardiovascular risk factors and comorbid conditions, which if treated, might reduce or eliminate AF recurrence and improve the overall outcome of the patient, independent of AF (see section 6).
      • Kannel W.B.
      • Abbott R.D.
      • Savage D.D.
      • McNamara P.M.
      Epidemiologic features of chronic atrial fibrillation: the Framingham study.
      ,
      • Wolf P.A.
      • Dawber T.R.
      • Thomas Jr., H.E.
      • Kannel W.B.
      Epidemiologic assessment of chronic atrial fibrillation and risk of stroke: the Framingham study.
      Past evaluations and treatments should be explored, including a record of all previous pharmacologic and nonpharmacologic AF interventions (eg, cardioversion and catheter ablation).
      AF-related health care utilization should be documented, including a record of emergency department (ED) visits, hospital admissions, and cardioversions.
      Risk factors for stroke (see section 8.1) and bleeding (see section 8.5.1) should be elicited.
      The precise frequency, duration, and intensity of sports participation (current and previous) needs to be assessed carefully for all AF patients (see section 11.3).
      In addition, the evaluation should include: a comprehensive review of all prescription, over the counter, and nonprescription medications; a social history with a focus on alcohol, tobacco, and recreational drug intake; and a family history of cardiac dysrhythmia or relevant risk conditions.

      4.2 Investigations

      In addition to a comprehensive physical examination several routine investigations are warranted for all patients who present with AF (Fig. 4):
      • AF must be electrocardiographically documented, because the perception of “irregularly irregular” palpitations might be the result of a variety of arrhythmias, including atrial tachycardia, atrial flutter (AFL), premature atrial and/or ventricular contractions, or nonarrhythmic causes.
      • An ECG is useful in AF and sinus rhythm to identify LA enlargement, left ventricular (LV) hypertrophy (LVH), preexcitation, conduction disease, or evidence of MI.
      • A transthoracic echocardiogram should also be performed in all patients to identify LVH or systolic dysfunction, significant valvular or congenital heart disease (CHD), LA enlargement, and rarely, complications such as intracardiac thrombus. LA dimension provides important information about the likelihood of AF recurrence or progression to persistent AF, which can help guide therapeutic decision-making.
      • Transesophageal echocardiography (TEE) might be indicated for more detailed evaluation of valvular or CHD, or for the exclusion of LA appendage (LAA) thrombus.
      • Routine blood biochemistry should be obtained at the time of the initial AF evaluation. A complete blood count and coagulation studies will inform decisions about the use of antithrombotic medications. Serum electrolytes and creatinine should be measured, and renal function determined to guide drug dosing (eg, creatinine clearance [CrCl], see section 8.3.1). Liver function should be assessed before the prescription of potentially hepatotoxic medications, such as amiodarone. Lipid profile, hemoglobin A1c, and fasting blood sugar are recommended in most patients as part of a comprehensive cardiovascular risk assessment. Thyroid function should be assessed because hyperthyroidism remains an important treatable cause of AF.
        • Kim D.D.
        • Young S.
        • Cutfield R.
        A survey of thyroid function test abnormalities in patients presenting with atrial fibrillation and flutter to a New Zealand district hospital.
        In select cases N-terminal pro-B-type natriuretic peptide (NT pro-BNP) and inflammatory biomarkers might aid in patient management.
      • Ambulatory ECG monitoring might aid in the documentation of AF, the identification of other arrhythmias, the assessment of ventricular rate control, and to correlate patient symptoms with heart rhythm or heart rate. In selected patients long-term monitoring using external loop recorders, wearable patch monitors, and cardiac implantable electronic devices (CIEDs) might be useful.
        • Charitos E.I.
        • Purerfellner H.
        • Glotzer T.V.
        • Ziegler P.D.
        Clinical classifications of atrial fibrillation poorly reflect its temporal persistence: insights from 1,195 patients continuously monitored with implantable devices.
        ,
        • Andrade J.G.
        • Yao R.R.J.
        • Deyell M.W.
        • et al.
        Clinical assessment of AF pattern is poorly correlated with AF burden and post ablation outcomes: a CIRCA-DOSE sub-study.
        ,
        • Gladstone D.J.
        • Spring M.
        • Dorian P.
        • et al.
        Atrial fibrillation in patients with cryptogenic stroke.
        ,
        • Sanna T.
        • Diener H.C.
        • Passman R.S.
        • et al.
        Cryptogenic stroke and underlying atrial fibrillation.
        In addition, consumer-facing devices (eg, handheld or wearable ECG devices) may be used to document heart rate or cardiac rhythm, potentially providing symptom-rhythm correlation and a measure of AF burden.
      • Sleep study or overnight oximetry should be performed in most patients because typical symptoms are less prevalent and screening questionnaires are less accurate in the AF population.
      • Exercise testing can be used to supplement ambulatory monitoring in certain patients with exercise-related symptoms and might be helpful to exclude significant ischemia before class Ic antiarrhythmic drug prescription.
      • Invasive electrophysiological studies may be considered in patients who are candidates for catheter ablation of AF or with suspected SVT, which could be triggering AF (see sections 9.4 and 11.7).

      4.3 Evaluation of the effect of AF on well-being, symptoms, and QOL

      Traditional rhythm-based outcome parameters, such as freedom from AF recurrence, are insufficient to evaluate the clinical effect of AF.
      • Hindricks G.
      • Piorkowski C.
      • Tanner H.
      • et al.
      Perception of atrial fibrillation before and after radiofrequency catheter ablation: relevance of asymptomatic arrhythmia recurrence.
      ,
      • Verma A.
      • Champagne J.
      • Sapp J.
      • et al.
      Discerning the incidence of symptomatic and asymptomatic episodes of atrial fibrillation before and after catheter ablation (DISCERN AF): a prospective, multicenter study.
      Although rarely life-threatening, AF causes a greater degree of impairment of QOL than is generally appreciated. AF can cause moderate and sometimes severe distress, and substantially alter everyday functioning.
      • Walters T.E.
      • Wick K.
      • Tan G.
      • et al.
      Psychological distress and suicidal ideation in patients with atrial fibrillation: prevalence and response to management strategy.
      Impaired QOL is primarily the result of AF-associated symptoms but can be influenced by AF therapies, illness perceptions, and patient factors such as anxiety or depression.
      • Hindricks G.
      • Piorkowski C.
      • Tanner H.
      • et al.
      Perception of atrial fibrillation before and after radiofrequency catheter ablation: relevance of asymptomatic arrhythmia recurrence.
      ,
      • Verma A.
      • Champagne J.
      • Sapp J.
      • et al.
      Discerning the incidence of symptomatic and asymptomatic episodes of atrial fibrillation before and after catheter ablation (DISCERN AF): a prospective, multicenter study.
      A consistent and standardized assessment of the effect of AF on HRQOL is recommended to evaluate the clinical effect of AF and quantitatively assess the changes in well-being resulting from therapeutic interventions. Specifically, multidimensional HRQOL instruments can be used to determine if an intervention had a beneficial effect across all domains concurrently or if a benefit in one domain (eg, physical health) was offset by a negative effect in another (eg, mental health). As such, the assessment of patient-reported outcomes with validated multidimensional instruments offers a relevant and complementary means to evaluate the consequences of AF and the effect of therapeutic interventions on patients’ functional status and health.
      To date, a large number of instruments have been used to evaluate HRQOL (Table 3). In broad terms, these instruments can be dichotomized into generic and disease-specific questionnaires. Generic instruments, such as the EuroQol-5D (EQ-5D) and Short Form-36 Health Survey (SF-36), are used to assess valuations of health and functioning across a predefined set of health-related domains. Generic instruments have the advantages of extensive validation across a wide range of populations and health conditions but lack precision for assessing the effect of AF. Disease-specific instruments include symptom-specific scales (eg, the University of Toronto Atrial Fibrillation Severity Scale [AFSS]), and AF-specific QOL symptom scales (eg, the Atrial Fibrillation Effect on Quality-of-Life [AFEQT] questionnaire). These instruments do not provide for the ability to compare between disease states (eg, the HRQOL of AF patients relative to HF patients) but are more sensitive to changes in AF patients’ health status (spontaneous or as a result of intervention).
      Table 3Instruments for the assessment of QOL and symptoms in patients with AF
      InstrumentTypeDomainsAdministrationComments
      SF-36
      • Brazier J.E.
      • Harper R.
      • Jones N.M.
      • et al.
      Validating the SF-36 health survey questionnaire: new outcome measure for primary care.
      Generic QOLVitality

      Physical functioning

      Bodily pain

      General health perceptions

      Physical role functioning

      Emotional role functioning

      Social role functioning

      Mental health
      PatientExtensive validation

      Widespread clinical use

      Good for comparing between diseases

      Can be used to evaluate cost-effectiveness

      Insensitive AF
      EQ-5D
      • Rabin R.
      • de Charro F.
      EQ-5D: a measure of health status from the EuroQol Group.
      Generic QOLMobility

      Self care

      Usual activities

      Pain/discomfort

      Anxiety/depression
      Patient
      AFEQT
      • Spertus J.
      • Dorian P.
      • Bubien R.
      • et al.
      Development and validation of the Atrial Fibrillation Effect on QualiTy-of-Life (AFEQT) questionnaire in patients with atrial fibrillation.
      Specific QOLSymptoms

      Daily activities

      Treatment concerns

      Treatment satisfaction
      PatientGood reliability

      Good validity

      Fair responsiveness (sensitive to change)
      AFQOL
      • Badia X.
      • Arribas F.
      • Ormaetxe J.M.
      • Peinado R.
      • de Los Terreros M.S.
      Development of a questionnaire to measure health-related quality of life (HRQoL) in patients with atrial fibrillation (AF-QoL).
      Specific QOLPhysical

      Psychological

      Sexual activity
      PatientPoor reliability

      Good validity

      Poor responsiveness
      AFSS
      • Dorian P.
      • Paquette M.
      • Newman D.
      • et al.
      Quality of life improves with treatment in the Canadian Trial of Atrial Fibrillation.
      SymptomSymptom frequency, duration, and severityPatient
      AFS/B
      • Koci F.
      • Forbes P.
      • Mansour M.C.
      • et al.
      New classification scheme for atrial fibrillation symptom severity and burden.
      SymptomSymptom severity and burdenPatient and caregiver
      EHRA
      • Kirchhof P.
      • Auricchio A.
      • Bax J.
      • et al.
      Outcome parameters for trials in atrial fibrillation: recommendations from a consensus conference organized by the German Atrial Fibrillation Competence NETwork and the European Heart Rhythm Association.
      ClassificationImpact of AF on ability to complete daily activitiesCaregiverSimple classification
      CCS SAF
      • Dorian P.
      • Cvitkovic S.S.
      • Kerr C.R.
      • et al.
      A novel, simple scale for assessing the symptom severity of atrial fibrillation at the bedside: the CCS-SAF scale.
      ClassificationEffect of AF on ability to complete daily activitiesCaregiverDetailed classification

      Effect of symptoms on QOL
      Reliability refers to the extent to which the instrument is free of measurement error (eg, internal consistency, test-retest reliability, and measurement error); validity refers to the extent to which the instrument measures the construct it purports to measure (eg, content, construct, and criterion validity); responsiveness refers to extent to which the measure can detect change over time.
      • Mokkink L.B.
      • Prinsen C.A.
      • Bouter L.M.
      • Vet H.C.
      • Terwee C.B.
      The COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) and how to select an outcome measurement instrument.
      AF, atrial fibrillation; AFEQT, Atrial Fibrillation Effect on QualiTy-of-Life questionnaire; AFQOL, Atrial Fibrillation Quality of Life; AFS/B, Atrial Fibrillation Symptom Severity and Burden; AFSS, Atrial Fibrillation Severity Scale; CCS SAF, Canadian Cardiovascular Society Symptoms of Atrial Fibrillation; EHRA, European Heart Rhythm Association; EQ-5D, EuroQol-5D; QOL, quality of life; SAF, Symptoms of Atrial Fibrillation; SF-36, Short Form-36 Health Survey.
      The Severity of Atrial Fibrillation (SAF; Table 4) is a semiquantitative scale ranging from 0 (no effect of AF or its treatment on overall QOL and patient functioning) to 4 (resulting in a severe impairment of functioning and overall QOL).
      • Dorian P.
      • Cvitkovic S.S.
      • K