graphic  For the Supplementary Data which include background information and detailed discussion of the data that have provided the basis for the Guidelines see European Heart Journal online.

graphic  Click here to access the corresponding chapter in section 41- Atrial fibrillation

Table of contents

  • 1 Preamble  379

  • 2 Introduction  380

  •  2.1 What is new in the 2020 Guidelines?  381

  • 3 Definition and diagnosis of atrial fibrillation  385

  •  3.1 Definition  385

  •  3.2 Diagnostic criteria for atrial fibrillation  386

  •  3.3 Diagnosis of atrial high-rate episodes/subclinical atrial fibrillation  386

  • 4 Epidemiology  386

  •  4.1 Prediction of incident atrial fibrillation  388

  •  4.2 Pathophysiology of atrial fibrillation  388

  • 5 Clinical features of atrial fibrillation  388

  • 6 Atrial fibrillation subtypes, burden, and progression  388

  •  6.1 Classification of atrial fibrillation  388

  •  6.2 Definition and assessment of atrial fibrillation burden  391

  •  6.3 Atrial fibrillation progression  392

  •  6.4 Atrial cardiomyopathy: definition, classification, clinical implications, and diagnostic assessment  392

  • 7 Screening for atrial fibrillation  392

  •  7.1 Screening tools  392

  •  7.2 Screening types and strategies  394

  •  7.3 Benefits from and risks of screening for atrial fibrillation  394

  •  7.4 Cost-effectiveness of screening for atrial fibrillation  394

  •  7.5 Screening in high-risk populations  395

  •   7.5.1 Elderly  395

  • 8 Diagnostic assessment in atrial fibrillation  395

  •  8.1 Symptoms and quality of life  395

  •  8.2 Substrate  395

  • 9 Integrated management of patients with atrial fibrillation  398

  •  9.1 Definitions and components of integrated management of atrial fibrillation patients  398

  •  9.2 Multidisciplinary atrial fibrillation teams  398

  •   9.2.1 Role of healthcare systems and budget constraints  398

  •  9.3 Patient involvement and shared decision making  398

  •   9.3.1 Patient values and preferences  398

  •   9.3.2 Patient education  399

  •  9.4 Healthcare professional education  399

  •  9.5 Adherence to treatment  399

  •  9.6 Technology tools supporting atrial fibrillation management  399

  •  9.7 Advantages of integrated management of atrial fibrillation patients  400

  •  9.8 Measures (or approaches) for implementation of integrated management  400

  •  9.9 Treatment burden  400

  •  9.10 Patient-reported outcomes  400

  • 10 Patient management: the integrated ABC pathway  401

  •  10.1 ‘A’ – Anticoagulation/Avoid stroke  401

  •   10.1.1 Stroke risk assessment  401

  •   10.1.2 Bleeding risk assessment  402

  •   10.1.3 Absolute contraindications to oral anticoagulants  404

  •   10.1.4 Stroke prevention therapies  404

  •    10.1.4.1 Vitamin K antagonists  404

  •    10.1.4.2 Non-vitamin K antagonist oral anticoagulants  405

  •    10.1.4.3 Other antithrombotic drugs  405

  •    10.1.4.4 Combination therapy with oral anticoagulant and antiplatelet drugs  406

  •    10.1.4.5 Left atrial appendage occlusion and exclusion  406

  •     10.1.4.5.1 Left atrial appendage occlusion devices  406

  •     10.1.4.5.2 Surgical left atrial appendage occlusion or exclusion  406

  •    10.1.4.6 Long-term oral anticoagulation per atrial fibrillation burden  407

  •    10.1.4.7 Long-term oral anticoagulation per symptom control strategy  407

  •   10.1.5 Management of anticoagulation-related bleeding risk  407

  •    10.1.5.1 Strategies to minimize the risk of bleeding  407

  •    10.1.5.2 High-risk groups  407

  •   10.1.6 Decision-making to avoid stroke  407

  •  10.2 ‘B’ – Better symptom control  409

  •   10.2.1 Rate control  409

  •    10.2.1.1 Target/optimal ventricular rate range  409

  •    10.2.1.2 Drugs  409

  •    10.2.1.3 Acute rate control  410

  •    10.2.1.4 Atrioventricular node ablation and pacing  410

  •   10.2.2 Rhythm control  413

  •    10.2.2.1 Indications for rhythm control  413

  •    10.2.2.2 Cardioversion  414

  •     10.2.2.2.1 Immediate cardioversion/elective cardioversion  414

  •     10.2.2.2.2 Electrical cardioversion  414

  •     10.2.2.2.3 Pharmacological cardioversion (including ‘pill in the pocket’)  414

  •     10.2.2.2.4 Follow-up after cardioversion  414

  •    10.2.2.3 Atrial fibrillation catheter ablation  417

  •     10.2.2.3.1 Indications  417

  •     10.2.2.3.2 Techniques and technologies  419

  •     10.2.2.3.3 Complications  419

  •     10.2.2.3.4 AF catheter ablation outcome and impact of modifiable risk factors  419

  •     10.2.2.3.5 Follow-up after atrial fibrillation ablation  420

  •     10.2.2.3.7 Risk assessment for recurrence of AF post catheter ablation  420

  •    10.2.2.4 Surgery for atrial fibrillation  421

  •     10.2.2.4.1 Concomitant surgery for atrial fibrillation: indications, outcome, complications  422

  •     10.2.2.4.2 Stand-alone surgery for atrial fibrillation: indications, outcome, complications  422

  •    10.2.2.5 Hybrid surgical/catheter ablation procedures  422

  •    10.2.2.6 Peri-procedural stroke risk management in patients undergoing rhythm control interventions  423

  •     10.2.2.6.1 Management of stroke risk and oral anticoagulant therapy in atrial fibrillation patients undergoing cardioversion  423

  •     10.2.2.6.2 Management of stroke risk and oral anticoagulant therapy in atrial fibrillation patients undergoing atrial fibrillation catheter ablation  424

  •     10.2.2.6.3 Postoperative anticoagulation after surgery for atrial fibrillation  424

  •    10.2.2.7 Long-term antiarrhythmic drug therapy for rhythm control  424

  •     10.2.2.7.1 Antiarrhythmic drugs  424

  •  10.3 ‘C – Cardiovascular risk factors and concomitant diseases: detection and management  429

  •   10.3.1 Lifestyle interventions  429

  •    10.3.1.1 Obesity and weight loss  429

  •    10.3.1.2 Alcohol and caffeine use  430

  •    10.3.1.3 Physical activity  430

  •   10.3.2 Specific cardiovascular risk factors/comorbidities  430

  •    10.3.2.1 Hypertension  430

  •    10.3.2.2 Heart failure  430

  •    10.3.2.3 Coronary artery disease  430

  •    10.3.2.4 Diabetes mellitus  430

  •    10.3.2.5 Sleep apnoea  430

  • 11 The ABC pathway in specific clinical settings/conditions/ patient populations  431

  •  11.1 Atrial fibrillation with haemodynamic instability  431

  •  11.2 First-diagnosed (new-onset) atrial fibrillation  431

  •  11.3 Acute coronary syndromes, percutaneous coronary intervention, and chronic coronary syndromes in patients with atrial fibrillation  432

  •  11.4 Acute stroke or intracranial haemorrhage in patients with atrial fibrillation  435

  •   11.4.1 Patients with atrial fibrillation and acute ischaemic stroke or transient ischaemic attack  435

  •   11.4.2 Cryptogenic stroke/embolic stroke with undetermined source  435

  •   11.4.3 Post-stroke patients without known atrial fibrillation  436

  •   11.4.4 Management of patients with atrial fibrillation postintracranial haemorrhage  436

  •  11.5 Active bleeding on anticoagulant therapy: management and reversal drugs  438

  •  11.6 Atrial fibrillation and heart failure  439

  •  11.7 Atrial fibrillation and valvular heart disease  439

  •  11.8 Atrial fibrillation and chronic kidney disease  440

  •  11.9 Atrial fibrillation and peripheral artery disease  440

  •  11.10 Atrial fibrillation and endocrine disorders  440

  •  11.11 Atrial fibrillation and gastrointestinal disorders  440

  •  11.12 Atrial fibrillation and haematological disorders  441

  •  11.13 The elderly and frail with atrial fibrillation  441

  •  11.14 Patients with cognitive impairment/dementia  441

  •  11.15 Atrial fibrillation and congenital heart disease  441

  •  11.16 Atrial fibrillation in inherited cardiomyopathies and primary arrhythmia syndromes  442

  •  11.17 Atrial fibrillation during pregnancy  442

  •  11.18 Atrial fibrillation in professional athletes  443

  •  11.19 Postoperative atrial fibrillation  443

  •   11.19.1 Prevention of postoperative AF  444

  •   11.19.2 Prevention of thrombo-embolic events  444

  • 12 Prevention of atrial fibrillation  445

  •  12.1 Primary prevention of atrial fibrillation  445

  •  12.2 Secondary prevention of atrial fibrillation  445

  • 13 Sex-related differences in atrial fibrillation  445

  • 14 Implementation of the atrial fibrillation guidelines  446

  • 15 Quality measures and clinical performance indicators in the management of atrial fibrillation  446

  • 16 Epidemiology, clinical implications, and management of atrial high-rate episodes/subclinical atrial fibrillation  446

  • 17 Atrial fibrillation and other atrial tachyarrhythmias (atrial flutter and atrial tachycardias)  449

  • 18 Key messages  449

  • 19 Gaps in evidence  450

  • 20 ‘What to do’ and ‘what not to do’ messages from the Guidelines  452

  • 21 Supplementary data  456

  • 22 Appendix  456

  • 23 References  457

List of recommendations

  • New recommendations  381

  • Changes in the recommendations  383

  • Recommendations for diagnosis of AF  386

  • Recommendations for structured characterization of AF   391

  • Recommendations for screening to detect AF  395

  • Recommendations for diagnostic evaluation of patients with AF  397

  • Recommendations about integrated AF management  401

  • Recommendations for the prevention of thrombo-embolic events in AF  408

  • Recommendations for ventricular rate control in patients with AF  412

  • Recommendations for rhythm control  414

  • Recommendations for cardioversion  417

  • Recommendations for rhythm control/catheter ablation of AF  421

  • Recommendations for surgical ablation of AF  422

  • Recommendations for stroke risk management peri-cardioversion  423

  • Recommendations for stroke risk management peri-catheter ablation  424

  • Recommendations for postoperative anticoagulation after AF surgery  424

  • Recommendations for long-term antiarrhythmic drugs  429

  • Recommendations for lifestyle interventions and management of risk factors and concomitant diseases in patients with AF  431

  • Recommendations for management of AF with haemodynamic instability  431

  • Recommendations for patients with AF and an ACS, PCI, or CCS  434

  • Recommendations for the search for AF in patients with cryptogenic stroke  436

  • Recommendations for secondary stroke prevention in AF patients after acute ischaemic stroke  437

  • Recommendations for stroke prevention in AF patients after intracranial haemorrhage  437

  • Recommendations for the management of active bleeding on OAC  439

  • Recommendations for patients with valvular heart disease and AF  439

  • Recommendations for the management of AF in patients with congenital heart disease  442

  • Recommendations for the management of AF during pregnancy  443

  • Recommendations for sports activity in patients with AF  443

  • Recommendations for postoperative AF  445

  • Recommendations pertaining to sex-related differences in AF  446

  • Recommendations for quality measures in patients with AF  446

  • Recommendations for management of patients with AHRE  449

List of tables

  • Table 1 Classes of recommendations  379

  • Table 2 Levels of evidence  380

  • Table 3 Definition of atrial fibrillation  385

  • Table 4 Classification of AF  390

  • Table 5 Sensitivity and specificity of various AF screening tools considering the 12-lead ECG as the gold standard  394

  • Table 6 EHRA symptom scale  396

  • Table 7 Stroke risk factors in patients with AF  402

  • Table 8 CHA2DS2-VASc score  403

  • Table 9 Risk factors for bleeding with OAC and antiplatelet therapy  403

  • Table 10 Clinical risk factors in the HAS-BLED score  404

  • Table 11 Dose selection criteria for NOACs  405

  • Table 12 Antithrombotic therapy after left atrial appendage occlusion  406

  • Table 13 Drugs for rate control in AF  411

  • Table 14 Antiarrhythmic drugs used for restoration of sinus rhythm  416

  • Table 15 Goals of follow-up after cardioversion of AF  417

  • Table 16 Procedure-related complications in catheter ablation and thoracoscopic ablation of AF  419

  • Table 17 Key issues in follow-up after AF catheter ablation  420

  • Table 18 Principles of antiarrhythmic drug therapy  425

  • Table 19 Rules to initiate antiarrhythmic drugs for long-term rhythm control in AF  425

  • Table 20 AADs used for long-term maintenance of sinus rhythm in AF patients  426

  • Table 21 Non-antiarrhythmic drugs with antiarrhythmic properties (upstream therapy)  428

  • Table 22 Summary of quality indicators for the diagnosis and management of AF  447

List of figures

  • Figure 1 Diagnosis of AHRE/subclinical AF  386

  • Figure 2 Epidemiology of AF: prevalence; and lifetime risk and projected rise in the incidence and prevalence  387

  • Figure 3 Summary of risk factors for incident AF  388

  • Figure 4 Clinical presentation of AF and AF-related outcomes  389

  • Figure 5 4S-AF scheme as an example of structured characterization of AF  391

  • Figure 6 Systems used for AF screening  393

  • Figure 7 Potential benefits from and risks of screening for AF  394

  • Figure 8 Diagnostic work-up and follow-up in AF patients  396

  • Figure 9 Imaging in AF  397

  • Figure 10 Components of integrated AF management  398

  • Figure 11 Integrated AF management team (an example)  399

  • Figure 12 ‘A’ - Anticoagulation/Avoid stroke: The ‘AF 3-step’ pathway  408

  • Figure 13 Outline of rate control therapy  410

  • Figure 14 Choice of rate control drugs  412

  • Figure 15 Rhythm control strategy  413

  • Figure 16 Flowchart for decision making on cardioversion of AF depending on clinical presentation, AF onset, oral anticoagulation intake, and risk factors  415

  • Figure 17 Indications for catheter ablation of symptomatic AF  418

  • Figure 18 Risk factors for AF contributing to the development of an abnormal substrate translating into poorer outcomes with rhythm control strategies  420

  • Figure 19 Long-term rhythm control therapy  428

  • Figure 20 Post-procedural management of patients with AF and ACS/PCI  433

  • Figure 21 (Re-) initiation of anticoagulation post-intracranial bleeding  437

  • Figure 22 Management of active bleeding in patients receiving anticoagulation  438

  • Figure 23 Management of postoperative AF  444

  • Figure 24 Progression of atrial high-rate episode burden and stroke rates according to AHRE daily burden and CHA2DS2-VASc score   448

  • Figure 25 Proposed management of AHRE/subclinical AF  448

  • Central Illustration. Management of AF 451

List of boxes

  • Box 1 About post-procedural management of patients with AF and ACS and/or PCI  432

  • Box 2 About acute ischaemic stroke in patients with AF  435

Abbreviations and acronyms

Abbreviations and acronyms

     
  • 4S-AF

    Stroke risk, Symptom severity, Severity of AF burden, Substrate severity

  •  
  • AAD

    Antiarrhythmic drug

  •  
  • ABC

    Atrial fibrillation Better Care [includes A (avoid stroke), B (better symptom control), and C (cardiovascular risk factors and comorbid conditions management)]

  •  
  • ABC-bleeding

    Age, Biomarkers (haemoglobin, cTnT hs T, GDF-15), and Clinical history (prior bleeding)

  •  
  • ABC-stroke

    Age, Biomarkers, Clinical history (stroke risk score)

  •  
  • ACS

    Acute coronary syndromes

  •  
  • ACTIVE W

    Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events trial

  •  
  • AF

    Atrial fibrillation

  •  
  • AFFIRM

    Atrial Fibrillation Follow-up Investigation of Rhythm Management

  •  
  • AFL

    Atrial flutter

  •  
  • AHRE

    Atrial high-rate episode

  •  
  • AMICA

    Atrial Fibrillation Management in Congestive Heart Failure With Ablation

  •  
  • ARCADIA

    AtRial Cardiopathy and Antithrombotic Drugs In Prevention After Cryptogenic Stroke

  •  
  • ARISTOTLE

    Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation

  •  
  • ARREST-AF

    Aggressive Risk Factor Reduction Study – Implication for AF

  •  
  • AST

    Aspartate aminotransferase

  •  
  • ATRIA

    Anticoagulation and Risk Factors in Atrial Fibrillation (score)

  •  
  • ATTICUS

    Apixaban for treatment of embolic stroke of undetermined source

  •  
  • AVERROES

    Apixaban Versus Acetylsalicylic Acid (ASA) to Prevent Stroke in Atrial Fibrillation Patients Who Have Failed or Are Unsuitable for Vitamin K Antagonist Treatment

  •  
  • b.i.d.

    bis in die (twice a day)

  •  
  • BP

    Blood pressure

  •  
  • bpm

    Beats per minute

  •  
  • C2HEST

    CAD/COPD (1 point each), Hypertension (1 point), Elderly ( ≥75 years, 2 points), Systolic heart failure (2 points), and Thyroid disease (hyperthyroidism, 1 point) (score)

  •  
  • CABANA

    Catheter ABlation vs. ANtiarrhythmic Drug Therapy for Atrial Fibrillation

  •  
  • CAD

    Coronary artery disease

  •  
  • CAPTAF

    Catheter Ablation compared with Pharmacological Therapy for Atrial Fibrillation

  •  
  • CASTLE-AF

    Catheter Ablation vs. Standard conventional Treatment in patients with LEft ventricular dysfunction and Atrial Fibrillation

  •  
  • CATCH-ME

    Characterizing AF by Translating its Causes into Health Modifiers in the Elderly

  •  
  • CCB

    Calcium channel blocker

  •  
  • CCS

    Chronic coronary syndrome

  •  
  • CHA2DS2- VASc

    Congestive heart failure, Hypertension, Age ≥75 years, Diabetes mellitus, Stroke, Vascular disease, Age 65–74 years, Sex category (female)

  •  
  • CHADS2

    CHF history, Hypertension history, Age ≥75 y, Diabetes mellitus history, Stroke or TIA symptoms previously

  •  
  • CHF

    Congestive heart failure

  •  
  • CI

    Confidence interval

  •  
  • CIED

    Cardiac implantable electronic device

  •  
  • CKD

    Chronic kidney disease

  •  
  • COP-AF

    Colchicine For The Prevention Of Perioperative Atrial Fibrillation In Patients Undergoing Thoracic Surgery

  •  
  • COPD

    Chronic obstructive pulmonary disease

  •  
  • CPAP

    Continuous positive airway pressure

  •  
  • CrCl

    Creatinine clearance

  •  
  • CRT

    Cardiac resynchronization therapy

  •  
  • CT

    Computed tomography

  •  
  • CTI

    Cavotricuspid isthmus

  •  
  • cTnT-hs

    High-sensitivity troponin T

  •  
  • DAPT

    Dual antiplatelet therapy

  •  
  • EAST

    Early treatment of Atrial fibrillation for Stoke prevention Trial

  •  
  • ECG

    Electrocardiogram

  •  
  • EHRA

    European Heart Rhythm Association

  •  
  • ELAN

    Early versus Late initiation of direct oral Anticoagulants in post-ischaemic stroke patients with atrial fibrillatioN

  •  
  • ENGAGE AF-TIMI 48

    Effective aNticoaGulation with factor XA next GEneration in Atrial Fibrillation-Thrombolysis In Myocardial Infarction 48

  •  
  • ENTRUST- AF PCI

    Edoxaban Treatment Versus Vitamin K Antagonist in Patients With Atrial Fibrillation Undergoing Percutaneous Coronary Intervention

  •  
  • ESC

    European Society of Cardiology

  •  
  • GARFIELD-AF

    Global Anticoagulant Registry in the FIELD − Atrial Fibrillation

  •  
  • GDF-15

    Growth differentiation factor-15

  •  
  • HAS-BLED

    Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile INR, Elderly (>65 years), Drugs/alcohol concomitantly

  •  
  • HCM

    Hypertrophic cardiomyopathy

  •  
  • HF

    Heart failure

  •  
  • HFpEF

    Heart failure with preserved ejection fraction

  •  
  • HFrEF

    Heart failure with reduced ejection fraction

  •  
  • HR

    Hazard ratio

  •  
  • i.v.

    intravenous

  •  
  • ICH

    Intracranial haemorrhage

  •  
  • IMPACT-AF

    Integrated Management Program Advancing Community Treatment of Atrial Fibrillation

  •  
  • INR

    International normalized ratio

  •  
  • LA

    Left atrium/atrial

  •  
  • LAA

    Left atrial appendage

  •  
  • LEGACY

    Long-term Effect of Goal-directed weight management on an Atrial fibrillation Cohort: a 5-Year follow-up study

  •  
  • LGE-CMR

    Late gadolinium contrast-enhanced cardiac magnetic resonance

  •  
  • LMWH

    Low-molecular-weight heparin

  •  
  • LV

    Left ventricular

  •  
  • LVEF

    Left ventricular ejection fraction

  •  
  • LVH

    Left ventricular hypertrophy

  •  
  • mAFA

    Mobile AF App

  •  
  • MANTRA-PAF

    Medical Antiarrhythmic Treatment or Radiofrequency Ablation in Paroxysmal Atrial Fibrillation

  •  
  • MRI

    Magnetic resonance imaging

  •  
  • NDCC

    Non-dihydropyridine calcium channel blocker

  •  
  • NOAC

    Non-vitamin K antagonist oral anticoagulant

  •  
  • NSAID

    Non-steroidal anti-inflammatory drug

  •  
  • NYHA

    New York Heart Association

  •  
  • o.d.

    omni die (once daily)

  •  
  • OAC

    Oral anticoagulant

  •  
  • OPTIMAS

    OPtimal TIMing of Anticoagulation after Stroke

  •  
  • OSA

    Obstructive sleep apnoea

  •  
  • PACES

    Anticoagulation for New-Onset Post-Operative Atrial Fibrillation After CABG

  •  
  • PAD

    Peripheral artery disease

  •  
  • PCI

    Percutaneous coronary intervention

  •  
  • PCORI

    Patient-Centred Outcomes Research Institute

  •  
  • 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

  •  
  • PREVAIL

    Watchman LAA Closure Device in Patients With Atrial Fibrillation Versus Long Term Warfarin Therapy

  •  
  • PRO

    Patient-reported outcome

  •  
  • PROTECT AF

    Watchman Left Atrial Appendage System for Embolic Protection in Patients With Atrial Fibrillation

  •  
  • PVI

    Pulmonary vein isolation

  •  
  • QoL

    Quality of life

  •  
  • QRS

    QRS interval

  •  
  • QTc

    Corrected QT interval

  •  
  • RACE

    Race Control Efficacy in Permanent Atrial Fibrillation

  •  
  • RCT

    Randomized controlled trial

  •  
  • RE-DUAL

    Randomized Evaluation of Dual Antithrombotic Therapy with Dabigatran vs. Triple Therapy with Warfarin in Patients with Nonvalvular Atrial Fibrillation Undergoing Percutaneous Coronary Intervention

  •  
  • RE-CIRCUIT

    Randomized Evaluation of dabigatran etexilate Compared to warfarIn in pulmonaRy vein ablation: assessment of different peri-proCedUral antIcoagulation sTrategies

  •  
  • REHEARSE-AF

    REmote HEArt Rhythm Sampling using the AliveCor hear monitor to scrEen for Atrial Fibrillation

  •  
  • RE-LY

    Randomized Evaluation of Long Term Anticoagulant 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

  •  
  • SAMe-TT2R2

    Sex (female), Age (<60 years), Medial history, Treatment, Tobacco use, Race (non-Caucasian) (score)

  •  
  • SBP

    Systolic blood pressure

  •  
  • START

    Optimal Delay Time to Initiate Anticoagulation After Ischemic Stroke in AF

  •  
  • STEMI

    ST-segment elevation myocardial infarction

  •  
  • TIA

    Transient ischaemic attack

  •  
  • TOE

    Transoesophageal echocardiography

  •  
  • TTR

    Time in therapeutic range

  •  
  • UFH

    Unfractionated heparin

  •  
  • US

    United States of America

  •  
  • VHD

    Valvular heart disease

  •  
  • VKA

    Vitamin K antagonist

  •  
  • WOEST

    What is the Optimal antiplatElet and anticoagulant therapy in patients with oral anticoagulation and coronary StenTing

1 Preamble

Guidelines summarize and evaluate available evidence with the aim of assisting health professionals in proposing the best management strategies for an individual patient with a given condition. Guidelines and their recommendations should facilitate decision making of health professionals in their daily practice. However, the final decisions concerning an individual patient must be made by the responsible health professional(s) in consultation with the patient and caregiver as appropriate.

A great number of Guidelines have been issued in recent years by the European Society of Cardiology (ESC), as well as by other societies and organizations. Because of their impact on clinical practice, quality criteria for the development of guidelines have been established in order to make all decisions transparent to the user. The recommendations for formulating and issuing ESC Guidelines can be found on the ESC website (https://www.escardio.org/Guidelines/Clinical-Practice-Guidelines/Guidelines-development/Writing-ESC-Guidelines). The ESC Guidelines represent the official position of the ESC on a given topic and are regularly updated.

In addition to the publication of Clinical Practice Guidelines, the ESC carries out the EurObservational Research Programme of international registries of cardiovascular diseases and interventions which are essential to assess, diagnostic/therapeutic processes, use of resources and adherence to Guidelines. These registries aim at providing a better understanding of medical practice in Europe and around the world, based on high-quality data collected during routine clinical practice.

Furthermore, the ESC has developed and embedded, in some of its guidelines, a set of quality indicators (QIs) which are tools to evaluate the level of implementation of the Guidelines and may be used by the ESC, hospitals, healthcare providers and professionals to measure clinical practice as well as used in educational programmes, alongside the key messages from the Guidelines, to improve quality of care and clinical outcomes.

The Members of this Task Force were selected by the ESC, including representation from its relevant ESC sub-specialty groups, in order to represent professionals involved with the medical care of patients with this pathology. Selected experts in the field undertook a comprehensive review of the published evidence for management of a given condition according to ESC Committee for Practice Guidelines (CPG) policy. A critical evaluation of diagnostic and therapeutic procedures was performed, including assessment of the risk–benefit ratio. The level of evidence and the strength of the recommendation of particular management options were weighed and graded according to predefined scales, as outlined below.

Table 1

Classes of recommendations

graphic
graphic
Table 1

Classes of recommendations

graphic
graphic
Table 2

Levels of evidence

graphic
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Table 2

Levels of evidence

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The experts of the writing and reviewing panels provided declaration of interest forms for all relationships that might be perceived as real or potential sources of conflicts of interest. Their declarations of interest were reviewed according to the ESC declaration of interest rules and can be found on the ESC website (http://www.escardio.org/guidelines). This process ensures transparency and prevents potential biases in the development and review processes. Any changes in declarations of interest that arise during the writing period were notified to the ESC and updated. The Task Force received its entire financial support from the ESC without any involvement from the healthcare industry.

The ESC CPG supervises and coordinates the preparation of new Guidelines. The Committee is also responsible for the endorsement process of these Guidelines. The ESC Guidelines undergo extensive review by the CPG and external experts. After appropriate revisions the Guidelines are approved by all the experts involved in the Task Force. The finalized document is approved by the CPG for publication in the European Heart Journal. The Guidelines were developed after careful consideration of the scientific and medical knowledge and the evidence available at the time of their dating.

The task of developing ESC Guidelines also includes the creation of educational tools and implementation programmes for the recommendations including condensed pocket guideline versions, summary slides, booklets with essential messages, summary cards for non-specialists, and an electronic version for digital applications (smartphones, etc.). These versions are abridged and thus, for more detailed information, the user should always access the full text version of the Guidelines, which is freely available via the ESC website and hosted on the EHJ website. The National Cardiac Societies of the ESC are encouraged to endorse, adopt, translate, and implement all ESC Guidelines. Implementation programmes are needed because it has been shown that the outcome of disease may be favourably influenced by the thorough application of clinical recommendations.

Health professionals are encouraged to take the ESC Guidelines fully into account when exercising their clinical judgment, as well as in the determination and the implementation of preventive, diagnostic or therapeutic medical strategies. However, the ESC Guidelines do not override in any way whatsoever the individual responsibility of health professionals to make appropriate and accurate decisions in consideration of each patient’s health condition and in consultation with that patient or the patient’s caregiver where appropriate and/or necessary. It is also the health professional’s responsibility to verify the rules and regulations applicable in each country to drugs and devices at the time of prescription.

2 Introduction

Atrial fibrillation (AF) poses significant burden to patients, physicians, and healthcare systems globally. Substantial research efforts and resources are being directed towards gaining detailed information about the mechanisms underlying AF, its natural course and effective treatments (see also the ESC Textbook of Cardiovascular Medicine: CardioMed) and new evidence is continuously generated and published.

The complexity of AF requires a multifaceted, holistic, and multidisciplinary approach to the management of AF patients, with their active involvement in partnership with clinicians. Streamlining the care of patients with AF in daily clinical practice is a challenging but essential requirement for effective management of AF. In recent years, substantial progress has been made in the detection of AF and its management, and new evidence is timely integrated in this third edition of the ESC guidelines on AF. The 2016 ESC AF Guidelines introduced the concept of the five domains to facilitate an integrated structured approach to AF care and promote consistent, guideline-adherent management for all patients. The Atrial Fibrillation Better Care (ABC) approach in the 2020 ESC AF Guidelines is a continuum of this approach, with the goal to further improve the structured management of AF patients, promote patient values, and finally improve patient outcomes.

Reflecting the multidisciplinary input into the management of patients with AF and interpretation of new evidence, the Task Force includes cardiologists with varying subspecialty expertise, cardiac surgeons, methodologists, and specialist nurses amongst its members.

Further to adhering to the standards for generating recommendations that are common to all ESC guidelines (see preamble), this Task Force discussed each draft recommendation during web-based conference calls dedicated to specific chapters, followed by consensus modifications and an online vote on each recommendation. Only recommendations that were supported by at least 75% of the Task Force members were included in the Guidelines.

2.1 What is new in the 2020 Guidelines?

New recommendations

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AAD = antiarrhythmic drug; ACS = acute coronary syndrome; AF = atrial fibrillation; CCS = chronic coronary syndrome; CHA2DS2-VASc = Congestive heart failure, Hypertension, Age ≥75 years, Diabetes mellitus, Stroke, Vascular disease, Age 65–74 years, Sex category (female); CrCl = creatinine clearance; ECG = electrocardiogram; HAS-BLED = Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile INR, Elderly (>65 years), Drugs/alcohol concomitantly; HCM = hypertrophic cardiomyopathy; i.v. = intravenous; LA = left atrium/atrial; NOAC = non-vitamin K antagonist oral anticoagulant; OAC = oral anticoagulant; OSA = obstructive sleep apnoea; PCI = percutaneous coronary intervention; PRO = patient-reported outcome; PVI = pulmonary vein isolation; QTc = corrected QT interval; TOE = transoesophageal echocardiography; VKA = vitamin K antagonist therapy.

aClass of recommendation.

New recommendations

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AAD = antiarrhythmic drug; ACS = acute coronary syndrome; AF = atrial fibrillation; CCS = chronic coronary syndrome; CHA2DS2-VASc = Congestive heart failure, Hypertension, Age ≥75 years, Diabetes mellitus, Stroke, Vascular disease, Age 65–74 years, Sex category (female); CrCl = creatinine clearance; ECG = electrocardiogram; HAS-BLED = Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile INR, Elderly (>65 years), Drugs/alcohol concomitantly; HCM = hypertrophic cardiomyopathy; i.v. = intravenous; LA = left atrium/atrial; NOAC = non-vitamin K antagonist oral anticoagulant; OAC = oral anticoagulant; OSA = obstructive sleep apnoea; PCI = percutaneous coronary intervention; PRO = patient-reported outcome; PVI = pulmonary vein isolation; QTc = corrected QT interval; TOE = transoesophageal echocardiography; VKA = vitamin K antagonist therapy.

aClass of recommendation.

Changes in the recommendations

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AAD = antiarrhythmic drug; AF = atrial fibrillation; BP = blood pressure; CTI = cavotricuspid isthmus; HFrEF = heart failure with reduced ejection fraction; ICH = intracranial haemorrhage; INR = international normalized ratio; LV = left ventricular; LVEF = left ventricular ejection fraction; NOAC = non-vitamin K antagonist oral anticoagulant; OAC = oral anticoagulant or oral anticoagulation; PVI = pulmonary vein isolation; TTR = time in therapeutic range; VKA = vitamin K antagonist.

aClass of recommendation.

Changes in the recommendations

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AAD = antiarrhythmic drug; AF = atrial fibrillation; BP = blood pressure; CTI = cavotricuspid isthmus; HFrEF = heart failure with reduced ejection fraction; ICH = intracranial haemorrhage; INR = international normalized ratio; LV = left ventricular; LVEF = left ventricular ejection fraction; NOAC = non-vitamin K antagonist oral anticoagulant; OAC = oral anticoagulant or oral anticoagulation; PVI = pulmonary vein isolation; TTR = time in therapeutic range; VKA = vitamin K antagonist.

aClass of recommendation.

3 Definition and diagnosis of atrial fibrillation

3.1 Definition

Table 3

Definition of atrial fibrillation

Definition
AFA supraventricular tachyarrhythmia with uncoordinated atrial electrical activation and consequently ineffective atrial contraction. Electrocardiographic characteristics of AF include:
  • Irregularly irregular R-R intervals (when atrioventricular conduction is not impaired),

  • Absence of distinct repeating P waves, and

  • Irregular atrial activations.

Currently used terms
Clinical AFSymptomatic or asymptomatic AF that is documented by surface ECG. The minimum duration of an ECG tracing of AF required to establish the diagnosis of clinical AF is at least 30 seconds, or entire 12-lead ECG.1,2
AHRE, subclinical AFRefers to individuals without symptoms attributable to AF, in whom clinical AF is NOT previously detected (that is, there is no surface ECG tracing of AF), see also section 3.3. AHRE − events fulfilling programmed or specified criteria for AHRE that are detected by CIEDs with an atrial lead allowing automated continuous monitoring of atrial rhythm and tracings storage. CIED-recorded AHRE need to be visually inspected because some AHRE may be electrical artefacts/false positives. Subclinical AF includes AHRE confirmed to be AF, AFL, or an AT, or AF episodes detected by insertable cardiac monitor or wearable monitor and confirmed by visually reviewed intracardiac electrograms or ECG-recorded rhythm.

Device-programmed rate criterion for AHRE is ≥175 bpm, whereas there is no specific rate limit for subclinical AF.

The criterion for AHRE duration is usually set at ≥5 min (mainly to reduce the inclusion of artefacts), whereas a wide range of subclinical AF duration cut-offs (from 10 − 20 seconds to >24 hours) is reported in studies of the association of subclinical AF with thromboembolism. The reported duration refers to either the longest single episode or, more commonly, total duration of AHRE/subclinical AF during the specified monitoring period.

Although not completely identical, the terms AHRE and subclinical AF are often used interchangeably (in this document the amalgamated term AHRE/subclinical AF will be used for practicality).3–5

Whereas a large body of high-quality evidence from RCTs informing the management of AF patients pertains exclusively to ‘clinical’ AF (that is, the ECG documentation of AF was a mandatory inclusion criterion in those RCTs), data on optimal management of AHRE and subclinical AF are lacking. For this reason, AF is currently described as either ‘clinical’ or ‘AHRE/subclinical’, until the results of several ongoing RCTs expected to inform the management of AHRE and ‘subclinical’ AF are available.

Definition
AFA supraventricular tachyarrhythmia with uncoordinated atrial electrical activation and consequently ineffective atrial contraction. Electrocardiographic characteristics of AF include:
  • Irregularly irregular R-R intervals (when atrioventricular conduction is not impaired),

  • Absence of distinct repeating P waves, and

  • Irregular atrial activations.

Currently used terms
Clinical AFSymptomatic or asymptomatic AF that is documented by surface ECG. The minimum duration of an ECG tracing of AF required to establish the diagnosis of clinical AF is at least 30 seconds, or entire 12-lead ECG.1,2
AHRE, subclinical AFRefers to individuals without symptoms attributable to AF, in whom clinical AF is NOT previously detected (that is, there is no surface ECG tracing of AF), see also section 3.3. AHRE − events fulfilling programmed or specified criteria for AHRE that are detected by CIEDs with an atrial lead allowing automated continuous monitoring of atrial rhythm and tracings storage. CIED-recorded AHRE need to be visually inspected because some AHRE may be electrical artefacts/false positives. Subclinical AF includes AHRE confirmed to be AF, AFL, or an AT, or AF episodes detected by insertable cardiac monitor or wearable monitor and confirmed by visually reviewed intracardiac electrograms or ECG-recorded rhythm.

Device-programmed rate criterion for AHRE is ≥175 bpm, whereas there is no specific rate limit for subclinical AF.

The criterion for AHRE duration is usually set at ≥5 min (mainly to reduce the inclusion of artefacts), whereas a wide range of subclinical AF duration cut-offs (from 10 − 20 seconds to >24 hours) is reported in studies of the association of subclinical AF with thromboembolism. The reported duration refers to either the longest single episode or, more commonly, total duration of AHRE/subclinical AF during the specified monitoring period.

Although not completely identical, the terms AHRE and subclinical AF are often used interchangeably (in this document the amalgamated term AHRE/subclinical AF will be used for practicality).3–5

Whereas a large body of high-quality evidence from RCTs informing the management of AF patients pertains exclusively to ‘clinical’ AF (that is, the ECG documentation of AF was a mandatory inclusion criterion in those RCTs), data on optimal management of AHRE and subclinical AF are lacking. For this reason, AF is currently described as either ‘clinical’ or ‘AHRE/subclinical’, until the results of several ongoing RCTs expected to inform the management of AHRE and ‘subclinical’ AF are available.

AHRE = atrial high-rate episode; AF = atrial fibrillation; ECG = electrocardiogram; AFL = atrial flutter; AT = atrial tachycardia; bpm = beats per minute; CIED = cardiac implantable electronic device; ECG = electrocardiogram; RCT = randomized controlled trial.

Table 3

Definition of atrial fibrillation

Definition
AFA supraventricular tachyarrhythmia with uncoordinated atrial electrical activation and consequently ineffective atrial contraction. Electrocardiographic characteristics of AF include:
  • Irregularly irregular R-R intervals (when atrioventricular conduction is not impaired),

  • Absence of distinct repeating P waves, and

  • Irregular atrial activations.

Currently used terms
Clinical AFSymptomatic or asymptomatic AF that is documented by surface ECG. The minimum duration of an ECG tracing of AF required to establish the diagnosis of clinical AF is at least 30 seconds, or entire 12-lead ECG.1,2
AHRE, subclinical AFRefers to individuals without symptoms attributable to AF, in whom clinical AF is NOT previously detected (that is, there is no surface ECG tracing of AF), see also section 3.3. AHRE − events fulfilling programmed or specified criteria for AHRE that are detected by CIEDs with an atrial lead allowing automated continuous monitoring of atrial rhythm and tracings storage. CIED-recorded AHRE need to be visually inspected because some AHRE may be electrical artefacts/false positives. Subclinical AF includes AHRE confirmed to be AF, AFL, or an AT, or AF episodes detected by insertable cardiac monitor or wearable monitor and confirmed by visually reviewed intracardiac electrograms or ECG-recorded rhythm.

Device-programmed rate criterion for AHRE is ≥175 bpm, whereas there is no specific rate limit for subclinical AF.

The criterion for AHRE duration is usually set at ≥5 min (mainly to reduce the inclusion of artefacts), whereas a wide range of subclinical AF duration cut-offs (from 10 − 20 seconds to >24 hours) is reported in studies of the association of subclinical AF with thromboembolism. The reported duration refers to either the longest single episode or, more commonly, total duration of AHRE/subclinical AF during the specified monitoring period.

Although not completely identical, the terms AHRE and subclinical AF are often used interchangeably (in this document the amalgamated term AHRE/subclinical AF will be used for practicality).3–5

Whereas a large body of high-quality evidence from RCTs informing the management of AF patients pertains exclusively to ‘clinical’ AF (that is, the ECG documentation of AF was a mandatory inclusion criterion in those RCTs), data on optimal management of AHRE and subclinical AF are lacking. For this reason, AF is currently described as either ‘clinical’ or ‘AHRE/subclinical’, until the results of several ongoing RCTs expected to inform the management of AHRE and ‘subclinical’ AF are available.

Definition
AFA supraventricular tachyarrhythmia with uncoordinated atrial electrical activation and consequently ineffective atrial contraction. Electrocardiographic characteristics of AF include:
  • Irregularly irregular R-R intervals (when atrioventricular conduction is not impaired),

  • Absence of distinct repeating P waves, and

  • Irregular atrial activations.

Currently used terms
Clinical AFSymptomatic or asymptomatic AF that is documented by surface ECG. The minimum duration of an ECG tracing of AF required to establish the diagnosis of clinical AF is at least 30 seconds, or entire 12-lead ECG.1,2
AHRE, subclinical AFRefers to individuals without symptoms attributable to AF, in whom clinical AF is NOT previously detected (that is, there is no surface ECG tracing of AF), see also section 3.3. AHRE − events fulfilling programmed or specified criteria for AHRE that are detected by CIEDs with an atrial lead allowing automated continuous monitoring of atrial rhythm and tracings storage. CIED-recorded AHRE need to be visually inspected because some AHRE may be electrical artefacts/false positives. Subclinical AF includes AHRE confirmed to be AF, AFL, or an AT, or AF episodes detected by insertable cardiac monitor or wearable monitor and confirmed by visually reviewed intracardiac electrograms or ECG-recorded rhythm.

Device-programmed rate criterion for AHRE is ≥175 bpm, whereas there is no specific rate limit for subclinical AF.

The criterion for AHRE duration is usually set at ≥5 min (mainly to reduce the inclusion of artefacts), whereas a wide range of subclinical AF duration cut-offs (from 10 − 20 seconds to >24 hours) is reported in studies of the association of subclinical AF with thromboembolism. The reported duration refers to either the longest single episode or, more commonly, total duration of AHRE/subclinical AF during the specified monitoring period.

Although not completely identical, the terms AHRE and subclinical AF are often used interchangeably (in this document the amalgamated term AHRE/subclinical AF will be used for practicality).3–5

Whereas a large body of high-quality evidence from RCTs informing the management of AF patients pertains exclusively to ‘clinical’ AF (that is, the ECG documentation of AF was a mandatory inclusion criterion in those RCTs), data on optimal management of AHRE and subclinical AF are lacking. For this reason, AF is currently described as either ‘clinical’ or ‘AHRE/subclinical’, until the results of several ongoing RCTs expected to inform the management of AHRE and ‘subclinical’ AF are available.

AHRE = atrial high-rate episode; AF = atrial fibrillation; ECG = electrocardiogram; AFL = atrial flutter; AT = atrial tachycardia; bpm = beats per minute; CIED = cardiac implantable electronic device; ECG = electrocardiogram; RCT = randomized controlled trial.

3.2 Diagnostic criteria for atrial fibrillation

The diagnosis of AF requires rhythm documentation with an electrocardiogram (ECG) tracing showing AF. By convention, an episode lasting at least 30 s is diagnostic for clinical AF.6

Recommendations for diagnosis of AF

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AF = atrial fibrillation; ECG = electrocardiogram.

a

Class of recommendation.

b

Level of evidence.

Recommendations for diagnosis of AF

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AF = atrial fibrillation; ECG = electrocardiogram.

a

Class of recommendation.

b

Level of evidence.

3.3 Diagnosis of atrial high-rate episodes/subclinical atrial fibrillation

Various implanted devices and wearable monitors allow detection of atrial high-rate episodes (AHRE) /subclinical AF (Figure 1).3 Owing to a short monitoring, detection of AHRE/subclinical AF via external ECG is less likely.7

Diagnosis of AHRE/subclinical AF. CIEDs with an atrial lead can monitor atrial rhythm and store the tracings. ICMs have no intracardiac leads but continuously monitor cardiac electrical activity by recording and analysing a single-lead bipolar surface ECG based on a specific algorithm. Left-bottom image: pacemaker with a right atrial lead, and a ventricular lead in the right ventricular apex. In addition to pacing at either site, these leads can sense activity in the respective cardiac chamber. The device can also detect pre-programmed events, such as AHRE. Right-bottom image: subcutaneous ICM: these devices have no intra-cardiac leads and essentially record a single, bipolar, surface ECG, with inbuilt algorithms for detection of AHRE or AF. AF = atrial fibrillation; AHRE = atrial high rate episode; CIED = cardiac implantable electronic device; ECG = electrocardiogram; ICM = insertable cardiac monitor; RCT = randomized clinical trial.
Figure 1

Diagnosis of AHRE/subclinical AF. CIEDs with an atrial lead can monitor atrial rhythm and store the tracings. ICMs have no intracardiac leads but continuously monitor cardiac electrical activity by recording and analysing a single-lead bipolar surface ECG based on a specific algorithm. Left-bottom image: pacemaker with a right atrial lead, and a ventricular lead in the right ventricular apex. In addition to pacing at either site, these leads can sense activity in the respective cardiac chamber. The device can also detect pre-programmed events, such as AHRE. Right-bottom image: subcutaneous ICM: these devices have no intra-cardiac leads and essentially record a single, bipolar, surface ECG, with inbuilt algorithms for detection of AHRE or AF. AF = atrial fibrillation; AHRE = atrial high rate episode; CIED = cardiac implantable electronic device; ECG = electrocardiogram; ICM = insertable cardiac monitor; RCT = randomized clinical trial.

When AHRE/subclinical AF is detected by a device/wearable, inspection of the stored electrograms/ECG rhythm strips is recommended to exclude artefacts or other causes of inappropriate detection.8,9

4 Epidemiology

Worldwide, AF is the most common sustained cardiac arrhythmia in adults10 (Figure 2, upper panel). AF is associated with substantial morbidity and mortality, thus portending significant burden to patients, societal health, and health economy (Figure 2, lower panel) (Supplementary section 1).

Epidemiology of AF: prevalence (upper panel)10–20; and lifetime risk and projected rise in the incidence and prevalence (lower panel).19,21–34 AF = atrial fibrillation; AFL = atrial flutter; BP = blood pressure; CI = confidence interval; EU = European Union. aSmoking, alcohol consumption, body mass index, BP, diabetes mellitus (type 1 or 2), and history of myocardial infarction or heart failure. bRisk profile: optimal − all risk factors are negative or within the normal range; borderline − no elevated risk factors but >1 borderline risk factor; elevated − >1 elevated risk factor.
Figure 2

Epidemiology of AF: prevalence (upper panel)10–20; and lifetime risk and projected rise in the incidence and prevalence (lower panel).19,21–34 AF = atrial fibrillation; AFL = atrial flutter; BP = blood pressure; CI = confidence interval; EU = European Union. aSmoking, alcohol consumption, body mass index, BP, diabetes mellitus (type 1 or 2), and history of myocardial infarction or heart failure. bRisk profile: optimal − all risk factors are negative or within the normal range; borderline − no elevated risk factors but >1 borderline risk factor; elevated − >1 elevated risk factor.

The currently estimated prevalence of AF in adults is between 2% and 4%,10 and a 2.3-fold rise11 is expected,12,13 owing to extended longevity in the general population and intensifying search for undiagnosed AF.15 Increasing age is a prominent AF risk factor, but increasing burden of other comorbidities including hypertension, diabetes mellitus, heart failure (HF), coronary artery disease (CAD), chronic kidney disease (CKD),21 obesity, and obstructive sleep apnoea (OSA) is also important;22–26 modifiable risk factors are potent contributors to AF development and progression27,28 (Figure 3). The age-adjusted incidence, prevalence, and lifetime risk of AF are lower in women vs. men and in non-Caucasian vs. Caucasian cohorts.10,14–20 A previous lifetime AF risk estimate of 1 in 4 individuals29,30 was recently revised to 1 in 3 individuals of European ancestry at index age of 55 years.31,32 The AF lifetime risk depends on age, genetic, and (sub)clinical factors.10,33,34 The observed impact of clinical risk factor burden/multiple comorbidity on AF risk (Figure 3, lower panel31) suggests that an early intervention and modifiable risk factor control could reduce incident AF.

Summary of risk factors for incident AF10,22,33,35–72 (Supplementary Table 1 for full list). AF = atrial fibrillation; COPD = chronic obstructive pulmonary disease.
Figure 3

Summary of risk factors for incident AF10,22,33,35–72 (Supplementary Table 1 for full list). AF = atrial fibrillation; COPD = chronic obstructive pulmonary disease.

4.1 Prediction of incident atrial fibrillation

Identifying individuals at higher risk of developing AF in the community could facilitate targeting of preventive interventions and screening programmes for early AF detection, for example in high-risk subgroups such as post-stroke patients.73 Various predictive scores for new-onset AF have been proposed (Supplementary Table 2), but none has been widely used in clinical practice.

4.2 Pathophysiology of atrial fibrillation

A complex interplay of triggers, perpetuators, and substrate development eventually resulting in AF occurrence is shown in Supplementary Figure 1.

5 Clinical features of atrial fibrillation

Clinical presentation of AF and AF-related outcomes are shown in Figure 4 (see also Supplementary section 2 and Supplementary Box 1).

Clinical presentation of AF and AF-related outcomes.10,31,74–140 AF = atrial fibrillation; HF = heart failure; HR = Hazard Ratio; LV = left ventricle; MI = myocardial infarction; QoL = quality of life. Patients with AF may have various symptoms92,108,109,128,131 but 50 − 87% are initially asymptomatic,75,82,88,111,117,120,125,127 with possibly a less favourable prognosis.79,82,87,88,117,119,127,134,139 First-onset AF symptoms are less well studied,92,105,108,109,,127 may change with treatment119 and AF recurrences are commonly asymptomatic.113Stroke/systolic embolism: annual AF-related stroke risk in AF patients depends on comorbidities.78,84,85,91,106,112 Cardioembolic strokes associated with AF are usually severe, highly recurrent, often fatal, or with permanent disability.10,83,115 In a population-based registry, patients with new-onset AF also had increased rates of systemic embolism.89 Left ventricular (LV) dysfunction and HF: multiple AF-associated mechanisms/myocardial alterations may lead to LV dysfunction and HF,102,138 resulting in a high prevalence and incidence of HF among AF patients. Sharing common risk factors, AF and HF often coexist, or may precipitate/exacerbate each other, resulting in significantly greater mortality than either condition alone.140Hospitalization: approximately 30% of AF patients have at least one, and 10% have ≥2, hospital admissions annually,99,110,129 being twice as likely to be hospitalized as age- and sex-matched non-AF individuals (37.5% vs. 17.5%, respectively).98 In a nationwide cohort, AF was the main cause for admission in 14% of hospitalized patients but their in-hospital mortality was <1%.101 The most common reasons for hospitalization of AF patients were cardiovascular disorders (49%), non-cardiovascular causes (43%) and bleeding (8%).129Quality of life (QoL) and functional status: >60% of AF patients have significantly impaired QoL/exercise tolerance,81,88,136 but only 17% have disabling symptoms.88 QoL is significantly lower in women,81,107,114,124 young individuals, and those with comorbidities.118 AF burden100 may also affect QoL, but only psychological functioning consistently predicted symptoms and QoL.136 Patients with AF more often developed anxiety disorders,126 had a higher burden of depressive symptoms,123 and poorer QoL with a Distressed personality type (Type D).103 Key symptom and QoL drivers are important to identify optimal AF treatment. It is also important to confirm that symptoms are related to AF or, if absent, to exclude a subconscious adaptation to living with suboptimal physical capacity by asking for breathlessness or fatigue on exertion and recording possible improvements after cardioversion. Cognitive impairment/dementia: AF may lead to cognitive impairment ranging from mild dysfunction to dementia97,104,141 via clinically apparent or silent stroke or insufficiently understood stroke-independent pathways.94,96,97,122 Magnetic resonance imaging (MRI) studies have shown that AF is associated with a greater than twofold increase in the odds of having silent cerebral ischaemia.90,121,142 A recent expert consensus paper summarized the available data.86Mortality: AF is independently associated with a twofold increased risk of all-cause mortality in women and a 1.5-fold increase in men,77,80,130,137 with an overall 3.5-fold mortality risk increase.31 Whereas the mechanistic explanation for this association is multifaceted, associated comorbidities play an important role.95 In a recent study, the most common causes of death among AF patients were HF (14.5%), malignancy (23.1%), and infection/sepsis (17.3%), whereas stroke-related mortality was only 6.5%.76 These and other recent data indicate that, in addition to anticoagulation and HF treatment, comorbid conditions need to be actively treated in the endeavour to reduce AF-related mortality.77,93,116,133
Figure 4

Clinical presentation of AF and AF-related outcomes.10,31,74–140 AF = atrial fibrillation; HF = heart failure; HR = Hazard Ratio; LV = left ventricle; MI = myocardial infarction; QoL = quality of life. Patients with AF may have various symptoms92,108,109,128,131 but 50 − 87% are initially asymptomatic,75,82,88,111,117,120,125,127 with possibly a less favourable prognosis.79,82,87,88,117,119,127,134,139 First-onset AF symptoms are less well studied,92,105,108,109,,127 may change with treatment119 and AF recurrences are commonly asymptomatic.113,Stroke/systolic embolism: annual AF-related stroke risk in AF patients depends on comorbidities.78,84,85,91,106,112 Cardioembolic strokes associated with AF are usually severe, highly recurrent, often fatal, or with permanent disability.10,83,115 In a population-based registry, patients with new-onset AF also had increased rates of systemic embolism.89, Left ventricular (LV) dysfunction and HF: multiple AF-associated mechanisms/myocardial alterations may lead to LV dysfunction and HF,102,138 resulting in a high prevalence and incidence of HF among AF patients. Sharing common risk factors, AF and HF often coexist, or may precipitate/exacerbate each other, resulting in significantly greater mortality than either condition alone.140,Hospitalization: approximately 30% of AF patients have at least one, and 10% have ≥2, hospital admissions annually,99,110,129 being twice as likely to be hospitalized as age- and sex-matched non-AF individuals (37.5% vs. 17.5%, respectively).98 In a nationwide cohort, AF was the main cause for admission in 14% of hospitalized patients but their in-hospital mortality was <1%.101 The most common reasons for hospitalization of AF patients were cardiovascular disorders (49%), non-cardiovascular causes (43%) and bleeding (8%).129,Quality of life (QoL) and functional status: >60% of AF patients have significantly impaired QoL/exercise tolerance,81,88,136 but only 17% have disabling symptoms.88 QoL is significantly lower in women,81,107,114,124 young individuals, and those with comorbidities.118 AF burden100 may also affect QoL, but only psychological functioning consistently predicted symptoms and QoL.136 Patients with AF more often developed anxiety disorders,126 had a higher burden of depressive symptoms,123 and poorer QoL with a Distressed personality type (Type D).103 Key symptom and QoL drivers are important to identify optimal AF treatment. It is also important to confirm that symptoms are related to AF or, if absent, to exclude a subconscious adaptation to living with suboptimal physical capacity by asking for breathlessness or fatigue on exertion and recording possible improvements after cardioversion. Cognitive impairment/dementia: AF may lead to cognitive impairment ranging from mild dysfunction to dementia97,104,141 via clinically apparent or silent stroke or insufficiently understood stroke-independent pathways.94,96,97,122 Magnetic resonance imaging (MRI) studies have shown that AF is associated with a greater than twofold increase in the odds of having silent cerebral ischaemia.90,121,142 A recent expert consensus paper summarized the available data.86,Mortality: AF is independently associated with a twofold increased risk of all-cause mortality in women and a 1.5-fold increase in men,77,80,130,137 with an overall 3.5-fold mortality risk increase.31 Whereas the mechanistic explanation for this association is multifaceted, associated comorbidities play an important role.95 In a recent study, the most common causes of death among AF patients were HF (14.5%), malignancy (23.1%), and infection/sepsis (17.3%), whereas stroke-related mortality was only 6.5%.76 These and other recent data indicate that, in addition to anticoagulation and HF treatment, comorbid conditions need to be actively treated in the endeavour to reduce AF-related mortality.77,93,116,133

6 Atrial fibrillation subtypes, burden, and progression

6.1 Classification of atrial fibrillation

Different AF classifications have been proposed but, traditionally, five patterns of AF are distinguished, based on presentation, duration, and spontaneous termination of AF episodes (Table 4).143

Table 4

Classification of AF

AF patternDefinition
First diagnosedAF not diagnosed before, irrespective of its duration or the presence/severity of AF-related symptoms.
ParoxysmalAF that terminates spontaneously or with intervention within 7 days of onset.
PersistentAF that is continuously sustained beyond 7 days, including episodes terminated by cardioversion (drugs or electrical cardioversion) after ≥7 days
Long-standing persistentContinuous AF of >12 months’ duration when decided to adopt a rhythm control strategy.
PermanentAF that is accepted by the patient and physician, and no further attempts to restore/maintain sinus rhythm will be undertaken. Permanent AF represents a therapeutic attitude of the patient and physician rather than an inherent pathophysiological attribute of AF, and the term should not be used in the context of a rhythm control strategy with antiarrhythmic drug therapy or AF ablation. Should a rhythm control strategy be adopted, the arrhythmia would be re-classified as ‘long-standing persistent AF’.
Terminology that should be abandoned
Lone AFA historical descriptor. Increasing knowledge about the pathophysiology of AF shows that in every patient a cause is present. Hence, this term is potentially confusing and should be abandoned.147
Valvular/non- valvular AFDifferentiates patients with moderate/severe mitral stenosis and those with mechanical prosthetic heart valve(s) from other patients with AF, but may be confusing148 and should not be used.
Chronic AFHas variable definitions and should not be used to describe populations of AF patients.
AF patternDefinition
First diagnosedAF not diagnosed before, irrespective of its duration or the presence/severity of AF-related symptoms.
ParoxysmalAF that terminates spontaneously or with intervention within 7 days of onset.
PersistentAF that is continuously sustained beyond 7 days, including episodes terminated by cardioversion (drugs or electrical cardioversion) after ≥7 days
Long-standing persistentContinuous AF of >12 months’ duration when decided to adopt a rhythm control strategy.
PermanentAF that is accepted by the patient and physician, and no further attempts to restore/maintain sinus rhythm will be undertaken. Permanent AF represents a therapeutic attitude of the patient and physician rather than an inherent pathophysiological attribute of AF, and the term should not be used in the context of a rhythm control strategy with antiarrhythmic drug therapy or AF ablation. Should a rhythm control strategy be adopted, the arrhythmia would be re-classified as ‘long-standing persistent AF’.
Terminology that should be abandoned
Lone AFA historical descriptor. Increasing knowledge about the pathophysiology of AF shows that in every patient a cause is present. Hence, this term is potentially confusing and should be abandoned.147
Valvular/non- valvular AFDifferentiates patients with moderate/severe mitral stenosis and those with mechanical prosthetic heart valve(s) from other patients with AF, but may be confusing148 and should not be used.
Chronic AFHas variable definitions and should not be used to describe populations of AF patients.

AF = atrial fibrillation.

Table 4

Classification of AF

AF patternDefinition
First diagnosedAF not diagnosed before, irrespective of its duration or the presence/severity of AF-related symptoms.
ParoxysmalAF that terminates spontaneously or with intervention within 7 days of onset.
PersistentAF that is continuously sustained beyond 7 days, including episodes terminated by cardioversion (drugs or electrical cardioversion) after ≥7 days
Long-standing persistentContinuous AF of >12 months’ duration when decided to adopt a rhythm control strategy.
PermanentAF that is accepted by the patient and physician, and no further attempts to restore/maintain sinus rhythm will be undertaken. Permanent AF represents a therapeutic attitude of the patient and physician rather than an inherent pathophysiological attribute of AF, and the term should not be used in the context of a rhythm control strategy with antiarrhythmic drug therapy or AF ablation. Should a rhythm control strategy be adopted, the arrhythmia would be re-classified as ‘long-standing persistent AF’.
Terminology that should be abandoned
Lone AFA historical descriptor. Increasing knowledge about the pathophysiology of AF shows that in every patient a cause is present. Hence, this term is potentially confusing and should be abandoned.147
Valvular/non- valvular AFDifferentiates patients with moderate/severe mitral stenosis and those with mechanical prosthetic heart valve(s) from other patients with AF, but may be confusing148 and should not be used.
Chronic AFHas variable definitions and should not be used to describe populations of AF patients.
AF patternDefinition
First diagnosedAF not diagnosed before, irrespective of its duration or the presence/severity of AF-related symptoms.
ParoxysmalAF that terminates spontaneously or with intervention within 7 days of onset.
PersistentAF that is continuously sustained beyond 7 days, including episodes terminated by cardioversion (drugs or electrical cardioversion) after ≥7 days
Long-standing persistentContinuous AF of >12 months’ duration when decided to adopt a rhythm control strategy.
PermanentAF that is accepted by the patient and physician, and no further attempts to restore/maintain sinus rhythm will be undertaken. Permanent AF represents a therapeutic attitude of the patient and physician rather than an inherent pathophysiological attribute of AF, and the term should not be used in the context of a rhythm control strategy with antiarrhythmic drug therapy or AF ablation. Should a rhythm control strategy be adopted, the arrhythmia would be re-classified as ‘long-standing persistent AF’.
Terminology that should be abandoned
Lone AFA historical descriptor. Increasing knowledge about the pathophysiology of AF shows that in every patient a cause is present. Hence, this term is potentially confusing and should be abandoned.147
Valvular/non- valvular AFDifferentiates patients with moderate/severe mitral stenosis and those with mechanical prosthetic heart valve(s) from other patients with AF, but may be confusing148 and should not be used.
Chronic AFHas variable definitions and should not be used to describe populations of AF patients.

AF = atrial fibrillation.

In patients experiencing both paroxysmal and persistent AF episodes, the more common type should be used for classification. However, clinically determined AF patterns do not correspond well to the AF burden measured by long-term ECG monitoring.144–146

Other classifications of AF reflect the presence of symptoms (asymptomatic AF is diagnosed with an opportune 12-lead ECG or rhythm strip in asymptomatic patients) or underlying cause of AF (e.g. postoperative AF, see section 11.19). Classifying AF by underlying drivers could inform management, but the evidence in support of the clinical use of such classification is lacking (Supplementary Table 3). Terms that should no longer be used to describe AF are listed in Table 4.

Recommendations for AF management are not based on the temporal AF patterns, except for the restoration of sinus rhythm.143,149,150 It is very unlikely that a simple but comprehensive AF classification will be proposed, given the multiplicity of factors relevant for its management, advances in AF monitoring, multiplicity of risk assessment tools, evolving treatments, and complexity of AF itself. Indeed, a paradigm shift from classification towards a structured characterization of AF, addressing specific domains with treatment and prognostic implications has been recently proposed.151 Such a scheme would streamline the assessment of AF patients at any healthcare level, thus facilitating communication among physicians, treatment decision making, and optimal management of AF patients, and should become a standard in clinical practice when reporting an AF case.

The proposed 4S-AF scheme (Stroke risk, Symptom severity, Severity of AF burden, Substrate severity) includes four AF-related domains (Figure 5).151 The currently used assessment tools/classifications pertinent to specific domains (e.g. stroke risk scores, symptom scores, clinical factors, imaging modalities, etc.) can be easily fitted in, but the 4S-AF has great potential for future refinements guided by advances in technology, and the most appropriate descriptors of AF domains are yet to be defined. Given the descriptors of AF included in the 4S-AF scheme, the structured characterization of AF patients using 4S-AF could also provide prognostic information, but the clinical utility and prognostic value of the 4S-AF scheme needs extensive validation in different AF cohorts and clinical settings.

4S-AF scheme as an example of structured characterization of AF.151 AF = atrial fibrillation; CHA2DS2-VASc = Congestive heart failure, Hypertension, Age ≥75 years, Diabetes mellitus, Stroke, Vascular disease, Age 65 − 74 years, Sex category (female); CT = computed tomography; EHRA = European Heart Rhythm Association; LA = left atrium; MRI = magnetic resonance imaging; QoL = quality of life; TOE = transoesophageal echocardiography; TTE = transthoracic echocardiography.
Figure 5

4S-AF scheme as an example of structured characterization of AF.151 AF = atrial fibrillation; CHA2DS2-VASc = Congestive heart failure, Hypertension, Age ≥75 years, Diabetes mellitus, Stroke, Vascular disease, Age 65 − 74 years, Sex category (female); CT = computed tomography; EHRA = European Heart Rhythm Association; LA = left atrium; MRI = magnetic resonance imaging; QoL = quality of life; TOE = transoesophageal echocardiography; TTE = transthoracic echocardiography.

Recommendations for structured characterization of AF

graphic
graphic

AF = atrial fibrillation

a

Class of recommendation.

b

Level of evidence.

Recommendations for structured characterization of AF

graphic
graphic

AF = atrial fibrillation

a

Class of recommendation.

b

Level of evidence.

6.2 Definition and assessment of atrial fibrillation burden

The term ‘burden’ refers to various AF aspects (e.g. epidemiological, economic).144 Regarding continuous device-based monitoring, ‘AF burden’ is currently defined as the overall time spent in AHRE/subclinical AF during a specified monitoring period (e.g. 1 day). Both the time in AF and the monitoring period should be acknowledged when reporting AF burden (most studies reported the maximum time spent in AF over a 24-h period), but optimal measures are yet to be determined.152 The term ‘AF burden’ is different from ‘burden of AF’, the latter referring to AF consequences.

Clinical AF burden is routinely determined by AF temporal pattern146 (Table 4) and intermittent ECG monitoring,153 neither corresponding well to the long-term ECG monitoring. The relationship of clinical AF burden with specific outcomes is not well characterized,154 but may be associated with higher risk of incident HF155 and all-cause mortality,156 while the association with quality of life (QoL) is complex and data about cognitive impairment/dementia are lacking.86 Recent randomized controlled trial (RCT) data consistently showed significantly lower residual thrombo-embolic risk among anticoagulated patients with paroxysmal vs. persistent AF,156–159 whereas earlier trial-based160 and observational data161,162 are contradictory. Among non-anticoagulated patients, stroke risk was lower with paroxysmal than non-paroxysmal AF,156 and a greater total AF burden (but not the longest AF episode) was independently associated with higher thrombo-embolic event rates.163 Clinical AF burden may influence the response to rhythm control therapy.164,165 The presence of >6 h of AF per week (especially when progressing to >24 h weekly) was associated with increased mortality, especially in women.166

Available evidence on the association of AF burden with AF-related outcomes is insufficient to guide treatment and should not be a major factor in treatment decisions. Comprehensive management of modifiable cardiovascular risk factors/comorbidity reduces AF burden (section 10.3).

6.3 Atrial fibrillation progression

Transition from paroxysmal to non-paroxysmal AF (or from subclinical to clinical AF)154,167–169 is often characterized by advancing atrial structural remodelling or worsening of atrial cardiomyopathy.170,171

Assessment of AF progression depends on duration of rhythm monitoring and underlying substrate.172,173 Reported annual rates of paroxysmal AF progression range from <1% to 15% (up to 27 − 36% in studies with ≥10-year follow-up).169,174 Risk factors for AF progression include age, HF, hypertension, CKD, chronic pulmonary diseases, diabetes mellitus, previous stroke, and left atrial (LA) size,167 whereas the added predictive value of biomarkers is presently not well defined. Older age is associated with permanent AF,82,117,154 and various triggers may also play a role, with different progression patterns resulting from their interaction with substrate remodelling.171 Progression to persistent/permanent AF is associated with adverse cardiovascular events, hospitalizations, and death,166 but it is unclear whether AF progression is a determinant of adverse prognosis or rather a marker of an underlying progressive disease/substrate.175,176 The true impact of different therapeutic interventions at different disease stages on AF progression and associated outcomes is also less well defined.

6.4 Atrial cardiomyopathy: definition, classification, clinical implications, and diagnostic assessment

Important progress in understanding AF mechanisms and thrombogenicity reconsiders the role of atrial cardiomyopathy (i.e. atrial structural, architectural, contractile, or electrophysiological changes with potentially relevant clinical manifestations).170

Clinical classification of atrial cardiomyopathy should be based on the atrial structure, morphology, electrical and mechanical function, and the diagnosis could be based on easily accessible parameters (e.g. aetiology, the prothrombotic state,177 and abnormal LA volume/function).178 Major clinical issues in AF (i.e. prevention of thrombo-embolic complications and AF progression) are influenced by atrial remodelling; and, importantly, AF is not only a risk factor for but also a marker of atrial cardiomyopathy, which could explain the lack of temporal relationship between detected AF and stroke.179

The diagnostic algorithm for atrial cardiomyopathy should follow a stepwise approach, identifying risk factors for atrial cardiomyopathy,170 atrial electrical and mechanical dysfunction,180 and increased thrombotic risk.181 More data are needed to define prognostic and treatment implications of different atrial cardiomyopathy morphofunctional forms.

7 Screening for atrial fibrillation

Multiple factors (i.e. increasing AF prevalence, previously unknown AF detection in about 10% of all ischaemic strokes,4,182 high prevalence of asymptomatic AF,117 potential to prevent AF-related strokes with appropriate treatment and increasing availability of AF detection tools) have fuelled international initiatives to implement screening for AF in clinical practice.172

Asymptomatic clinical AF has been independently associated with increased risk of stroke and mortality compared with symptomatic AF.82,117,127,183 Data derived from studies of incidentally detected asymptomatic AF are the closest possible approximation of the risk of stroke and death in screen-detected AF subjects, because delaying treatment to discern a natural history would be unethical. Observational data suggest that screen-detected AF responds to treatment similarly to AF detected by routine care,183 thus favouring AF screening.

Although AF fulfils many of the criteria for disease screening184 (Supplementary Figure 2), RCT data to confirm the health benefits from screening for AF and inform the choice of optimal screening programmes and strategies for its implementation are scarce.185,186 Advances in wearable technology will likely yield inexpensive and practical options for AF detection and AF burden assessment in the near future.

7.1 Screening tools

The systems used for AF screening are shown in Table 5 and Figure 6.173,187

Systems used for AF screening. Pulse palpation, automated BP monitors, single-lead ECG devices, PPG devices, other sensors (using seismocardiography, accelerometers, and gyroscopes, etc.) used in applications for smartphones, wrist bands, and watches. Intermittent smartwatch detection of AF is possible through PPG or ECG recordings. Smartwatches and other ‘wearables’ can passively measure pulse rate from the wrist using an optical sensor for PPG and alerting the consumer of a pulse irregularity (based on a specific algorithm for AF detection analysing pulse irregularity and variability).172,173,188–196 AF = atrial fibrillation; BP = blood pressure; ECG = electrocardiogram; PPG = photoplethysmography.
Figure 6

Systems used for AF screening. Pulse palpation, automated BP monitors, single-lead ECG devices, PPG devices, other sensors (using seismocardiography, accelerometers, and gyroscopes, etc.) used in applications for smartphones, wrist bands, and watches. Intermittent smartwatch detection of AF is possible through PPG or ECG recordings. Smartwatches and other ‘wearables’ can passively measure pulse rate from the wrist using an optical sensor for PPG and alerting the consumer of a pulse irregularity (based on a specific algorithm for AF detection analysing pulse irregularity and variability).172,173,188–196 AF = atrial fibrillation; BP = blood pressure; ECG = electrocardiogram; PPG = photoplethysmography.

Table 5

Sensitivity and specificity of various AF screening tools considering the 12-lead ECG as the gold standard173

SensitivitySpecificity
Pulse taking20387 − 97%70 − 81%
Automated BP monitors204–20793 − 100%86 − 92%
Single lead ECG208–21194 − 98%76 − 95%
Smartphone apps188,189,191,195,212,21391.5 − 98.5%91.4 − 100%
Watches196,198,213,21497 − 99%83 − 94%
SensitivitySpecificity
Pulse taking20387 − 97%70 − 81%
Automated BP monitors204–20793 − 100%86 − 92%
Single lead ECG208–21194 − 98%76 − 95%
Smartphone apps188,189,191,195,212,21391.5 − 98.5%91.4 − 100%
Watches196,198,213,21497 − 99%83 − 94%

AF = atrial fibrillation; BP = blood pressure; ECG = electrocardiogram.

Table 5

Sensitivity and specificity of various AF screening tools considering the 12-lead ECG as the gold standard173

SensitivitySpecificity
Pulse taking20387 − 97%70 − 81%
Automated BP monitors204–20793 − 100%86 − 92%
Single lead ECG208–21194 − 98%76 − 95%
Smartphone apps188,189,191,195,212,21391.5 − 98.5%91.4 − 100%
Watches196,198,213,21497 − 99%83 − 94%
SensitivitySpecificity
Pulse taking20387 − 97%70 − 81%
Automated BP monitors204–20793 − 100%86 − 92%
Single lead ECG208–21194 − 98%76 − 95%
Smartphone apps188,189,191,195,212,21391.5 − 98.5%91.4 − 100%
Watches196,198,213,21497 − 99%83 − 94%

AF = atrial fibrillation; BP = blood pressure; ECG = electrocardiogram.

Mobile health technologies are rapidly developing for AF detection and other purposes (>100 000 mHealth apps and ≥400 wearable activity monitors are currently available).197 Caution is needed in their clinical use, as many are not clinically validated. Several studies evaluated AF detection using smartwatches,198,199 thus opening new perspectives for AF detection targeting specific populations at risk. Machine learning and artificial intelligence may be capable of identifying individuals with previous AF episodes from a sinus rhythm ECG recording,200 which would be a major technological breakthrough in AF detection.200

The Apple Heart study201 included 419 297 self-enrolled smartwatch app users (mean age 40 years) in the United States of America (USA), of whom 0.5% received an irregular pulse notification (0.15% of those aged <40 years, 3.2% among those aged >65 years). Subsequent (notification-triggered) 1-week ECG patch monitoring revealed AF in 34% of monitored participants. The Huawei Heart study202 included 187 912 individuals (mean age 35 years, 86.7% male), of whom 0.23% received a ‘suspected AF’ notification. Of those effectively followed up, 87.0% were confirmed as having AF, with the positive predictive value of photoplethysmography signals being 91.6% [95% confidence interval (CI) 91.5 − 91.8]. Of those with identified AF, 95.1% entered an integrated AF management programme using a mobile AF App (mAFA).

When AF is detected by a screening tool, including mobile or wearable devices, a single-lead ECG tracing of ≥30 s or 12-lead ECG showing AF analysed by a physician with expertise in ECG rhythm interpretation is necessary to establish a definitive diagnosis of AF (devices capable of ECG recording enable direct analysis of the device-provided tracings). When AF detection is not based on an ECG recording (e.g. with devices using photoplethysmography) or in case of uncertainty in the interpretation of device-provided ECG tracing, a confirmatory ECG diagnosis has to be obtained using additional ECG recording (e.g. 12-lead ECG, Holter monitoring, etc.)

The data reported in Table 5 should be interpreted with caution, as assessment of sensitivity and specificity in many studies was based on small observational cohorts, with a substantial risk of bias due to signal selection. Moreover, there is a continuous evolution of algorithms and technologies available in commercial devices.

Two recent meta-analyses reported that screening for AF using an ECG would not detect more cases than would screening with pulse palpation.215

7.2 Screening types and strategies

Commonly used AF screening types and strategies172,173,216 include opportunistic or systematic screening of individuals above a certain age (usually ≥65 years) or with other characteristics suggestive of increased stroke risk, using intermittent single-point or repeated 30-s ECG recording over 2 weeks. The appropriate frequency of monitoring using smartphones or watches is undefined. Primary care, pharmacies, or community screening during special events is a good setting for AF screening.172,173 Overall, there was no significant difference between systematic vs. opportunistic or general practice vs. community screening in a meta-analysis, but repeated heart rhythm monitoring was associated with significantly better effectiveness compared with single assessment.215 Importantly, a structured referral of screen-detected or suspected AF cases for further clinical evaluation should be organized, to provide an appropriate management.

7.3 Benefits from and risks of screening for atrial fibrillation

Potential advantages and disadvantages of detecting a previously undiagnosed AF through screening are shown in Figure 7.173

Potential benefits from and risks of screening for AF. AF = atrial fibrillation; ECG = electrocardiogram; OAC = oral anticoagulant; SE =systemic embolism.
Figure 7

Potential benefits from and risks of screening for AF. AF = atrial fibrillation; ECG = electrocardiogram; OAC = oral anticoagulant; SE =systemic embolism.

Screening can also highlight cases of known suboptimally managed AF.217 Intermittent ECG recording increased new AF detection four-fold.217 In the REHEARSE-AF (REmote HEArt Rhythm Sampling using the AliveCor heart monitor to scrEen for Atrial Fibrillation) controlled study using a smartphone/tablet-based single-lead ECG system twice weekly over 12 months vs. routine care resulted in a 3.9-fold increase in AF detection in patients aged ≥65 years.218 Appropriate patient information and screening programme organization with rapid ECG clarification may reduce anxiety induced by suspicion of abnormality.

7.4 Cost-effectiveness of screening for atrial fibrillation

Higher AF-related medical costs justify strategies to identify and treat undiagnosed AF.219 Opportunistic AF screening is associated with lower costs than systematic screening.173 Appropriate choice of the screening tool and setting is important,220 and a favourable cost-effectiveness profile has been estimated for screening programmes based on pulse palpation, hand-held ECG devices, and smartphones with pulse photoplethysmography algorithms.172 Both systematic and opportunistic screening are more cost-effective than routine practice for patients ≥65 years, with opportunistic screening more likely to be cost-effective than systematic population screening.1491

7.5 Screening in high-risk populations

7.5.1 Elderly

The risk of AF (often asymptomatic) and stroke increase with age,82,127,221 thus justifying AF screening in the elderly. Opportunistic AF screening seems to be cost-effective in elderly populations (≥65 years)222 and among 75 − 76-year-old individuals undergoing a 2-week intermittent ECG screening.223

Pulse palpation and/or short-term ECG among the elderly (≥65 years) yielded an AF prevalence of 4.4%, with previously undiagnosed AF in 1.4%, suggesting a number needed to screen of 70.224 Repeated hand-held ECG recordings over 2 weeks in an unselected population aged 75 − 76 years increased the detection of asymptomatic AF up to 7.4% in subjects with ≥2 stroke risk factors.225

Recommendations for screening to detect AF

graphic
graphic

AF = atrial fibrillation; AHRE = atrial high-rate episode; ECG = electrocardiogram.

a

Class of recommendation.

b

Level of evidence.

c

See sections 3.2 and 3.3 for diagnostic criteria for AF and AHRE, and section 16 for the management of patients with AHRE.

Recommendations for screening to detect AF

graphic
graphic

AF = atrial fibrillation; AHRE = atrial high-rate episode; ECG = electrocardiogram.

a

Class of recommendation.

b

Level of evidence.

c

See sections 3.2 and 3.3 for diagnostic criteria for AF and AHRE, and section 16 for the management of patients with AHRE.

8 Diagnostic assessment in atrial fibrillation

Often occurring in patients with cardiovascular risk factors/comorbidities, AF may sometimes be a marker of undiagnosed conditions. Hence, all AF patients will benefit from a comprehensive cardiovascular assessment (Figure 8).

Diagnostic work-up and follow-up in AF patients. AF = atrial fibrillation; BNP = B-type natriuretic peptide; CHA2DS2-VASc = Congestive heart failure, Hypertension, Age ≥75 years, Diabetes mellitus, Stroke, Vascular disease, Age 65 − 74 years, Sex category (female); CAD = coronary artery disease; CRP = C-reactive protein; CT = computed tomography; CTA = computed tomography angiography; cTnT-hs = high-sensitivity cardiac troponin T; ECG = electrocardiogram; LAA = left atrial appendage; LGE-CMR = late gadolinium contrast-enhanced cardiac magnetic resonance; MRI = magnetic resonance imaging; NT-ProBNP = N-terminal (NT)-prohormone B-type natriuretic peptide.
Figure 8

Diagnostic work-up and follow-up in AF patients. AF = atrial fibrillation; BNP = B-type natriuretic peptide; CHA2DS2-VASc = Congestive heart failure, Hypertension, Age ≥75 years, Diabetes mellitus, Stroke, Vascular disease, Age 65 − 74 years, Sex category (female); CAD = coronary artery disease; CRP = C-reactive protein; CT = computed tomography; CTA = computed tomography angiography; cTnT-hs = high-sensitivity cardiac troponin T; ECG = electrocardiogram; LAA = left atrial appendage; LGE-CMR = late gadolinium contrast-enhanced cardiac magnetic resonance; MRI = magnetic resonance imaging; NT-ProBNP = N-terminal (NT)-prohormone B-type natriuretic peptide.

The ‘standard package’ for diagnostic evaluation of AF patients should include complete medical history and assessment of concomitant conditions, AF pattern, stroke risk, AF-related symptoms, thrombo-embolism, and LV dysfunction.143 A 12-lead ECG is recommended in all AF patients, to establish the diagnosis of AF, assess ventricular rate during AF, and check for the presence of conduction defects, ischaemia, or signs of structural heart disease. Laboratory tests (thyroid and kidney function, serum electrolytes, full blood count) and transthoracic echocardiography (LV size and function, LA size, valvular disease, and right heart size and systolic function) are needed to guide treatment. Based on the patient’s characteristics, specific additional information can be obtained. Most AF patients need regular follow-up (primary care) to ensure continued optimal management.

8.1 Symptoms and quality of life

As symptoms related to AF may range from none to disabling, and rhythm control treatment decisions (including catheter ablation) are influenced by symptom severity, symptom status should be characterized using the European Heart Rhythm Association (EHRA) symptom scale228 (Table 6), and the relation of symptoms (especially if non-specific, such as shortness of breath, fatigue, chest discomfort, etc.) to AF should be elucidated because symptoms may also result from undiagnosed or suboptimally managed concomitant cardiovascular risk factors or pathological conditions.229

Table 6

EHRA symptom scale

ScoreSymptomsDescription
1NoneAF does not cause any symptoms
2aMildNormal daily activity not affected by symptoms related to AF
2bModerateNormal daily activity not affected by symptoms related to AF, but patient troubled by symptoms
3SevereNormal daily activity affected by symptoms related to AF
4DisablingNormal daily activity discontinued
ScoreSymptomsDescription
1NoneAF does not cause any symptoms
2aMildNormal daily activity not affected by symptoms related to AF
2bModerateNormal daily activity not affected by symptoms related to AF, but patient troubled by symptoms
3SevereNormal daily activity affected by symptoms related to AF
4DisablingNormal daily activity discontinued

Six symptoms, including palpitations, fatigue, dizziness, dyspnoea, chest pain, and anxiety during AF, are evaluated with regard to how it affects the patient’s daily activity, ranging from none to symptom frequency or severity that leads to a discontinuation of daily activities.

To measure treatment effects, QoL and symptom questionnaires should be sensitive to changes in AF burden. The EHRA symptom scale is a physician-assessed tool for quantification of AF-related symptoms that is used to guide symptom-driven AF treatment decisions,228 and has been related to adverse outcomes in more symptomatic patients (score 3 − 4) versus those with a score of 1 − 2.228,230 However, it does not consider the symptom dimensions such as anxiety, treatment concerns, and medication adverse effects that are captured by general QoL scales,230 or the patient-reported symptom-related outcomes. As discrepancies between patient-reported and physician-assessed outcomes are frequently observed,231 the AF-related treatment decisions also need to be informed by a quantified patient perception of symptoms, but further research is needed to identify optimal tool(s) for capturing this information.

AF = atrial fibrillation; EHRA = European Heart Rhythm Association; QoL = quality of life.

Table 6

EHRA symptom scale

ScoreSymptomsDescription
1NoneAF does not cause any symptoms
2aMildNormal daily activity not affected by symptoms related to AF
2bModerateNormal daily activity not affected by symptoms related to AF, but patient troubled by symptoms
3SevereNormal daily activity affected by symptoms related to AF
4DisablingNormal daily activity discontinued
ScoreSymptomsDescription
1NoneAF does not cause any symptoms
2aMildNormal daily activity not affected by symptoms related to AF
2bModerateNormal daily activity not affected by symptoms related to AF, but patient troubled by symptoms
3SevereNormal daily activity affected by symptoms related to AF
4DisablingNormal daily activity discontinued

Six symptoms, including palpitations, fatigue, dizziness, dyspnoea, chest pain, and anxiety during AF, are evaluated with regard to how it affects the patient’s daily activity, ranging from none to symptom frequency or severity that leads to a discontinuation of daily activities.

To measure treatment effects, QoL and symptom questionnaires should be sensitive to changes in AF burden. The EHRA symptom scale is a physician-assessed tool for quantification of AF-related symptoms that is used to guide symptom-driven AF treatment decisions,228 and has been related to adverse outcomes in more symptomatic patients (score 3 − 4) versus those with a score of 1 − 2.228,230 However, it does not consider the symptom dimensions such as anxiety, treatment concerns, and medication adverse effects that are captured by general QoL scales,230 or the patient-reported symptom-related outcomes. As discrepancies between patient-reported and physician-assessed outcomes are frequently observed,231 the AF-related treatment decisions also need to be informed by a quantified patient perception of symptoms, but further research is needed to identify optimal tool(s) for capturing this information.

AF = atrial fibrillation; EHRA = European Heart Rhythm Association; QoL = quality of life.

In selected AF patients, long-term ECG monitoring is recommended to assess the adequacy of rate control or to relate symptoms with AF episodes. Sometimes the association of symptoms with AF can be established only retrospectively, after successful rhythm control intervention. In selected patients, a trial of sinus rhythm using cardioversion and a quantified patient perception of symptoms using a validated assessment tool (Supplementary Table 4) may inform the decision about subsequent AF catheter ablation (section 10.2).

Symptomatic and functional improvement with rhythm control therapies (cardioversion,232–234 antiarrhythmic medications, and AF catheter-ablation procedures235–242) largely depends on sinus rhythm maintenance243; however, QoL may improve despite AF recurrences, unless AF burden is high244 (e.g. >2 h daily100) owing to optimized management of cardiovascular risk factors or comorbidities245 or a treatment expectancy effect. The effect of AF treatment246,247 is supported by reports of persistently improved QoL 10 years after paroxysmal AF catheter ablation in patients with a low AF progression rate.248

8.2 Substrate

The substrate for AF relates to LA dilation and fibrosis with subsequent LA dysfunction and delay in electromechanical conduction. Non-invasive, multimodality imaging can provide all needed information (Figure 9).249,250

Imaging in AF. Anatomical imaging provides the LA size, shape, and fibrosis. Most accurate assessment of LA dilation is obtained by CMR or CT. For routine assessment, two-dimensional (2D) or (preferably) three-dimensional (3D) transthoracic echocardiography is used. The 3D echocardiographic normal volume values are 15 − 42 mL/m2 for men and 15 − 39 mL/m2 for women.250 Assessment of LA fibrosis with LGE-CMR has been described but only rarely applied in clinical practice.251 Functional imaging includes TDI and strain. TDI measures the velocities of the myocardium in diastole and systole, whereas LA strain reflects active LA contraction. The PA-TDI interval reflects the atrial electromechanical delay (total LA conduction time, the time interval between the P-wave on the ECG and the A’ [atrial peak velocity] on TDI) and reflects LA strain.252 LA wall infiltration by epicardial fat is a potential early marker of inflammation and can be detected with CT or cardiac MRI.253 Before AF ablation, the pulmonary vein anatomy can be visualized with CT or CMR. AF = atrial fibrillation; CT = computed tomography; EP = electrophysiology; LA = left atrium; LAA = left atrial appendage; LV = left ventricular; LGE-CMR = late gadolinium contrast-enhanced cardiac magnetic resonance; MRI = magnetic resonance imaging; TDI = tissue doppler imaging; TOE = transoesophageal echocardiography; TTE = transthoracic echocardiography.
Figure 9

Imaging in AF. Anatomical imaging provides the LA size, shape, and fibrosis. Most accurate assessment of LA dilation is obtained by CMR or CT. For routine assessment, two-dimensional (2D) or (preferably) three-dimensional (3D) transthoracic echocardiography is used. The 3D echocardiographic normal volume values are 15 − 42 mL/m2 for men and 15 − 39 mL/m2 for women.250 Assessment of LA fibrosis with LGE-CMR has been described but only rarely applied in clinical practice.251 Functional imaging includes TDI and strain. TDI measures the velocities of the myocardium in diastole and systole, whereas LA strain reflects active LA contraction. The PA-TDI interval reflects the atrial electromechanical delay (total LA conduction time, the time interval between the P-wave on the ECG and the A’ [atrial peak velocity] on TDI) and reflects LA strain.252 LA wall infiltration by epicardial fat is a potential early marker of inflammation and can be detected with CT or cardiac MRI.253 Before AF ablation, the pulmonary vein anatomy can be visualized with CT or CMR. AF = atrial fibrillation; CT = computed tomography; EP = electrophysiology; LA = left atrium; LAA = left atrial appendage; LV = left ventricular; LGE-CMR = late gadolinium contrast-enhanced cardiac magnetic resonance; MRI = magnetic resonance imaging; TDI = tissue doppler imaging; TOE = transoesophageal echocardiography; TTE = transthoracic echocardiography.

In selected patients, transoesophageal echocardiography (TOE) can be used to evaluate valvular heart disease (VHD) or left atrial appendage (LAA) thrombus; CT coronary angiography can be performed for assessment of CAD; CT/MRI of the brain can be performed when stroke is suspected. Specific predictors of stroke have been suggested: LA dilation, spontaneous LA contrast, reduced LA strain, LAA thrombus, low peak LAA velocity (<20 cm/s), and LAA non-chicken wing configuration (on CT).250

Recommendations for diagnostic evaluation of patients with AF

graphic
graphic

AF = atrial fibrillation; EHRA = European Heart Rhythm Association.

a

Class of recommendation.

b

Level of evidence.

Recommendations for diagnostic evaluation of patients with AF

graphic
graphic

AF = atrial fibrillation; EHRA = European Heart Rhythm Association.

a

Class of recommendation.

b

Level of evidence.

9 Integrated management of patients with atrial fibrillation

9.1 Definitions and components of integrated management of atrial fibrillation patients

Integrated management of AF patients requires a coordinated and agreed patient-individualized care pathway to deliver optimized treatment (Figure 10) by an interdisciplinary team (Figure 11). Central to this approach is the patient; treatment options should be discussed, and the management plan agreed in discussion with healthcare professionals. Treatment is subject to change over time with the development of new risk factors, symptoms, disease progression, and the advent of new treatments.

Components of integrated AF management. AF = atrial fibrillation; HCP = healthcare professional; MDT = multidisciplinary team.
Figure 10

Components of integrated AF management. AF = atrial fibrillation; HCP = healthcare professional; MDT = multidisciplinary team.

9.2 Multidisciplinary atrial fibrillation teams

Integrated AF management requires a coordinated multidisciplinary team (Figure 11) composed according to individual patient needs and local availability of services. Complex patients would benefit from a multidisciplinary team that includes relevant specialists, as well as their primary care physician (for post-discharge care) and their family/carer. Involvement of patient and family/carers is integral to the success of AF management.

Integrated AF management team (an example). The figure gives an example on the potential composition of AF teams showing a variety of different specialists supporting individual patients as needed. AF = atrial fibrillation. aAccording to local standards, this could be a general cardiologist with special interest in arrhythmias/AF or an electrophysiologist.
Figure 11

Integrated AF management team (an example). The figure gives an example on the potential composition of AF teams showing a variety of different specialists supporting individual patients as needed. AF = atrial fibrillation. aAccording to local standards, this could be a general cardiologist with special interest in arrhythmias/AF or an electrophysiologist.

9.2.1 Role of healthcare systems and budget constraints

Optimized AF treatment requires a well-structured healthcare system and significant financial resources.254 Allocation of resources will vary due to differing healthcare system structures and budget constraints in diverse geographies. The significant inequalities in the access to AF management-related resources are documented in the recent ESC Atlas on Cardiovascular Disease.255 It is important to consider optimizing use of available resources to reduce stroke, improve symptoms, and treat comorbidities.

9.3 Patient involvement and shared decision making

9.3.1 Patient values and preferences

Exploring patient’s values, goals, and preferences should be the first step of shared decision making.256,257 Qualitative research demonstrates recurring discordance between caregivers reporting shared decision making and patients experiencing a paternalistic model,109,258–261 and a misperception that many prefer not to be involved in decision making, rather deferring to their physician.259,262–266 For shared decision making,261 the importance attached by the patient to stroke prevention and rhythm control and the respective risk of death, stroke, and major bleeding, as well as the burden of treatment, should be thoroughly assessed and respected.257,264,266–268

9.3.2 Patient education

Patient knowledge about AF and its management is often limited257,269–272 particularly when first diagnosed, when the majority of treatment decisions are discussed and made.

Information on useful resources to help educate AF patients273 can be found in the ESC Textbook of Cardiovascular Medicine, but education alone is often insufficient to produce and maintain medication adherence and lifestyle modifications.

9.4 Healthcare professional education

A mixed-methods approach has been used when targeting healthcare professionals including individual needs assessment followed by bespoke education and training, whether by smart technology, online resources, or upskilling face-to-face workshops or a combination.274 The mAFA, integrating clinical-decision support and education for healthcare professionals, has been successfully piloted and subsequently tested in an outcome RCT.275 Education alone is insufficient to change healthcare-professional behaviour.276 In the Integrated Management Program Advancing Community Treatment of Atrial Fibrillation (IMPACT-AF) trial,277 a multifaceted educational intervention including healthcare-professional education and feedback resulted in a significant increase in the proportion of patients treated with oral anticoagulant (OAC) therapy.

9.5 Adherence to treatment

Factors affecting adherence to treatment can be grouped into patient-related (e.g. demographics, comorbidities, cognitive impairment, polypharmacy, treatment side-effects, psychological health, patient understanding of the treatment regimen), physician-related (knowledge, awareness of guidelines, expertise, multidisciplinary team approach), and healthcare system-related (work-setting, access to treatments, cost) factors.278

Ensuring patients are appropriately informed about treatment options, how to adhere to treatment, potential consequences of non-adherence, in addition to managing patient’s expectations of treatment goals, are crucial to promote adherence. Regular review by any member of the multidisciplinary team is important to identify non-adherence and implement strategies to improve adherence where appropriate.

9.6 Technology tools supporting atrial fibrillation management

Clinical decision support systems are intelligent systems that digitize and provide evidence-based guidelines, clinical pathways, and algorithms facilitating personalized, timely, and evidence-based treatment.

The MobiGuide project279 and several applications280–283 (Supplementary Tables 5 and 6) have been used to enhance patient education, improve communication between patients and healthcare professionals, and encourage active patient involvement. The ESC/CATCH-ME (Characterizing AF by Translating its Causes into Health Modifiers in the Elderly) consortium also has a smartphone/tablet app281 for AF patients, but this is yet to be tested prospectively. A Cochrane review284 demonstrated that patient decision-support aids reduce decision conflict.285–288 Nevertheless, contradictory results277,289,290 illustrate the need for more carefully designed studies, including assessment of the intervention’s effect on clinical events.

9.7 Advantages of integrated management of atrial fibrillation patients

Limited evidence exists on the effectiveness of integrated management of AF. Available intervention studies vary widely in number and content of ‘integrated care’ employed. Six studies—one cluster RCT,291 four RCTs,277,292–295 and one before-and-after study294—of integrated AF management have demonstrated mixed findings (Supplementary Table 7). Two studies292,294 and one meta-analysis296 report significantly lower rates of cardiovascular hospitalization and death with nurse-led, integrated care, whereas others reported no effect of integrated care on these outcomes. One multifaceted study277 demonstrated improved OAC rates in the intervention group at 12 months. The IMPACT-AF study277 found no significant difference in the composite efficacy outcome (unplanned emergency department visit or cardiovascular hospitalization) or the primary safety outcome of major bleeding between intervention and usual care.

9.8 Measures (or approaches) for implementation of integrated management

Integrated management of AF requires a change in the current approach to patient care, to focus on moving from a multidisciplinary team to interdisciplinary working, including behaviour change for all AF team members and key stakeholders including patients and their family297,298 (Supplementary Figure 3).

To understand whether integrated AF management has been implemented into clinical practice and had an impact on important outcomes (mortality, stroke, hospitalization, QoL, symptom reduction, etc.), a specific international standard set of outcome measures should be collected (Supplementary Figure 4).299 This would also highlight areas requiring further development.

9.9 Treatment burden

Patient-perceived treatment burden300 is defined as the workload imposed by healthcare on patients and its effect on patient functioning and well-being apart from specific treatment side-effects.301,302 It includes everything patients do for their health (drug management, self-monitoring, visits to the doctor, laboratory tests, lifestyle changes) and healthcare impact on their social relationships, potentially affecting adherence to treatment,303,304 QoL, and outcomes (e.g. hospitalization and survival).305,306 Patient-perceived treatment burden is influenced by their knowledge about disease.302 Patients with similar treatment regimens may have very different treatment burden,307 with only a weak agreement between patient’s and physicians’ treatment burden evaluation, suggesting that the patient’s experience is not shared in depth during consultations.302,308,309

Treatment burden can be overwhelming for patients with multiple chronic conditions301 (e.g. those with three chronic conditions would have to take 6 − 12 medications daily, visit a healthcare giver 1.2 − 5.9 times per month, and spend 49.6 − 71.0 h monthly in healthcare-related activities310). Treatment burden in AF patients is largely unknown. In a single-centre prospective study, AF patient-perceived total treatment burden was higher than in patients with other chronic conditions (27.6% vs. 24.3%, P =0.011), and 1 in 5 AF patients reported a high treatment burden that could question the sustainability of their treatment. Notably, AF patients attributed the highest proportion of treatment burden to healthcare system-related aspects (e.g. attending appointments etc.) and lifestyle modification requirements. Female sex and younger age were independently significantly associated with a higher treatment burden, whereas non-vitamin K antagonist oral anticoagulants (NOACs) and rhythm control reduced the odds for high treatment burden by >50%.311

The discussion of treatment burden should be an integral part of shared, informed treatment decision making, and treatment burden can be assessed using a validated questionnaire.312

9.10 Patient-reported outcomes

There is increasing advocacy for including patient-reported outcomes (PROs) as endpoints in clinical trials313 and their routine collection314–316 to improve care and assess treatment success from the patient’s perspective. Patients’ experience of AF and its management is highly subjective; AF management has become increasingly complex, potentially resulting in significant treatment burden and poorer health-related QoL.

Measuring outcomes that are important to patients, in addition to ‘hard’ clinical endpoints (death, stroke, major bleeding, etc.), can inform AF management. An international consortium of AF patients and healthcare professionals has identified the following PROs as important to measure for AF: health-related QoL, physical and emotional functioning, cognitive function, symptom severity, exercise tolerance, and ability to work (Supplementary Figure 4)299; PRO measures can be used to assess these factors and the international standard set of AF outcome measures proposes some tools for assessing PROs.299 Health informatics systems could help capture PRO data. Despite increasing support for the role of PRO measures in healthcare management, few studies and registries report collecting PRO data using validated tools.313 Implementation of PRO measures in the management of AF patients is addressed in a dedicated expert consensus paper developed in collaboration with patient representatives by the EHRA.317

Recommendations about integrated AF management

graphic
graphic

AF = atrial fibrillation; PRO = patient-reported outcome.

a

Class of recommendation.

b

Level of evidence.

Recommendations about integrated AF management

graphic
graphic

AF = atrial fibrillation; PRO = patient-reported outcome.

a

Class of recommendation.

b

Level of evidence.

10 Patient management: the integrated ABC pathway

The simple Atrial fibrillation Better Care (ABC) holistic pathway ('A' Anticoagulation/Avoid stroke; ‘B’ Better symptom management; ‘C’ Cardiovascular and Comorbidity optimization318) streamlines integrated care of AF patients across all healthcare levels and among different specialties. Compared with usual care, implementation of the ABC pathway has been significantly associated with lower risk of all-cause death, composite outcome of stroke/major bleeding/cardiovascular death and first hospitalization,319 lower rates of cardiovascular events,320,321 and lower health-related costs.322 In the prospective, randomized mAFA-II trial, the composite outcome was significantly lowered with ABC pathway management intervention compared with usual care [1.9% vs. 6.0%; hazard ratio (HR) 0.39; 95% CI 0.22 − 0.67; P <0.001].323

10. 1 ‘A’ – Anticoagulation/Avoid stroke

This section refers to AF in the absence of severe mitral stenosis or prosthetic heart valves (for AF with concomitant VHD see section 11.7).148

10.1.1 Stroke risk assessment

Overall, AF increases the risk of stroke five-fold, but this risk is not homogeneous, depending on the presence of specific stroke risk factors/modifiers. Main clinical stroke risk factors have been identified from non-anticoagulated arms of the historical RCTs conducted >20 years ago, notwithstanding that these trials only randomized <10% of patients screened, whereas many common risk factors were not recorded or consistently defined.324 These data have been supplemented by evidence from large observational cohorts also studying patients who would not have been included in the RCTs. Subsequently, various imaging, blood, and urine biological markers (biomarkers) have been associated with stroke risk (Table 7).324,325 In addition, non-paroxysmal AF is associated with an increase in thrombo-embolism (multivariable adjusted HR 1.38; 95% CI 1.19 − 1.61; P <0.001) compared with paroxysmal AF.156 Notably, many of the risk factors for AF-related complications are also risk factors for incident AF.33

Table 7

Stroke risk factors in patients with AF

Most commonly studied clinical risk factors (a systematic review)324Positive studies/All studiesOther clinical risk factors325Imaging biomarkers291,326–328Blood/urine biomarkers329–332
Stroke/TIA/systemic embolism15/16Impaired renal function/CKD

Echocardiography

Cardiac troponin T and I

Natriuretic peptides

Cystatin C

Proteinuria

CrCl/eGFR

CRP

IL-6

GDF-15

von Willebrand factor

D-dimer

Hypertension11/20OSA

LA dilatation

Spontaneous contrast or thrombus in LA

Low LAA velocities

Complex aortic plaque

Ageing (per decade)9/13HCM
Structural heart disease9/13Amyloidosis in degenerative cerebral and heart diseases
Diabetes mellitus9/14Hyperlipidaemia
Vascular disease6/17Smoking

Cerebral imaging

CHF/LV dysfunction7/18Metabolic syndrome333

Small-vessel disease

Sex category (female)8/22Malignancy
Most commonly studied clinical risk factors (a systematic review)324Positive studies/All studiesOther clinical risk factors325Imaging biomarkers291,326–328Blood/urine biomarkers329–332
Stroke/TIA/systemic embolism15/16Impaired renal function/CKD

Echocardiography

Cardiac troponin T and I

Natriuretic peptides

Cystatin C

Proteinuria

CrCl/eGFR

CRP

IL-6

GDF-15

von Willebrand factor

D-dimer

Hypertension11/20OSA

LA dilatation

Spontaneous contrast or thrombus in LA

Low LAA velocities

Complex aortic plaque

Ageing (per decade)9/13HCM
Structural heart disease9/13Amyloidosis in degenerative cerebral and heart diseases
Diabetes mellitus9/14Hyperlipidaemia
Vascular disease6/17Smoking

Cerebral imaging

CHF/LV dysfunction7/18Metabolic syndrome333

Small-vessel disease

Sex category (female)8/22Malignancy

CHF = congestive heart failure; CKD = chronic kidney disease; CrCl = creatinine clearance; CRP = C-reactive protein; eGFR = estimated glomerular filtration rate; GDF-15 = growth differentiation factor-15; IL-6 = interleukin 6; LA = left atrium; LAA = left atrial appendage; LV = left ventricular; OSA = obstructive sleep apnoea; TIA = transient ischaemic attack.

Table 7

Stroke risk factors in patients with AF

Most commonly studied clinical risk factors (a systematic review)324Positive studies/All studiesOther clinical risk factors325Imaging biomarkers291,326–328Blood/urine biomarkers329–332
Stroke/TIA/systemic embolism15/16Impaired renal function/CKD

Echocardiography

Cardiac troponin T and I

Natriuretic peptides

Cystatin C

Proteinuria

CrCl/eGFR

CRP

IL-6

GDF-15

von Willebrand factor

D-dimer

Hypertension11/20OSA

LA dilatation

Spontaneous contrast or thrombus in LA

Low LAA velocities

Complex aortic plaque

Ageing (per decade)9/13HCM
Structural heart disease9/13Amyloidosis in degenerative cerebral and heart diseases
Diabetes mellitus9/14Hyperlipidaemia
Vascular disease6/17Smoking

Cerebral imaging

CHF/LV dysfunction7/18Metabolic syndrome333

Small-vessel disease

Sex category (female)8/22Malignancy
Most commonly studied clinical risk factors (a systematic review)324Positive studies/All studiesOther clinical risk factors325Imaging biomarkers291,326–328Blood/urine biomarkers329–332
Stroke/TIA/systemic embolism15/16Impaired renal function/CKD

Echocardiography

Cardiac troponin T and I

Natriuretic peptides

Cystatin C

Proteinuria

CrCl/eGFR

CRP

IL-6

GDF-15

von Willebrand factor

D-dimer

Hypertension11/20OSA

LA dilatation

Spontaneous contrast or thrombus in LA

Low LAA velocities

Complex aortic plaque

Ageing (per decade)9/13HCM
Structural heart disease9/13Amyloidosis in degenerative cerebral and heart diseases
Diabetes mellitus9/14Hyperlipidaemia
Vascular disease6/17Smoking

Cerebral imaging

CHF/LV dysfunction7/18Metabolic syndrome333

Small-vessel disease

Sex category (female)8/22Malignancy

CHF = congestive heart failure; CKD = chronic kidney disease; CrCl = creatinine clearance; CRP = C-reactive protein; eGFR = estimated glomerular filtration rate; GDF-15 = growth differentiation factor-15; IL-6 = interleukin 6; LA = left atrium; LAA = left atrial appendage; LV = left ventricular; OSA = obstructive sleep apnoea; TIA = transient ischaemic attack.

Table 8

CHA2DS2-VASc score334

CHA2DS2-VASc score
Risk factors and definitionsPoints awardedComment
CCongestive heart failure
  • Clinical HF, or objective evidence of moderate to severe LV dysfunction, or HCM

1Recent decompensated HF irrespective of LVEF (thus incorporating HFrEF or HFpEF), or the presence (even if asymptomatic) of moderate-severe LV systolic impairment on cardiac imaging335; HCM confers a high stroke risk336 and OAC is beneficial for stroke reduction.337
HHypertension
  • or on antihypertensive therapy

1History of hypertension may result in vascular changes that predispose to stroke, and a well-controlled BP today may not be well-controlled over time.324 Uncontrolled BP − the optimal BP target associated with the lowest risk of ischaemic stroke, death, and other cardiovascular outcomes is 120 − 129/<80 mmHg.338
AAge 75 years or older2Age is a powerful driver of stroke risk, and most population cohorts show that the risk rises from age 65 years upwards.339 Age-related risk is a continuum, but for reasons of simplicity and practicality, 1 point is given for age 65 − 74 years and 2 points for age ≥75 years.
DDiabetes mellitus
  • Treatment with oral hypoglycaemic drugs and/or insulin or fasting blood glucose >125 mg/dL (7 mmol/L)

1Diabetes mellitus is a well-established risk factor for stroke, and more recently stroke risk has been related to duration of diabetes mellitus (the longer the duration of diabetes mellitus, the higher the risk of thromboembolism340) and presence of diabetic target organ damage, e.g. retinopathy.341 Both type 1 and type 2 diabetes mellitus confer broadly similar thromboembolic risk in AF, although the risk may be slightly higher in patients aged <65 years with type 2 diabetes mellitus compared to patients with type 1 diabetes mellitus.342
SStrokePrevious stroke, TIA, or thromboembolism2Previous stroke, systemic embolism, or TIA confers a particularly high risk of ischaemic stroke, hence weighted 2 points. Although excluded from RCTs, AF patients with ICH (including haemorrhagic stroke) are at very high risk of subsequent ischaemic stroke, and recent observational studies suggest that such patients would benefit from oral anticoagulation.343–345
VVascular disease
  • Angiographically significant CAD, previous myocardial infarction, PAD, or aortic plaque

1Vascular disease (PAD or myocardial infarction) confers a 17 − 22% excess risk, particularly in Asian patients.346–348 Angiographically significant CAD is also an independent risk factor for ischaemic stroke among AF patients (adjusted incidence rate ratio 1.29, 95% CI 1.08 − 1.53).349 Complex aortic plaque on the descending aorta, as an indicator of significant vascular disease, is also a strong predictor of ischaemic stroke.350
AAge 65 − 74 years1See above. Recent data from Asia suggest that the risk of stroke may rise from age 50 − 55 years upwards and that a modified CHA2DS2-VASc score may be used in Asian patients.351,352
ScSex category (female)1A stroke risk modifier rather than a risk factor.353
Maximum score9
CHA2DS2-VASc score
Risk factors and definitionsPoints awardedComment
CCongestive heart failure
  • Clinical HF, or objective evidence of moderate to severe LV dysfunction, or HCM

1Recent decompensated HF irrespective of LVEF (thus incorporating HFrEF or HFpEF), or the presence (even if asymptomatic) of moderate-severe LV systolic impairment on cardiac imaging335; HCM confers a high stroke risk336 and OAC is beneficial for stroke reduction.337
HHypertension
  • or on antihypertensive therapy

1History of hypertension may result in vascular changes that predispose to stroke, and a well-controlled BP today may not be well-controlled over time.324 Uncontrolled BP − the optimal BP target associated with the lowest risk of ischaemic stroke, death, and other cardiovascular outcomes is 120 − 129/<80 mmHg.338
AAge 75 years or older2Age is a powerful driver of stroke risk, and most population cohorts show that the risk rises from age 65 years upwards.339 Age-related risk is a continuum, but for reasons of simplicity and practicality, 1 point is given for age 65 − 74 years and 2 points for age ≥75 years.
DDiabetes mellitus
  • Treatment with oral hypoglycaemic drugs and/or insulin or fasting blood glucose >125 mg/dL (7 mmol/L)

1Diabetes mellitus is a well-established risk factor for stroke, and more recently stroke risk has been related to duration of diabetes mellitus (the longer the duration of diabetes mellitus, the higher the risk of thromboembolism340) and presence of diabetic target organ damage, e.g. retinopathy.341 Both type 1 and type 2 diabetes mellitus confer broadly similar thromboembolic risk in AF, although the risk may be slightly higher in patients aged <65 years with type 2 diabetes mellitus compared to patients with type 1 diabetes mellitus.342
SStrokePrevious stroke, TIA, or thromboembolism2Previous stroke, systemic embolism, or TIA confers a particularly high risk of ischaemic stroke, hence weighted 2 points. Although excluded from RCTs, AF patients with ICH (including haemorrhagic stroke) are at very high risk of subsequent ischaemic stroke, and recent observational studies suggest that such patients would benefit from oral anticoagulation.343–345
VVascular disease
  • Angiographically significant CAD, previous myocardial infarction, PAD, or aortic plaque

1Vascular disease (PAD or myocardial infarction) confers a 17 − 22% excess risk, particularly in Asian patients.346–348 Angiographically significant CAD is also an independent risk factor for ischaemic stroke among AF patients (adjusted incidence rate ratio 1.29, 95% CI 1.08 − 1.53).349 Complex aortic plaque on the descending aorta, as an indicator of significant vascular disease, is also a strong predictor of ischaemic stroke.350
AAge 65 − 74 years1See above. Recent data from Asia suggest that the risk of stroke may rise from age 50 − 55 years upwards and that a modified CHA2DS2-VASc score may be used in Asian patients.351,352
ScSex category (female)1A stroke risk modifier rather than a risk factor.353
Maximum score9

AF = atrial fibrillation; BP = blood pressure; CAD = coronary artery disease; CHA2DS2-VASc = Congestive heart failure, Hypertension, Age ≥75 years, Diabetes mellitus, Stroke, Vascular disease, Age 65-74 years, Sex category (female); CI = confidence interval; EF = ejection fraction; HCM = hypertrophic cardiomyopathy; HF = heart failure; HFpEF = heart failure with preserved ejection fraction; HFrEF = heart failure with reduced ejection fraction; ICH = intracranial haemorrhage; LV = left ventricular; LVEF = left ventricular ejection fraction; OAC = oral anticoagulant; PAD = peripheral artery disease; RCT = randomized controlled trial; TIA = transient ischaemic attack.

Table 8

CHA2DS2-VASc score334

CHA2DS2-VASc score
Risk factors and definitionsPoints awardedComment
CCongestive heart failure
  • Clinical HF, or objective evidence of moderate to severe LV dysfunction, or HCM

1Recent decompensated HF irrespective of LVEF (thus incorporating HFrEF or HFpEF), or the presence (even if asymptomatic) of moderate-severe LV systolic impairment on cardiac imaging335; HCM confers a high stroke risk336 and OAC is beneficial for stroke reduction.337
HHypertension
  • or on antihypertensive therapy

1History of hypertension may result in vascular changes that predispose to stroke, and a well-controlled BP today may not be well-controlled over time.324 Uncontrolled BP − the optimal BP target associated with the lowest risk of ischaemic stroke, death, and other cardiovascular outcomes is 120 − 129/<80 mmHg.338
AAge 75 years or older2Age is a powerful driver of stroke risk, and most population cohorts show that the risk rises from age 65 years upwards.339 Age-related risk is a continuum, but for reasons of simplicity and practicality, 1 point is given for age 65 − 74 years and 2 points for age ≥75 years.
DDiabetes mellitus
  • Treatment with oral hypoglycaemic drugs and/or insulin or fasting blood glucose >125 mg/dL (7 mmol/L)

1Diabetes mellitus is a well-established risk factor for stroke, and more recently stroke risk has been related to duration of diabetes mellitus (the longer the duration of diabetes mellitus, the higher the risk of thromboembolism340) and presence of diabetic target organ damage, e.g. retinopathy.341 Both type 1 and type 2 diabetes mellitus confer broadly similar thromboembolic risk in AF, although the risk may be slightly higher in patients aged <65 years with type 2 diabetes mellitus compared to patients with type 1 diabetes mellitus.342
SStrokePrevious stroke, TIA, or thromboembolism2Previous stroke, systemic embolism, or TIA confers a particularly high risk of ischaemic stroke, hence weighted 2 points. Although excluded from RCTs, AF patients with ICH (including haemorrhagic stroke) are at very high risk of subsequent ischaemic stroke, and recent observational studies suggest that such patients would benefit from oral anticoagulation.343–345
VVascular disease
  • Angiographically significant CAD, previous myocardial infarction, PAD, or aortic plaque

1Vascular disease (PAD or myocardial infarction) confers a 17 − 22% excess risk, particularly in Asian patients.346–348 Angiographically significant CAD is also an independent risk factor for ischaemic stroke among AF patients (adjusted incidence rate ratio 1.29, 95% CI 1.08 − 1.53).349 Complex aortic plaque on the descending aorta, as an indicator of significant vascular disease, is also a strong predictor of ischaemic stroke.350
AAge 65 − 74 years1See above. Recent data from Asia suggest that the risk of stroke may rise from age 50 − 55 years upwards and that a modified CHA2DS2-VASc score may be used in Asian patients.351,352
ScSex category (female)1A stroke risk modifier rather than a risk factor.353
Maximum score9
CHA2DS2-VASc score
Risk factors and definitionsPoints awardedComment
CCongestive heart failure
  • Clinical HF, or objective evidence of moderate to severe LV dysfunction, or HCM

1Recent decompensated HF irrespective of LVEF (thus incorporating HFrEF or HFpEF), or the presence (even if asymptomatic) of moderate-severe LV systolic impairment on cardiac imaging335; HCM confers a high stroke risk336 and OAC is beneficial for stroke reduction.337
HHypertension
  • or on antihypertensive therapy

1History of hypertension may result in vascular changes that predispose to stroke, and a well-controlled BP today may not be well-controlled over time.324 Uncontrolled BP − the optimal BP target associated with the lowest risk of ischaemic stroke, death, and other cardiovascular outcomes is 120 − 129/<80 mmHg.338
AAge 75 years or older2Age is a powerful driver of stroke risk, and most population cohorts show that the risk rises from age 65 years upwards.339 Age-related risk is a continuum, but for reasons of simplicity and practicality, 1 point is given for age 65 − 74 years and 2 points for age ≥75 years.
DDiabetes mellitus
  • Treatment with oral hypoglycaemic drugs and/or insulin or fasting blood glucose >125 mg/dL (7 mmol/L)

1Diabetes mellitus is a well-established risk factor for stroke, and more recently stroke risk has been related to duration of diabetes mellitus (the longer the duration of diabetes mellitus, the higher the risk of thromboembolism340) and presence of diabetic target organ damage, e.g. retinopathy.341 Both type 1 and type 2 diabetes mellitus confer broadly similar thromboembolic risk in AF, although the risk may be slightly higher in patients aged <65 years with type 2 diabetes mellitus compared to patients with type 1 diabetes mellitus.342
SStrokePrevious stroke, TIA, or thromboembolism2Previous stroke, systemic embolism, or TIA confers a particularly high risk of ischaemic stroke, hence weighted 2 points. Although excluded from RCTs, AF patients with ICH (including haemorrhagic stroke) are at very high risk of subsequent ischaemic stroke, and recent observational studies suggest that such patients would benefit from oral anticoagulation.343–345
VVascular disease
  • Angiographically significant CAD, previous myocardial infarction, PAD, or aortic plaque

1Vascular disease (PAD or myocardial infarction) confers a 17 − 22% excess risk, particularly in Asian patients.346–348 Angiographically significant CAD is also an independent risk factor for ischaemic stroke among AF patients (adjusted incidence rate ratio 1.29, 95% CI 1.08 − 1.53).349 Complex aortic plaque on the descending aorta, as an indicator of significant vascular disease, is also a strong predictor of ischaemic stroke.350
AAge 65 − 74 years1See above. Recent data from Asia suggest that the risk of stroke may rise from age 50 − 55 years upwards and that a modified CHA2DS2-VASc score may be used in Asian patients.351,352
ScSex category (female)1A stroke risk modifier rather than a risk factor.353
Maximum score9

AF = atrial fibrillation; BP = blood pressure; CAD = coronary artery disease; CHA2DS2-VASc = Congestive heart failure, Hypertension, Age ≥75 years, Diabetes mellitus, Stroke, Vascular disease, Age 65-74 years, Sex category (female); CI = confidence interval; EF = ejection fraction; HCM = hypertrophic cardiomyopathy; HF = heart failure; HFpEF = heart failure with preserved ejection fraction; HFrEF = heart failure with reduced ejection fraction; ICH = intracranial haemorrhage; LV = left ventricular; LVEF = left ventricular ejection fraction; OAC = oral anticoagulant; PAD = peripheral artery disease; RCT = randomized controlled trial; TIA = transient ischaemic attack.

Common stroke risk factors are summarized in the clinical risk-factor−based CHA2DS2-VASc [Congestive heart failure, Hypertension, Age ≥75 years, Diabetes mellitus, Stroke, Vascular disease, Age 65–74 years, Sex category (female)] score (Table 8).334

Stroke risk scores have to balance simplicity and practicality against precision.354–356 As any clinical risk-factor−based score, CHA2DS2-VASc performs only modestly in predicting high-risk patients who will sustain thrombo-embolic events, but those identified as low-risk [CHA2DS2-VASc 0 (males), or score of 1 (females)] consistently have low ischaemic stroke or mortality rates (<1%/year) and do not need any stroke prevention treatment.

Female sex is an age-dependent stroke risk modifier rather than a risk factor per se.357,358 Observational studies showed that women with no other risk factors (CHA2DS2-VASc score of 1) have a low stroke risk, similar to men with a CHA2DS2-VASc score of 0.359 The simplified CHA2DS2-VA score could guide the initial decision about OAC in AF patients, but not considering the sex component would underestimate stroke risk in women with AF.360,361 In the presence of >1 non-sex stroke risk factor, women with AF consistently have significantly higher stroke risk than men.353,362

Many clinical stroke risk factors (e.g. renal impairment, OSA, LA dilatation291,326,363–365) are closely related to the CHA2DS2-VASc components, and their consideration does not improve its predictive value (the relationship of smoking or obesity to stroke risk in AF is also contentious).366 Various biomarkers [e.g. troponin, natriuretic peptides, growth differentiation factor (GDF)-15, von Willebrand factor] have shown improved performance of biomarker-based over clinical scores in the assessment of residual stroke risk among anticoagulated AF patients329,367; notwithstanding, many of these biomarkers (as well as some clinical risk factors) are predictive of both stroke and bleeding329 or non-AF and non-cardiovascular conditions, often (non-specifically) reflecting simply a sick heart or patient.

More complex clinical scores [e.g. Global Anticoagulant Registry in the FIELD − Atrial Fibrillation (GARFIELD-AF)]368 and those inclusive of biomarkers [e.g. Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA),369,370 Intermountain Risk Score,371ABC-stroke (Age, Biomarkers, Clinical history)]372 improve stroke risk prediction modestly but statistically significantly. The ABC-stroke risk score that considers age, previous stroke/transient ischaemic attack (TIA), high-sensitivity troponin T (cTnT-hs) and N-terminal (NT)-prohormone B-type natriuretic peptide has been validated in the cohorts of landmark NOAC trials.373–375 A biomarker score-guided treatment strategy to reduce stroke and mortality in AF patients is being evaluated in an ongoing RCT (the ABC-AF Study, NCT03753490).

Whereas the routine use of biomarker-based risk scores currently would not substantially add to initial stroke prevention treatment decisions in patients already qualifying for treatment based on the CHA2DS2-VASc score (and a limited practicality would be accompanied by increased healthcare costs),355,376,377 biomarkers could further refine stroke risk differentiation among patients initially classified as low risk and those with a single non-sex CHA2DS2-VASc risk factor.378

Studies of the CHA2DS2-VASc score report a broad range of stroke rates depending on study setting (community vs. hospital), methodology (e.g. excluding patients subsequently treated with OAC would bias stroke rates towards lower levels), ethnicity, and prevalence of specific stroke risk factors in the study population (different risk factors carry different weight, and age thresholds for initiating NOACs may even differ for patients with a different single non-sex stroke risk factor, as follows: age 35 years for HF, 50 years for hypertension or diabetes, and 55 years for vascular disease).379,380 No RCT has specifically addressed the need for OAC in patients with a single non-sex CHA2DS2-VASc risk factor (to obtain high event rates and timely complete the study, anticoagulation trials have preferentially included high-risk patients), but an overview of subgroup analyses and observational data suggests that OAC use in such patients confers a positive net clinical benefit when balancing the reduction in stroke against the potential for harm with serious bleeding.339,381

For many risk factors (e.g. age), stroke risk is a continuum rather than an artificial low-, moderate-, or high-risk category. Risk factors are dynamic and, given the elderly AF population with multiple (often changing) comorbidities, stroke risk needs to be re-evaluated at each clinical review. Recent studies have shown that patients with a change in their risk profile are more likely to sustain strokes.382,383 Many initially low-risk patients (>15%) would have ≥1 non-sex CHA2DS2-VASc risk factor at 1 year after incident AF,384–386 and 90% of new comorbidities were evident at 4.4 months after AF was diagnosed.387

A Patient-Centred Outcomes Research Institute (PCORI)-commissioned systematic review of 61 studies compared diagnostic accuracy and impact on clinical decision making of available clinical and imaging tools and associated risk factors for predicting thrombo-embolic and bleeding risk in AF patients.388 The authors concluded that the CHADS2 (CHF history, Hypertension history, Age ≥75 y, Diabetes mellitus history, Stroke or TIA symptoms previously), CHA2DS2-VASc, and ABC risk scores have the best evidence for predicting thrombo-embolic risk (moderate strength of evidence for limited prediction ability of each score).

10.1.2 Bleeding risk assessment

When initiating antithrombotic therapy, potential risk for bleeding also needs to be assessed. Non-modifiable and partially modifiable bleeding risks (Table 9) are important drivers of bleeding events in synergy with modifiable factors.389 Notably, a history of falls is not an independent predictor of bleeding on OAC (a modelling study estimated that a patient would need to fall 295 times per year for the benefits of ischaemic stroke reduction with OAC to be outweighed by the potential for serious bleeding).390

Table 9

Risk factors for bleeding with OAC and antiplatelet therapy

Non-modifiablePotentially modifiableModifiableBiomarkers

Age >65 years

Previous major bleeding

Severe renal impairment (on dialysis or renal transplant)

Severe hepatic dysfunction (cirrhosis)

Malignancy

Genetic factors (e.g. CYP 2C9 polymorphisms)

Previous stroke, small-vessel disease, etc.

Diabetes mellitus

Cognitive impairment/dementia

Extreme frailty ± excessive risk of fallsa

Anaemia

Reduced platelet count or function

Renal impairment with CrCl <60 mL/min

VKA management strategyb

Hypertension/elevated SBP

Concomitant antiplatelet/NSAID

Excessive alcohol intake

Non-adherence to OAC

Hazardous hobbies/occupations

Bridging therapy with heparin

INR control (target 2.0 − 3.0), target TTR >70%c

Appropriate choice of OAC and correct dosingd

GDF-15

Cystatin C/CKD-EPI

cTnT-hs

von Willebrand factor (+ other coagulation markers)

Non-modifiablePotentially modifiableModifiableBiomarkers

Age >65 years

Previous major bleeding

Severe renal impairment (on dialysis or renal transplant)

Severe hepatic dysfunction (cirrhosis)

Malignancy

Genetic factors (e.g. CYP 2C9 polymorphisms)

Previous stroke, small-vessel disease, etc.

Diabetes mellitus

Cognitive impairment/dementia

Extreme frailty ± excessive risk of fallsa

Anaemia

Reduced platelet count or function

Renal impairment with CrCl <60 mL/min

VKA management strategyb

Hypertension/elevated SBP

Concomitant antiplatelet/NSAID

Excessive alcohol intake

Non-adherence to OAC

Hazardous hobbies/occupations

Bridging therapy with heparin

INR control (target 2.0 − 3.0), target TTR >70%c

Appropriate choice of OAC and correct dosingd

GDF-15

Cystatin C/CKD-EPI

cTnT-hs

von Willebrand factor (+ other coagulation markers)

CKD-EPI= Chronic Kidney Disease Epidemiology Collaboration; CrCl = creatinine clearance; cTnT-hs = high-sensitivity troponin T; CYP = cytochrome P; GDF-15 = growth differentiation factor-15; INR = international normalized ratio; NSAID = non-steroidal anti-inflammatory drug; OAC = oral anticoagulant; SBP = systolic blood pressure; TTR = time in therapeutic range; VKA = vitamin K antagonist.

a

Walking aids; appropriate footwear; home review to remove trip hazards; neurological assessment where appropriate.

b

Increased INR monitoring, dedicated OAC clinicals, self-monitoring/self-management, educational/behavioural interventions.

c

For patients receiving VKA treatment.

d

Dose adaptation based on patient’s age, body weight, and serum creatinine level.

Table 9

Risk factors for bleeding with OAC and antiplatelet therapy

Non-modifiablePotentially modifiableModifiableBiomarkers

Age >65 years

Previous major bleeding

Severe renal impairment (on dialysis or renal transplant)

Severe hepatic dysfunction (cirrhosis)

Malignancy

Genetic factors (e.g. CYP 2C9 polymorphisms)

Previous stroke, small-vessel disease, etc.

Diabetes mellitus

Cognitive impairment/dementia

Extreme frailty ± excessive risk of fallsa

Anaemia

Reduced platelet count or function

Renal impairment with CrCl <60 mL/min

VKA management strategyb

Hypertension/elevated SBP

Concomitant antiplatelet/NSAID

Excessive alcohol intake

Non-adherence to OAC

Hazardous hobbies/occupations

Bridging therapy with heparin

INR control (target 2.0 − 3.0), target TTR >70%c

Appropriate choice of OAC and correct dosingd

GDF-15

Cystatin C/CKD-EPI

cTnT-hs

von Willebrand factor (+ other coagulation markers)

Non-modifiablePotentially modifiableModifiableBiomarkers

Age >65 years

Previous major bleeding

Severe renal impairment (on dialysis or renal transplant)

Severe hepatic dysfunction (cirrhosis)

Malignancy

Genetic factors (e.g. CYP 2C9 polymorphisms)

Previous stroke, small-vessel disease, etc.

Diabetes mellitus

Cognitive impairment/dementia

Extreme frailty ± excessive risk of fallsa

Anaemia

Reduced platelet count or function

Renal impairment with CrCl <60 mL/min

VKA management strategyb

Hypertension/elevated SBP

Concomitant antiplatelet/NSAID

Excessive alcohol intake

Non-adherence to OAC

Hazardous hobbies/occupations

Bridging therapy with heparin

INR control (target 2.0 − 3.0), target TTR >70%c

Appropriate choice of OAC and correct dosingd

GDF-15

Cystatin C/CKD-EPI

cTnT-hs

von Willebrand factor (+ other coagulation markers)

CKD-EPI= Chronic Kidney Disease Epidemiology Collaboration; CrCl = creatinine clearance; cTnT-hs = high-sensitivity troponin T; CYP = cytochrome P; GDF-15 = growth differentiation factor-15; INR = international normalized ratio; NSAID = non-steroidal anti-inflammatory drug; OAC = oral anticoagulant; SBP = systolic blood pressure; TTR = time in therapeutic range; VKA = vitamin K antagonist.

a

Walking aids; appropriate footwear; home review to remove trip hazards; neurological assessment where appropriate.

b

Increased INR monitoring, dedicated OAC clinicals, self-monitoring/self-management, educational/behavioural interventions.

c

For patients receiving VKA treatment.

d

Dose adaptation based on patient’s age, body weight, and serum creatinine level.

Modifiable and non-modifiable bleeding risk factors have been used to formulate various bleeding risk scores,368,391–395 generally with a modest predictive ability for bleeding events.396,397 Studies comparing specific bleeding risk scores provided conflicting findings.393,394,398 Various biomarkers have been proposed as bleeding risk predictors, but many have been studied in anticoagulated trial cohorts (while bleeding risk assessment is needed at all parts of the patient pathway—when initially not using OAC, if taking aspirin, and, subsequently, on OAC). Additionally, biomarkers are non-specifically predictive of stroke, death, HF, etc.399,400 or even non-cardiovascular conditions (e.g. glaucoma),401 and the availability of some biomarkers is limited in routine clinical practice.

The biomarker-based ABC-bleeding risk score [Age, Biomarkers (GDF-15, cTnT-hs, haemoglobin) and Clinical history (prior bleeding)]375,402 reportedly outperformed clinical scores, but in another study there was no long-term advantage of ABC-bleeding over HAS-BLED score (Table 10), whereas HAS-BLED was better in identifying patients at low risk of bleeding (HAS-BLED 0 − 2).403 In the PCORI-commissioned systematic review,388 encompassing 38 studies of bleeding risk prediction, the HAS-BLED score had the best evidence for predicting bleeding risk (moderate strength of evidence), consistent with other systematic reviews and meta-analyses comparing bleeding risk prediction approaches.404–406

Table 10

Clinical risk factors in the HAS-BLED score395

Risk factors and definitions
Points awarded
HUncontrolled hypertension
  • SBP >160 mmHg

1
AAbnormal renal and/or hepatic function Dialysis, transplant, serum creatinine >200 µmol/L, cirrhosis, bilirubin > × 2 upper limit of normal, AST/ALT/ALP >3 × upper limit of normal1 point for each
SStroke
  • Previous ischaemic or haemorrhagica stroke

1
BBleeding history or predisposition
  • Previous major haemorrhage or anaemia or severe thrombocytopenia

1
LLabile INRb
  • TTR <60% in patient receiving VKA

1
EElderly
  • Aged >65 years or extreme frailty

1
DDrugs or excessive alcohol drinking
  • Concomitant use of antiplatelet or NSAID; and/or excessivec alcohol per week

1 point for each
Maximum score9
Risk factors and definitions
Points awarded
HUncontrolled hypertension
  • SBP >160 mmHg

1
AAbnormal renal and/or hepatic function Dialysis, transplant, serum creatinine >200 µmol/L, cirrhosis, bilirubin > × 2 upper limit of normal, AST/ALT/ALP >3 × upper limit of normal1 point for each
SStroke
  • Previous ischaemic or haemorrhagica stroke

1
BBleeding history or predisposition
  • Previous major haemorrhage or anaemia or severe thrombocytopenia

1
LLabile INRb
  • TTR <60% in patient receiving VKA

1
EElderly
  • Aged >65 years or extreme frailty

1
DDrugs or excessive alcohol drinking
  • Concomitant use of antiplatelet or NSAID; and/or excessivec alcohol per week

1 point for each
Maximum score9

ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; SBP = systolic blood pressure; INR = international normalized ratio; NSAID = Non-steroidal anti-inflammatory drug; TTR = time in therapeutic range; VKA = vitamin K antagonist.

a

Haemorrhagic stroke would also score 1 point under the ‘B’ criterion.

b

Only relevant if patient receiving a VKA.

c

Alcohol excess or abuse refers to a high intake (e.g. >14 units per week), where the clinician assesses there would be an impact on health or bleeding risk.

Table 10

Clinical risk factors in the HAS-BLED score395

Risk factors and definitions
Points awarded
HUncontrolled hypertension
  • SBP >160 mmHg

1
AAbnormal renal and/or hepatic function Dialysis, transplant, serum creatinine >200 µmol/L, cirrhosis, bilirubin > × 2 upper limit of normal, AST/ALT/ALP >3 × upper limit of normal1 point for each
SStroke
  • Previous ischaemic or haemorrhagica stroke

1
BBleeding history or predisposition
  • Previous major haemorrhage or anaemia or severe thrombocytopenia

1
LLabile INRb
  • TTR <60% in patient receiving VKA

1
EElderly
  • Aged >65 years or extreme frailty

1
DDrugs or excessive alcohol drinking
  • Concomitant use of antiplatelet or NSAID; and/or excessivec alcohol per week

1 point for each
Maximum score9
Risk factors and definitions
Points awarded
HUncontrolled hypertension
  • SBP >160 mmHg

1
AAbnormal renal and/or hepatic function Dialysis, transplant, serum creatinine >200 µmol/L, cirrhosis, bilirubin > × 2 upper limit of normal, AST/ALT/ALP >3 × upper limit of normal1 point for each
SStroke
  • Previous ischaemic or haemorrhagica stroke

1
BBleeding history or predisposition
  • Previous major haemorrhage or anaemia or severe thrombocytopenia

1
LLabile INRb
  • TTR <60% in patient receiving VKA

1
EElderly
  • Aged >65 years or extreme frailty

1
DDrugs or excessive alcohol drinking
  • Concomitant use of antiplatelet or NSAID; and/or excessivec alcohol per week

1 point for each
Maximum score9

ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; SBP = systolic blood pressure; INR = international normalized ratio; NSAID = Non-steroidal anti-inflammatory drug; TTR = time in therapeutic range; VKA = vitamin K antagonist.

a

Haemorrhagic stroke would also score 1 point under the ‘B’ criterion.

b

Only relevant if patient receiving a VKA.

c

Alcohol excess or abuse refers to a high intake (e.g. >14 units per week), where the clinician assesses there would be an impact on health or bleeding risk.

A high bleeding risk score should not lead to withholding OAC, as the net clinical benefit of OAC is even greater amongst such patients. However, the formal assessment of bleeding risk informs management of patients taking OAC, focusing attention on modifiable bleeding risk factors that should be managed and (re)assessed at every patient contact, and identifying high-risk patients with non-modifiable bleeding risk factors who should be reviewed earlier (for instance in 4 weeks rather than 4 − 6 months) and more frequently.389,407 Identification of ‘high bleeding risk’ patients is also needed when determining the antithrombotic strategy in specific AF patient groups, such as those undergoing percutaneous coronary intervention (PCI).

Overall, bleeding risk assessment based solely on modifiable bleeding risk factors is an inferior strategy compared with formal bleeding risk assessment using a bleeding risk score,408–410 thus also considering the interaction between modifiable and non-modifiable bleeding risk factors. Bleeding risk is dynamic, and attention to the change in bleeding risk profile is a stronger predictor of major bleeding events compared with simply relying on baseline bleeding risk. In a recent study, there was a 3.5-fold higher risk of major bleeding in the first 3 months amongst patients who had a change in their bleeding risk profile.389

In the mAFA-II trial, prospective dynamic monitoring and reassessment using the HAS-BLED score (together with holistic App-based management) was associated with fewer major bleeding events, mitigated modifiable bleeding risk factors, and increased OAC uptake; in contrast, bleeding rates were higher and OAC use overall decreased by 25% in the ‘usual care’ arm when comparing baseline with 12 months.411

10.1.3 Absolute contraindications to oral anticoagulants

The few absolute contraindications to OAC include active serious bleeding (where the source should be identified and treated), associated comorbidities (e.g. severe thrombocytopenia <50 platelets/μL, severe anaemia under investigation, etc.), or a recent high-risk bleeding event such as intracranial haemorrhage (ICH). Non-drug options may be considered in such cases (section 11.4.3).

10.1.4 Stroke prevention therapies

10.1.4.1 Vitamin K antagonists

Compared with control or placebo, vitamin K antagonist (VKA) therapy (mostly warfarin) reduces stroke risk by 64% and mortality by 26%,412 and is still used in many AF patients worldwide. VKAs are currently the only treatment with established safety in AF patients with rheumatic mitral valve disease and/or an artificial heart valve.

The use of VKAs is limited by the narrow therapeutic interval, necessitating frequent international normalized ratio (INR) monitoring and dose adjustments.413 At adequate time in therapeutic range [(TTR) >70%], VKAs are effective and relatively safe drugs. Quality of VKA management (quantified using the TTR based on the Rosendaal method, or the percentage of INRs in range) correlates with haemorrhagic and thrombo-embolic rates.414 At high TTR values, the efficacy of VKAs in stroke prevention may be similar to NOACs, whereas the relative safety benefit with NOACs is less affected by TTR, with consistently lower serious bleeding rates (e.g. ICH) seen with NOACs compared with warfarin, notwithstanding that the absolute difference is small.415,416

Numerous factors (including genetics, concomitant drugs, etc.) influence the intensity of VKA anticoagulant effect; the more common ones have been used to derive and validate the SAMe-TT2R2 {Sex [female], Age [<60 years], Medical history of ≥2 comorbidities [hypertension, diabetes mellitus, CAD/myocardial infarction, peripheral artery disease (PAD), HF, previous stroke, pulmonary disease, and hepatic or renal disease], Treatment [interacting drugs, e.g. amiodarone], Tobacco use, Race [non-Caucasian]} score,417 which can help to identify patients who are less likely to achieve a good TTR on VKA therapy (score >2) and would do better with a NOAC. If such patients with SAMe-TT2R2>2 are prescribed a VKA, greater efforts to improve TTR, such as more intense regular reviews, education/counselling, and frequent INR monitoring are needed or, more conveniently, the use of a NOAC should be reconsidered.418

10.1.4.2 Non-vitamin K antagonist oral anticoagulants

In four pivotal RCTs, apixaban, dabigatran, edoxaban, and rivaroxaban have shown non-inferiority to warfarin in the prevention of stroke/systemic embolism.419–422 In a meta-analysis of these RCTs, NOACs were associated with a 19% significant stroke/systemic embolism risk reduction, a 51% reduction in haemorrhagic stroke,423 and similar ischaemic stroke risk reduction compared with VKAs, but NOACs were associated with a significant 10% reduction in all-cause mortality (Supplementary Table 8). There was a non-significant 14% reduction in major bleeding risk, significant 52% reduction in ICH, and 25% increase in gastrointestinal bleeding with NOACs vs. warfarin.423

The major bleeding relative risk reduction with NOACs was significantly greater when INR control was poor (i.e. centre-based TTR<66%). A meta-analysis of the five NOAC trials [RE-LY (Randomized Evaluation of Long Term Anticoagulant 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), J-ROCKET AF, ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation), and ENGAGE AF TIMI 48 (Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation–Thrombolysis in Myocardial Infarction 48)] showed that, compared with warfarin, standard-dose NOACs were more effective and safer in Asians than in non-Asians.424 In the AVERROES [Apixaban Versus Acetylsalicylic Acid (ASA) to Prevent Stroke in Atrial Fibrillation Patients Who Have Failed or Are Unsuitable for Vitamin K Antagonist Treatment] trial of AF patients who refused or were deemed ineligible for VKA therapy, apixaban 5 mg b.i.d. (twice a day) significantly reduced the risk of stroke/systemic embolism with no significant difference in major bleeding or ICH compared with aspirin.425

Post-marketing observational data on the effectiveness and safety of dabigatran,426,427 rivaroxaban,428,429 apixaban,430 and edoxaban431 vs. warfarin show general consistency with the respective RCT. Given the compelling evidence about NOACs, AF patients should be informed of this treatment option.

Persistence to NOAC therapy is generally higher than to VKAs, being facilitated by a better pharmacokinetic profile of NOACs432 (Supplementary Table 9) and favourable safety and efficacy, especially amongst vulnerable patients including the elderly, those with renal dysfunction or previous stroke, and so on.433 Whereas patients with end-stage renal dysfunction were excluded from the pivotal RCTs, reduced dose regimens of rivaroxaban, edoxaban, and apixaban are feasible options for severe CKD [creatinine clearance (CrCl) 15 − 30 mL/min using the Cockcroft-Gault equation].434,435 Considering that inappropriate dose reductions are frequent in clinical practice,436 thus increasing the risks of stroke/systemic embolism, hospitalization, and death, but without decreasing bleeding risk,437 NOAC therapy should be optimized based on the efficacy and safety profile of each NOAC in different patient subgroups (Table 11).

Table 11

Dose selection criteria for NOACs

DabigatranRivaroxabanApixabanEdoxaban
Standard dose150 mg b.i.d.20 mg o.d.5 mg b.i.d.60 mg o.d.
Lower dose110 mg b.i.d.
Reduced dose15 mg o.d.2.5 mg b.i.d.30 mg o.d.
Dose-reduction criteriaDabigatran 110 mg b.i.d. in patients with:
  • Age ≥80 years

  • Concomitant use of verapamil, or

  • Increased bleeding risk

CrCl 15 − 49 mL/minAt least 2 of 3 criteria:
  • Age ≥80 years,

  • Body weight ≤60 kg, or

  • Serum creatinine ≥1.5 mg/dL (133 μmol/L)

If any of the following:
  • CrCl 15 − 50 mL/min,

  • Body weight ≤60 kg,

  • Concomitant use of dronedarone, ciclosporine, erythromycin, or ketoconazole

DabigatranRivaroxabanApixabanEdoxaban
Standard dose150 mg b.i.d.20 mg o.d.5 mg b.i.d.60 mg o.d.
Lower dose110 mg b.i.d.
Reduced dose15 mg o.d.2.5 mg b.i.d.30 mg o.d.
Dose-reduction criteriaDabigatran 110 mg b.i.d. in patients with:
  • Age ≥80 years

  • Concomitant use of verapamil, or

  • Increased bleeding risk

CrCl 15 − 49 mL/minAt least 2 of 3 criteria:
  • Age ≥80 years,

  • Body weight ≤60 kg, or

  • Serum creatinine ≥1.5 mg/dL (133 μmol/L)

If any of the following:
  • CrCl 15 − 50 mL/min,

  • Body weight ≤60 kg,

  • Concomitant use of dronedarone, ciclosporine, erythromycin, or ketoconazole

b.i.d. = bis in die (twice a day); CrCl = creatinine clearance; o.d. = omni die (once daily).

Table 11

Dose selection criteria for NOACs

DabigatranRivaroxabanApixabanEdoxaban
Standard dose150 mg b.i.d.20 mg o.d.5 mg b.i.d.60 mg o.d.
Lower dose110 mg b.i.d.
Reduced dose15 mg o.d.2.5 mg b.i.d.30 mg o.d.
Dose-reduction criteriaDabigatran 110 mg b.i.d. in patients with:
  • Age ≥80 years

  • Concomitant use of verapamil, or

  • Increased bleeding risk

CrCl 15 − 49 mL/minAt least 2 of 3 criteria:
  • Age ≥80 years,

  • Body weight ≤60 kg, or

  • Serum creatinine ≥1.5 mg/dL (133 μmol/L)

If any of the following:
  • CrCl 15 − 50 mL/min,

  • Body weight ≤60 kg,

  • Concomitant use of dronedarone, ciclosporine, erythromycin, or ketoconazole

DabigatranRivaroxabanApixabanEdoxaban
Standard dose150 mg b.i.d.20 mg o.d.5 mg b.i.d.60 mg o.d.
Lower dose110 mg b.i.d.
Reduced dose15 mg o.d.2.5 mg b.i.d.30 mg o.d.
Dose-reduction criteriaDabigatran 110 mg b.i.d. in patients with:
  • Age ≥80 years

  • Concomitant use of verapamil, or

  • Increased bleeding risk

CrCl 15 − 49 mL/minAt least 2 of 3 criteria:
  • Age ≥80 years,

  • Body weight ≤60 kg, or

  • Serum creatinine ≥1.5 mg/dL (133 μmol/L)

If any of the following:
  • CrCl 15 − 50 mL/min,

  • Body weight ≤60 kg,

  • Concomitant use of dronedarone, ciclosporine, erythromycin, or ketoconazole

b.i.d. = bis in die (twice a day); CrCl = creatinine clearance; o.d. = omni die (once daily).

10.1.4.3 Other antithrombotic drugs

In the ACTIVE W (Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events) trial, dual antiplatelet therapy (DAPT) with aspirin and clopidogrel was less effective than warfarin for prevention of stroke, systemic embolism, myocardial infarction, and vascular death (the annual risk of events was 5.6% vs. 3.9%, P =0.0003), with a similar rate of major bleeding.438 In the ACTIVE-A trial, patients unsuitable for anticoagulation had a lower rate of thrombo-embolic complications when clopidogrel was added to aspirin compared with aspirin alone, but with a significant increase in major bleeding.439 Aspirin monotherapy was ineffective for stroke prevention compared with no antithrombotic treatment and was associated with a higher risk of ischaemic stroke in elderly patients.440

Overall, antiplatelet monotherapy is ineffective for stroke prevention and is potentially harmful, (especially amongst elderly AF patients),441,442 whereas DAPT is associated with a bleeding risk similar to OAC therapy. Hence, antiplatelet therapy should not be used for stroke prevention in AF patients.

10.1.4.4 Combination therapy with oral anticoagulant and antiplatelet drugs

The use of antiplatelet therapy remains common in clinical practice, often in patients without an indication (e.g. PAD, CAD, or cerebrovascular disease) beyond AF.443 There is limited evidence to support the combination therapy solely for stroke prevention in AF, with no effect on reductions in stroke, myocardial infarction, or death, but with a substantial increase in the risk of major bleeding and ICH.441,442

10.1.4.5 Left atrial appendage occlusion and exclusion
Left atrial appendage occlusion devices

Only the Watchman device has been compared with VKA therapy in RCTs [the PROTECT AF (WATCHMAN Left Atrial Appendage System for Embolic Protection in Patients With Atrial Fibrillation) and PREVAIL (Watchman LAA Closure Device in Patients With Atrial Fibrillation Versus Long Term Warfarin Therapy)],444–446 where LAA occlusion was non-inferior to VKA stroke prevention treatment in AF patients with moderate stroke risk, with a possibility of lower bleeding rates on longer follow-up.447 The LAA occlusion may also reduce stroke risk in patients with contraindications to OAC.448,449

A large European registry reported a high implantation success rate (98%), with an acceptable procedure-related complication rate of 4% at 30 days.450 Nevertheless, the implantation procedure can cause serious complications (higher event rates have been reported in real-world analyses compared with industry-sponsored studies, possibly identifying some reporting bias) and device-related thrombosis may not be a benign finding.451–454 Antithrombotic management after LAA occlusion has never been evaluated in a randomized manner and is based on historical studies, at least including aspirin (Table 12). For patients who do not tolerate any antiplatelet therapy, either an epicardial catheter approach (e.g. Lariat system) or thoracoscopic clipping of the LAA may be an option.455,456

Table 12

Antithrombotic therapy after left atrial appendage occlusion

Device/patient AspirinOAC Clopidogrel Comments 
Watchman/low bleeding risk75 − 325 mg/day indefinitelyStart warfarin after procedure (target INR 2 − 3) until 45 days or continue until adequate LAA sealing is confirmeda by TOE. NOAC is a possible alternativeStart 75 mg/day when OAC stopped, continue until 6 months after the procedure Some centres do not withhold OAC at the time of procedure (no data to support/deny this approach)
Watchman/high bleeding risk75 − 325 mg/day indefinitelyNone 75 mg/day for 1 − 6 months while ensuring adequate LAA sealingaClopidogrel often given for shorter time in very high-risk situations
ACP/Amulet75 − 325 mg/day indefinitelyNone 75 mg/day for 1 − 6 months while ensuring adequate LAA sealingaClopidogrel may replace long-term aspirin if better tolerated
Device/patient AspirinOAC Clopidogrel Comments 
Watchman/low bleeding risk75 − 325 mg/day indefinitelyStart warfarin after procedure (target INR 2 − 3) until 45 days or continue until adequate LAA sealing is confirmeda by TOE. NOAC is a possible alternativeStart 75 mg/day when OAC stopped, continue until 6 months after the procedure Some centres do not withhold OAC at the time of procedure (no data to support/deny this approach)
Watchman/high bleeding risk75 − 325 mg/day indefinitelyNone 75 mg/day for 1 − 6 months while ensuring adequate LAA sealingaClopidogrel often given for shorter time in very high-risk situations
ACP/Amulet75 − 325 mg/day indefinitelyNone 75 mg/day for 1 − 6 months while ensuring adequate LAA sealingaClopidogrel may replace long-term aspirin if better tolerated

ACP = AmplatzerTM Cardiac Plug; INR = international normalized ratio; LAA = left atrial appendage; LMWH = low-molecular-weight heparin; NOAC = non-vitamin K antagonist oral anticoagulant; OAC = oral anticoagulant ; TOE = transoesophageal echocardiography.

Note: Load aspirin or clopidogrel before procedure if untreated. Heparin with activated clotting time >250 seconds before or immediately after trans-septal punctures for all patients, followed by LMWH when warfarin needed.

a

Less than 5 mm leak.

Table 12

Antithrombotic therapy after left atrial appendage occlusion

Device/patient AspirinOAC Clopidogrel Comments 
Watchman/low bleeding risk75 − 325 mg/day indefinitelyStart warfarin after procedure (target INR 2 − 3) until 45 days or continue until adequate LAA sealing is confirmeda by TOE. NOAC is a possible alternativeStart 75 mg/day when OAC stopped, continue until 6 months after the procedure Some centres do not withhold OAC at the time of procedure (no data to support/deny this approach)
Watchman/high bleeding risk75 − 325 mg/day indefinitelyNone 75 mg/day for 1 − 6 months while ensuring adequate LAA sealingaClopidogrel often given for shorter time in very high-risk situations
ACP/Amulet75 − 325 mg/day indefinitelyNone 75 mg/day for 1 − 6 months while ensuring adequate LAA sealingaClopidogrel may replace long-term aspirin if better tolerated
Device/patient AspirinOAC Clopidogrel Comments 
Watchman/low bleeding risk75 − 325 mg/day indefinitelyStart warfarin after procedure (target INR 2 − 3) until 45 days or continue until adequate LAA sealing is confirmeda by TOE. NOAC is a possible alternativeStart 75 mg/day when OAC stopped, continue until 6 months after the procedure Some centres do not withhold OAC at the time of procedure (no data to support/deny this approach)
Watchman/high bleeding risk75 − 325 mg/day indefinitelyNone 75 mg/day for 1 − 6 months while ensuring adequate LAA sealingaClopidogrel often given for shorter time in very high-risk situations
ACP/Amulet75 − 325 mg/day indefinitelyNone 75 mg/day for 1 − 6 months while ensuring adequate LAA sealingaClopidogrel may replace long-term aspirin if better tolerated

ACP = AmplatzerTM Cardiac Plug; INR = international normalized ratio; LAA = left atrial appendage; LMWH = low-molecular-weight heparin; NOAC = non-vitamin K antagonist oral anticoagulant; OAC = oral anticoagulant ; TOE = transoesophageal echocardiography.

Note: Load aspirin or clopidogrel before procedure if untreated. Heparin with activated clotting time >250 seconds before or immediately after trans-septal punctures for all patients, followed by LMWH when warfarin needed.

a

Less than 5 mm leak.

Notably, the non-inferiority of LAA occlusion to VKA treatment was mostly driven by the prevention of haemorrhagic stroke, with a trend for more ischaemic strokes. The limitations of LAA occlusion as a strategy to reduce the risk of stroke associated with AF also include the consideration that AF acts as a risk marker of stroke. Withholding OAC after LAA occlusion is likely to result in undertreating the overall risk of stroke related to atrial cardiomyopathy.

Surgical left atrial appendage occlusion or exclusion

Multiple observational studies indicate the feasibility and safety of surgical LAA occlusion/exclusion, but only limited controlled trial data are available.457–459 Residual LAA flow or incomplete LAA occlusion may be associated with an increased risk of stroke.460 In most studies, LAA occlusion/exclusion was performed during other open heart surgery, and in more recent years in combination with surgical ablation of AF459,461 or as an isolated thoracoscopic procedure. A large RCT in patients with an associated cardiac surgical procedure is ongoing.462

The most common justification for LAA occlusion/exclusion in clinical practice is a perceived high bleeding risk or, less often, contraindications for OAC.450 However, LAA occluders have not been randomly tested in such populations. Most patients who some years ago would be considered unsuitable for OAC therapy with VKA now seem to do relatively well on NOAC,433,463,464 and LAA occluders have not been compared with NOAC therapy in patients at risk for bleeding, or with surgical LAA occlusion/exclusion. Long-term aspirin is a common strategy in these patients,465 and one may question whether a NOAC would not be a better strategy if aspirin is tolerated. There is the need for adequately powered trials to define the best indications of LAA occlusion/exclusion compared with NOAC therapy in patients with relative or absolute contraindications for anticoagulation, in those suffering from an ischaemic stroke on anticoagulant therapy, and for assessment of the appropriate antithrombotic therapy after LAA occlusion.

10.1.4.6 Long-term oral anticoagulation per atrial fibrillation burden

Although the risk of ischaemic stroke/systemic embolism is higher with non-paroxysmal vs. paroxysmal AF, and AF progression is associated with an excess of adverse outcomes,169,466 the clinically determined temporal pattern of AF should not affect the decision regarding long-term OAC, which is driven by the presence of stroke risk factors.156 Management of patients with AHRE/subclinical AF is reviewed in section 16. Stroke risk in AHRE patients may be lower than in patients with diagnosed AF,467 and strokes often occur without a clear temporal relationship with AHRE/subclinical AF,179,226 underscoring its role as a risk marker rather than a stroke risk factor.4,172 Whether AHRE and subclinical AF have the same therapeutic requirements as clinical AF7 is presently unclear, and the net clinical benefit of OAC for AHRE/subclinical AF>24 h is currently being studied in several RCTs.4

Notably, patients with subclinical AF/AHRE may develop atrial tachyarrhythmias lasting more than 24 h468 or clinical AF; hence careful monitoring of these patients is recommended, even considering remote monitoring, especially with longer AHRE and higher risk profile.469 Given the dynamic nature of AF as well as stroke risk, a recorded duration in one monitoring period would not necessarily be the same in the next.

10.1.4.7 Long-term oral anticoagulation per symptom control strategy

Symptom control focuses on patient-centred and symptom-directed approaches to rate or rhythm control. Again, symptom control strategy should not affect the decision regarding long-term OAC, which is driven by the presence of stroke risk factors, and not the estimated success in maintaining sinus rhythm.

10.1.5 Management of anticoagulation-related bleeding risk

10.1.5.1 Strategies to minimize the risk of bleeding

Ensuring good quality of VKA treatment (TTR>70%) and selecting the appropriate dose of a NOAC (as per the dose reduction criteria specified on the respective drug label) are important considerations to minimize bleeding risk. As discussed in section 10.1.2, attention to modifiable bleeding risk factors should be made at every patient contact, and formal bleeding risk assessment is needed to help identify high-risk patients who should be followed up or reviewed earlier (e.g. 4 weeks rather than 4 − 6 months).407 Concomitant regular administration of antiplatelet drugs or non-steroidal anti-inflammatory drug (NSAID) should be avoided in anticoagulated patients. Bleeding risk is dynamic, and attention to the change in bleeding risk profile is a stronger predictor of major bleeding events, especially in the first 3 months.389

10.1.5.2 High-risk groups

Certain high-risk AF populations have been under-represented in RCTs, including the extreme elderly (≥90 years), those with cognitive impairment/dementia, recent bleeding or previous ICH, end-stage renal failure, liver impairment, cancer, and so on. Observational data suggest that such patients are at high risk for ischaemic stroke and death, and many would benefit from OAC.

Patients with liver function abnormalities may be at higher risk of bleeding on VKA, possibly less so on NOACs. Observational data in cirrhotic patients suggest that ischaemic stroke reduction may outweigh bleeding risk.470–472

In patients with a recent bleeding event, attention should be directed towards addressing the predisposing pathology (e.g. bleeding ulcer or polyp in a patient with gastrointestinal bleeding), and the reintroduction of OAC as soon as feasible, as part of a multidisciplinary team decision. Consideration should be made for drugs such as apixaban or dabigatran 110 mg b.i.d., which are not associated with an excess of gastrointestinal bleeding compared with warfarin. Where OAC is not reintroduced, there is a higher risk of stroke and death compared with restarting OAC, although the risk of re-bleeding may be higher.473 Similarly, thromboprophylaxis in cancer may require a multidisciplinary team decision balancing stroke reduction against serious bleeding, which may be dependent on cancer type, site(s), staging, anti-cancer therapy and so on.

Thromboprophylaxis in specific high-risk groups is discussed in detail throughout section 11.

10.1.6 Decision making to avoid stroke

In observational population cohorts, both stroke and death are relevant endpoints, as some deaths could be due to fatal strokes (given that endpoints are not adjudicated in population cohorts, and cerebral imaging or post-mortems are not mandated). As OAC significantly reduces stroke (by 64%) and all-cause mortality (by 26%) compared with control or placebo,412 the endpoints of stroke and/or mortality are relevant in relation to decision making for thromboprophylaxis.

The threshold for initiating OAC for stroke prevention, balancing ischaemic stroke reduction against the risk of ICH and associated QoL, has been estimated to be 1.7%/year for warfarin and 0.9%/year for a NOAC (dabigatran data were used for the modelling analysis).474 The threshold for warfarin may be even lower, if good-quality anticoagulation control is achieved, with average TTR>70%.475

Given the limitations of clinical risk scores, the dynamic nature of stroke risk, the greater risk of stroke and death among AF patients with ≥1 non-sex stroke risk factor, and the positive net clinical benefit of OAC among such patients, we recommend a risk-factor–based approach to stroke prevention rather than undue focus on (artificially defined) ‘high-risk’ patients. As the default is to offer stroke prevention unless the patient is low risk, the CHA2DS2-VASc score should be applied in a reductionist manner, to decide on OAC or not.476

Thus, the first step in decision making (‘A’ Anticoagulation/Avoid stroke) is to identify low-risk patients who do not need antithrombotic therapy. Step 2 is to offer stroke prevention (i.e. OAC) to those with ≥1 non-sex stroke risk factors (the strength of evidence differs, with multiple clinical trials for patients with ≥2 stroke risk factors, and subgroups from trials/observational data on patients with 1 non-sex stroke risk factor). Step 3 is the choice of OAC—a NOAC (given their relative effectiveness, safety and convenience, these drugs are generally first choice as OAC for stroke prevention in AF) or VKA (with good TTR at >70%). This ‘AF 3-step’ patient pathway182,477 for stroke risk stratification and treatment decision making is shown in Figure 12.

‘A’ - Anticoagulation/Avoid stroke: The ‘AF 3-step’ pathway. AF = atrial fibrillation; CHA2DS2-VASc = Congestive heart failure, Hypertension, Age ≥75 years, Diabetes mellitus, Stroke, Vascular disease, Age 65 − 74 years, Sex category (female); HAS-BLED = Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile INR, Elderly (>65 years), Drugs/alcohol concomitantly; INR = international normalized ratio; NOAC = non-vitamin K antagonist oral anticoagulant; OAC = oral anticoagulant; SAMe-TT2R2 = Sex (female), Age (<60 years), Medical history, Treatment (interacting drug(s)), Tobacco use, Race (non-Caucasian) (score); TTR = time in therapeutic range; VKA = vitamin K antagonist. aIf a VKA being considered, calculate SAMe-TT2R2 score: if score 0–2, may consider VKA treatment (e.g. warfarin) or NOAC; if score >2, should arrange regular review/frequent INR checks/ counselling for VKA users to help good anticoagulation control, or reconsider the use of NOAC instead; TTR ideally >70%.
Figure 12

‘A’ - Anticoagulation/Avoid stroke: The ‘AF 3-step’ pathway. AF = atrial fibrillation; CHA2DS2-VASc = Congestive heart failure, Hypertension, Age ≥75 years, Diabetes mellitus, Stroke, Vascular disease, Age 65 − 74 years, Sex category (female); HAS-BLED = Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile INR, Elderly (>65 years), Drugs/alcohol concomitantly; INR = international normalized ratio; NOAC = non-vitamin K antagonist oral anticoagulant; OAC = oral anticoagulant; SAMe-TT2R2 = Sex (female), Age (<60 years), Medical history, Treatment (interacting drug(s)), Tobacco use, Race (non-Caucasian) (score); TTR = time in therapeutic range; VKA = vitamin K antagonist. aIf a VKA being considered, calculate SAMe-TT2R2 score: if score 0–2, may consider VKA treatment (e.g. warfarin) or NOAC; if score >2, should arrange regular review/frequent INR checks/ counselling for VKA users to help good anticoagulation control, or reconsider the use of NOAC instead; TTR ideally >70%.

Recommendations for the prevention of thrombo-embolic events in AF

graphic
graphic
graphic
graphic

AF = atrial fibrillation; BP = blood pressure; CHA2DS2-VASc = Congestive heart failure, Hypertension, Age ≥75 years, Diabetes mellitus, Stroke, Vascular disease, Age 65 − 74 years, Sex category (female); HAS-BLED = Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile INR, Elderly (>65 years), Drugs/alcohol concomitantly; INR = international normalized ratio; LAA = left atrial appendage; NOAC = non-vitamin K antagonist oral anticoagulant; NSAID = non-steroidal anti-inflammatory drug; OAC = oral anticoagulant ; TTR = time in therapeutic range; VKA = vitamin K antagonist.

a

Class of recommendation.

b

Level of evidence.

c

Including uncontrolled BP; labile INRs (in a patient taking VKA); alcohol excess; concomitant use of NSAIDs or aspirin in an anticoagulated patient; bleeding tendency or predisposition (e.g. treat gastric ulcer, optimize renal or liver function, etc.).

Recommendations for the prevention of thrombo-embolic events in AF

graphic
graphic
graphic
graphic

AF = atrial fibrillation; BP = blood pressure; CHA2DS2-VASc = Congestive heart failure, Hypertension, Age ≥75 years, Diabetes mellitus, Stroke, Vascular disease, Age 65 − 74 years, Sex category (female); HAS-BLED = Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile INR, Elderly (>65 years), Drugs/alcohol concomitantly; INR = international normalized ratio; LAA = left atrial appendage; NOAC = non-vitamin K antagonist oral anticoagulant; NSAID = non-steroidal anti-inflammatory drug; OAC = oral anticoagulant ; TTR = time in therapeutic range; VKA = vitamin K antagonist.

a

Class of recommendation.

b

Level of evidence.

c

Including uncontrolled BP; labile INRs (in a patient taking VKA); alcohol excess; concomitant use of NSAIDs or aspirin in an anticoagulated patient; bleeding tendency or predisposition (e.g. treat gastric ulcer, optimize renal or liver function, etc.).

10.2 ‘B’ – Better symptom control

10.2.1 Rate control

Rate control is an integral part of AF management, and is often sufficient to improve AF-related symptoms. Very little robust evidence exists to inform the best type and intensity of rate control treatment.484–486

10.2.1.1 Target/optimal ventricular rate range

The optimal heart-rate target in AF patients is unclear. In the RACE (Race Control Efficacy in Permanent Atrial Fibrillation) II RCT of permanent AF patients, there was no difference in a composite of clinical events, New York Heart Association (NYHA) class, or hospitalizations between the strict [target heart rate <80 beats per minute (bpm) at rest and <110 bpm during moderate exercise] and lenient (heart-rate target <110 bpm) arm,487,488 similar to an analysis from the AFFIRM (Atrial Fibrillation Follow-up Investigation of Rhythm Management) and RACE trials.489 Therefore, lenient rate control is an acceptable initial approach, regardless of HF status (with the exception of tachycardia-induced cardiomyopathy), unless symptoms call for stricter rate control (Figure 13).

Outline of rate control therapy.490 AF = atrial fibrillation; AVN = atrioventricular node; bpm = beats per minute; BV = biventricular; CRT = cardiac resynchronization therapy; CRT-D: cardiac resynchronization therapy defibrillator; CRT-P = cardiac resynchronization therapy pacemaker; ECG = electrocardiogram; LV = left ventricular; SR = sinus rhythm.
Figure 13

Outline of rate control therapy.490 AF = atrial fibrillation; AVN = atrioventricular node; bpm = beats per minute; BV = biventricular; CRT = cardiac resynchronization therapy; CRT-D: cardiac resynchronization therapy defibrillator; CRT-P = cardiac resynchronization therapy pacemaker; ECG = electrocardiogram; LV = left ventricular; SR = sinus rhythm.

10.2.1.2 Drugs

Pharmacological rate control can be achieved with beta-blockers, digoxin, diltiazem, and verapamil, or combination therapy (Table 13). Some antiarrhythmic drugs (AADs) also have rate-limiting properties (e.g. amiodarone, dronedarone, sotalol) but generally they should be used only for rhythm control. The choice of rate control drugs depends on symptoms, comorbidities, and potential side-effects (Table 13).

Beta-blockers are often first-line rate-controlling agents, largely based on better acute rate control. Interestingly, the prognostic benefit of beta-blockers seen in HF with reduced ejection fraction (HFrEF) patients with sinus rhythm has been questioned in patients with AF.491

Non-dihydropyridine calcium channel blockers (NDCC) verapamil and diltiazem provide reasonable rate control492 and can improve AF-related symptoms486 compared with beta-blockers. In one small trial of patients with preserved LVEF, NDCC preserved exercise capacity and reduced B-type natriuretic peptide.493,494

Digoxin and digitoxin are not effective in patients with increased sympathetic drive. Observational studies have associated digoxin use with excess mortality in AF patients.495–497 This finding was likely due to selection and prescription biases rather than harm caused by digoxin,498–501 particularly as digoxin is commonly prescribed to sicker patients.502 Lower doses of digoxin may be associated with better prognosis.502 An ongoing RCT is addressing digitoxin use in patients with HFrEF.503

Amiodarone can be useful as a last resort when heart rate cannot be controlled with combination therapy in patients who do not qualify for non-pharmacological rate control, i.e. atrioventricular node ablation and pacing, notwithstanding the extracardiac adverse effects of the drug504 (Table 13).

Table 13

Drugs for rate control in AFa

Intravenous administrationUsual oral maintenance doseContraindicated
Beta-blockersb
Metoprolol tartrate2.5 − 5 mg i.v. bolus; up to 4 doses25 − 100 mg b.i.d.In case of asthma use beta-1-blockers
  • Contraindicated in acute HF and history of severe bronchospasm

Metoprolol XL (succinate)N/A50 − 400 mg o.d.
BisoprololN/A1.25 − 20 mg o.d.
AtenololcN/A25 − 100 mg o.d.
Esmolol500 µg/kg i.v. bolus over 1 min; followed by 50 − 300 µg/kg/minN/A
Landiolol100 µg/kg i.v. bolus over 1 min, followed by 10 - 40 µg/kg/min; in patients with cardiac dysfunction: 1 - 10 µg/kg/minN/A
NebivololN/A2.5 − 10 mg o.d.
CarvedilolN/A3.125 − 50 mg b.i.d.
Non-dihydropyridine calcium channel antagonists
Verapamil2.5 − 10 mg i.v. bolus over 5 min40 mg b.i.d. to 480 mg (extended release) o.d.Contraindicated in HFrEF
  • Adapt doses in hepatic and renal impairment

Diltiazem0.25 mg/kg i.v. bolus over 5 min, then 5 − 15 mg/h60 mg t.i.d. to 360 mg (extended release) o.d.
Digitalis glycosides
Digoxin0.5 mg i.v. bolus (0.75 − 1.5 mg over 24 hours in divided doses)0.0625 − 0.25 mg o.d.

High plasma levels associated with increased mortality

Check renal function before starting and adapt dose in CKD patients

Digitoxin0.4 − 0.6 mg0.05 − 0.1 mg o.d.High plasma levels associated with increased mortality
Other
Amiodarone300 mg i.v. diluted in 250 mL 5% dextrose over 30 − 60 min (preferably via central venous cannula), followed by 900 − 1200 mg i.v. over 24 hours diluted in 500 − 1000 mL via a central venous cannula200 mg o.d. after loading 3 × 200 mg daily over 4 weeks, then 200 mg daily536d(reduce other rate controlling drugs according to heart rate)In case of thyroid disease, only if no other options
Intravenous administrationUsual oral maintenance doseContraindicated
Beta-blockersb
Metoprolol tartrate2.5 − 5 mg i.v. bolus; up to 4 doses25 − 100 mg b.i.d.In case of asthma use beta-1-blockers
  • Contraindicated in acute HF and history of severe bronchospasm

Metoprolol XL (succinate)N/A50 − 400 mg o.d.
BisoprololN/A1.25 − 20 mg o.d.
AtenololcN/A25 − 100 mg o.d.
Esmolol500 µg/kg i.v. bolus over 1 min; followed by 50 − 300 µg/kg/minN/A
Landiolol100 µg/kg i.v. bolus over 1 min, followed by 10 - 40 µg/kg/min; in patients with cardiac dysfunction: 1 - 10 µg/kg/minN/A
NebivololN/A2.5 − 10 mg o.d.
CarvedilolN/A3.125 − 50 mg b.i.d.
Non-dihydropyridine calcium channel antagonists
Verapamil2.5 − 10 mg i.v. bolus over 5 min40 mg b.i.d. to 480 mg (extended release) o.d.Contraindicated in HFrEF
  • Adapt doses in hepatic and renal impairment

Diltiazem0.25 mg/kg i.v. bolus over 5 min, then 5 − 15 mg/h60 mg t.i.d. to 360 mg (extended release) o.d.
Digitalis glycosides
Digoxin0.5 mg i.v. bolus (0.75 − 1.5 mg over 24 hours in divided doses)0.0625 − 0.25 mg o.d.

High plasma levels associated with increased mortality

Check renal function before starting and adapt dose in CKD patients

Digitoxin0.4 − 0.6 mg0.05 − 0.1 mg o.d.High plasma levels associated with increased mortality
Other
Amiodarone300 mg i.v. diluted in 250 mL 5% dextrose over 30 − 60 min (preferably via central venous cannula), followed by 900 − 1200 mg i.v. over 24 hours diluted in 500 − 1000 mL via a central venous cannula200 mg o.d. after loading 3 × 200 mg daily over 4 weeks, then 200 mg daily536d(reduce other rate controlling drugs according to heart rate)In case of thyroid disease, only if no other options

AF = atrial fibrillation; b.i.d. = bis in die (twice a day); CKD = chronic kidney disease; HF = heart failure; HFrEF = HF with reduced ejection fraction; i.v. = intravenous; min = minutes; N/A = not available or not widely available; o.d. = omni die (once daily); t.i.d. = ter in die (three times a day).

a

All rate control drugs are contraindicated in Wolff−Parkinson−White syndrome, also i.v. amiodarone.

b

Other beta-blockers are available but not recommended as specific rate control therapy in AF and therefore not mentioned here (e.g. propranolol and labetalol).

c

No data on atenolol; should not be used in HFrEF.

d

Loading regimen may vary; i.v. dosage should be considered when calculating total load.

Table 13

Drugs for rate control in AFa

Intravenous administrationUsual oral maintenance doseContraindicated
Beta-blockersb
Metoprolol tartrate2.5 − 5 mg i.v. bolus; up to 4 doses25 − 100 mg b.i.d.In case of asthma use beta-1-blockers
  • Contraindicated in acute HF and history of severe bronchospasm

Metoprolol XL (succinate)N/A50 − 400 mg o.d.
BisoprololN/A1.25 − 20 mg o.d.
AtenololcN/A25 − 100 mg o.d.
Esmolol500 µg/kg i.v. bolus over 1 min; followed by 50 − 300 µg/kg/minN/A
Landiolol100 µg/kg i.v. bolus over 1 min, followed by 10 - 40 µg/kg/min; in patients with cardiac dysfunction: 1 - 10 µg/kg/minN/A
NebivololN/A2.5 − 10 mg o.d.
CarvedilolN/A3.125 − 50 mg b.i.d.
Non-dihydropyridine calcium channel antagonists
Verapamil2.5 − 10 mg i.v. bolus over 5 min40 mg b.i.d. to 480 mg (extended release) o.d.Contraindicated in HFrEF
  • Adapt doses in hepatic and renal impairment

Diltiazem0.25 mg/kg i.v. bolus over 5 min, then 5 − 15 mg/h60 mg t.i.d. to 360 mg (extended release) o.d.
Digitalis glycosides
Digoxin0.5 mg i.v. bolus (0.75 − 1.5 mg over 24 hours in divided doses)0.0625 − 0.25 mg o.d.

High plasma levels associated with increased mortality

Check renal function before starting and adapt dose in CKD patients

Digitoxin0.4 − 0.6 mg0.05 − 0.1 mg o.d.High plasma levels associated with increased mortality
Other
Amiodarone300 mg i.v. diluted in 250 mL 5% dextrose over 30 − 60 min (preferably via central venous cannula), followed by 900 − 1200 mg i.v. over 24 hours diluted in 500 − 1000 mL via a central venous cannula200 mg o.d. after loading 3 × 200 mg daily over 4 weeks, then 200 mg daily536d(reduce other rate controlling drugs according to heart rate)In case of thyroid disease, only if no other options
Intravenous administrationUsual oral maintenance doseContraindicated
Beta-blockersb
Metoprolol tartrate2.5 − 5 mg i.v. bolus; up to 4 doses25 − 100 mg b.i.d.In case of asthma use beta-1-blockers
  • Contraindicated in acute HF and history of severe bronchospasm

Metoprolol XL (succinate)N/A50 − 400 mg o.d.
BisoprololN/A1.25 − 20 mg o.d.
AtenololcN/A25 − 100 mg o.d.
Esmolol500 µg/kg i.v. bolus over 1 min; followed by 50 − 300 µg/kg/minN/A
Landiolol100 µg/kg i.v. bolus over 1 min, followed by 10 - 40 µg/kg/min; in patients with cardiac dysfunction: 1 - 10 µg/kg/minN/A
NebivololN/A2.5 − 10 mg o.d.
CarvedilolN/A3.125 − 50 mg b.i.d.
Non-dihydropyridine calcium channel antagonists
Verapamil2.5 − 10 mg i.v. bolus over 5 min40 mg b.i.d. to 480 mg (extended release) o.d.Contraindicated in HFrEF
  • Adapt doses in hepatic and renal impairment

Diltiazem0.25 mg/kg i.v. bolus over 5 min, then 5 − 15 mg/h60 mg t.i.d. to 360 mg (extended release) o.d.
Digitalis glycosides
Digoxin0.5 mg i.v. bolus (0.75 − 1.5 mg over 24 hours in divided doses)0.0625 − 0.25 mg o.d.

High plasma levels associated with increased mortality

Check renal function before starting and adapt dose in CKD patients

Digitoxin0.4 − 0.6 mg0.05 − 0.1 mg o.d.High plasma levels associated with increased mortality
Other
Amiodarone300 mg i.v. diluted in 250 mL 5% dextrose over 30 − 60 min (preferably via central venous cannula), followed by 900 − 1200 mg i.v. over 24 hours diluted in 500 − 1000 mL via a central venous cannula200 mg o.d. after loading 3 × 200 mg daily over 4 weeks, then 200 mg daily536d(reduce other rate controlling drugs according to heart rate)In case of thyroid disease, only if no other options

AF = atrial fibrillation; b.i.d. = bis in die (twice a day); CKD = chronic kidney disease; HF = heart failure; HFrEF = HF with reduced ejection fraction; i.v. = intravenous; min = minutes; N/A = not available or not widely available; o.d. = omni die (once daily); t.i.d. = ter in die (three times a day).

a

All rate control drugs are contraindicated in Wolff−Parkinson−White syndrome, also i.v. amiodarone.

b

Other beta-blockers are available but not recommended as specific rate control therapy in AF and therefore not mentioned here (e.g. propranolol and labetalol).

c

No data on atenolol; should not be used in HFrEF.

d

Loading regimen may vary; i.v. dosage should be considered when calculating total load.

10.2.1.3 Acute rate control

In acute settings, physicians should always evaluate underlying causes, such as infection or anaemia. Beta-blockers and diltiazem/verapamil are preferred over digoxin because of their rapid onset of action and effectiveness at high sympathetic tone.507–511 The choice of drug (Table 13 and Figure 14) and target heart rate will depend on the patient characteristics, symptoms, LVEF value, and haemodynamics, but a lenient initial rate control approach seems acceptable (Figure 13). Combination therapy may be required. In patients with HFrEF, beta-blockers, digitalis, or their combination should be used.512,513 In critically ill patients and those with severely impaired LV systolic function, i.v. amiodarone can be used.504,514,515 In unstable patients, urgent cardioversion should be considered (section 11.1).

Choice of rate control drugs.490 AF = atrial fibrillation; AFL = atrial flutter; COPD = chronic obstructive pulmonary disease; CRT-D = cardiac resynchronization therapy defibrillator; CRT-P = cardiac resynchronization therapy pacemaker; HFpEF = heart failure with preserved ejection fraction; HFrEF = heart failure with reduced ejection fraction; NDCC = Non-dihydropyridine calcium channel blocker. aClinical reassessment should be focused on evaluation of resting heart rate, AF/AFL-related symptoms and quality of life. In case suboptimal rate control (resting heart rate >110 bpm), worsening of symptoms or quality of life consider 2nd line and, if necessary, 3rd line treatment options. bCareful institution of beta-blocker and NDCC, 24-hour Holter to check for bradycardia.
Figure 14

Choice of rate control drugs.490 AF = atrial fibrillation; AFL = atrial flutter; COPD = chronic obstructive pulmonary disease; CRT-D = cardiac resynchronization therapy defibrillator; CRT-P = cardiac resynchronization therapy pacemaker; HFpEF = heart failure with preserved ejection fraction; HFrEF = heart failure with reduced ejection fraction; NDCC = Non-dihydropyridine calcium channel blocker. aClinical reassessment should be focused on evaluation of resting heart rate, AF/AFL-related symptoms and quality of life. In case suboptimal rate control (resting heart rate >110 bpm), worsening of symptoms or quality of life consider 2nd line and, if necessary, 3rd line treatment options. bCareful institution of beta-blocker and NDCC, 24-hour Holter to check for bradycardia.

10.2.1.4 Atrioventricular node ablation and pacing

Ablation of the atrioventricular node and pacemaker implantation can control ventricular rate when medication fails. The procedure is relatively simple and has a low complication rate and low long-term mortality risk,516,517 especially when the pacemaker is implanted a few weeks before the atrioventricular node ablation and the initial pacing rate after ablation is set at 70–90 bpm.518,519 The procedure does not worsen LV function520 and may even improve LVEF in selected patients.521–523 Most studies have included older patients with limited life expectancy. For younger patients, ablation of the atrioventricular node should only be considered if there is urgent need for rate control and all other pharmacological and non-pharmacological treatment options have been carefully considered. The choice of pacing therapy (right ventricular or biventricular pacing) will depend on patient characteristics.524,525 His-bundle pacing after atrioventricular node ablation may evolve as an attractive alternative pacing mode,526 as currently tested in ongoing clinical trials (NCT02805465, NCT02700425).

In severely symptomatic patients with permanent AF and at least one hospitalization for HF, atrioventricular node ablation combined with cardiac resynchronization therapy (CRT) may be preferred. In a small RCT, the primary composite outcome (death or hospitalization for HF, or worsening HF) was significantly less common in the ablation + CRT group vs. the drug arm (P =0.013), and ablation + CRT patients showed a 36% decrease in symptoms and physical limitations at 1-year follow-up (P =0.004).527 Emerging evidence suggest that His-bundle pacing could be an alternative in these patients.528

Recommendations for ventricular rate control in patients with AFa

graphic
graphic

AF = atrial fibrillation; bpm = beats per minute; ECG = electrocardiogram; LA = left atrial; LVEF = left ventricular ejection fraction.

a

See section 11 for ventricular rate control in various concomitant conditions and AF populations

b

Class of recommendation.

c

Level of evidence.

d

Combining beta-blocker with verapamil or diltiazem should be performed with careful monitoring of heart rate by 24-h ECG to check for bradycardia.488

Recommendations for ventricular rate control in patients with AFa

graphic
graphic

AF = atrial fibrillation; bpm = beats per minute; ECG = electrocardiogram; LA = left atrial; LVEF = left ventricular ejection fraction.

a

See section 11 for ventricular rate control in various concomitant conditions and AF populations

b

Class of recommendation.

c

Level of evidence.

d

Combining beta-blocker with verapamil or diltiazem should be performed with careful monitoring of heart rate by 24-h ECG to check for bradycardia.488

10.2.2 Rhythm control

The ‘rhythm control strategy’ refers to attempts to restore and maintain sinus rhythm, and may engage a combination of treatment approaches, including cardioversion,164,234 antiarrhythmic medication,233,537,538 and catheter ablation,539–541 along with an adequate rate control, anticoagulation therapy (section 10.2.2.6) and comprehensive cardiovascular prophylactic therapy (upstream therapy, including lifestyle and sleep apnoea management) (Figure 15).

Rhythm control strategy. AAD = antiarrhythmic drug; AF = atrial fibrillation; CMP = cardiomyopathy; CV = cardioversion; LAVI = left atrial volume index; PAF = paroxysmal atrial fibrillation; PVI = pulmonary vein isolation; QoL = quality of life; SR = sinus rhythm. aConsider cardioversion to confirm that the absence of symptoms is not due to unconscious adaptation to reduced physical and/or mental capacity.
Figure 15

Rhythm control strategy. AAD = antiarrhythmic drug; AF = atrial fibrillation; CMP = cardiomyopathy; CV = cardioversion; LAVI = left atrial volume index; PAF = paroxysmal atrial fibrillation; PVI = pulmonary vein isolation; QoL = quality of life; SR = sinus rhythm. aConsider cardioversion to confirm that the absence of symptoms is not due to unconscious adaptation to reduced physical and/or mental capacity.

10.2.2.1 Indications for rhythm control

Based on the currently available evidence from RCTs, the primary indication for rhythm control is to reduce AF-related symptoms and improve QoL (Figure 15). In case of uncertainty, an attempt to restore sinus rhythm in order to evaluate the response to therapy may be a rational first step. Factors that may favour an attempt at rhythm control should be considered542,543 (Figure 15).

As AF progression is associated with a decrease in QoL544 and, with time, becomes irreversible or less amenable to treatment,176 rhythm control may be a relevant choice, although currently there is no substantial evidence that this may result in a different outcome. Reportedly, rates of AF progression were significantly lower with rhythm control than rate control.545 Older age, persistent AF, and previous stroke/TIA independently predicted AF progression,545 which may be considered when deciding the treatment strategy. For many patients, an early intervention to prevent AF progression may be worth considering,546 including optimal risk-factor management.245 Ongoing trials in patients with newly diagnosed symptomatic AF will assess whether early rhythm control interventions such as AF catheter ablation offer an opportunity to halt the progressive patho-anatomical changes associated with AF.547 However, there is evidence that, at least in some patients, a successful rhythm control strategy with AF catheter ablation may not affect atrial substrate development.548 Important evidence regarding the effect of early rhythm control therapy on clinical outcomes are expected in 2020 from the ongoing EAST (Early treatment of Atrial fibrillation for Stoke prevention Trial) trial.549

General recommendations regarding active informed patient involvement in shared decision making (section 9) also apply for rhythm control strategies. The same principles should be applied in female and male AF patients when considering rhythm control therapy.550

Recommendations for rhythm control

graphic
graphic

AF = atrial fibrillation; QoL = quality of life.

a

Class of recommendation.

b

Level of evidence.

Recommendations for rhythm control

graphic
graphic

AF = atrial fibrillation; QoL = quality of life.

a

Class of recommendation.

b

Level of evidence.

10.2.2.2 Cardioversion
Immediate cardioversion/elective cardioversion

Acute rhythm control can be performed as an emergency cardioversion in a haemodynamically unstable AF patient or in a non-emergency situation. Synchronized direct current electrical cardioversion is the preferred choice in haemodynamically compromised AF patients as it is more effective than pharmacological cardioversion and results in immediate restoration of sinus rhythm.554,555 In stable patients, either pharmacological cardioversion or electrical cardioversion can be attempted; pharmacological cardioversion is less effective but does not require sedation. Of note, pre-treatment with AADs can improve the efficacy of elective electrical cardioversion.556 A RCT showed maximum fixed-energy electrical cardioversion was more effective than an energy-escalation strategy.557

In a RCT, a wait-and-watch approach with rate control medication only and cardioversion when needed within 48 h of symptom onset was as safe as and non-inferior to immediate cardioversion of paroxysmal AF, which often resolves spontaneously within 24 h.558

Elective cardioversion refers to the situation when cardioversion can be planned beyond the nearest hours. Observational data243 showed that cardioversion did not result in improved AF-related QoL or halted AF progression, but many of these patients did not receive adjunctive rhythm control therapies.243 Other studies reported significant QoL improvement in patients who maintain sinus rhythm after electrical cardioversion and the only variable independently associated with a moderate to large effect size was sinus rhythm at 3 months.232

Factors associated with an increased risk for AF recurrence after elective cardioversion include older age, female sex, previous cardioversion, chronic obstructive pulmonary disease (COPD), renal impairment, structural heart disease, larger LA volume index, and HF.164,559,560 Treatment of potentially modifiable conditions should be considered before cardioversion to facilitate maintenance of sinus rhythm (Figure 15).245 In case of AF recurrence after cardioversion in patients with persistent AF, an early re-cardioversion may prolong subsequent duration of sinus rhythm.561

Non-emergency cardioversion is contraindicated in the presence of known LA thrombus. Peri-procedural thrombo-embolic risk should be evaluated and peri-procedural and long-term OAC use considered irrespective of cardioversion mode (i.e. pharmacological cardioversion or electrical cardioversion) (section 10.2.2.6). A flowchart for decision making on cardioversion is shown in Figure 16.

Flowchart for decision making on cardioversion of AF depending on clinical presentation, AF onset, oral anticoagulation intake, and risk factors for stroke. AF = atrial fibrillation; CHA2DS2-VASc = Congestive heart failure, Hypertension, Age ≥75 years, Diabetes mellitus, Stroke, Vascular disease, Age 65 − 74 years, Sex category (female); cardioversion = cardioversion; ECV = electrical cardioversion; h = hour; LA = left atrium; LAA = left atrial appendage; LMWH = low-molecular-weight heparin; NOAC = non-vitamin K antagonist oral anticoagulant; OAC = oral anticoagulant; TE = thromboembolism; TOE = transoesophageal echocardiography; UFH = unfractionated heparin; VKA = vitamin K antagonist.
Figure 16

Flowchart for decision making on cardioversion of AF depending on clinical presentation, AF onset, oral anticoagulation intake, and risk factors for stroke. AF = atrial fibrillation; CHA2DS2-VASc = Congestive heart failure, Hypertension, Age ≥75 years, Diabetes mellitus, Stroke, Vascular disease, Age 65 − 74 years, Sex category (female); cardioversion = cardioversion; ECV = electrical cardioversion; h = hour; LA = left atrium; LAA = left atrial appendage; LMWH = low-molecular-weight heparin; NOAC = non-vitamin K antagonist oral anticoagulant; OAC = oral anticoagulant; TE = thromboembolism; TOE = transoesophageal echocardiography; UFH = unfractionated heparin; VKA = vitamin K antagonist.

Electrical cardioversion

Electrical cardioversion can be performed safely in sedated patients treated with i.v. midazolam and/or propofol or etomidate.562 BP monitoring and oximetry during the procedure should be used routinely. Skin burns may occasionally be observed. Intravenous atropine or isoproterenol, or temporary transcutaneous pacing, should be available in case of post-cardioversion bradycardia. Biphasic defibrillators are standard because of their superior efficacy compared with monophasic defibrillators.563,564 Anterior–posterior electrode positions restore sinus rhythm more effectively,554,555 while other reports suggest that specific electrical pad positioning is not critically important for successful cardioversion.565

Pharmacological cardioversion (including ‘pill in the pocket’)

Pharmacological cardioversion to sinus rhythm is an elective procedure indicated in haemodynamically stable patients. Its true efficacy is biased by the spontaneous restoration of sinus rhythm within 48 h of hospitalization in 76 − 83% of patients with recent onset AF (10 − 18% within first 3 h, 55 − 66% within 24 h, and 69% within 48 h).566–568 Therefore, a ‘wait-and-watch’ strategy (usually for <24 h) may be considered in patients with recent-onset AF as a non-inferior alternative to early cardioversion.558

Table 14

Antiarrhythmic drugs used for restoration of sinus rhythm

Antiarrhythmic drugs for restoration of sinus rhythm (pharmacological cardioversion)
DrugAdministration routeInitial dose for cardioversionFurther dosing for cardioversionAcute success rate and expected time to sinus rhythmContraindications/precautions/comments
Flecainidea

Oralb

i.v.

200–300 mg

2 mg/kg over 10 min

Overall: 59–78% (51% at 3 h, 72% at 8 h)

  • Should not be used in ischaemic heart disease and/or significant structural heart disease

  • May induce hypotension, AFL with 1:1 conduction (in 3.5 − 5.0% of patients)

  • Flecainide may induce mild QRS complex widening

  • Do NOT use for pharmacological cardioversion of AFL

Propafenonea

Oralb

i.v.

450–600 mg

1.5 − 2 mg/kg over 10 min

Oral: 45–55% at 3 h,

69–78% at 8 h;

i.v.: 43–89%

Up to 6 h

Vernakalantci.v.3 mg/kg over 10 min

2 mg/kg over 10 min

(10 − 15 min after the initial dose)

<1 h (50% conversion within 10 min)
  • Should not be used in patients with arterial hypotension (SBP <100 mmHg), recent ACS (within 1 month), NYHA III or IV HF, prolonged QT, or severe aortic stenosis

  • May cause arterial hypotension, QT prolongation, QRS widening, or non-sustained ventricular tachycardia

Amiodaroneai.v.5 − 7 mg/kg over 1 − 2 h50 mg/h (maximum 1.2 g for 24 h)

44% (8–12 h to several days)

  • May cause phlebitis (use a large peripheral vein, avoid i.v. administration >24 hours and use preferably volumetric pump)

  • May cause hypotension, bradycardia/atrioventricular block, QT prolongation

  • Only if no other options in patients with hyperthyroidism (risk of thyrotoxicosis)

Ibutilideci.v.

1 mg over 10 min

0.01 mg/kg if body weight <60 kg

1 mg over 10 min (10 − 20 min after the initial dose)

31–51% (AF)

63–73% (AFL)

≈1 h

  • Effective for conversion of AFL

  • Should not be used in patients with prolonged QT, severe LVH, or low LVEF

  • Should be used in the setting of a cardiac care unit as it may cause QT prolongation, polymorphic ventricular tachycardia (torsades de pointes)

  • ECG monitoring for at least 4 hours after administration to detect a proarrhythmic event

Antiarrhythmic drugs for restoration of sinus rhythm (pharmacological cardioversion)
DrugAdministration routeInitial dose for cardioversionFurther dosing for cardioversionAcute success rate and expected time to sinus rhythmContraindications/precautions/comments
Flecainidea

Oralb

i.v.

200–300 mg

2 mg/kg over 10 min

Overall: 59–78% (51% at 3 h, 72% at 8 h)

  • Should not be used in ischaemic heart disease and/or significant structural heart disease

  • May induce hypotension, AFL with 1:1 conduction (in 3.5 − 5.0% of patients)

  • Flecainide may induce mild QRS complex widening

  • Do NOT use for pharmacological cardioversion of AFL

Propafenonea

Oralb

i.v.

450–600 mg

1.5 − 2 mg/kg over 10 min

Oral: 45–55% at 3 h,

69–78% at 8 h;

i.v.: 43–89%

Up to 6 h

Vernakalantci.v.3 mg/kg over 10 min

2 mg/kg over 10 min

(10 − 15 min after the initial dose)

<1 h (50% conversion within 10 min)
  • Should not be used in patients with arterial hypotension (SBP <100 mmHg), recent ACS (within 1 month), NYHA III or IV HF, prolonged QT, or severe aortic stenosis

  • May cause arterial hypotension, QT prolongation, QRS widening, or non-sustained ventricular tachycardia

Amiodaroneai.v.5 − 7 mg/kg over 1 − 2 h50 mg/h (maximum 1.2 g for 24 h)

44% (8–12 h to several days)

  • May cause phlebitis (use a large peripheral vein, avoid i.v. administration >24 hours and use preferably volumetric pump)

  • May cause hypotension, bradycardia/atrioventricular block, QT prolongation

  • Only if no other options in patients with hyperthyroidism (risk of thyrotoxicosis)

Ibutilideci.v.

1 mg over 10 min

0.01 mg/kg if body weight <60 kg

1 mg over 10 min (10 − 20 min after the initial dose)

31–51% (AF)

63–73% (AFL)

≈1 h

  • Effective for conversion of AFL

  • Should not be used in patients with prolonged QT, severe LVH, or low LVEF

  • Should be used in the setting of a cardiac care unit as it may cause QT prolongation, polymorphic ventricular tachycardia (torsades de pointes)

  • ECG monitoring for at least 4 hours after administration to detect a proarrhythmic event

AAD = antiarrhythmic drug; ACS = acute coronary syndrome; AF = atrial fibrillation; AFL = atrial flutter; b.i.d. = bis in die (twice a day); CrCl = creatinine clearance; CYP2D6 = cytochrome P450 2D6; ECG = electrocardiogram; EHRA = European Heart Rhythm Association; HCM = hypertrophic cardiomyopathy; HF = heart failure; i.v. = intravenous; LV = left ventricular; LVEF = left ventricular ejection fraction; LVH = LV hypertrophy; NYHA = New York Heart Association; QRS = QRS interval; QT = QT interval; SA = sinoatrial; SBP = systolic blood pressure; VKA = vitamin K antagonist.

a

Most frequently used for cardioversion of AF, available in most countries.

b

May be self-administered by selected outpatients as a ‘pill-in-the-pocket’ treatment strategy.

c

Not available in some countries.

For more details regarding pharmacokinetic or pharmacodynamic properties refer to EHRA AADs–clinical use and clinical decision making: a consensus document.568

Table 14

Antiarrhythmic drugs used for restoration of sinus rhythm

Antiarrhythmic drugs for restoration of sinus rhythm (pharmacological cardioversion)
DrugAdministration routeInitial dose for cardioversionFurther dosing for cardioversionAcute success rate and expected time to sinus rhythmContraindications/precautions/comments
Flecainidea

Oralb

i.v.

200–300 mg

2 mg/kg over 10 min

Overall: 59–78% (51% at 3 h, 72% at 8 h)

  • Should not be used in ischaemic heart disease and/or significant structural heart disease

  • May induce hypotension, AFL with 1:1 conduction (in 3.5 − 5.0% of patients)

  • Flecainide may induce mild QRS complex widening

  • Do NOT use for pharmacological cardioversion of AFL

Propafenonea

Oralb

i.v.

450–600 mg

1.5 − 2 mg/kg over 10 min

Oral: 45–55% at 3 h,

69–78% at 8 h;

i.v.: 43–89%

Up to 6 h

Vernakalantci.v.3 mg/kg over 10 min

2 mg/kg over 10 min

(10 − 15 min after the initial dose)

<1 h (50% conversion within 10 min)
  • Should not be used in patients with arterial hypotension (SBP <100 mmHg), recent ACS (within 1 month), NYHA III or IV HF, prolonged QT, or severe aortic stenosis

  • May cause arterial hypotension, QT prolongation, QRS widening, or non-sustained ventricular tachycardia

Amiodaroneai.v.5 − 7 mg/kg over 1 − 2 h50 mg/h (maximum 1.2 g for 24 h)

44% (8–12 h to several days)

  • May cause phlebitis (use a large peripheral vein, avoid i.v. administration >24 hours and use preferably volumetric pump)

  • May cause hypotension, bradycardia/atrioventricular block, QT prolongation

  • Only if no other options in patients with hyperthyroidism (risk of thyrotoxicosis)

Ibutilideci.v.

1 mg over 10 min

0.01 mg/kg if body weight <60 kg

1 mg over 10 min (10 − 20 min after the initial dose)

31–51% (AF)

63–73% (AFL)

≈1 h

  • Effective for conversion of AFL

  • Should not be used in patients with prolonged QT, severe LVH, or low LVEF

  • Should be used in the setting of a cardiac care unit as it may cause QT prolongation, polymorphic ventricular tachycardia (torsades de pointes)

  • ECG monitoring for at least 4 hours after administration to detect a proarrhythmic event

Antiarrhythmic drugs for restoration of sinus rhythm (pharmacological cardioversion)
DrugAdministration routeInitial dose for cardioversionFurther dosing for cardioversionAcute success rate and expected time to sinus rhythmContraindications/precautions/comments
Flecainidea

Oralb

i.v.

200–300 mg

2 mg/kg over 10 min

Overall: 59–78% (51% at 3 h, 72% at 8 h)

  • Should not be used in ischaemic heart disease and/or significant structural heart disease

  • May induce hypotension, AFL with 1:1 conduction (in 3.5 − 5.0% of patients)

  • Flecainide may induce mild QRS complex widening

  • Do NOT use for pharmacological cardioversion of AFL

Propafenonea

Oralb

i.v.

450–600 mg

1.5 − 2 mg/kg over 10 min

Oral: 45–55% at 3 h,

69–78% at 8 h;

i.v.: 43–89%

Up to 6 h

Vernakalantci.v.3 mg/kg over 10 min

2 mg/kg over 10 min

(10 − 15 min after the initial dose)

<1 h (50% conversion within 10 min)
  • Should not be used in patients with arterial hypotension (SBP <100 mmHg), recent ACS (within 1 month), NYHA III or IV HF, prolonged QT, or severe aortic stenosis

  • May cause arterial hypotension, QT prolongation, QRS widening, or non-sustained ventricular tachycardia

Amiodaroneai.v.5 − 7 mg/kg over 1 − 2 h50 mg/h (maximum 1.2 g for 24 h)

44% (8–12 h to several days)

  • May cause phlebitis (use a large peripheral vein, avoid i.v. administration >24 hours and use preferably volumetric pump)

  • May cause hypotension, bradycardia/atrioventricular block, QT prolongation

  • Only if no other options in patients with hyperthyroidism (risk of thyrotoxicosis)

Ibutilideci.v.

1 mg over 10 min

0.01 mg/kg if body weight <60 kg

1 mg over 10 min (10 − 20 min after the initial dose)

31–51% (AF)

63–73% (AFL)

≈1 h

  • Effective for conversion of AFL

  • Should not be used in patients with prolonged QT, severe LVH, or low LVEF

  • Should be used in the setting of a cardiac care unit as it may cause QT prolongation, polymorphic ventricular tachycardia (torsades de pointes)

  • ECG monitoring for at least 4 hours after administration to detect a proarrhythmic event

AAD = antiarrhythmic drug; ACS = acute coronary syndrome; AF = atrial fibrillation; AFL = atrial flutter; b.i.d. = bis in die (twice a day); CrCl = creatinine clearance; CYP2D6 = cytochrome P450 2D6; ECG = electrocardiogram; EHRA = European Heart Rhythm Association; HCM = hypertrophic cardiomyopathy; HF = heart failure; i.v. = intravenous; LV = left ventricular; LVEF = left ventricular ejection fraction; LVH = LV hypertrophy; NYHA = New York Heart Association; QRS = QRS interval; QT = QT interval; SA = sinoatrial; SBP = systolic blood pressure; VKA = vitamin K antagonist.

a

Most frequently used for cardioversion of AF, available in most countries.

b

May be self-administered by selected outpatients as a ‘pill-in-the-pocket’ treatment strategy.

c

Not available in some countries.

For more details regarding pharmacokinetic or pharmacodynamic properties refer to EHRA AADs–clinical use and clinical decision making: a consensus document.568

The choice of a specific drug is based on the type and severity of associated heart disease (Table 14), and pharmacological cardioversion is more effective in recent onset AF. Flecainide (and other class Ic agents), indicated in patients without significant LV hypertrophy (LVH), LV systolic dysfunction, or ischaemic heart disease, results in prompt (3 − 5 h) and safe569 restoration of sinus rhythm in >50% of patients,570–574 while i.v. amiodarone, mainly indicated in HF patients, has a limited and delayed effect but can slow heart rate within 12 h.570, 575–577 Intravenous vernakalant is the most rapidly cardioverting drug, including patients with mild HF and ischaemic heart disease, and is more effective than amiodarone578–583 or flecainide.584 Dofetilide is not used in Europe and is rarely used outside Europe. Ibutilide is effective to convert atrial flutter (AFL) to sinus rhythm.585

In selected outpatients with rare paroxysmal AF episodes, a self-administered oral dose of flecainide or propafenone is slightly less effective than in-hospital pharmacological cardioversion but may be preferred (permitting an earlier conversion), provided that the drug safety and efficacy has previously been established in the hospital setting.586 An atrioventricular node-blocking drug should be instituted in patients treated with class Ic AADs (especially flecainide) to avoid transformation to AFL with 1:1 conduction.587

Follow-up after cardioversion

The goals of follow-up after cardioversion are shown in Table 15. When assessing the efficacy of a rhythm control strategy, it is important to balance symptoms and AAD side-effects. Patients should be reviewed after cardioversion to detect whether an alternative rhythm control strategy including AF catheter ablation, or a rate control approach is needed instead of current treatment.

Table 15

Goals of follow-up after cardioversion of AF

Goals
Early recognition of AF recurrence by ECG recording after cardioversion
Evaluation of the efficacy of rhythm control by symptom assessment
Monitoring of risk for proarrhythmia by regular control of PR, QRS, and QTc intervals in patients on Class I or III AADs
Evaluation of balance between symptoms and side-effects of therapy considering QoL and symptoms
Evaluation of AF-related morbidities and AAD-related side-effects on concomitant cardiovascular conditions and LV function
Optimization of conditions for maintenance of sinus rhythm including cardiovascular risk management (BP control, HF treatment, increasing cardiorespiratory fitness, and other measures, see section 11).
Goals
Early recognition of AF recurrence by ECG recording after cardioversion
Evaluation of the efficacy of rhythm control by symptom assessment
Monitoring of risk for proarrhythmia by regular control of PR, QRS, and QTc intervals in patients on Class I or III AADs
Evaluation of balance between symptoms and side-effects of therapy considering QoL and symptoms
Evaluation of AF-related morbidities and AAD-related side-effects on concomitant cardiovascular conditions and LV function
Optimization of conditions for maintenance of sinus rhythm including cardiovascular risk management (BP control, HF treatment, increasing cardiorespiratory fitness, and other measures, see section 11).

AAD = antiarrhythmic drug; AF = atrial fibrillation; BP = blood pressure; ECG = electrocardiogram; HF = heart failure; LV = left ventricular; PR = PR interval; QoL = quality of life; QRS = QRS interval; QTc = corrected QT interval.

Table 15

Goals of follow-up after cardioversion of AF

Goals
Early recognition of AF recurrence by ECG recording after cardioversion
Evaluation of the efficacy of rhythm control by symptom assessment
Monitoring of risk for proarrhythmia by regular control of PR, QRS, and QTc intervals in patients on Class I or III AADs
Evaluation of balance between symptoms and side-effects of therapy considering QoL and symptoms
Evaluation of AF-related morbidities and AAD-related side-effects on concomitant cardiovascular conditions and LV function
Optimization of conditions for maintenance of sinus rhythm including cardiovascular risk management (BP control, HF treatment, increasing cardiorespiratory fitness, and other measures, see section 11).
Goals
Early recognition of AF recurrence by ECG recording after cardioversion
Evaluation of the efficacy of rhythm control by symptom assessment
Monitoring of risk for proarrhythmia by regular control of PR, QRS, and QTc intervals in patients on Class I or III AADs
Evaluation of balance between symptoms and side-effects of therapy considering QoL and symptoms
Evaluation of AF-related morbidities and AAD-related side-effects on concomitant cardiovascular conditions and LV function
Optimization of conditions for maintenance of sinus rhythm including cardiovascular risk management (BP control, HF treatment, increasing cardiorespiratory fitness, and other measures, see section 11).

AAD = antiarrhythmic drug; AF = atrial fibrillation; BP = blood pressure; ECG = electrocardiogram; HF = heart failure; LV = left ventricular; PR = PR interval; QoL = quality of life; QRS = QRS interval; QTc = corrected QT interval.

Recommendations for cardioversion

graphic
graphic

ACS = acute coronary syndrome; AF = atrial fibrillation; HF = heart failure; ms = milliseconds; i.v. = intravenous; QTc = corrected QT interval. Note: For cardioversion in various specific conditions and AF populations see section 11.

a

Class of recommendation.

b

Level of evidence.

Recommendations for cardioversion

graphic
graphic

ACS = acute coronary syndrome; AF = atrial fibrillation; HF = heart failure; ms = milliseconds; i.v. = intravenous; QTc = corrected QT interval. Note: For cardioversion in various specific conditions and AF populations see section 11.

a

Class of recommendation.

b

Level of evidence.

10.2.2.3 Atrial fibrillation catheter ablation

AF catheter ablation is a well-established treatment for the prevention of AF recurrences.1,602–604 When performed by appropriately trained operators, AF catheter ablation is a safe and superior alternative to AADs for maintenance of sinus rhythm and symptom improvement.165,235–242,246,247,605–618 It is advised to discuss the efficacy and complication rates of AF catheter ablation and AADs with the patient once rhythm control as long-term management has been selected.

Indications

In the following section, indications for AF catheter ablation are presented for paroxysmal and persistent AF in patients with and without risk factors for post-ablation AF recurrence. Differentiation of persistent and long-standing persistent AF was omitted because the latter only expresses the duration of persistent AF above an arbitrary and artificial cut-off at 12 months’ duration. The significance of such a cut-off as a single measure has never been substantially proven.

A number of risk factors for AF recurrence after AF ablation have been identified, including LA size, AF duration, patient age, renal dysfunction, and substrate visualization by means of MRI.619–625 Recent systematic reviews on prediction models for AF recurrence after catheter ablation showed the potential benefits of risk predictions, but a more robust evaluation of such models is desirable.167,626 The model variables can be measured before ablation; therefore models could be used pre-procedurally to predict the likelihood of recurrence.627–635 However, no single score has been presently identified as consistently superior to others. Thus, at present, for an improved and more balanced indication for ablation in patients with persistent AF and risk factors for recurrence, the most intensely evaluated risk predictors (including duration of AF) should be considered, and adjusted to the individual patient’s situation including their preferences. Notably, patients must also be explicitly informed about the importance of treating modifiable risk factors to reduce risk of recurrent AF.621,636–652

The indications for AF catheter ablation are summarized in Figure 17. AF catheter ablation is effective in maintaining sinus rhythm in patients with paroxysmal and persistent AF.165,235–242,605–616 The main clinical benefit of AF catheter ablation is the reduction of arrhythmia-related symptoms.246,247,603,604,607,617,653,654 This has been confirmed in a recent RCT showing that the improvement in QoL was significantly higher in the ablation vs. medical therapy group, as was the associated reduction in AF burden.246 Symptom improvement has also been confirmed in the recent large CABANA (Catheter ABlation vs. ANtiarrhythmic Drug Therapy for Atrial Fibrillation) RCT,655 but the trial showed that the strategy of AF catheter ablation did not significantly reduce the primary composite outcome of death, disabling stroke, serious bleeding, or cardiac arrest compared with medical therapy.617 As no RCT has yet demonstrated a significant reduction in all-cause mortality, stroke, or major bleeding with AF catheter ablation in the 'general' AF population, the indications for the procedure have not been broadened beyond symptom relief,617 and AF catheter ablation is generally not indicated in asymptomatic patients. Further important evidence regarding the impact of ablation on major cardiovascular events is expected from the EAST trial.656

Indications for catheter ablation of symptomatic AF. The arrows from AAD to ablation indicate failed drug therapy. AAD = antiarrhythmic drug; AF = atrial fibrillation; EF = ejection fraction; LA = left atrial. aSignificantly enlarged LA volume, advanced age, long AF duration, renal dysfunction, and other cardiovascular risk factors. bIn rare individual circumstances, catheter ablation may be carefully considered as first-line therapy. cRecommended to reverse LV dysfunction when tachycardiomyopathy is highly probable. dTo improve survival and reduce hospitalization.
Figure 17

Indications for catheter ablation of symptomatic AF. The arrows from AAD to ablation indicate failed drug therapy. AAD = antiarrhythmic drug; AF = atrial fibrillation; EF = ejection fraction; LA = left atrial. aSignificantly enlarged LA volume, advanced age, long AF duration, renal dysfunction, and other cardiovascular risk factors. bIn rare individual circumstances, catheter ablation may be carefully considered as first-line therapy. cRecommended to reverse LV dysfunction when tachycardiomyopathy is highly probable. dTo improve survival and reduce hospitalization.

In selected patients with HF and reduced LVEF, two RCTs have shown a reduction in all-cause mortality and hospitalizations with AF catheter ablation,611,657 although combined mortality and HF hospitalization was a primary endpoint only in the CASTLE-AF (Catheter Ablation vs. Standard conventional Treatment in patients with LEft ventricular dysfunction and Atrial Fibrillation) trial.657 The generalizability of the trial has recently been evaluated in a large HF patient population.658 This analysis showed that only a small number of patients met the trial inclusion criteria (<10%) and patients who met the CASTLE-AF inclusion criteria had a significant benefit from treatment as demonstrated in the trial.658 The smaller AMICA (Atrial Fibrillation Management in Congestive Heart Failure With Ablation) RCT, which included patients with more advanced HFrEF, did not show benefits gained by AF catheter ablation at 1-year follow-up,659 whereas a recent CABANA subgroup analysis supported the benefits of AF catheter ablation in patients with HFrEF, showing a significant reduction in the study primary endpoint (death, stroke, bleeding, cardiac arrest) and reduced mortality in the ablation group.617,660 Overall, AF catheter ablation in patients with HFrEF results in higher rates of preserved sinus rhythm and greater improvement in LVEF, exercise performance, and QoL compared with AAD and rate control.611,657,661–671 Accordingly, ablation should be considered in patients with HFrEF who have been selected for rhythm control treatment to improve QoL and LV function, and to reduce HF hospitalization and, potentially, mortality.

When AF-mediated tachycardia-induced cardiomyopathy (i.e. ventricular dysfunction secondary to rapid and/or asynchronous/irregular myocardial contraction, partially or completely reversed after treatment of the causative arrhythmia) is highly suspected, AF catheter ablation is recommended to restore LV function.672–676

Ablation is recommended, in general, as a second-line therapy after failure (or intolerance) of class I or class III AADs. This recommendation is based on the results of multiple RCTs showing superiority of AF catheter ablation vs. AADs regarding freedom from recurrent arrhythmia or improvement in symptoms, exercise capacity, and QoL after medication failure.235–239,246,247,605–607,609,611,613–617

Clinical trials considering AF catheter ablation before any AAD suggest that AF catheter ablation is more effective in maintaining sinus rhythm, with comparable complication rates in experienced centres.240–242,614 The 5-year follow-up in the MANTRA-PAF (Medical Antiarrhythmic Treatment or Radiofrequency Ablation in Paroxysmal Atrial Fibrillation) trial showed a significantly lower AF burden in the ablation arm that did not, however, translate into improved QoL compared with AAD treatment,615 whereas the CAPTAF (Catheter Ablation compared with Pharmacological Therapy for Atrial Fibrillation) study showed that, in AF patients mostly naive to class I and III AADs, the greater improvement in QoL in the ablation arm was directly associated with greater reduction in AF burden compared with the AAD arm.246 Based on these studies and patient preferences, AF catheter ablation should be considered before a trial of AAD in patients with paroxysmal AF episodes (class IIa), or may be considered in patients with persistent AF without risk factors for recurrence (class IIb).

Techniques and technologies

The cornerstone of AF catheter ablation is the complete isolation of pulmonary veins by linear lesions around their antrum, either using point-by-point radiofrequency ablation or single-shot ablation devices.235,237,239,607–609,612,613,654,677–686 Unfortunately, persistent pulmonary vein electrical isolation is difficult to achieve (pulmonary vein reconnection rates of >70% are reported683,687–697, but could be significantly lower with the newer generation of catheters698–700).

Particularly in persistent and long-standing persistent AF, more extensive ablation has been advocated. This may include linear lesions in the atria, isolation of the LAA or of the superior vena cava, ablation of complex fractionated electrograms, rotors, non-pulmonary foci, or ganglionated plexi, fibrosis-guided voltage and/or MRI-mapping, or ablation of high dominant frequency sites.701–710 However, additional benefit vs. pulmonary vein isolation (PVI) alone, justifying its use during the first procedure, is yet to be confirmed.677,680,711–730 A RCT-based data suggest improved outcome with targeting extrapulmonary (particularly the LAA) foci and selective ablation of low-voltage areas as adjunct to PVI.708,725 In patients with documented cavotricuspid isthmus (CTI)-dependent flutter undergoing AF catheter ablation, right isthmus ablation may be considered.731–734 In case of non−CTI-dependent atrial tachycardia, the ablation technique depends on the underlying mechanism and tachycardia focus or circuit.1,614

Several RCTs and observational studies have compared point-by-point radiofrequency and cryoballoon ablation, mostly in the first procedure for paroxysmal AF.612,681,735–755 They reported broadly similar arrhythmia-free survival and overall complications with either technique, with slightly shorter procedure duration but longer fluoroscopy time with cryoballoon ablation.612,681,735–755 However, some studies showed reduced hospitalization and lower complication rates with cryoballoon ablation.746,756,757 The choice of energy source may depend on centre availability, operator preference/experience, and patient preference. Alternative catheter designs and energy sources have been developed in an attempt to simplify the ablation procedure and improve outcomes,613,755,758–761 but further evidence is required before changing current recommendations.

Complications

Prospective, registry-based data show that approximately 4 − 14% of patients undergoing AF catheter ablation experience complications, 2 − 3% of which are potentially life-threatening.602–604,762–765 In the recent CABANA trial, mostly including experienced high-volume centres, complications occurred in the lower range of these rates.617 Complications occur mostly within the first 24 h after the procedure, but some may appear 1 − 2 months after ablation1,602–604 (Table 16 and Supplementary Table 10). Peri-procedural death is rare (<0.2%) and usually related to cardiac tamponade.603,604,766–770

Table 16

Procedure-related complications in catheter ablation and thoracoscopic ablation of AF771

Complication severityComplication typeComplication rate
Catheter ablationThoracoscopic ablation
Life-threatening complicationsPeriprocedural death<0.1%<0.1%
Oesophageal perforation/fistula<0.5%N/A
Periprocedural thromboembolic event<1.0%<1.5%
Cardiac tamponade≈1%<1.0%
Severe complicationsPulmonary vein stenosis<1.0%N/A
Persistent phrenic nerve palsy<1.0%N/A
Vascular complications2-4%N/A
Conversion to sternotomyN/A<1.7%
PneumothoraxN/A<6.5%
Moderate or minor complicationsVarious1 − 2%1 − 3%
Complications of unknown significanceAsymptomatic cerebral embolism5 − 15%N/A
Complication severityComplication typeComplication rate
Catheter ablationThoracoscopic ablation
Life-threatening complicationsPeriprocedural death<0.1%<0.1%
Oesophageal perforation/fistula<0.5%N/A
Periprocedural thromboembolic event<1.0%<1.5%
Cardiac tamponade≈1%<1.0%
Severe complicationsPulmonary vein stenosis<1.0%N/A
Persistent phrenic nerve palsy<1.0%N/A
Vascular complications2-4%N/A
Conversion to sternotomyN/A<1.7%
PneumothoraxN/A<6.5%
Moderate or minor complicationsVarious1 − 2%1 − 3%
Complications of unknown significanceAsymptomatic cerebral embolism5 − 15%N/A

NA = not available.

Table 16

Procedure-related complications in catheter ablation and thoracoscopic ablation of AF771

Complication severityComplication typeComplication rate
Catheter ablationThoracoscopic ablation
Life-threatening complicationsPeriprocedural death<0.1%<0.1%
Oesophageal perforation/fistula<0.5%N/A
Periprocedural thromboembolic event<1.0%<1.5%
Cardiac tamponade≈1%<1.0%
Severe complicationsPulmonary vein stenosis<1.0%N/A
Persistent phrenic nerve palsy<1.0%N/A
Vascular complications2-4%N/A
Conversion to sternotomyN/A<1.7%
PneumothoraxN/A<6.5%
Moderate or minor complicationsVarious1 − 2%1 − 3%
Complications of unknown significanceAsymptomatic cerebral embolism5 − 15%N/A
Complication severityComplication typeComplication rate
Catheter ablationThoracoscopic ablation
Life-threatening complicationsPeriprocedural death<0.1%<0.1%
Oesophageal perforation/fistula<0.5%N/A
Periprocedural thromboembolic event<1.0%<1.5%
Cardiac tamponade≈1%<1.0%
Severe complicationsPulmonary vein stenosis<1.0%N/A
Persistent phrenic nerve palsy<1.0%N/A
Vascular complications2-4%N/A
Conversion to sternotomyN/A<1.7%
PneumothoraxN/A<6.5%
Moderate or minor complicationsVarious1 − 2%1 − 3%
Complications of unknown significanceAsymptomatic cerebral embolism5 − 15%N/A

NA = not available.

AF catheter ablation outcome and impact of modifiable risk factors

Multiple RCTs have compared AADs with AF catheter ablation using different technologies/energy sources, either as ‘first-line’ therapy or after AAD failure, showing superiority of AF catheter ablation in arrhythmia-free survival.165,235–242,605–616 However, many patients require several procedures and late recurrences are not infrequent.248,639,772–780

Key outcomes include QoL, HF, stroke, and mortality.539–541,608,781,782 Compared with AADs, AF catheter ablation was associated with significant and sustained improvement in QoL scores in several RCTs and meta-analyses.1,235,239–242,246,247,539–541,783,784 To date, there is no RCT sufficiently large to properly evaluate a reduction in stroke by catheter ablation.

Several factors, including AF type and duration,235–237,239,607,609,612,613,654,680,682,785 and the presence of comorbidities such as hypertension,621,639–641 obesity,638,639,643,646,772,786–791 metabolic syndrome,792–794 and sleep apnoea643–645,647–652 may influence the outcome of catheter ablation (Figure 18 and Supplementary Box 2). Prospective cohort studies suggest that aggressive control of modifiable risk factors may improve arrhythmia-free survival after catheter ablation.636

Risk factors for AF contributing to the development of an abnormal substrate translating into poorer outcomes with rhythm control strategies. AF = atrial fibrillation; BMI = body mass index; CPAP = continuous positive airway pressure; HbA1C = haemoglobin A1c; OSA = obstructive sleep apnoea. Several AF risk factors may contribute to the development of LA substrates and thus affect the outcome of AF catheter ablation, predisposing to a higher recurrence rate. Aggressive control of modifiable risk factors may reduce recurrence rate.
Figure 18

Risk factors for AF contributing to the development of an abnormal substrate translating into poorer outcomes with rhythm control strategies. AF = atrial fibrillation; BMI = body mass index; CPAP = continuous positive airway pressure; HbA1C = haemoglobin A1c; OSA = obstructive sleep apnoea. Several AF risk factors may contribute to the development of LA substrates and thus affect the outcome of AF catheter ablation, predisposing to a higher recurrence rate. Aggressive control of modifiable risk factors may reduce recurrence rate.

Follow-up after atrial fibrillation ablation

AF catheter ablation is a complex procedure that may be associated with a range of specific post-procedural complications (section 10.2.2.3.3)603,604,766–770. Although mostly rare, potentially catastrophic complications may initially present with non-specific symptoms and signs to which managing physicians should be attuned. Key issues in follow-up are shown in Table 17.

Table 17

Key issues in follow-up after AF catheter ablation

Key issues
Recognition and management of complications
  • Patients must be fully informed about the clinical signs and symptoms of rare but potentially dangerous ablation-related complications that may occur after hospital discharge (e.g. atrio-oesophageal fistula, pulmonary vein stenosis).

Follow-up monitoring:
  •  Useful to assess procedural success and correlate symptom status with rhythm.795,796 Recurrences beyond the first month post-ablation are generally predictive of late recurrences,797,798 but recurrent symptoms may be due to ectopic beats or other non-sustained arrhythmia640,799,800; conversely the presence of asymptomatic AF after ablation is well described.801–803

  •  Monitoring may be performed with intermittent ECG, Holter, Patch recordings, external or implanted loop recorder, or smart phone monitor (although the latter has not been validated for such use). Patients should be first reviewed at a minimum of 3 months and annually thereafter.1

Management of antiarrhythmic medication and treatment of AF recurrences
  •  a. Continuing AAD treatment for 6 weeks to 3 months may reduce early AF recurrences, rehospitalizations and cardioversions during this period.797,804 Clinical practice regarding routine AAD treatment after ablation varies and there is no convincing evidence that such treatment is routinely needed.

  •  b. Subsequently, AADs may be weaned, ceased, or continued according to symptoms and rhythm status. Recent findings suggest that in AAD-treated patients remaining free of AF at the end of the blanking period, AAD continuation beyond the blanking period reduces arrhythmia recurrences.805

Management of anticoagulation therapy
  •  a. In general, OAC therapy is continued for 2 months following ablation in all patients.1,806 Beyond this time, a decision to continue OAC is determined primarily by the presence of CHA2DS2-VASc stroke risk factors rather than the rhythm status (section 10.2.2.6).

Key issues
Recognition and management of complications
  • Patients must be fully informed about the clinical signs and symptoms of rare but potentially dangerous ablation-related complications that may occur after hospital discharge (e.g. atrio-oesophageal fistula, pulmonary vein stenosis).

Follow-up monitoring:
  •  Useful to assess procedural success and correlate symptom status with rhythm.795,796 Recurrences beyond the first month post-ablation are generally predictive of late recurrences,797,798 but recurrent symptoms may be due to ectopic beats or other non-sustained arrhythmia640,799,800; conversely the presence of asymptomatic AF after ablation is well described.801–803

  •  Monitoring may be performed with intermittent ECG, Holter, Patch recordings, external or implanted loop recorder, or smart phone monitor (although the latter has not been validated for such use). Patients should be first reviewed at a minimum of 3 months and annually thereafter.1

Management of antiarrhythmic medication and treatment of AF recurrences
  •  a. Continuing AAD treatment for 6 weeks to 3 months may reduce early AF recurrences, rehospitalizations and cardioversions during this period.797,804 Clinical practice regarding routine AAD treatment after ablation varies and there is no convincing evidence that such treatment is routinely needed.

  •  b. Subsequently, AADs may be weaned, ceased, or continued according to symptoms and rhythm status. Recent findings suggest that in AAD-treated patients remaining free of AF at the end of the blanking period, AAD continuation beyond the blanking period reduces arrhythmia recurrences.805

Management of anticoagulation therapy
  •  a. In general, OAC therapy is continued for 2 months following ablation in all patients.1,806 Beyond this time, a decision to continue OAC is determined primarily by the presence of CHA2DS2-VASc stroke risk factors rather than the rhythm status (section 10.2.2.6).

AAD = antiarrhythmic drug; AF = atrial fibrillation; CHA2DS2-VASc = Congestive heart failure, Hypertension, Age ≥75 years, Diabetes mellitus, Stroke, Vascular disease, Age 65 − 74 years, Sex category (female); ECG=electrocardiogram; OAC = oral anticoagulant.

Table 17

Key issues in follow-up after AF catheter ablation

Key issues
Recognition and management of complications
  • Patients must be fully informed about the clinical signs and symptoms of rare but potentially dangerous ablation-related complications that may occur after hospital discharge (e.g. atrio-oesophageal fistula, pulmonary vein stenosis).

Follow-up monitoring:
  •  Useful to assess procedural success and correlate symptom status with rhythm.795,796 Recurrences beyond the first month post-ablation are generally predictive of late recurrences,797,798 but recurrent symptoms may be due to ectopic beats or other non-sustained arrhythmia640,799,800; conversely the presence of asymptomatic AF after ablation is well described.801–803

  •  Monitoring may be performed with intermittent ECG, Holter, Patch recordings, external or implanted loop recorder, or smart phone monitor (although the latter has not been validated for such use). Patients should be first reviewed at a minimum of 3 months and annually thereafter.1

Management of antiarrhythmic medication and treatment of AF recurrences
  •  a. Continuing AAD treatment for 6 weeks to 3 months may reduce early AF recurrences, rehospitalizations and cardioversions during this period.797,804 Clinical practice regarding routine AAD treatment after ablation varies and there is no convincing evidence that such treatment is routinely needed.

  •  b. Subsequently, AADs may be weaned, ceased, or continued according to symptoms and rhythm status. Recent findings suggest that in AAD-treated patients remaining free of AF at the end of the blanking period, AAD continuation beyond the blanking period reduces arrhythmia recurrences.805

Management of anticoagulation therapy
  •  a. In general, OAC therapy is continued for 2 months following ablation in all patients.1,806 Beyond this time, a decision to continue OAC is determined primarily by the presence of CHA2DS2-VASc stroke risk factors rather than the rhythm status (section 10.2.2.6).

Key issues
Recognition and management of complications
  • Patients must be fully informed about the clinical signs and symptoms of rare but potentially dangerous ablation-related complications that may occur after hospital discharge (e.g. atrio-oesophageal fistula, pulmonary vein stenosis).

Follow-up monitoring:
  •  Useful to assess procedural success and correlate symptom status with rhythm.795,796 Recurrences beyond the first month post-ablation are generally predictive of late recurrences,797,798 but recurrent symptoms may be due to ectopic beats or other non-sustained arrhythmia640,799,800; conversely the presence of asymptomatic AF after ablation is well described.801–803

  •  Monitoring may be performed with intermittent ECG, Holter, Patch recordings, external or implanted loop recorder, or smart phone monitor (although the latter has not been validated for such use). Patients should be first reviewed at a minimum of 3 months and annually thereafter.1

Management of antiarrhythmic medication and treatment of AF recurrences
  •  a. Continuing AAD treatment for 6 weeks to 3 months may reduce early AF recurrences, rehospitalizations and cardioversions during this period.797,804 Clinical practice regarding routine AAD treatment after ablation varies and there is no convincing evidence that such treatment is routinely needed.

  •  b. Subsequently, AADs may be weaned, ceased, or continued according to symptoms and rhythm status. Recent findings suggest that in AAD-treated patients remaining free of AF at the end of the blanking period, AAD continuation beyond the blanking period reduces arrhythmia recurrences.805

Management of anticoagulation therapy
  •  a. In general, OAC therapy is continued for 2 months following ablation in all patients.1,806 Beyond this time, a decision to continue OAC is determined primarily by the presence of CHA2DS2-VASc stroke risk factors rather than the rhythm status (section 10.2.2.6).

AAD = antiarrhythmic drug; AF = atrial fibrillation; CHA2DS2-VASc = Congestive heart failure, Hypertension, Age ≥75 years, Diabetes mellitus, Stroke, Vascular disease, Age 65 − 74 years, Sex category (female); ECG=electrocardiogram; OAC = oral anticoagulant.

Risk assessment for recurrence of atrial fibrillation post catheter ablation

Recurrence of AF after catheter ablation is driven by the complex interaction of various factors. These include increasing AF duration, age, and LA size,619–624 and structural factors such as the abundance of epicardial fat tissue807–810 and the presence of atrial substrate as evident from electrical or morphological markers.811 A number of risk-prediction scores have been evaluated (for detailed description see Supplementary Table 11 and Supplementary Box 2). Whereas these scores only moderately predict AF recurrence, one of the strongest predictors is early recurrent AF, indicating the need for further refinement of these scoring systems.629

Recommendations for rhythm control/catheter ablation of AF

graphic
graphic

AAD = antiarrhythmic drug; AF = atrial fibrillation; AFL = atrial flutter; CTI = cavotricuspid isthmus; HF = heart failure; LV = left ventricular; LVEF = left ventricular ejection fraction; PVI = pulmonary vein isolation.

a

Class of recommendation.

b

Level of evidence.

Recommendations for rhythm control/catheter ablation of AF

graphic
graphic

AAD = antiarrhythmic drug; AF = atrial fibrillation; AFL = atrial flutter; CTI = cavotricuspid isthmus; HF = heart failure; LV = left ventricular; LVEF = left ventricular ejection fraction; PVI = pulmonary vein isolation.

a

Class of recommendation.

b

Level of evidence.

10.2.2.4 Surgery for atrial fibrillation

With development of the maze procedure for surgical cure from AF, Cox et al. opened up a new window of therapeutic opportunities for AF patients.822 The classical cut-and-sew maze procedure underwent several modifications and various device-based surgical ablation procedures have been developed.823,824 More than 200 publications documented the application of these techniques and technologies in various clinical scenarios.825 Most studies are retrospective and/or observational, but some RCTs and meta-analyses have also been published.771,826–828 While the effects of surgical ablation on rhythm outcome (i.e. restoration of sinus rhythm/freedom from AF) have been clearly demonstrated, the effects on endpoints such as QoL, hospitalization, stroke, and mortality are not well established.461,827,829,830 The only RCT with longer follow-up has shown a significant reduction in stroke risk at 5 years and a greater likelihood of maintaining sinus rhythm although the trial was underpowered for stroke risk assessment.828 The largest registry published, from the Polish National Health Service, describes better survival when ablation is performed concomitant to mitral or coronary surgery.831,832 Close cooperation between cardiac surgeons and electrophysiologists (heart team) for proper patient selection and postoperative management, especially for handling of arrhythmia recurrences, seems advisable for high-standard quality care.

Concomitant surgery for atrial fibrillation: indications, outcome, complications

Most trials of concomitant AF ablation have been based mainly on patients undergoing mitral valve repair or replacement. While surgical PVI has been shown to be effective for maintaining sinus rhythm,833 the most effective ablation treatment for AF isolates the pulmonary veins and the LA posterior wall, creates ablation lines that impede electrical impulses around the most important structures (mitral and tricuspid annuli, venae cavae and appendages), and excludes the LAA. Most evidence supports bipolar radiofrequency clamps and cryothermy to perform a maze.834 For non-paroxysmal AF, a biatrial lesion pattern is more effective than left-sided only, performed by sternotomy or minimally invasive techniques.826

In general, the same preoperative risk factors for AF recurrence after concomitant AF surgery as for AF catheter ablation have been identified. These include LA size, patient age, AF duration, HF/reduced LVEF, and renal dysfunction.379,636,835–841 The significant positive effects of concomitant surgical ablation on freedom from atrial arrhythmias is clearly documented. Most RCTs with 1-year follow-up show no effect on QoL, stroke, and mortality,842–845 but some reported reduced event rates.828,830,846

Surgical AF ablation concomitant to other cardiac surgery significantly increases the need for pacemaker implantation with biatrial (but not left-sided) lesions,827 being reported from 6.8% to 21.5%, while other complications are not increased.827–830,846,847

Stand-alone surgery for atrial fibrillation: indications, outcome, complications

Thoracoscopic radiofrequency ablation targets the pulmonary veins, LA posterior wall, and LAA closure in AF patients with no structural heart disease. Freedom from AF after the procedure is well documented, but only a few studies have reported improved QoL.844,845,848–850 A recent meta-analysis of three RCTs showed a significantly higher freedom from atrial tachyarrhythmia and less need for repeat ablations after thoracoscopic ablation compared with AF catheter ablation for paroxysmal or persistent AF.851 The FAST trial randomized patients who were prone to AF catheter-ablation failure (i.e. failed previous ablation or LA dilatation and hypertension) and reported common but substantially lower recurrence after thoracoscopic compared with AF catheter ablation (56% vs. 87%) at long-term follow-up (mean 7 years).849 Hospitalization was longer and complication rates of surgical ablation were higher compared with catheter ablation771 (Table 16). A systematic safety analysis of thoracoscopic ablation showed a 30-day complication rate of 11.3%, mainly self-limiting, whereas it was significantly lower (3.6%) in a multicentre registry.456 In RCTs, thoracoscopic ablation proved more effective in rhythm control than catheter ablation; however, surgical ablation is more invasive, with higher complication rates and longer hospitalization.461,852 Because of this risk−benefit ratio of surgical vs. catheter ablation, it seems reasonable to consider thoracoscopic surgery preferentially in patients with previous failed catheter ablation or with a high risk of catheter-ablation failure. There are no convincing data on the effects on stroke of surgical ablation as a stand-alone procedure or in combination with LAA occlusion or exclusion. Hence, OAC therapy should be continued after the procedure regardless of rhythm outcome in AF patients with stroke risk factors.

10.2.2.5 Hybrid surgical/catheter ablation procedures

Hybrid AF procedures combine a minimally invasive epicardial non-sternotomy ablation not using cardiopulmonary bypass with a percutaneous endocardial approach. They can be performed as a single intervention or sequentially, when the endocardial catheter mapping and, if needed, additional ablations are done within 6 months after the epicardial procedure.853 There are no studies comparing these two hybrid strategies.

A systematic review on rhythm outcome and complications with a hybrid procedure or AF catheter ablation in patients with persistent or long-standing persistent AF showed that at 12 months or longer, a hybrid procedure achieved a significantly higher rate of freedom from atrial arrhythmias with and without the use of AAD compared with AF catheter ablation. Although the overall complication rate was low for both strategies, hybrid ablations had more complications (13.8% vs. 5.9%).854 The difference in outcome could be explained by a long-lasting isolation of the pulmonary veins after bipolar radiofrequency clamping of the pulmonary veins, epicardial clipping of the LAA, and the add-on possibility of an endocardial touch-up.855,856

Recommendations for surgical ablation of AF

graphic
graphic

AAD = antiarrhythmic drug; AF = atrial fibrillation.

a

Class of recommendation.

b

Level of evidence.

Recommendations for surgical ablation of AF

graphic
graphic

AAD = antiarrhythmic drug; AF = atrial fibrillation.

a

Class of recommendation.

b

Level of evidence.

10.2.2.6 Peri-procedural stroke risk management in patients undergoing rhythm control interventions

10.2.2.6.1 Management of stroke risk and oral anticoagulant therapy in atrial fibrillation patients undergoing cardioversion. Patients undergoing cardioversion of AF are at increased risk of stroke and thrombo-embolism, especially in the absence of OAC and if AF has been present for ≥12 h.860–862 The exact duration of an AF episode before cardioversion may be difficult to ascertain, as many patients develop AF asymptomatically, seeking help only when symptoms or complications occur. If there is uncertainty over the exact onset of AF (i.e. unknown duration of AF), peri-cardioversion anticoagulation is managed as for AF of >12 h to 24 h. Mechanisms of the increased propensity to peri-cardioversion thrombo-embolism include the presence of pre-existing thrombus (especially if not anticoagulated), change in the atrial mechanical function with restoration of sinus rhythm, atrial stunning post-cardioversion, and a transient prothrombotic state.863

No RCT has evaluated anticoagulation vs. no anticoagulation in AF patients undergoing cardioversion with a definite duration of AF<48 h. Observational data suggest that the risk of stroke/thrombo-embolism is very low (0 − 0.2%) in patients with a definite AF duration of <12 h and a very low stroke risk (CHA2DS2-VASc 0 in men, 1 in women),860,864,865 in whom the benefit of 4-week anticoagulation after cardioversion is undefined and the prescription of anticoagulants can be optional, based on an individualized approach.

Peri-cardioversion anticoagulation with a VKA results in a significant decrease of stroke and thrombo-embolism,863 but achieving the necessary therapeutic anticoagulation (INR 2.0 − 3.0) for a minimum of 3 weeks before cardioversion may be difficult. This 3-week period is arbitrary, based on the time presumably needed for endothelialization or resolution of pre-existing AF thrombus. To shorten this time, TOE-guided cardioversion was introduced. If there is no atrial thrombus on TOE, cardioversion is performed after administration of heparin, and OAC is continued post-cardioversion.866,867

As NOACs act rapidly, cardioversion can be scheduled 3 weeks after NOAC initiation, provided that patients are counselled about the need for compliance to NOAC therapy868–870; NOACs have at least comparable efficacy and safety to warfarin in AF patients undergoing cardioversion.871–874 A review of the three largest prospective trials (n =5203 patients) showed that the composite primary outcome (stroke/systemic embolism, myocardial infarction, or cardiovascular death) was significantly reduced with NOACs compared with VKA.873

Long-term OAC therapy after cardioversion should not be based on successful restoration of sinus rhythm, but on the stroke risk profile (using the CHA2DS2-VASc score), balanced against bleeding risk (e.g. HAS-BLED score).

For patients in whom a thrombus is identified on TOE, effective anticoagulation for at least 3 weeks before reassessment for cardioversion is recommended. A repeat TOE to ensure thrombus resolution should be considered before cardioversion.875 Antithrombotic management for these patients is challenging and decided on an individual basis based on the efficacy (or inefficacy) of previous treatments.

Recommendations for stroke risk management peri-cardioversion

graphic
graphic

AF = atrial fibrillation; AFL = atrial flutter; CHA2DS2-VASc = Congestive heart failure, Hypertension, Age ≥75 years, Diabetes mellitus, Stroke, Vascular disease, Age 65 − 74 years, Sex category (female); NOAC = non-vitamin K antagonist oral anticoagulant; OAC = oral anticoagulant; TOE = transoesophageal echocardiography.

a

Class of recommendation.

b

Level of evidence.

Recommendations for stroke risk management peri-cardioversion

graphic
graphic

AF = atrial fibrillation; AFL = atrial flutter; CHA2DS2-VASc = Congestive heart failure, Hypertension, Age ≥75 years, Diabetes mellitus, Stroke, Vascular disease, Age 65 − 74 years, Sex category (female); NOAC = non-vitamin K antagonist oral anticoagulant; OAC = oral anticoagulant; TOE = transoesophageal echocardiography.

a

Class of recommendation.

b

Level of evidence.

Management of stroke risk and oral anticoagulant therapy in atrial fibrillation patients undergoing atrial fibrillation catheter ablation

Although there is some variability in the peri-procedural OAC management in patients undergoing AF ablation, more recently operators have moved towards a strategy of performing the ablation under uninterrupted VKA or NOAC treatment, provided the INR is within therapeutic range. In non-anticoagulated patients, initiating therapeutic anticoagulation 3 − 4 weeks before ablation may be considered.1

In a meta-analysis of 12 studies,877 uninterrupted anticoagulation using NOACs vs. VKAs for AF catheter ablation was associated with low rates of stroke/TIA (NOACs, 0.08%; VKA, 0.16%) and similar rates of silent cerebral embolic events (8.0% vs 9.6%). However, major bleeding was significantly reduced with uninterrupted NOACs (0.9%) compared with VKAs (2%).

In the largest RCT comparing peri-procedural NOAC vs. warfarin [the RE-CIRCUIT trial (Randomized Evaluation of dabigatran etexilate Compared to warfarIn in pulmonaRy vein ablation: assessment of different peri-proCedUral antIcoagulation sTrategies)],878 the incidence of major bleeding events during and up to 8 weeks after ablation was significantly lower with dabigatran vs. warfarin (1.6% vs. 6.9%). Other RCTs (VENTURE-AF with rivaroxaban,879 AXAFA-AF NET 5 with apixaban,880 and ELIMINATE-AF with edoxaban881) also showed similar event rates under uninterrupted NOACs vs. VKAs. Overall, uninterrupted peri-procedural NOACs were associated with a low incidence of stroke/TIA and a significant reduction in major bleeding compared with uninterrupted VKAs in patients undergoing AF catheter ablation. In contrast, heparin bridging increases the bleeding risk and should be avoided.

Frequently, the term ‘uninterrupted’ is used in clinical practice for the description of regimens where one or two NOAC doses are omitted before ablation, whereas in the RCTs comparing uninterrupted NOACs vs. warfarin, NOAC administration before ablation was truly uninterrupted.869,878 Hence, there is no reason to recommend omitting one or two NOAC doses before ablation. After the procedure, administration of the first dose the evening after ablation or the next morning (if this corresponds to the timing of the next dose according to the patient’s previous OAC regimen) appears to be safe.878,881.

Recommendations for stroke risk management peri-catheter ablation

graphic
graphic

AF = atrial fibrillation; LA = left atrial; NOAC = non-vitamin K antagonist oral anticoagulant; OAC = oral anticoagulant therapy; TOE=transoesophageal echocardiography.

a

Class of recommendation

b

Level of evidence

Recommendations for stroke risk management peri-catheter ablation

graphic
graphic

AF = atrial fibrillation; LA = left atrial; NOAC = non-vitamin K antagonist oral anticoagulant; OAC = oral anticoagulant therapy; TOE=transoesophageal echocardiography.

a

Class of recommendation

b

Level of evidence

Postoperative anticoagulation after surgery for atrial fibrillation

Owing to endothelial damage during ablation, OAC is advisable in all patients after AF surgery, starting as soon as possible (balancing the risk of postoperative bleeding). There are no RCT data regarding interruption of OAC over the long term. Non-randomized studies with longer follow-up have shown better long-term freedom from stroke in patients with persistent sinus rhythm, but not in those with AF despite LAA exclusion.824 Therefore, long-term OAC is recommended in all patients at risk of stroke despite a successful maze surgery and appendage closure.

Recommendations for postoperative anticoagulation after AF surgery

graphic
graphic

AF = atrial fibrillation; CHA2DS2-VASc = Congestive heart failure, Hypertension, Age ≥75 years, Diabetes mellitus, Stroke, Vascular disease, Age 65 − 74 years, Sex category (female); OAC = oral anticoagulant.

a

Class of recommendation.

b

Level of evidence.

Recommendations for postoperative anticoagulation after AF surgery

graphic
graphic

AF = atrial fibrillation; CHA2DS2-VASc = Congestive heart failure, Hypertension, Age ≥75 years, Diabetes mellitus, Stroke, Vascular disease, Age 65 − 74 years, Sex category (female); OAC = oral anticoagulant.

a

Class of recommendation.

b

Level of evidence.

10.2.2.7 Long-term antiarrhythmic drug therapy for rhythm control
Antiarrhythmic drugs

The aim of AAD therapy is to improve AF-related symptoms.484,882,883 Hence, the decision to initiate long-term AAD therapy needs to balance symptom burden, possible adverse drug reactions, and patient preferences. The principles of AAD therapy are shown in Tables 18 and19.

Table 18

Principles of antiarrhythmic drug therapy143

Principles
AAD therapy aims to reduce AF-related symptoms
Efficacy of AADs to maintain sinus rhythm is modest
Clinically successful AAD therapy may reduce rather than eliminate AF recurrences
If one AAD ‘fails’, a clinically acceptable response may be achieved by another drug
Drug-induced proarrhythmia or extracardiac side-effects are frequent
Safety rather than efficacy considerations should primarily guide the choice of AAD
Principles
AAD therapy aims to reduce AF-related symptoms
Efficacy of AADs to maintain sinus rhythm is modest
Clinically successful AAD therapy may reduce rather than eliminate AF recurrences
If one AAD ‘fails’, a clinically acceptable response may be achieved by another drug
Drug-induced proarrhythmia or extracardiac side-effects are frequent
Safety rather than efficacy considerations should primarily guide the choice of AAD

AAD = antiarrhythmic drug; AF = atrial fibrillation.

Table 18

Principles of antiarrhythmic drug therapy143

Principles
AAD therapy aims to reduce AF-related symptoms
Efficacy of AADs to maintain sinus rhythm is modest
Clinically successful AAD therapy may reduce rather than eliminate AF recurrences
If one AAD ‘fails’, a clinically acceptable response may be achieved by another drug
Drug-induced proarrhythmia or extracardiac side-effects are frequent
Safety rather than efficacy considerations should primarily guide the choice of AAD
Principles
AAD therapy aims to reduce AF-related symptoms
Efficacy of AADs to maintain sinus rhythm is modest
Clinically successful AAD therapy may reduce rather than eliminate AF recurrences
If one AAD ‘fails’, a clinically acceptable response may be achieved by another drug
Drug-induced proarrhythmia or extracardiac side-effects are frequent
Safety rather than efficacy considerations should primarily guide the choice of AAD

AAD = antiarrhythmic drug; AF = atrial fibrillation.

Table 19

Rules to initiate antiarrhythmic drugs for long-term rhythm control in AF

ConsiderationCriteria
Indication for AAD
  • Is the patient symptomatic?

  • Are AF symptoms severe enough (EHRA class) to justify AAD use?

  • Are there associated conditions predicting poor tolerance of AF episodes?

When to start AAD
  • Usually not for the first episode, but it may enhance efficacy of cardioversion

How to choose among AADs
  • Minimize proarrhythmic risk and organ toxicity

Evaluate for:
  • basal ECG abnormalities (QRS duration, PR, QTc) and possible interference with AAD

  • impact on LV function

  • important pharmacokinetic and pharmacodynamic interactions (i.e. antithrombotic drugs)

  • Risk factors for proarrhythmia may be dynamic and change over time

How to minimize proarrhythmic risk
  • Evaluate ECG after the treatment, as indicated in these Guidelines

  • Evaluate periodically for organ toxicity (amiodarone)

  • Long-term Holter monitoring and exercise test in selected cases

  • Avoid AAD combinations

How to verify efficacy
  • Estimate AF burden under therapy (ask patient for noting episodes)

  • If the patient is already on AAD and it was effective but was stopped because of intolerance, choose preferably from the same class

Adjuvant interventions and hybrid therapy
  • In patients with atrioventricular conduction abnormalities and/or sinus node dysfunction, pacemaker implantation should be considered if AAD therapy is deemed necessary

  • Short-term AAD therapy could prevent early recurrences after AF ablation

ConsiderationCriteria
Indication for AAD
  • Is the patient symptomatic?

  • Are AF symptoms severe enough (EHRA class) to justify AAD use?

  • Are there associated conditions predicting poor tolerance of AF episodes?

When to start AAD
  • Usually not for the first episode, but it may enhance efficacy of cardioversion

How to choose among AADs
  • Minimize proarrhythmic risk and organ toxicity

Evaluate for:
  • basal ECG abnormalities (QRS duration, PR, QTc) and possible interference with AAD

  • impact on LV function

  • important pharmacokinetic and pharmacodynamic interactions (i.e. antithrombotic drugs)

  • Risk factors for proarrhythmia may be dynamic and change over time

How to minimize proarrhythmic risk
  • Evaluate ECG after the treatment, as indicated in these Guidelines

  • Evaluate periodically for organ toxicity (amiodarone)

  • Long-term Holter monitoring and exercise test in selected cases

  • Avoid AAD combinations

How to verify efficacy
  • Estimate AF burden under therapy (ask patient for noting episodes)

  • If the patient is already on AAD and it was effective but was stopped because of intolerance, choose preferably from the same class

Adjuvant interventions and hybrid therapy
  • In patients with atrioventricular conduction abnormalities and/or sinus node dysfunction, pacemaker implantation should be considered if AAD therapy is deemed necessary

  • Short-term AAD therapy could prevent early recurrences after AF ablation

AAD = antiarrhythmic drug; AF = atrial fibrillation; ECG = electrocardiogram; EHRA = European Heart Rhythm Association; LV = left ventricular; PR = PR interval; QRS = QRS interval; QTc = corrected QT interval.

Table 19

Rules to initiate antiarrhythmic drugs for long-term rhythm control in AF

ConsiderationCriteria
Indication for AAD
  • Is the patient symptomatic?

  • Are AF symptoms severe enough (EHRA class) to justify AAD use?

  • Are there associated conditions predicting poor tolerance of AF episodes?

When to start AAD
  • Usually not for the first episode, but it may enhance efficacy of cardioversion

How to choose among AADs
  • Minimize proarrhythmic risk and organ toxicity

Evaluate for:
  • basal ECG abnormalities (QRS duration, PR, QTc) and possible interference with AAD

  • impact on LV function

  • important pharmacokinetic and pharmacodynamic interactions (i.e. antithrombotic drugs)

  • Risk factors for proarrhythmia may be dynamic and change over time

How to minimize proarrhythmic risk
  • Evaluate ECG after the treatment, as indicated in these Guidelines

  • Evaluate periodically for organ toxicity (amiodarone)

  • Long-term Holter monitoring and exercise test in selected cases

  • Avoid AAD combinations

How to verify efficacy
  • Estimate AF burden under therapy (ask patient for noting episodes)

  • If the patient is already on AAD and it was effective but was stopped because of intolerance, choose preferably from the same class

Adjuvant interventions and hybrid therapy
  • In patients with atrioventricular conduction abnormalities and/or sinus node dysfunction, pacemaker implantation should be considered if AAD therapy is deemed necessary

  • Short-term AAD therapy could prevent early recurrences after AF ablation

ConsiderationCriteria
Indication for AAD
  • Is the patient symptomatic?

  • Are AF symptoms severe enough (EHRA class) to justify AAD use?

  • Are there associated conditions predicting poor tolerance of AF episodes?

When to start AAD
  • Usually not for the first episode, but it may enhance efficacy of cardioversion

How to choose among AADs
  • Minimize proarrhythmic risk and organ toxicity

Evaluate for:
  • basal ECG abnormalities (QRS duration, PR, QTc) and possible interference with AAD

  • impact on LV function

  • important pharmacokinetic and pharmacodynamic interactions (i.e. antithrombotic drugs)

  • Risk factors for proarrhythmia may be dynamic and change over time

How to minimize proarrhythmic risk
  • Evaluate ECG after the treatment, as indicated in these Guidelines

  • Evaluate periodically for organ toxicity (amiodarone)

  • Long-term Holter monitoring and exercise test in selected cases

  • Avoid AAD combinations

How to verify efficacy
  • Estimate AF burden under therapy (ask patient for noting episodes)

  • If the patient is already on AAD and it was effective but was stopped because of intolerance, choose preferably from the same class

Adjuvant interventions and hybrid therapy
  • In patients with atrioventricular conduction abnormalities and/or sinus node dysfunction, pacemaker implantation should be considered if AAD therapy is deemed necessary

  • Short-term AAD therapy could prevent early recurrences after AF ablation

AAD = antiarrhythmic drug; AF = atrial fibrillation; ECG = electrocardiogram; EHRA = European Heart Rhythm Association; LV = left ventricular; PR = PR interval; QRS = QRS interval; QTc = corrected QT interval.

Compared with no therapy, AAD therapy approximately doubles sinus rhythm maintenance,883 but it is difficult to draw firm conclusions from existing trials on their comparative efficacy.884 In general, AAD therapy is less effective than AF catheter ablation,114,611,615 but previously ineffective AADs can be continued after PVI, to reduce recurrent AF.805 A shorter duration of AAD therapy would likely reduce the risk of side-effects883,885 but late recurrences may occur.595 Short-term AAD therapy is also used to prevent early AF recurrences after catheter ablation,886 although the benefit is still debated797,887; this strategy may be reasonable in patients deemed at increased risk of AAD side-effects or in those with a low perceived risk of recurrent AF. Concomitant management of underlying cardiovascular conditions is pivotal to reduce AF symptom burden and facilitate the maintenance of sinus rhythm.245,636,888,889

Available antiarrhythmic drugs

Several AADs have been shown to reduce AF recurrences (Table 20).890 Class Ia (quinidine and disopyramide) and sotalol have been associated with increased overall mortality.884 Again, safety should dictate both the initiation and continuation of AADs.

Table 20

Antiarrhythmic drugs used for long-term maintenance of sinus rhythm in AF patients890

DrugAdministration routeDoseContraindications/precautions/comments
Amiodarone233,506,891–896Oral

3 × 200 mg daily over

4 weeks, then 200 mg daily506

  • The most effective AAD890,897

  • RCTs showed lower AF recurrence compared with sotalol and dronedarone884

  • Also reduces ventricular rate (for 10 − 12 bpm), safe in patients with HF898–900

  • Concomitant use with other QT-prolonging drugs with caution

  • Concomitant use with VKAs or digitalis (their dose should be reduced)

  • Increased risk of myopathy when used with statins

  • Requires regular surveillance for liver, lung, and thyroid toxicity

  • Has atrioventricular nodal-slowing properties, but should not be used as first intention for rate control

  • QT prolongation is common but rarely associated with torsades de pointes (<0.5%)901

  • Torsades de pointes occurs infrequently during treatment with amiodarone (the proarrhythmia caution requires QT-interval and TU-wave monitoring)902

  • Should be discontinued in case of excessive QT prolongation (>500 ms)

  • ECG at baseline, after 4 weeks

  • Contraindicated in manifest hyperthyroidism

  • Numerous and frequent extracardiac side-effects may warrant discontinuation of amiodarone, thus making it a second-line treatment when other choices are possible903–907

Flecainide

Flecainide slow release896,908,909

Oral100 − 200 mg b.i.d., or 200 mg once daily (flecainide slow release)
  • Effective in preventing recurrence of AF891,908,910

  • Should not be used in patients with CrCl <35 mL/min/1.73 m2 and significant liver disease

  • Both are contraindicated in patients with ischaemic heart disease or reduced LVEF911–913

  • Should be discontinued in case of QRS widening >25% above baseline and patients with left bundle-branch block or any other conduction block >120 ms

  • Caution when sinoatrial/atrioventricular conduction disturbances presenta

  • CYP2D6 inhibitors increase concentration

  • May increase AFL cycle length, thus promoting 1:1 atrioventricular conduction and increasing ventricular rate.914 This risk can be reduced by concomitant administration of an atrioventricular nodal-blocking drug such as a beta-blocker or NDCC

  • In patients properly screened for propensity to proarrhythmias, both flecainide and propafenone are associated with a low proarrhythmic risk915

  • ECG at baseline, after 1 − 2 weeks

Propafenone

Propafenone slow release895,896,916–922

Oral150 − 300 mg three times daily, or 225 − 425 mg b.i.d. (propafenone slow release)
  • Should not be used in patients with significant renal or liver disease, ischaemic heart disease, reduced LV systolic function, or asthma

  • Should be discontinued in case of QRS widening >25% above baseline and in patients left bundle-branch block and any other conduction block >120 ms

  • Caution when sinoatrial/atrioventricular conduction disturbances presenta

  • Increases concentration of warfarin/acenocoumarin and digoxin when used in combination

  • May increase AFL cycle length, thus promoting 1:1 atrioventricular conduction and increasing ventricular rate

  • ECG at baseline and after 1 − 2 weeks

Dronedarone923–927Oral400 mg b.i.d.
  • Less effective than amiodarone in rhythm control but has very few extracardiac side-effects925,928–930

  • Reduces cardiovascular hospitalizations and death in patients with paroxysmal or persistent AF or AFL and cardiovascular comorbidity923,931

  • Associated with increased mortality in patients with recent decompensated HF927 or permanent AF932

  • Dronedarone has the most solid safety data and may thus be a preferable first choice,933,934 however not indicated in patients with HF and permanent AF935,936

  • Should not be used in NYHA class III or IV or unstable HF, in combination with QT-prolonging drugs or with strong CYP3A4 inhibitors (e.g. verapamil, diltiazem) and in patients with CrCl <30 mL/min

  • Concomitant use with dabigatran is contraindicated

  • Combination with digoxin may significantly increase digoxin serum concentration

  • When used with digitalis or beta-blockers their doses should be reduced

  • Should be discontinued in case of excessive QT prolongation (>500 ms or >60 ms increase)

  • A modest increase in serum creatinine is common and reflects drug-induced reduction in CrCl rather than a decline in renal function937

  • Has atrioventricular nodal-slowing properties

  • ECG at baseline and after 4 weeks

Sotalol (d,l racemic mixture)233,891,894,895,920,938–940Oral80 − 160 mg b.i.d.
  • Only class III effects if dosing >160 mg daily

  • Considering its safety and efficacy and potential drug alternatives, sotalol should be used with a caution

  • Should not be used in patients with HFrEF, significant LVH, prolonged QT, asthma, hypokalaemia, or CrCl <30 mL/min

  • Dose-related torsades de pointes may occur in >2% of patients941

  • Should be discontinued in case of excessive QT prolongation (>500 ms or >60 ms increase)

  • The potassium channel-blocking effect increases with increasing dose and, consequently, the risk of ventricular proarrhythmia (torsades de pointes) increases

  • Observational data and a recent meta-analysis revealed a correlation with an increased all-cause mortality890,897,934 , whereas a nationwide registry analysis and two RCTs found no evidence for increased safety concerns with sotalol233,933,942,943

  • ECG at baseline, after 1 day and after 1 − 2 weeks

Disopyramide944–946Oral100 − 400 mg two or t.i.d. (maximum 800 mg/24 h)
  • Associated with significantly increased mortality890,947, and rarely used for rhythm control in AF.948,949 Should not be used in patients with a structural heart disease. Rarely used for rhythm control in AF patients, due to increased mortality and frequent intolerance to side-effects

  • May be useful in ‘vagal’ AF occurring in athletes or during sleep901

  • Reduces LV outflow obstruction and symptoms in patients with HCM950

DrugAdministration routeDoseContraindications/precautions/comments
Amiodarone233,506,891–896Oral

3 × 200 mg daily over

4 weeks, then 200 mg daily506

  • The most effective AAD890,897

  • RCTs showed lower AF recurrence compared with sotalol and dronedarone884

  • Also reduces ventricular rate (for 10 − 12 bpm), safe in patients with HF898–900

  • Concomitant use with other QT-prolonging drugs with caution

  • Concomitant use with VKAs or digitalis (their dose should be reduced)

  • Increased risk of myopathy when used with statins

  • Requires regular surveillance for liver, lung, and thyroid toxicity

  • Has atrioventricular nodal-slowing properties, but should not be used as first intention for rate control

  • QT prolongation is common but rarely associated with torsades de pointes (<0.5%)901

  • Torsades de pointes occurs infrequently during treatment with amiodarone (the proarrhythmia caution requires QT-interval and TU-wave monitoring)902

  • Should be discontinued in case of excessive QT prolongation (>500 ms)

  • ECG at baseline, after 4 weeks

  • Contraindicated in manifest hyperthyroidism

  • Numerous and frequent extracardiac side-effects may warrant discontinuation of amiodarone, thus making it a second-line treatment when other choices are possible903–907

Flecainide

Flecainide slow release896,908,909

Oral100 − 200 mg b.i.d., or 200 mg once daily (flecainide slow release)
  • Effective in preventing recurrence of AF891,908,910

  • Should not be used in patients with CrCl <35 mL/min/1.73 m2 and significant liver disease

  • Both are contraindicated in patients with ischaemic heart disease or reduced LVEF911–913

  • Should be discontinued in case of QRS widening >25% above baseline and patients with left bundle-branch block or any other conduction block >120 ms

  • Caution when sinoatrial/atrioventricular conduction disturbances presenta

  • CYP2D6 inhibitors increase concentration

  • May increase AFL cycle length, thus promoting 1:1 atrioventricular conduction and increasing ventricular rate.914 This risk can be reduced by concomitant administration of an atrioventricular nodal-blocking drug such as a beta-blocker or NDCC

  • In patients properly screened for propensity to proarrhythmias, both flecainide and propafenone are associated with a low proarrhythmic risk915

  • ECG at baseline, after 1 − 2 weeks

Propafenone

Propafenone slow release895,896,916–922

Oral150 − 300 mg three times daily, or 225 − 425 mg b.i.d. (propafenone slow release)
  • Should not be used in patients with significant renal or liver disease, ischaemic heart disease, reduced LV systolic function, or asthma

  • Should be discontinued in case of QRS widening >25% above baseline and in patients left bundle-branch block and any other conduction block >120 ms

  • Caution when sinoatrial/atrioventricular conduction disturbances presenta

  • Increases concentration of warfarin/acenocoumarin and digoxin when used in combination

  • May increase AFL cycle length, thus promoting 1:1 atrioventricular conduction and increasing ventricular rate

  • ECG at baseline and after 1 − 2 weeks

Dronedarone923–927Oral400 mg b.i.d.
  • Less effective than amiodarone in rhythm control but has very few extracardiac side-effects925,928–930

  • Reduces cardiovascular hospitalizations and death in patients with paroxysmal or persistent AF or AFL and cardiovascular comorbidity923,931

  • Associated with increased mortality in patients with recent decompensated HF927 or permanent AF932

  • Dronedarone has the most solid safety data and may thus be a preferable first choice,933,934 however not indicated in patients with HF and permanent AF935,936

  • Should not be used in NYHA class III or IV or unstable HF, in combination with QT-prolonging drugs or with strong CYP3A4 inhibitors (e.g. verapamil, diltiazem) and in patients with CrCl <30 mL/min

  • Concomitant use with dabigatran is contraindicated

  • Combination with digoxin may significantly increase digoxin serum concentration

  • When used with digitalis or beta-blockers their doses should be reduced

  • Should be discontinued in case of excessive QT prolongation (>500 ms or >60 ms increase)

  • A modest increase in serum creatinine is common and reflects drug-induced reduction in CrCl rather than a decline in renal function937

  • Has atrioventricular nodal-slowing properties

  • ECG at baseline and after 4 weeks

Sotalol (d,l racemic mixture)233,891,894,895,920,938–940Oral80 − 160 mg b.i.d.
  • Only class III effects if dosing >160 mg daily

  • Considering its safety and efficacy and potential drug alternatives, sotalol should be used with a caution

  • Should not be used in patients with HFrEF, significant LVH, prolonged QT, asthma, hypokalaemia, or CrCl <30 mL/min

  • Dose-related torsades de pointes may occur in >2% of patients941

  • Should be discontinued in case of excessive QT prolongation (>500 ms or >60 ms increase)

  • The potassium channel-blocking effect increases with increasing dose and, consequently, the risk of ventricular proarrhythmia (torsades de pointes) increases

  • Observational data and a recent meta-analysis revealed a correlation with an increased all-cause mortality890,897,934 , whereas a nationwide registry analysis and two RCTs found no evidence for increased safety concerns with sotalol233,933,942,943

  • ECG at baseline, after 1 day and after 1 − 2 weeks

Disopyramide944–946Oral100 − 400 mg two or t.i.d. (maximum 800 mg/24 h)
  • Associated with significantly increased mortality890,947, and rarely used for rhythm control in AF.948,949 Should not be used in patients with a structural heart disease. Rarely used for rhythm control in AF patients, due to increased mortality and frequent intolerance to side-effects

  • May be useful in ‘vagal’ AF occurring in athletes or during sleep901

  • Reduces LV outflow obstruction and symptoms in patients with HCM950

AAD = antiarrhythmic drug; AF = atrial fibrillation; AFL = atrial flutter; b.i.d. = bis in die (twice a day); bpm = beats per minute; CrCl = creatinine clearance; CYP2D6 = cytochrome P450 2D6; CYP34A = cytochrome 34A; ECG=electrocardiogram; HCM = hypertrophic cardiomyopathy; HF = heart failure; HFrEF = HF with reduced ejection fraction; LV = left ventricular; LVEF = LV ejection fraction; LVH = LV hypertrophy; NDCC = non-dihydropyridinecalcium-channel blocker; NYHA = New York Heart Association; QRS = QRS interval; QT = QT interval; RCT=randomized controlled trial; SBP = systolic blood pressure; t.i.d. = ter in die (three times a day); VKA = vitamin K antagonist.

a

Caution is needed when using any AAD in patients with conduction-system disease (e.g. sinoatrial or atrioventricular node disease).

Table 20

Antiarrhythmic drugs used for long-term maintenance of sinus rhythm in AF patients890

DrugAdministration routeDoseContraindications/precautions/comments
Amiodarone233,506,891–896Oral

3 × 200 mg daily over

4 weeks, then 200 mg daily506

  • The most effective AAD890,897

  • RCTs showed lower AF recurrence compared with sotalol and dronedarone884

  • Also reduces ventricular rate (for 10 − 12 bpm), safe in patients with HF898–900

  • Concomitant use with other QT-prolonging drugs with caution

  • Concomitant use with VKAs or digitalis (their dose should be reduced)

  • Increased risk of myopathy when used with statins

  • Requires regular surveillance for liver, lung, and thyroid toxicity

  • Has atrioventricular nodal-slowing properties, but should not be used as first intention for rate control

  • QT prolongation is common but rarely associated with torsades de pointes (<0.5%)901

  • Torsades de pointes occurs infrequently during treatment with amiodarone (the proarrhythmia caution requires QT-interval and TU-wave monitoring)902

  • Should be discontinued in case of excessive QT prolongation (>500 ms)

  • ECG at baseline, after 4 weeks

  • Contraindicated in manifest hyperthyroidism

  • Numerous and frequent extracardiac side-effects may warrant discontinuation of amiodarone, thus making it a second-line treatment when other choices are possible903–907

Flecainide

Flecainide slow release896,908,909

Oral100 − 200 mg b.i.d., or 200 mg once daily (flecainide slow release)
  • Effective in preventing recurrence of AF891,908,910

  • Should not be used in patients with CrCl <35 mL/min/1.73 m2 and significant liver disease

  • Both are contraindicated in patients with ischaemic heart disease or reduced LVEF911–913

  • Should be discontinued in case of QRS widening >25% above baseline and patients with left bundle-branch block or any other conduction block >120 ms

  • Caution when sinoatrial/atrioventricular conduction disturbances presenta

  • CYP2D6 inhibitors increase concentration

  • May increase AFL cycle length, thus promoting 1:1 atrioventricular conduction and increasing ventricular rate.914 This risk can be reduced by concomitant administration of an atrioventricular nodal-blocking drug such as a beta-blocker or NDCC

  • In patients properly screened for propensity to proarrhythmias, both flecainide and propafenone are associated with a low proarrhythmic risk915

  • ECG at baseline, after 1 − 2 weeks

Propafenone

Propafenone slow release895,896,916–922

Oral150 − 300 mg three times daily, or 225 − 425 mg b.i.d. (propafenone slow release)
  • Should not be used in patients with significant renal or liver disease, ischaemic heart disease, reduced LV systolic function, or asthma

  • Should be discontinued in case of QRS widening >25% above baseline and in patients left bundle-branch block and any other conduction block >120 ms

  • Caution when sinoatrial/atrioventricular conduction disturbances presenta

  • Increases concentration of warfarin/acenocoumarin and digoxin when used in combination

  • May increase AFL cycle length, thus promoting 1:1 atrioventricular conduction and increasing ventricular rate

  • ECG at baseline and after 1 − 2 weeks

Dronedarone923–927Oral400 mg b.i.d.
  • Less effective than amiodarone in rhythm control but has very few extracardiac side-effects925,928–930

  • Reduces cardiovascular hospitalizations and death in patients with paroxysmal or persistent AF or AFL and cardiovascular comorbidity923,931

  • Associated with increased mortality in patients with recent decompensated HF927 or permanent AF932

  • Dronedarone has the most solid safety data and may thus be a preferable first choice,933,934 however not indicated in patients with HF and permanent AF935,936

  • Should not be used in NYHA class III or IV or unstable HF, in combination with QT-prolonging drugs or with strong CYP3A4 inhibitors (e.g. verapamil, diltiazem) and in patients with CrCl <30 mL/min

  • Concomitant use with dabigatran is contraindicated

  • Combination with digoxin may significantly increase digoxin serum concentration

  • When used with digitalis or beta-blockers their doses should be reduced

  • Should be discontinued in case of excessive QT prolongation (>500 ms or >60 ms increase)

  • A modest increase in serum creatinine is common and reflects drug-induced reduction in CrCl rather than a decline in renal function937

  • Has atrioventricular nodal-slowing properties

  • ECG at baseline and after 4 weeks

Sotalol (d,l racemic mixture)233,891,894,895,920,938–940Oral80 − 160 mg b.i.d.
  • Only class III effects if dosing >160 mg daily

  • Considering its safety and efficacy and potential drug alternatives, sotalol should be used with a caution

  • Should not be used in patients with HFrEF, significant LVH, prolonged QT, asthma, hypokalaemia, or CrCl <30 mL/min

  • Dose-related torsades de pointes may occur in >2% of patients941

  • Should be discontinued in case of excessive QT prolongation (>500 ms or >60 ms increase)

  • The potassium channel-blocking effect increases with increasing dose and, consequently, the risk of ventricular proarrhythmia (torsades de pointes) increases

  • Observational data and a recent meta-analysis revealed a correlation with an increased all-cause mortality890,897,934 , whereas a nationwide registry analysis and two RCTs found no evidence for increased safety concerns with sotalol233,933,942,943

  • ECG at baseline, after 1 day and after 1 − 2 weeks

Disopyramide944–946Oral100 − 400 mg two or t.i.d. (maximum 800 mg/24 h)
  • Associated with significantly increased mortality890,947, and rarely used for rhythm control in AF.948,949 Should not be used in patients with a structural heart disease. Rarely used for rhythm control in AF patients, due to increased mortality and frequent intolerance to side-effects

  • May be useful in ‘vagal’ AF occurring in athletes or during sleep901

  • Reduces LV outflow obstruction and symptoms in patients with HCM950

DrugAdministration routeDoseContraindications/precautions/comments
Amiodarone233,506,891–896Oral

3 × 200 mg daily over

4 weeks, then 200 mg daily506

  • The most effective AAD890,897

  • RCTs showed lower AF recurrence compared with sotalol and dronedarone884

  • Also reduces ventricular rate (for 10 − 12 bpm), safe in patients with HF898–900

  • Concomitant use with other QT-prolonging drugs with caution

  • Concomitant use with VKAs or digitalis (their dose should be reduced)

  • Increased risk of myopathy when used with statins

  • Requires regular surveillance for liver, lung, and thyroid toxicity

  • Has atrioventricular nodal-slowing properties, but should not be used as first intention for rate control

  • QT prolongation is common but rarely associated with torsades de pointes (<0.5%)901

  • Torsades de pointes occurs infrequently during treatment with amiodarone (the proarrhythmia caution requires QT-interval and TU-wave monitoring)902

  • Should be discontinued in case of excessive QT prolongation (>500 ms)

  • ECG at baseline, after 4 weeks

  • Contraindicated in manifest hyperthyroidism

  • Numerous and frequent extracardiac side-effects may warrant discontinuation of amiodarone, thus making it a second-line treatment when other choices are possible903–907

Flecainide

Flecainide slow release896,908,909

Oral100 − 200 mg b.i.d., or 200 mg once daily (flecainide slow release)
  • Effective in preventing recurrence of AF891,908,910

  • Should not be used in patients with CrCl <35 mL/min/1.73 m2 and significant liver disease

  • Both are contraindicated in patients with ischaemic heart disease or reduced LVEF911–913

  • Should be discontinued in case of QRS widening >25% above baseline and patients with left bundle-branch block or any other conduction block >120 ms

  • Caution when sinoatrial/atrioventricular conduction disturbances presenta

  • CYP2D6 inhibitors increase concentration

  • May increase AFL cycle length, thus promoting 1:1 atrioventricular conduction and increasing ventricular rate.914 This risk can be reduced by concomitant administration of an atrioventricular nodal-blocking drug such as a beta-blocker or NDCC

  • In patients properly screened for propensity to proarrhythmias, both flecainide and propafenone are associated with a low proarrhythmic risk915

  • ECG at baseline, after 1 − 2 weeks

Propafenone

Propafenone slow release895,896,916–922

Oral150 − 300 mg three times daily, or 225 − 425 mg b.i.d. (propafenone slow release)
  • Should not be used in patients with significant renal or liver disease, ischaemic heart disease, reduced LV systolic function, or asthma

  • Should be discontinued in case of QRS widening >25% above baseline and in patients left bundle-branch block and any other conduction block >120 ms

  • Caution when sinoatrial/atrioventricular conduction disturbances presenta

  • Increases concentration of warfarin/acenocoumarin and digoxin when used in combination

  • May increase AFL cycle length, thus promoting 1:1 atrioventricular conduction and increasing ventricular rate

  • ECG at baseline and after 1 − 2 weeks

Dronedarone923–927Oral400 mg b.i.d.
  • Less effective than amiodarone in rhythm control but has very few extracardiac side-effects925,928–930

  • Reduces cardiovascular hospitalizations and death in patients with paroxysmal or persistent AF or AFL and cardiovascular comorbidity923,931

  • Associated with increased mortality in patients with recent decompensated HF927 or permanent AF932

  • Dronedarone has the most solid safety data and may thus be a preferable first choice,933,934 however not indicated in patients with HF and permanent AF935,936

  • Should not be used in NYHA class III or IV or unstable HF, in combination with QT-prolonging drugs or with strong CYP3A4 inhibitors (e.g. verapamil, diltiazem) and in patients with CrCl <30 mL/min

  • Concomitant use with dabigatran is contraindicated

  • Combination with digoxin may significantly increase digoxin serum concentration

  • When used with digitalis or beta-blockers their doses should be reduced

  • Should be discontinued in case of excessive QT prolongation (>500 ms or >60 ms increase)

  • A modest increase in serum creatinine is common and reflects drug-induced reduction in CrCl rather than a decline in renal function937

  • Has atrioventricular nodal-slowing properties

  • ECG at baseline and after 4 weeks

Sotalol (d,l racemic mixture)233,891,894,895,920,938–940Oral80 − 160 mg b.i.d.
  • Only class III effects if dosing >160 mg daily

  • Considering its safety and efficacy and potential drug alternatives, sotalol should be used with a caution

  • Should not be used in patients with HFrEF, significant LVH, prolonged QT, asthma, hypokalaemia, or CrCl <30 mL/min

  • Dose-related torsades de pointes may occur in >2% of patients941

  • Should be discontinued in case of excessive QT prolongation (>500 ms or >60 ms increase)

  • The potassium channel-blocking effect increases with increasing dose and, consequently, the risk of ventricular proarrhythmia (torsades de pointes) increases

  • Observational data and a recent meta-analysis revealed a correlation with an increased all-cause mortality890,897,934 , whereas a nationwide registry analysis and two RCTs found no evidence for increased safety concerns with sotalol233,933,942,943

  • ECG at baseline, after 1 day and after 1 − 2 weeks

Disopyramide944–946Oral100 − 400 mg two or t.i.d. (maximum 800 mg/24 h)
  • Associated with significantly increased mortality890,947, and rarely used for rhythm control in AF.948,949 Should not be used in patients with a structural heart disease. Rarely used for rhythm control in AF patients, due to increased mortality and frequent intolerance to side-effects

  • May be useful in ‘vagal’ AF occurring in athletes or during sleep901

  • Reduces LV outflow obstruction and symptoms in patients with HCM950

AAD = antiarrhythmic drug; AF = atrial fibrillation; AFL = atrial flutter; b.i.d. = bis in die (twice a day); bpm = beats per minute; CrCl = creatinine clearance; CYP2D6 = cytochrome P450 2D6; CYP34A = cytochrome 34A; ECG=electrocardiogram; HCM = hypertrophic cardiomyopathy; HF = heart failure; HFrEF = HF with reduced ejection fraction; LV = left ventricular; LVEF = LV ejection fraction; LVH = LV hypertrophy; NDCC = non-dihydropyridinecalcium-channel blocker; NYHA = New York Heart Association; QRS = QRS interval; QT = QT interval; RCT=randomized controlled trial; SBP = systolic blood pressure; t.i.d. = ter in die (three times a day); VKA = vitamin K antagonist.

a

Caution is needed when using any AAD in patients with conduction-system disease (e.g. sinoatrial or atrioventricular node disease).

A flow chart for use of AADs for long-term rhythm control, depending on the underlying disease, is given in Figure 19.

Long-term rhythm control therapy. ACEi = angiotensin converting enzyme inhibitor; AF = atrial fibrillation; ARB = angiotensin receptor blocker; CAD=coronary artery disease; HFpEF = heart failure with preserved ejection fraction; HFrEF = heart failure with reduced ejection fraction; LV = left ventricular; LVH = left ventricular hypertrophy; MRA=mineralocorticoid receptor antagonist.
Figure 19

Long-term rhythm control therapy. ACEi = angiotensin converting enzyme inhibitor; AF = atrial fibrillation; ARB = angiotensin receptor blocker; CAD=coronary artery disease; HFpEF = heart failure with preserved ejection fraction; HFrEF = heart failure with reduced ejection fraction; LV = left ventricular; LVH = left ventricular hypertrophy; MRA=mineralocorticoid receptor antagonist.

Post-procedural management of patients with AF and ACS/PCI (full-outlined arrows represent a default strategy; graded/dashed arrows show treatment modifications depending on individual patient’s ischaemic and bleeding risks). Pretreatment with a P2Y12 inhibitor is recommended in STEMI patients or when coronary anatomy is known; it should be withheld in non-STEMI ACS until the time of coronary angiography in case of an early invasive strategy within 24 hours. Observational studies indicate that PCI on uninterrupted VKAs is generally safe compared with OAC interruption and heparin-bridging therapy,1073 particularly with radial artery access; in contrast, studies on NOACs are conflicting, predominantly discouraging a PCI on fully uninterrupted NOAC therapy.1074,1075 If urgent PCI is needed, administration of a parenteral anticoagulant (UFH, LMWH, or bivalirudin) is suggested, with temporary withdrawal of NOAC at least for the initial post-procedural period (e.g. 24 h) depending on the patient’s thrombotic and bleeding risk profile. Where thrombolysis is being considered in a patient with STEMI, the initial step should be to assess the anticoagulation status (e.g. INR in a patient taking VKA; with a NOAC, assessing, for example, activated partial thromboplastin time on dabigatran or anti-factor Xa activity on factor Xa inhibitors). Thrombolytic therapy may be associated with an increased risk of bleeding in systemically anticoagulated patients, especially if parenteral heparin and antiplatelet drugs are coadministered. A balance between the potential benefit (e.g. large anterior myocardial infarction) and harm (e.g. ICH) is needed, as well as the reassessment of urgent transfer to a PCI centre. If the supposedly anticoagulated patient does not have evidence of a therapeutic anticoagulation effect (e.g. INR <2.0 on warfarin; or no NOAC anticoagulant effect detected), systemic thrombolysis may be considered if no access to primary PCI is possible. ACS = acute coronary syndromes; ASA = acetylsalicylic acid; CAD = coronary artery disease; CCS = chronic coronary syndromes; CKD = chronic kidney disease; DAPT = dual antithrombotic therapy; eGFR = estimated glomerular filtration rate; ICH = intracranial haemorrhage; INR = international normalized ratio; LMWH = low-molecular-weight heparin; MI = myocardial infarction; NOAC = non-vitamin K antagonist oral anticoagulant; NSAID = non-steroidal anti-inflammatory drug; OAC = oral anticoagulant; PAD = peripheral artery disease; PCI = percutaneous coronary intervention; PPI = proton-pump inhibitor; STEMI = ST-segment elevation myocardial infarction; UFH = unfractionated heparin; VKA = vitamin K antagonist.
Figure 20

Post-procedural management of patients with AF and ACS/PCI (full-outlined arrows represent a default strategy; graded/dashed arrows show treatment modifications depending on individual patient’s ischaemic and bleeding risks). Pretreatment with a P2Y12 inhibitor is recommended in STEMI patients or when coronary anatomy is known; it should be withheld in non-STEMI ACS until the time of coronary angiography in case of an early invasive strategy within 24 hours. Observational studies indicate that PCI on uninterrupted VKAs is generally safe compared with OAC interruption and heparin-bridging therapy,1073 particularly with radial artery access; in contrast, studies on NOACs are conflicting, predominantly discouraging a PCI on fully uninterrupted NOAC therapy.1074,1075 If urgent PCI is needed, administration of a parenteral anticoagulant (UFH, LMWH, or bivalirudin) is suggested, with temporary withdrawal of NOAC at least for the initial post-procedural period (e.g. 24 h) depending on the patient’s thrombotic and bleeding risk profile. Where thrombolysis is being considered in a patient with STEMI, the initial step should be to assess the anticoagulation status (e.g. INR in a patient taking VKA; with a NOAC, assessing, for example, activated partial thromboplastin time on dabigatran or anti-factor Xa activity on factor Xa inhibitors). Thrombolytic therapy may be associated with an increased risk of bleeding in systemically anticoagulated patients, especially if parenteral heparin and antiplatelet drugs are coadministered. A balance between the potential benefit (e.g. large anterior myocardial infarction) and harm (e.g. ICH) is needed, as well as the reassessment of urgent transfer to a PCI centre. If the supposedly anticoagulated patient does not have evidence of a therapeutic anticoagulation effect (e.g. INR <2.0 on warfarin; or no NOAC anticoagulant effect detected), systemic thrombolysis may be considered if no access to primary PCI is possible. ACS = acute coronary syndromes; ASA = acetylsalicylic acid; CAD = coronary artery disease; CCS = chronic coronary syndromes; CKD = chronic kidney disease; DAPT = dual antithrombotic therapy; eGFR = estimated glomerular filtration rate; ICH = intracranial haemorrhage; INR = international normalized ratio; LMWH = low-molecular-weight heparin; MI = myocardial infarction; NOAC = non-vitamin K antagonist oral anticoagulant; NSAID = non-steroidal anti-inflammatory drug; OAC = oral anticoagulant; PAD = peripheral artery disease; PCI = percutaneous coronary intervention; PPI = proton-pump inhibitor; STEMI = ST-segment elevation myocardial infarction; UFH = unfractionated heparin; VKA = vitamin K antagonist.

Non-antiarrhythmic drugs with antiarrhythmic properties (upstream therapy)

Either resulting from, or being a marker of structural atrial remodelling, AF is closely related to atrial cardiomyopathy. Drugs that affect the atrial-remodelling process could prevent new-onset AF acting as non-conventional AADs (i.e. upstream therapy) (Table 21).

Table 21

Non-antiarrhythmic drugs with antiarrhythmic properties (upstream therapy)

DrugsComment
ACEi, ARBsActivated renin-angiotensin-aldosterone system is up-regulated in AF.951,952 ACEi and ARBs showed encouraging results in preventing AF in preclinical studies.953
As suggested by retrospective analyses and studies where AF was a prespecified secondary endpoint, ACEi/ARBs could prevent new-onset AF in patients with LV dysfunction, LVH, or hypertension.954–961
As initial treatment, ACEi and ARBs seem to be superior to other antihypertensive regimens,962 but ARBs did not reduce AF burden in patients without structural heart disease.963 Despite several positive small-scale prospective studies and retrospective analyses, larger RCTs have shown controversial results and failed to confirm the role of ACEi or ARBs in secondary (post-cardioversion) prevention of AF.964 The multifactorial pathways for AF promotion and study design could explain these negative results and should not discourage the use of ACEi or ARB to AAD in patients with structural heart disease.
MRAsAldosterone is implicated in inducibility and perpetuation of AF.965–967 Evidence from RCTs showed that MRAs reduced new-onset atrial arrhythmias in patients with HFrEF in parallel with improvement of other cardiovascular outcomes.968,969
Recently, the positive impact of MRAs was also shown in patients with HFpEF970 irrespective of baseline AF status. Regarding other renin-angiotensin-aldosterone system inhibitors, the role of MRAs as upstream therapy in rhythm control strategy for patients with HF and AF has not been clarified. As AF is a marker of HF severity, the beneficial antiarrhythmic effect could be driven indirectly, through improvement of HF. A recent meta-analysis showed that MRAs significantly reduced new-onset AF and recurrent AF, but not postoperative AF.971
Beta-blockersSeveral small studies suggested a lower AF recurrence rate with beta-blockers, with a comparable efficacy with sotalol.939,972,973 However, most evidence pleads against a significant role of beta-blockers in preventing AF.890 The observed beneficial effect could also result from transformation of clinically manifested AF to silent AF, because of the rate control with beta-blockers.
StatinsStatins are attractive candidates for upstream therapy, as the role of inflammation in AF is well established. However, in an adequately designed RCT,974 statins failed to show a beneficial effect, and their preventive effect was not confirmed in other settings.975,976 Specific patient groups in whom statins could induce reverse remodelling are not identified yet, but findings from the CARAF registry suggested that AF patients already on beta-blockers could benefit from statin therapy.977 Polyunsaturated fatty acids also failed to show convincing benefit in preventing AF.978–982
DrugsComment
ACEi, ARBsActivated renin-angiotensin-aldosterone system is up-regulated in AF.951,952 ACEi and ARBs showed encouraging results in preventing AF in preclinical studies.953
As suggested by retrospective analyses and studies where AF was a prespecified secondary endpoint, ACEi/ARBs could prevent new-onset AF in patients with LV dysfunction, LVH, or hypertension.954–961
As initial treatment, ACEi and ARBs seem to be superior to other antihypertensive regimens,962 but ARBs did not reduce AF burden in patients without structural heart disease.963 Despite several positive small-scale prospective studies and retrospective analyses, larger RCTs have shown controversial results and failed to confirm the role of ACEi or ARBs in secondary (post-cardioversion) prevention of AF.964 The multifactorial pathways for AF promotion and study design could explain these negative results and should not discourage the use of ACEi or ARB to AAD in patients with structural heart disease.
MRAsAldosterone is implicated in inducibility and perpetuation of AF.965–967 Evidence from RCTs showed that MRAs reduced new-onset atrial arrhythmias in patients with HFrEF in parallel with improvement of other cardiovascular outcomes.968,969
Recently, the positive impact of MRAs was also shown in patients with HFpEF970 irrespective of baseline AF status. Regarding other renin-angiotensin-aldosterone system inhibitors, the role of MRAs as upstream therapy in rhythm control strategy for patients with HF and AF has not been clarified. As AF is a marker of HF severity, the beneficial antiarrhythmic effect could be driven indirectly, through improvement of HF. A recent meta-analysis showed that MRAs significantly reduced new-onset AF and recurrent AF, but not postoperative AF.971
Beta-blockersSeveral small studies suggested a lower AF recurrence rate with beta-blockers, with a comparable efficacy with sotalol.939,972,973 However, most evidence pleads against a significant role of beta-blockers in preventing AF.890 The observed beneficial effect could also result from transformation of clinically manifested AF to silent AF, because of the rate control with beta-blockers.
StatinsStatins are attractive candidates for upstream therapy, as the role of inflammation in AF is well established. However, in an adequately designed RCT,974 statins failed to show a beneficial effect, and their preventive effect was not confirmed in other settings.975,976 Specific patient groups in whom statins could induce reverse remodelling are not identified yet, but findings from the CARAF registry suggested that AF patients already on beta-blockers could benefit from statin therapy.977 Polyunsaturated fatty acids also failed to show convincing benefit in preventing AF.978–982

AAD = antiarrhythmic drug; ACEi = angiotensin converting enzyme inhibitor; AF = atrial fibrillation; ARB=angiotensin receptor blocker; CARAF = Canadian Registry of Atrial Fibrillation; HF = heart failure; HFrEF = HF with reduced ejection fraction; HFpEF = HF with preserved ejection fraction; LV = left ventricular; LVH = LV hypertrophy; MRA = mineralocorticoid receptor antagonist; RCT = randomized controlled trial.

Table 21

Non-antiarrhythmic drugs with antiarrhythmic properties (upstream therapy)

DrugsComment
ACEi, ARBsActivated renin-angiotensin-aldosterone system is up-regulated in AF.951,952 ACEi and ARBs showed encouraging results in preventing AF in preclinical studies.953
As suggested by retrospective analyses and studies where AF was a prespecified secondary endpoint, ACEi/ARBs could prevent new-onset AF in patients with LV dysfunction, LVH, or hypertension.954–961
As initial treatment, ACEi and ARBs seem to be superior to other antihypertensive regimens,962 but ARBs did not reduce AF burden in patients without structural heart disease.963 Despite several positive small-scale prospective studies and retrospective analyses, larger RCTs have shown controversial results and failed to confirm the role of ACEi or ARBs in secondary (post-cardioversion) prevention of AF.964 The multifactorial pathways for AF promotion and study design could explain these negative results and should not discourage the use of ACEi or ARB to AAD in patients with structural heart disease.
MRAsAldosterone is implicated in inducibility and perpetuation of AF.965–967 Evidence from RCTs showed that MRAs reduced new-onset atrial arrhythmias in patients with HFrEF in parallel with improvement of other cardiovascular outcomes.968,969
Recently, the positive impact of MRAs was also shown in patients with HFpEF970 irrespective of baseline AF status. Regarding other renin-angiotensin-aldosterone system inhibitors, the role of MRAs as upstream therapy in rhythm control strategy for patients with HF and AF has not been clarified. As AF is a marker of HF severity, the beneficial antiarrhythmic effect could be driven indirectly, through improvement of HF. A recent meta-analysis showed that MRAs significantly reduced new-onset AF and recurrent AF, but not postoperative AF.971
Beta-blockersSeveral small studies suggested a lower AF recurrence rate with beta-blockers, with a comparable efficacy with sotalol.939,972,973 However, most evidence pleads against a significant role of beta-blockers in preventing AF.890 The observed beneficial effect could also result from transformation of clinically manifested AF to silent AF, because of the rate control with beta-blockers.
StatinsStatins are attractive candidates for upstream therapy, as the role of inflammation in AF is well established. However, in an adequately designed RCT,974 statins failed to show a beneficial effect, and their preventive effect was not confirmed in other settings.975,976 Specific patient groups in whom statins could induce reverse remodelling are not identified yet, but findings from the CARAF registry suggested that AF patients already on beta-blockers could benefit from statin therapy.977 Polyunsaturated fatty acids also failed to show convincing benefit in preventing AF.978–982
DrugsComment
ACEi, ARBsActivated renin-angiotensin-aldosterone system is up-regulated in AF.951,952 ACEi and ARBs showed encouraging results in preventing AF in preclinical studies.953
As suggested by retrospective analyses and studies where AF was a prespecified secondary endpoint, ACEi/ARBs could prevent new-onset AF in patients with LV dysfunction, LVH, or hypertension.954–961
As initial treatment, ACEi and ARBs seem to be superior to other antihypertensive regimens,962 but ARBs did not reduce AF burden in patients without structural heart disease.963 Despite several positive small-scale prospective studies and retrospective analyses, larger RCTs have shown controversial results and failed to confirm the role of ACEi or ARBs in secondary (post-cardioversion) prevention of AF.964 The multifactorial pathways for AF promotion and study design could explain these negative results and should not discourage the use of ACEi or ARB to AAD in patients with structural heart disease.
MRAsAldosterone is implicated in inducibility and perpetuation of AF.965–967 Evidence from RCTs showed that MRAs reduced new-onset atrial arrhythmias in patients with HFrEF in parallel with improvement of other cardiovascular outcomes.968,969
Recently, the positive impact of MRAs was also shown in patients with HFpEF970 irrespective of baseline AF status. Regarding other renin-angiotensin-aldosterone system inhibitors, the role of MRAs as upstream therapy in rhythm control strategy for patients with HF and AF has not been clarified. As AF is a marker of HF severity, the beneficial antiarrhythmic effect could be driven indirectly, through improvement of HF. A recent meta-analysis showed that MRAs significantly reduced new-onset AF and recurrent AF, but not postoperative AF.971
Beta-blockersSeveral small studies suggested a lower AF recurrence rate with beta-blockers, with a comparable efficacy with sotalol.939,972,973 However, most evidence pleads against a significant role of beta-blockers in preventing AF.890 The observed beneficial effect could also result from transformation of clinically manifested AF to silent AF, because of the rate control with beta-blockers.
StatinsStatins are attractive candidates for upstream therapy, as the role of inflammation in AF is well established. However, in an adequately designed RCT,974 statins failed to show a beneficial effect, and their preventive effect was not confirmed in other settings.975,976 Specific patient groups in whom statins could induce reverse remodelling are not identified yet, but findings from the CARAF registry suggested that AF patients already on beta-blockers could benefit from statin therapy.977 Polyunsaturated fatty acids also failed to show convincing benefit in preventing AF.978–982

AAD = antiarrhythmic drug; ACEi = angiotensin converting enzyme inhibitor; AF = atrial fibrillation; ARB=angiotensin receptor blocker; CARAF = Canadian Registry of Atrial Fibrillation; HF = heart failure; HFrEF = HF with reduced ejection fraction; HFpEF = HF with preserved ejection fraction; LV = left ventricular; LVH = LV hypertrophy; MRA = mineralocorticoid receptor antagonist; RCT = randomized controlled trial.

Recently, the RACE 3 study245 confirmed the importance of assessing underlying conditions and targeted upstream therapy for intense risk-factor control in AF patients with mild or moderate HF in optimizing rhythm control. The results showed that targeted therapy of underlying conditions improves maintenance of sinus rhythm in patients with persistent AF.

A list of new investigational antiarrhythmic drugs is provided in Supplementary Box 3.

Recommendations for long-term antiarrhythmic drugs

graphic
graphic

AAD = antiarrhythmic drug; AF = atrial fibrillation; CrCl = Creatinine clearance; HFpEF = heart failure with preserved ejection fraction; HFrEF = heart failure with reduced ejection fraction; LV = left ventricular; LVH = LV hypertrophy; VHD = valvular heart disease.

a

Class of recommendation.

b

Level of evidence.

Recommendations for long-term antiarrhythmic drugs

graphic
graphic

AAD = antiarrhythmic drug; AF = atrial fibrillation; CrCl = Creatinine clearance; HFpEF = heart failure with preserved ejection fraction; HFrEF = heart failure with reduced ejection fraction; LV = left ventricular; LVH = LV hypertrophy; VHD = valvular heart disease.

a

Class of recommendation.

b

Level of evidence.

Assessment and long-term monitoring of the risk of proarrhythmia with antiarrhythmic drugs

A variety of clinical, echocardiographic, and ECG criteria have been associated with a higher risk of proarrhythmia.986–989 Increasing age, female sex, impaired renal and/or liver function, and known CAD have been variously identified as associated with higher risk.890,990–992 Concomitant AAD use, hypokalaemia, or family history of sudden death have also been implicated.990 Proarrhythmic events tend to cluster shortly after drug initiation, especially if a loading dose or a change in usual dosage is prescribed.568 For quinidine, the risk is idiosyncratic independent of dosage. Impaired LV function and LVH are echocardiographic markers of increased proarrhythmic risk. Sotalol has a proarrhythmic risk even in the absence of structural heart disease. On the 12-lead ECG, prolonged corrected QT interval (QTc), widened QRS, and prolonged PR interval have all been associated with proarrhythmia.993–995 Significant ion-channel mutations have been detected in only a minority of cases of drug-induced torsade.996 Periodic ECG analysis for proarrhythmia signs has been used successfully in recent AAD trials594,.997 Specifically, ECG monitoring was used systematically on days 1–3 in patients receiving flecainide, propafenone, or sotalol to identify those at risk of proarrhythmia233,594,.998 The role of routine use of exercise stress testing in patients commencing 1C drugs who had no evidence of structural heart disease is still debatable915,.999

10.3 ‘C’ – Cardiovascular risk factors and concomitant diseases: detection and management

Cardiovascular risk-factor burden and comorbidities, including lifestyle factors and borderline conditions, significantly affect the lifetime risk for AF development (Supplementary Figure 5). The continuum of unhealthy lifestyle, risk factor(s), and cardiovascular disease can contribute to atrial remodelling/cardiomyopathy and development of AF that commonly results from a combined effect of multiple interacting factors (often without specific threshold values).

The ‘C’ component of the ABC pathway includes identification and management of concomitant diseases, cardiometabolic risk factors, and unhealthy lifestyle factors. Management of risk factors and cardiovascular disease complements stroke prevention and reduces AF burden and symptom severity. In a recent RCT, for example, targeted therapy of underlying conditions significantly improved maintenance of sinus rhythm in patients with persistent AF and HF.245

Whereas strategies on comprehensive risk-factor modification and interventions targeting underlying conditions have shown reduction of AF burden and recurrence, studies addressing isolated management of specific conditions alone (e.g. hypertension) yielded inconsistent findings,1000 likely because the condition was not a sole contributor to AF.

10.3.1 Lifestyle interventions

10.3.1.1 Obesity and weight loss

Obesity increases the risk for AF progressively according to body mass index.366,1001–1005 It may also increase the risk for ischaemic stroke, thrombo-embolism, and death in AF patients,366 notwithstanding an obesity paradox in AF patients, especially regarding all-cause and cardiovascular death, with an inverse relationship between overweight/obesity and better cardiovascular prognosis in long-term follow-up.1006

Intense weight reduction with comprehensive management of concomitant cardiovascular risk factors resulted in fewer AF recurrences and symptoms than general advice in obese patients with AF636,888,.889 Achieving a healthy weight may reduce blood pressure (BP), dyslipidaemia, and risk of developing type 2 diabetes mellitus, thus improving the cardiovascular risk profile.1007 Obesity may increase AF recurrence rates after AF catheter ablation (with OSA as a potential confounder).638,643,789,1008 It has also been linked to a higher radiation dose and complication rate during AF ablation,1009,1010 whereas symptom improvement after AF catheter ablation seems comparable in obese and normal-weight patients.1008 Given the potential to reduce AF episodes by weight reduction, AF catheter ablation should be offered to obese patients in conjunction with lifestyle modifications for weight reduction (Figure 18).

10.3.1.2 Alcohol and caffeine use

Alcohol excess is a risk factor for incident AF1011–1014 and bleeding395 in anticoagulated patients (mediated by poor adherence, liver disease, variceal bleeding, and risk of major trauma), and high alcohol intake may be associated with thrombo-embolism or death.1015 In a recent RCT, alcohol abstinence reduced arrhythmia recurrence in regular drinkers with AF.1016

By contrast, it is unlikely that caffeine consumption causes or contributes to AF.47 Habitual caffeine consumption might be associated with lower risk of AF, but caffeine intake may increase symptoms of palpitations unrelated to AF.

10.3.1.3 Physical activity

Many studies have demonstrated beneficial effects of moderate exercise/physical activity on cardiovascular health.1017–1019 Nevertheless, the incidence of AF appears to be increased among elite athletes, and multiple small studies reported a relationship between AF and vigorous physical activity, mainly related to long-term or endurance sport participation.1020–1023 A non-linear relationship between physical activity and AF seems likely. Based on these data, patients should be encouraged to undertake moderate-intensity exercise and remain physically active to prevent AF incidence or recurrence, but maybe avoid chronic excessive endurance exercise (such as marathons and long-distance triathlons, etc.), especially if aged >50 years. Owing to few randomized patients and outcomes, the effect of exercise-based cardiac rehabilitation on mortality or serious adverse events is uncertain.1024

10.3.2 Specific cardiovascular risk factors/comorbidities

10.3.2.1 Hypertension

Hypertension is the most common aetiological factor associated with the development of AF, and patients with hypertension have a 1.7-fold higher risk of developing AF compared with normotensives.26,1025

Hypertension also adds to the complications of AF, particularly stroke, HF, and bleeding risk. AF patients with a longer hypertension duration or uncontrolled systolic BP (SBP) levels should be categorized as ‘high-risk’, and strict BP control in addition to OAC is important to reduce the risk of ischaemic stroke and ICH.

Given the importance of hypertension as a precipitating factor for AF, which should be regarded as a manifestation of hypertension target-organ damage, treatment of hypertension consistent with current BP guidelines1026 is mandatory in AF patients, aiming to achieve BP≤130/80 mmHg to reduce adverse outcomes.338,1027,1028 A recent randomized trial in patients with paroxysmal AF and hypertension reported fewer recurrences in patients undergoing renal denervation in addition to PVI compared with patients undergoing PVI only.1029 Sotalol should not be used in the presence of hypertensive LVH or renal impairment, owing to the risk of proarrhythmia. There is some evidence of angiotensin converting enzyme or angiotensin receptor blocker use to improve outcomes in AF or reduce progression of the arrhythmia26,.1025 Other lifestyle changes, including obesity management, alcohol reduction, and attention to OSA, may also help in patients with AF and hypertension.

10.3.2.2 Heart failure

The interactions between AF and HF and the optimal management of patients with both AF and HF are discussed in section 11.6.

10.3.2.3 Coronary artery disease

The interactions between AF and CAD and the optimal management of patients with both AF and CAD are discussed in section 11.3.

10.3.2.4 Diabetes mellitus

In addition to shared risk factors (e.g. hypertension and obesity),1004,1030 diabetes is an independent risk factor for AF, especially in young patients.1031 Silent AF episodes are favoured by concurrent autonomic dysfunction,1032 thus suggesting an opportunity for routine screening for AF in diabetes mellitus patients. The prevalence of AF is at least two-fold higher in patients with diabetes compared with people without diabetes,1033 and AF incidence rises with increasing severity of microvascular complications (retinopathy, renal disease).1034 Both type 1 and type 2 diabetes mellitus are the risk factors for stroke.342,1035

Intensive glycaemic control does not affect the rate of new-onset AF,1036 but metformin and pioglitazone could be associated with lower long-term risk of AF in patients with diabetes,1037 while this was not confirmed for rosiglitazone.1038 Currently there is no evidence that glucagon-like peptide-1 agonists, sodium glucose co-transporter-2 inhibitors, and dipeptidyl peptidase-4 inhibitors affect the development of AF.1039

Previous meta-analyses showed no significant interaction between diabetes mellitus and NOAC effects in AF patients,423,1040 but vascular mortality was lower in patients with diabetes treated with NOACs than in those on warfarin.1040 Bleeding risk reduction with NOACs was similar in diabetic and non-diabetic patients except for apixaban, where a lower reduction in haemorrhagic complications was reported in the AF patients with diabetes compared with AF patients without diabetes.1041 Regarding potential side-effects of OAC, there is no evidence that bleeding risk is increased in patients with diabetes and retinopathy.341

Optimal glycaemic control in 12 months before AF catheter ablation was associated with significant reduction in recurrent AF after ablation.1042

10.3.2.5 Sleep apnoea

The most common form of sleep-disordered breathing, OSA, is highly prevalent in patients with AF, HF, and hypertension, and is associated with increased risk of mortality or major cardiovascular events.1043 In a prospective analysis, approximately 50% of AF patients had OSA compared with 32% of controls.1044 The mechanisms facilitating AF include intermittent nocturnal hypoxemia/hypercapnia, intrathoracic pressure shifts, sympathovagal imbalance, oxidative stress, inflammation, and neurohumoral activation.1045 OSA has been shown to reduce success rates of AADs, electrical cardioversion, and catheter ablation in AF.1045

Continuous positive airway pressure (CPAP) is the therapy of choice for OSA, and may ameliorate OSA effects on AF recurrences.1046,1047 Observational studies and meta-analyses showed that appropriate CPAP treatment of OSA may improve rhythm control in AF patients.648,649,1047–1051

It seems reasonable to test for OSA before the initiation of rhythm control therapy in symptomatic AF patients, with the aim to reduce symptomatic AF recurrences (Figure 18). In the ARREST-AF (Aggressive Risk Factor Reduction Study – Implication for AF) and LEGACY (Long-term Effect of Goal-directed weight management on an Atrial fibrillation Cohort: a 5-Year follow-up study) studies, an aggressive risk-factor reduction programme focusing on weight management, hyperlipidaemia, OSA, hypertension, diabetes, smoking cessation, and alcohol-intake reduction significantly reduced AF burden after PVI.636,1052 However, it remains unclear how and when to test for OSA and implement OSA management in the standard work-up of AF patients.

Recommendations for lifestyle interventions and management of risk factors and concomitant diseases in patients with AF

graphic
graphic

AF = atrial fibrillation; BP = blood pressure; OAC = oral anticoagulant; OSA = obstructive sleep apnoea.

a

Class of recommendation.

b

Level of evidence.

Recommendations for lifestyle interventions and management of risk factors and concomitant diseases in patients with AF

graphic
graphic

AF = atrial fibrillation; BP = blood pressure; OAC = oral anticoagulant; OSA = obstructive sleep apnoea.

a

Class of recommendation.

b

Level of evidence.

11 The ABC pathway in specific clinical settings/conditions/patient populations

In this section, the management of AF in patient populations with specific conditions is described. The principles of the ABC pathway apply in these settings as well. Additionally, specific considerations are given for each of these special conditions and populations.

11.1 Atrial fibrillation with haemodynamic instability

Acute haemodynamic instability (i.e. syncope, acute pulmonary oedema, ongoing myocardial ischaemia, symptomatic hypotension, or cardiogenic shock) in AF patients presenting with a rapid ventricular rate requires prompt intervention. In severely compromised patients, emergency electrical cardioversion should be attempted without delay, and anticoagulation should be started as soon as possible.

In critically ill patients and those with severely impaired LV systolic function, AF is often precipitated/exacerbated by increased sympathetic tone, inotropes, and vasopressors, and rhythm control is often unsuccessful. It is important to identify and correct precipitating factors and secondary causes and optimize background treatment. Owing to their rate-controlling effect during exertion and increased sympathetic tone, rather than only at rest, beta-blockers are preferred over digitalis glycosides for ventricular rate control in AF.490 Beta-blockers and NDCC antagonists may exert a negative inotropic effect (the latter are contraindicated in HFrEF). Digoxin is often unsuccessful due to the increased sympathetic tone in these patients.

As conventional therapy is often ineffective or not well-tolerated,490 electrical cardioversion should always be considered, even as initial therapy, whereas intravenous amiodarone may be instituted for rate control (or potential cardioversion to sinus rhythm), with or without electrical cardioversion.504,514,515 Intravenous administration of amiodarone may lead to a further decrease in BP.

Recommendations for management of AF with haemodynamic instability

graphic
graphic

AF = atrial fibrillation.

a

Class of recommendation.

b

Level of evidence.

Recommendations for management of AF with haemodynamic instability

graphic
graphic

AF = atrial fibrillation.

a

Class of recommendation.

b

Level of evidence.

11.2 First-diagnosed (new-onset) atrial fibrillation

First-diagnosed or new-onset AF is a working diagnosis in a patient without a history of AF, until the pattern of AF can be defined more precisely. Although the clinical profile and outcome of patients with first-diagnosed AF in AF registries were less favourable than those with paroxysmal AF, rather resembling permanent AF,1055,1056 OAC prescription rates were the lowest in patients with first-diagnosed AF.1057 In patients with first-diagnosed AF, the ABC pathway should resemble all steps outlined in the Central Illustration.

11.3 Acute coronary syndromes, percutaneous coronary intervention, and chronic coronary syndromes in patients with atrial fibrillation

The incidence of AF in acute coronary syndromes (ACS) ranges from 2 − 23%,1058 the risk of new-onset AF is increased by 60 − 77%1059 in myocardial infarction patients, and AF per se may be associated with an increased risk of ST-segment elevation myocardial infarction (STEMI) or non−STEMI ACS.381,1060–1063 Overall, 10 − 15% of AF patients undergo PCI for CAD.1064 In observational studies, patients with AF and ACS were less likely to receive appropriate antithrombotic therapy1065 and more likely to experience adverse outcomes1066 than ACS patients without AF.

Peri-procedural management of patients with an ACS or undergoing PCI is detailed in the respective ESC Guidelines on myocardial revascularization1067 and chronic coronary syndromes (CCS).1068

Post-procedural management of atrial fibrillation patients with acute coronary syndrome and/or percutaneous coronary intervention

In AF patients having an ACS or undergoing PCI, concomitant risks of ischaemic stroke/systemic embolism, coronary ischaemic events, and antithrombotic treatment-related bleeding need to be carefully balanced when considering the use and duration of combined antithrombotic therapy.1069 Overall, dual antithrombotic therapy including OAC (preferably NOAC) and a P2Y12 inhibitor (preferably clopidogrel) is associated with significantly less major bleeding (and ICH) than triple therapy. However, available evidence suggests that at least a short course of triple therapy (e.g. ≤1 week) would be desirable in some AF patients after a recent ACS or undergoing PCI, especially in those at increased risk of ischaemic events1070,1071 (Figure 20).

Box 1 About post-procedural management of patients with AF and ACS and/or PCI

Shorter courses of triple therapy (OAC + DAPT) may be safe in post-ACS/PCI patients requiring OAC.1076 Observational data1077 and the WOEST trial with warfarin (a safety RCT, underpowered for ischaemic outcomes)1078 suggested better safety and similar efficacy with dual (OAC + clopidogrel) vs. triple therapy.

RCTs of NOACs in AF patients after a recent ACS/PCI

Four RCTs compared dual therapy with a P2Y12 inhibitor (mostly clopidogrel) plus a NOAC—dabigatran 110 mg or 150 mg b.i.d. (RE-DUAL PCI),1079 rivaroxaban 15 mg o.d. (PIONEER AF-PCI),1080 apixaban 5 mg b.i.d. (AUGUSTUS),1081 or edoxaban 60 mg o.d. (ENTRUST-AF PCI)1082 —vs. triple therapy with a VKA in AF patients with a recent ACS or undergoing PCI. The two-by-two factorial AUGUSTUS trial design enabled the comparison of aspirin vs. placebo (see Supplementary Table 12 for detailed information about these studies). All four trials had a primary safety endpoint (i.e. bleeding) and were underpowered to assess ischaemic outcomes.

Despite some heterogeneity among these trials, all have consistently:

  • Included a proportion of patients with an ACS/PCI (37 − 52%); nevertheless, the highest risk patients (e.g. previous stent thrombosis or a complex PCI with stent-in-stent placement) were largely under-represented;

  • Used triple therapy during PCI and until randomization (1 − 14 days post PCI);

  • Most commonly used the P2Y12 inhibitor clopidogrel (overall, >90%); and

  • Reported a significant reduction of major/clinically significant bleeding, comparable rates of ischaemic stroke, similar or non-significantly higher rates of myocardial infarction and stent thrombosis, and a neutral effect on trial-defined major adverse cardiovascular events and all-cause mortality with dual (NOAC + P2Y12) vs. triple (VKA + P2Y12 + aspirin) therapy.

In AUGUSTUS,1081 both placebo (vs. aspirin) and apixaban (vs. VKA) regimens were associated with significant reduction in bleeding, and apixaban (vs. VKA) was associated with significantly lower rates of stroke, death, or hospitalization.

Meta-analyses of RCTs

  • Bleeding outcomes: Meta-analyses1070,1071,1083,1084 consistently showed a significant reduction in major bleeding with dual vs. triple and NOAC- vs. VKA-based therapies (NOAC-based treatments were also associated with a significant reduction in ICH).

  • Ischaemic events: Stroke rates were similar across all treatment arms, but the rates of myocardial infarction and stent thrombosis were numerically higher with dual vs. triple therapy. In two meta-analyses1070,,1071 stent thrombosis was statistically significantly increased on dual (i.e. no aspirin) vs. triple therapy. Also, the risk of myocardial infarction or stent thrombosis was slightly higher with dabigatran 110 mg but not dabigatran 150 mg.

  • The trial-defined major adverse cardiovascular events and mortality rates were similar in all treatment arms, suggesting that the benefit from major bleeding and ICH reduction is counterbalanced by a higher risk for coronary (mainly stent-related) ischaemic events with dual therapy.

ACS = acute coronary syndromes; AF = atrial fibrillation; b.i.d. = bis in die (twice a day); DAPT = dual antiplatelet therapy; ENTRUST-AF PCI = Edoxaban Treatment Versus Vitamin K Antagonist in Patients With Atrial Fibrillation Undergoing Percutaneous Coronary Intervention; ICH = intracranial haemorrhage; NOAC = non-vitamin K antagonist oral anticoagulant; OAC = oral anticoagulant; o.d. = omni die (once daily); PCI = percutaneous coronary intervention; 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; RCT = randomized controlled trial; RE-DUAL PCI = Randomized Evaluation of Dual Antithrombotic Therapy with Dabigatran vs. Triple Therapy with Warfarin in Patients with Nonvalvular Atrial Fibrillation Undergoing Percutaneous Coronary Intervention; VKA = vitamin K antagonist; WOEST = What is the Optimal antiplatElet and anticoagulant therapy in patients with oral anticoagulation and coronary StenTing.

Whichever initial treatment plan was chosen, dual therapy with OAC and an antiplatelet drug (preferably clopidogrel) is recommended for the first 12 months after PCI for ACS, or 6 months after PCI in patients with CCS.1067 Thereafter, OAC monotherapy is to be continued (irrespective of the stent type) provided that there were no recurrent ischaemic events in the interim. In 1-year event-free (i.e. ‘stable’) AF patients with CAD and no PCI, OAC monotherapy is also recommended.1072

Use of prasugrel or ticagrelor has been associated with a greater risk of major bleeding compared with clopidogrel1085–1089 and should be avoided in ACS patients with AF. In the RE-DUAL PCI (Randomized Evaluation of Dual Antithrombotic Therapy with Dabigatran vs. Triple Therapy with Warfarin in Patients with Nonvalvular Atrial Fibrillation Undergoing Percutaneous Coronary Intervention) trial, 12% of patients received ticagrelor with dabigatran, but experience with ticagrelor or prasugrel was minimal in PIONEER-AF (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), AUGUSTUS, and ENTRUST-AF PCI (Edoxaban Treatment Versus Vitamin K Antagonist in Patients With Atrial Fibrillation Undergoing Percutaneous Coronary Intervention). In patients at potential risk of gastrointestinal bleeding, concomitant use of proton-pump inhibitors is reasonable.1084

In AF patients treated with surgical coronary revascularization, OAC should be resumed as soon as bleeding is controlled, possibly in combination with clopidogrel, and triple therapy should be avoided.

Poor ventricular rate control during AF may exacerbate symptoms of myocardial ischaemia and precipitate or worsen HF. Appropriate treatment may include a beta-blocker or rate-limiting calcium antagonist. In haemodynamic instability, acute cardioversion may be indicated. Vernakalant, flecainide, and propafenone should not be used for rhythm control in patients with known CAD (section 10.2.2.2).

In all AF patients with an ACS/CCS, optimized management of risk factors is needed, and cardiovascular prevention strategies such as good BP control,338 lipid management, and other cardiovascular prevention interventions1007 should be implemented as needed, once the acute presentation is stabilized.

Recommendations for patients with AF and an ACS, PCI, or CCS1068

graphic
graphic

ACS = acute coronary syndrome; AF = atrial fibrillation; b.i.d. = bis in die (twice a day); CCS = chronic coronary syndrome; CKD = chronic kidney disease; DAPT = Dual antiplatelet therapy; HAS-BLED = Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile INR, Elderly (>65 years), Drugs/alcohol concomitantly; INR = international normalized ratio; NOAC = non-vitamin K antagonist oral anticoagulant; o.d. = omni die (once daily); OAC = oral anticoagulant; PCI=percutaneous coronary intervention; TTR = time in therapeutic range; VKA = vitamin K antagonist.

a

Class of recommendation.

b

Level of evidence.

c

See summary of product characteristics for reduced doses or contraindications for each NOAC in patients with CKD, body weight <60 kg, age >75 − 80 years, and/or drug interactions.

d

Risk of stent thrombosis encompasses: (i) risk of thrombosis occurring, and (ii) risk of death should stent thrombosis occur, both of which relate to anatomical, procedural, and clinical characteristics. Risk factors for CCS patients include: stenting of left main stem or last remaining patent artery; suboptimal stent deployment; stent length >60 mm; diabetes mellitus; CKD; bifurcation with two stents implanted; treatment of chronic total occlusion; and previous stent thrombosis on adequate antithrombotic therapy.

e

Bleeding risk in AF patients may be assessed using the HAS-BLED score (section 10.1.2), which draws attention to modifiable bleeding risk factors; those at high risk (score ≥3) can have more frequent or early review and follow-up. Bleeding risk is highly dynamic and does not remain static, and relying on modifiable bleeding risk factors alone is an inferior strategy to evaluate bleeding risk.389

f

When dabigatran is used in triple therapy, dabigatran 110 mg b.i.d may be used instead of 150 mg b.i.d, but the evidence is insufficient.

Recommendations for patients with AF and an ACS, PCI, or CCS1068

graphic
graphic

ACS = acute coronary syndrome; AF = atrial fibrillation; b.i.d. = bis in die (twice a day); CCS = chronic coronary syndrome; CKD = chronic kidney disease; DAPT = Dual antiplatelet therapy; HAS-BLED = Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile INR, Elderly (>65 years), Drugs/alcohol concomitantly; INR = international normalized ratio; NOAC = non-vitamin K antagonist oral anticoagulant; o.d. = omni die (once daily); OAC = oral anticoagulant; PCI=percutaneous coronary intervention; TTR = time in therapeutic range; VKA = vitamin K antagonist.

a

Class of recommendation.

b

Level of evidence.

c

See summary of product characteristics for reduced doses or contraindications for each NOAC in patients with CKD, body weight <60 kg, age >75 − 80 years, and/or drug interactions.

d

Risk of stent thrombosis encompasses: (i) risk of thrombosis occurring, and (ii) risk of death should stent thrombosis occur, both of which relate to anatomical, procedural, and clinical characteristics. Risk factors for CCS patients include: stenting of left main stem or last remaining patent artery; suboptimal stent deployment; stent length >60 mm; diabetes mellitus; CKD; bifurcation with two stents implanted; treatment of chronic total occlusion; and previous stent thrombosis on adequate antithrombotic therapy.

e

Bleeding risk in AF patients may be assessed using the HAS-BLED score (section 10.1.2), which draws attention to modifiable bleeding risk factors; those at high risk (score ≥3) can have more frequent or early review and follow-up. Bleeding risk is highly dynamic and does not remain static, and relying on modifiable bleeding risk factors alone is an inferior strategy to evaluate bleeding risk.389

f

When dabigatran is used in triple therapy, dabigatran 110 mg b.i.d may be used instead of 150 mg b.i.d, but the evidence is insufficient.

11.4 Acute stroke or intracranial haemorrhage in patients with atrial fibrillation

11.4.1 Patients with atrial fibrillation and acute ischaemic stroke or transient ischaemic attack

Management of acute stroke in AF patients is beyond the scope of this document. In AF patients presenting with acute ischaemic stroke while taking OAC, acute therapy depends on the treatment regimen and intensity of anticoagulation. Patients on VKA with an INR<1.7 are eligible for thrombolysis according to the neurological indication (if presenting with a clinically relevant neurological deficit within the appropriate time window and ICH is excluded with cerebral imaging). In patients taking NOACs, measurement of activated partial thromboplastin time or thrombin time (for dabigatran), or antifactor Xa levels (for factor Xa inhibitors) will provide information on whether the patient is systemically anticoagulated. Whenever possible, the time when the last NOAC dose was taken should be elucidated (generally, thrombolysis is considered to be safe in patients with last NOAC intake being ≥48 h, assuming normal renal function).1090

If the patient is systemically anticoagulated, thrombolysis should not be performed due to the risk of haemorrhage, and endovascular treatment should be considered. In patients taking dabigatran, systemic thrombolysis may be performed after reversal of the dabigatran action by idarucizumab.1091

Secondary prevention of stroke/systemic embolism in patients after acute AF-related ischaemic stroke or TIA includes early prevention of recurrent ischaemic stroke in the 2 weeks after the index event and long-term prevention thereafter.

Box 2 About acute ischaemic stroke in patients with AF

AF-related ischaemic strokes are often fatal or disabling 106 , with increased risk of early recurrence within 48 h 1092 to 2 weeks,1092–1095 or haemorrhagic transformation,1096 especially in the first days after large cardio-embolic lesions and acute recanalization therapy.1097,1098 Notably, ICH is generally associated with higher mortality and morbidity than recurrent ischaemic stroke.

Timing of OAC (re)initiation after acute ischaemic stroke

  • Early anticoagulation after acute ischaemic stroke might cause parenchymal haemorrhage, with potentially serious clinical consequences1097,.1099 Using UFH, LMWH, heparinoids, or VKAs <48 h after acute ischaemic stroke was associated with an increased risk of symptomatic ICH, without significant reduction in recurrent ischaemic stroke.1095

  • Reportedly, the 90-day risk of recurrent ischaemic stroke outweighs the risk of symptomatic ICH in AF patients receiving a NOAC 4 − 14 days after the acute event1100–1102 (ischaemic stroke recurrence rates after mild/moderate ischaemic stroke significantly increased with a later NOAC administration,1101 e.g. >14 days).1100 In a small RCT, rivaroxaban use within 5 days after mild ischaemic stroke in AF patients was associated with similar event rates compared with VKA.1103

As high-quality RCT-derived evidence to inform optimal timing of anticoagulation after acute ischaemic stroke is lacking, OAC use in the early post-stroke period is currently based on expert consensus.505 Several ongoing RCTs [ELAN (NCT03148457), OPTIMAS (EudraCT, 2018-003859-3), TIMING (NCT02961348), and START (NCT03021928)] are investigating early (<1 week) vs. late NOAC initiation in patients with AF-related ischaemic stroke (first results are not expected before 2021).

Long-term secondary stroke prevention

  • There is no evidence that the addition of aspirin to OAC or supratherapeutic INRs would improve outcomes in secondary stroke prevention.

  • Compared with VKAs, NOACs were associated with better efficacy in secondary stroke prevention and better safety regarding ICH in a meta-analysis of landmark NOAC AF trial.1104

  • Good adherence to OAC treatment is essential for effective secondary stroke prevention.

There is some evidence to support that strokes can induce AF through neurogenic mechanisms1105,.1106 The first study showed that damage to the insula increases the odds of AF detection after ischaemic stroke and is more prevalent in patients with AF diagnosed after stroke than among those without AF.1105 The second study explained the reason why AFDAS detected soon after ischaemic stroke is associated with a low risk of ischaemic stroke recurrence.1106

AF = atrial fibrillation; ELAN = Early versus Late Initiation of Direct Oral Anticoagulants in Post-ischaemic Stroke Patients With AF; ICH = intracranial haemorrhage; INR = international normalized ratio; LMWH = low-molecular-weight heparin; NOAC = non-vitamin K antagonist oral anticoagulant; OAC = oral anticoagulant; OPTIMAS = OPtimal TIMing of Anticoagulation after Stroke; RCT = randomized controlled trial; START = Optimal Delay Time to Initiate Anticoagulation After Ischemic Stroke in AF; TIMING = TIMING of Oral Anticoagulant Therapy in Acute Ischemic Stroke With AF; UFH = unfractionated heparin; VKA = vitamin K antagonist.

Whereas infarct size/stroke severity is used clinically to guide timing of OAC initiation,1090 the usefulness of such an approach in estimating the net benefit of early treatment may be limited. Robust data to inform optimal timing for (re)initiation of OAC after acute stroke are lacking. From the cardiological perspective, OAC should be (re)initiated as soon as considered possible from the neurological perspective (in most cases within the first 2 weeks). A multidisciplinary approach with involvement of stroke specialists, cardiologists, and patients is considered appropriate.

In AF patients who presented with acute ischaemic stroke despite taking OAC, optimization of OAC therapy is of key importance—if on VKA, optimize TTR (ideally >70%) or switch to a NOAC; if on NOAC, ensure appropriate dosing and good adherence to treatment. Inappropriate NOAC under-dosing using lower or reduced doses of specific NOACs has been associated with increased risk of stroke/systemic embolism, hospitalization, and deaths without appreciable reduction in major bleeding.1107

11.4.2 Cryptogenic stroke/embolic stroke with undetermined source

Currently available evidence including two recently completed RCTs1108,1109 does not support routine OAC use in patients with acute ischaemic stroke of uncertain aetiology (cryptogenic stroke) or acute embolic stroke of undetermined source in patients without documented AF (Supplementary Box 4). Of note, subgroup analyses of those two RCTs suggested that certain subgroups (i.e. age ≥75 years, impaired renal function,1109 or enlarged LA1110) could benefit from OAC, but more data are needed to inform optimal use of NOACs among patients with a cryptogenic stroke. Two ongoing trials will study the use of apixaban in this setting [ATTICUS (Apixaban for treatment of embolic stroke of undetermined source)]1111 and ARCADIA [(AtRial Cardiopathy and Antithrombotic Drugs In Prevention After Cryptogenic Stroke) (NCT03192215)].

Efforts to improve detection of AF are needed in such patients (see also section 8). Clinical risk scores {e.g. C2HEST [CAD/COPD (1 point each), Hypertension (1 point), Elderly ( ≥75 years, 2 points), Systolic heart failure (2 points), and Thyroid disease (hyperthyroidism, 1 point) (score)]} have been proposed for identification of ‘high-risk’ patients for AF diagnosis1112 and facilitation of prolonged monitoring.

Recommendations for the search for AF in patients with cryptogenic stroke

graphic
graphic

AF = atrial fibrillation; C2HEST = CAD/COPD (1 point each), Hypertension (1 point), Elderly ( ≥75 years, 2 points), Systolic heart failure (2 points), and Thyroid disease (hyperthyroidism, 1 point) (score); ECG=electrocardiogram; LA = left atrial; TIA=transient ischaemic attack.

a

Class of recommendation.

b

Level of evidence.

c

Not all stroke patients would benefit from prolonged ECG monitoring; those deemed at risk of developing AF (e.g. elderly, with cardiovascular risk factors or comorbidities, indices of LA remodelling, high C2HEST score, etc.) or those with cryptogenic stroke and stroke characteristics suggestive of an embolic stroke should be scheduled for prolonged ECG monitoring.

Recommendations for the search for AF in patients with cryptogenic stroke

graphic
graphic

AF = atrial fibrillation; C2HEST = CAD/COPD (1 point each), Hypertension (1 point), Elderly ( ≥75 years, 2 points), Systolic heart failure (2 points), and Thyroid disease (hyperthyroidism, 1 point) (score); ECG=electrocardiogram; LA = left atrial; TIA=transient ischaemic attack.

a

Class of recommendation.

b

Level of evidence.

c

Not all stroke patients would benefit from prolonged ECG monitoring; those deemed at risk of developing AF (e.g. elderly, with cardiovascular risk factors or comorbidities, indices of LA remodelling, high C2HEST score, etc.) or those with cryptogenic stroke and stroke characteristics suggestive of an embolic stroke should be scheduled for prolonged ECG monitoring.

11.4.3 Post-stroke patients without known atrial fibrillation

Detection of previously unknown AF after stroke has important implications for secondary prevention. Several RCTs have established the effectiveness of ECG monitoring for post-stroke AF detection, with numbers needed to screen of 8–14.1117,1118

Looking harder and longer and using more sophisticated monitoring may generally improve AF detection. In a meta-analysis1118 of 50 post-stroke studies, the proportion of patients with post-stroke AF was 7.7% in the emergency room using admission ECG; 5.1% in the wards using serial ECG, continuous inpatient ECG monitoring/cardiac telemetry, and in-hospital Holter monitoring; 10.7% in the first ambulatory period using ambulatory Holter; and, after discharge, 16.9% using mobile cardiac outpatient telemetry and external or implantable loop recording. The overall post-stroke AF detection after all phases of cardiac monitoring reached 23.7%.1118

In patients with ischaemic stroke/TIA, monitoring for AF is recommended by short-term ECG recording followed by continuous ECG monitoring for at least 72 h, also considering a tiered longer ECG monitoring approach1113 and insertion of an intracardiac monitor in case of cryptogenic stroke.1114,1119 Post-stroke ECG monitoring is likely cost-effective1120,1121; however, RCTs have not been powered to assess the effect of prolonged ECG monitoring and subsequent prescription of OAC on stroke or mortality in patients with detected AF.

11.4.4 Management of patients with atrial fibrillation post-intracranial haemorrhage

As ICH is the most feared, often lethal, complication of anticoagulant and antiplatelet therapy, there is a considerable reluctance to (re)initiate OAC in AF patients who survived an ICH, despite their high estimated risk of AF-related ischaemic stroke.

Patients with a history of recent ICH were excluded from RCTs of stroke prevention in AF, but available observational data suggest than many AF patients would benefit from (re)institution of OAC, depending on the cause(s) of ICH and findings on brain CT and MRI (Supplementary Box 5).

Treatment decision to (re)start OAC in AF patients after an ICH requires multidisciplinary-team input from cardiologists, stroke specialists, neurosurgeons, patients, and their family/carers. After acute spontaneous ICH (which includes epidural, subdural, subarachnoid, or intracerebral haemorrhage), OAC may be considered after careful assessment of risks and benefits, and cerebral imaging may help. The risk of recurrent ICH may be increased in the presence of specific risk factors, shown in Figure 21. Of note, the risk of OAC-related ICH is increased especially in Asian patients.1122

(Re-) initiation of anticoagulation post-intracranial bleeding. A pooled analysis of individual patient data from cohort studies (n=20 322 patients; 38 cohorts; >35 225 patient-years) showed that although cerebral microbleeds can inform regarding the risk for ICH in patients with recent ischaemic stroke/TIA treated with antithrombotic therapy, the absolute risk of ischaemic stroke is substantially higher than that of ICH, regardless of the presence, burden, or location of cerebral microbleeds.505,1123 IS = ischaemic stroke;ACS = acute coronary syndrome; CMB = cerebral microbleeds; ICH = intracranial haemorrhage; LAA = left atrial appendage; LDL = low-density lipoprotein; LoE = level of evidence; NOAC = non-vitamin K antagonist oral anticoagulant; OAC = oral anticoagulant; PCI = percutaneous coronary intervention; RCT = randomized controlled trial; TIA = transient ischaemic attack.
Figure 21

(Re-) initiation of anticoagulation post-intracranial bleeding. A pooled analysis of individual patient data from cohort studies (n=20 322 patients; 38 cohorts; >35 225 patient-years) showed that although cerebral microbleeds can inform regarding the risk for ICH in patients with recent ischaemic stroke/TIA treated with antithrombotic therapy, the absolute risk of ischaemic stroke is substantially higher than that of ICH, regardless of the presence, burden, or location of cerebral microbleeds.505,1123 IS = ischaemic stroke;ACS = acute coronary syndrome; CMB = cerebral microbleeds; ICH = intracranial haemorrhage; LAA = left atrial appendage; LDL = low-density lipoprotein; LoE = level of evidence; NOAC = non-vitamin K antagonist oral anticoagulant; OAC = oral anticoagulant; PCI = percutaneous coronary intervention; RCT = randomized controlled trial; TIA = transient ischaemic attack.

Compared with VKAs, the use of NOACs in patients without previous ICH is associated with an approximately 50% lower risk of ICH,423 whereas the size and outcome of OAC-related ICH is similar with NOACs and VKAs.1124 Hence, NOACs should be preferred in NOAC-eligible ICH survivors with AF although there is no RCT to prove this.

The optimal timing of anticoagulation after ICH is unknown, but should be delayed beyond the acute phase, probably for at least 4 weeks; in AF patients at very high risk of recurrent ICH, LAA occlusion may be considered. Ongoing RCTs of NOACs and LAA occlusion may inform decision making in the future.

graphic
graphic

AF = atrial fibrillation; ICH = intracranial haemorrhage; LMWH = low-molecular-weight heparin; NOAC = non-vitamin K antagonist oral anticoagulant; OAC = oral anticoagulant; TIA = transient ischaemic attack; UFH = unfractionated heparin; VKA = vitamin K antagonist.

a

Class of recommendation.

b

Level of evidence.

c

A more favourable net benefit is likely with deep ICH or without neuroimaging evidence of cerebral amyloid angiopathy or microbleeds.

graphic
graphic

AF = atrial fibrillation; ICH = intracranial haemorrhage; LMWH = low-molecular-weight heparin; NOAC = non-vitamin K antagonist oral anticoagulant; OAC = oral anticoagulant; TIA = transient ischaemic attack; UFH = unfractionated heparin; VKA = vitamin K antagonist.

a

Class of recommendation.

b

Level of evidence.

c

A more favourable net benefit is likely with deep ICH or without neuroimaging evidence of cerebral amyloid angiopathy or microbleeds.

11.5 Active bleeding on anticoagulant therapy: management and reversal drugs

Management of patients with active bleeding while on OAC is shown in Figure 22. General assessment should include detection of the bleeding site, assessment of bleeding severity, and evaluation of the time-point of last OAC intake. Concomitant antithrombotic drugs and other factors influencing bleeding risk (alcohol abuse, renal function) should be explored. Laboratory tests, such as INR, are useful in case of VKA therapy. More specific coagulation tests for NOACs include diluted thrombin time, ecarin clotting time, or ecarin chromogenic assay for dabigatran, and chromogenic anti-factor Xa assay for rivaroxaban, apixaban, and edoxaban.1131 However, these tests or measurement of NOAC plasma levels are not always readily available in practice and are often unnecessary for bleeding management.1132 An overview of reversal drugs for NOACs is given in Supplementary Table 13 and Supplementary Figure 6.

Management of active bleeding in patients receiving anticoagulation (institutions should have an agreed procedure in place).143 FFP = fresh frozen plasma; INR = international normalized ratio; i.v. = intravenous; NOAC = non-vitamin K antagonist oral anticoagulant; OAC = oral anticoagulation therapy; PCC = prothrombin complex concentrates; VKA = vitamin K antagonist.
Figure 22

Management of active bleeding in patients receiving anticoagulation (institutions should have an agreed procedure in place).143 FFP = fresh frozen plasma; INR = international normalized ratio; i.v. = intravenous; NOAC = non-vitamin K antagonist oral anticoagulant; OAC = oral anticoagulation therapy; PCC = prothrombin complex concentrates; VKA = vitamin K antagonist.

Notably, the time of last drug ingestion combined with assessment of renal function, haemoglobin, haematocrit, and platelet count enable appropriate clinical decision making in most of the cases.

Minor bleeding events should be treated with supportive measures such as mechanical compression or minor surgery to achieve haemostasis. Withdrawal of VKAs is not associated with a prompt reduction of anticoagulant effect, while NOACs have a short plasma half-life and haemostasis can be expected within 12 − 24 h after an omitted dose.

Treatment of moderate bleeding events may require blood transfusions and fluid replacement. If the last intake of NOACs was less than 2 − 4 h before bleeding assessment, charcoal administration and/or gastric lavage will reduce further exposure. Specific diagnostic and treatment interventions to identify and manage the cause of bleeding (e.g. gastroscopy) should be performed promptly. Dialysis is effective in reducing dabigatran concentration and has been associated with reduction in the duration and/or severity of associated bleeding.1133

Severe or life-threatening bleeding requires immediate reversal of the antithrombotic effect of OACs. For VKAs, administration of fresh frozen plasma restores coagulation more rapidly than vitamin K, but prothrombin complex concentrates achieve even faster blood coagulation1134 and are first-line therapy for VKA reversal.1135 Specific reversal drugs are available for NOACs: idarucizumab (for dabigatran) and andexanet alfa (for factor Xa inhibitors) effectively reverse the anticoagulation action of NOACs and restore physiological haemostasis.1136,1137 However, their use is often associated with subsequent non-reinitiation of OAC and increased rates of thrombotic events. These drugs can be effectively applied in case of severe life-threatening bleeding or urgent surgery, but their use is only very rarely necessary in daily clinical practice. Ciraparantag is an investigational synthetic drug that binds and inhibits direct factor Xa inhibitors, dabigatran, and heparin. The use of four-factor prothrombin complex concentrates may be considered as an alternative treatment for reversing the anticoagulant effect of rivaroxaban, apixaban, and edoxaban, although scientific evidence is very limited in this context and is frequently from healthy volunteers.1138–1140

Recommendations for the management of active bleeding on OAC

graphic
graphic

AF = atrial fibrillation; OAC = oral anticoagulant; VKA=vitamin K antagonist.

a

Class of recommendation.

b

Level of evidence.

Recommendations for the management of active bleeding on OAC

graphic
graphic

AF = atrial fibrillation; OAC = oral anticoagulant; VKA=vitamin K antagonist.

a

Class of recommendation.

b

Level of evidence.

11.6 Atrial fibrillation and heart failure

Both AF and HF facilitate the occurrence and aggravate the prognosis of each other, and often coexist (see also sections 4.2 and 5.3); HF is also a thrombo-embolic risk factor in AF. The efficacy and safety of NOACs do not seem to differ in AF patients with and without HF.1141,1142

The management of patients with AF and HF is often challenging (section 10.2). The optimal heart-rate target in AF patients with HF remains unclear, but a rate of <100 − 110 bpm is usually recommended.1143–1145 Pharmacological rate control strategies are different for patients with heart failure with preserved ejection fraction (HFpEF) and HFrEF. Beta-blockers, diltiazem, verapamil, and digoxin are all viable options in HFpEF, while beta-blockers and digoxin can be used in those with HFrEF. Amiodarone may be considered for rate control in both forms of HF, but only in the acute setting. Atrioventricular-node ablation and pacing can control ventricular rate when medication fails (section 10.2.1.). However, in an observation study, rhythm control strategies showed a lower 1-year all-cause death over rate control in older patients (≥65 years) with HFpEF.1146

Haemodynamic instability or worsening of HF may require emergency or immediate electrical cardioversion of AF, whereas pharmacological cardioversion using i.v. amiodarone may be attempted if a delayed cardioversion is consistent with the clinical situation (section 10.2.2.2.2). AF catheter ablation has been shown to improve symptoms, exercise capacity, QoL, and LVEF in AF patients with HF,661 whereas the recent CASTLE-AF RCT showed a reduction in all-cause mortality and hospitalization for worsening HF after AF catheter ablation in patients with HFrEF657 (section 10.2.2.3).

All patients with HF and AF should receive guideline-adherent HF therapy.1145 The benefit of beta-blocker therapy in reducing mortality in AF patients with HFrEF has been questioned by some meta-analyses,491 although this is not a universal finding, especially with some real-world studies supporting an improved prognosis.1147,1148

11.7 Atrial fibrillation and valvular heart disease

VHD is independently associated with AF1149 and more than one-third of patients with AF have some form of VHD.512

Among patients with severe VHD, including those undergoing surgical and transcatheter aortic or mitral valve intervention, AF is associated with less favourable clinical outcomes.1150–1155 Compared to AF patients without VHD, the risk of thrombo-embolism and stroke is increased among AF patients with VHD other than mitral stenosis and mechanical heart prostheses, mostly owing to older age and more frequent comorbidities.1156,1157 While patients with moderate-to-severe mitral stenosis and mechanical prosthetic heart valves require anticoagulation with VKAs,1158 there is no evidence that the presence of other VHDs including aortic stenosis/regurgitation, mitral regurgitation, bioprostheses, or valve repair should modify the choice of OAC.1156,1159 In a meta-analysis of the four pivotal RCTs comparing NOACs with VKAs, the effects of NOACs vs. VKAs in terms of stroke/systemic embolism and bleeding risk in patients with VHD other than mitral stenosis and mechanical prosthetic heart valves were consistent with those in the main RCTs.1160 In an observational study, NOACs were associated with better outcomes, with reduced rates of ischaemic stroke and major bleeding compared to warfarin in AF patients with mitral stenosis.1161

Recently, a functional categorization of VHD in relation to OAC use was introduced, categorizing patients with moderate-severe or rheumatic mitral stenosis as type 1 and all other VHD as type 2.148,1157,1162 There are gaps in evidence on NOAC use in AF patients with rheumatic mitral valve disease, and during the first 3 months after surgical or transcatheter implantation of a bioprosthesis, and observational data regarding NOACs use after transcatheter aortic valve implantation are conflicting.1163 An RCT in non-AF patients comparing rivaroxaban 10 mg daily with aspirin after transcatheter aortic valve implantation was stopped early due to higher risks of death or thrombo-embolic complications and bleeding in the rivaroxaban arm.1164

Recommendations for patients with valvular heart disease and AF

graphic
graphic

AF = atrial fibrillation; NOAC = non-vitamin K antagonist oral anticoagulant.

a

Class of recommendation.

b

Level of evidence.

Recommendations for patients with valvular heart disease and AF

graphic
graphic

AF = atrial fibrillation; NOAC = non-vitamin K antagonist oral anticoagulant.

a

Class of recommendation.

b

Level of evidence.

11.8 Atrial fibrillation and chronic kidney disease

Independently of AF, CKD is a prothrombotic and prohaemorrhagic condition (Supplementary Figure 7),1166,1167,1168 and AF may accelerate CKD progression. Coexisting in 15–20% of CKD patients,1169 AF is associated with increased mortality,1170 whereas CKD may be present in 40 − 50% of AF patients.1171 In AF patients, renal function can deteriorate over time,1172 and worsening CrCl is a better independent predictor of ischaemic stroke/systemic embolism and bleeding than renal impairment per se.1172 In RCTs of OAC for stroke prevention in AF, renal function was usually estimated using the Cockcroft–Gault formula for CrCl, and a CrCl cut-off of <50 mL/min was used to adapt NOAC dosage.

In patients with mild-to-moderate CKD (CrCl 30 − 49 mL/min), the safety and efficacy of NOACs vs. warfarin was consistent with patients without CKD in landmark NOAC trials1173–1176, hence the same considerations for stroke risk assessment and choice of OAC may apply.

In patients with CrCl 15 − 29 mL/min, RCT-derived data on the effect of VKA or NOACs are lacking. These patients were essentially excluded from the major RCTs. The evidence for the benefits of OAC in patients with end-stage kidney disease with CrCl≤15 mL/min or on dialysis is even more limited, and to some extent controversial. There are no RCTs, whereas observational data question the benefit of OAC in this patient population. Data from observational studies suggest possible bleeding risk reduction in patients with end-stage kidney disease taking a NOAC compared with VKA,435,1177 but there is no solid evidence for a reduction in embolic events with either NOACs or VKAs, as recently shown in a systematic review.1178 Notably, NOACs have not been approved in Europe for patients with CrCl ≤15 mL/min or on dialysis.

Several RCTs are currently assessing OAC use and comparing NOACs with VKAs in patients with end-stage renal disease (NCT02933697, NCT03987711). The RENAL-AF trial, investigating apixaban vs. warfarin in AF patients on haemodialysis, was terminated early with inconclusive data on relative stroke and bleeding rates.1179

There are no RCT data on OAC use in patients with AF after kidney transplantation. The prescription and dosing of NOACs should be guided by the estimated glomerular filtration rate of the transplanted kidney and taking into account potential interactions with concomitant medication.

Particular attention must be given to the dosing of NOACs in patients with CKD (Supplementary Table 9).

11.9 Atrial fibrillation and peripheral artery disease

Patients with AF often have atherosclerotic vascular disease. With the inclusion of asymptomatic ankle-brachial index≤0.90 in the definition PAD, the prevalence of vascular disease increased significantly.1180 In a systematic review and meta-analysis, the presence of PAD was significantly associated with a 1.3- to 2.5-fold increased risk of stroke.347 Complex aortic plaque in the descending aorta, as identified on TOE, is also a significant vascular stroke risk factor (section 10.1.1).

In patients with asymptomatic PAD, the risk of cardiovascular events progressively increases with increasing vascular disease burden.470 Therefore, PAD patients should be opportunistically screened for AF. Patients with AF and PAD should be prescribed OAC, unless contraindicated. Those with stable vascular disease (arbitrarily defined as no new vascular event in the past 12 months) should be managed with OAC alone (section 11.3), as concomitant use of antiplatelet therapy has not been shown to reduce stroke or other cardiovascular events, but may increase serious bleeds, including ICH.

The principles of rate and rhythm control outlined in section 10.2 also apply for AF patients with PAD. Special considerations include possibly limited exercise capacity in these patients, owing to intermittent claudication. Beta-blockers may exacerbate PAD symptoms in some patients, in whom NDCC blockers may be more appropriate for rate control.

11.10 Atrial fibrillation and endocrine disorders

Electrolyte disturbances and altered glucose and/or hormone levels in endocrine disorders such as thyroid disorders, acromegaly, pheochromocytoma, diseases of adrenal cortex, parathyroid disease, or pancreas dysfunction including diabetes mellitus may contribute to development of AF. Data on management of AF in these settings are limited.3 Diabetes is discussed in section 10.3.2.4. Stroke prevention should follow the same principles as in other AF patients, with risk stratification using the CHA2DS2-VASc score.3,1181 In AF patients with hyperthyroidism, spontaneous conversion of AF often occurs once a euthyroid state is achieved.1182 Withdrawal of amiodarone is mandatory in hyperthyroidism. AF catheter ablation should be performed under stable electrolytic and metabolic conditions and should not be carried out during active hyperthyroidism.

11.11 Atrial fibrillation and gastrointestinal disorders

While gastrointestinal lesions can lead to bleeding events in anticoagulated AF patients, some gastrointestinal conditions such as active inflammatory bowel disease increase the risk of AF and stroke.1183 Gastrointestinal bleeding is a well-known complication of OAC. Overall, NOAC use is associated with an increased risk of gastrointestinal bleeding,1184,1185 but in patients treated with apixaban or dabigatran 110 mg the risk is similar to warfarin.419,421 Bleeding lesions can be identified in more than 50% of cases of major gastrointestinal bleeding.1186 After correction of the bleeding source, OAC should be restarted, as this strategy has been associated with decreased risks of thrombo-embolism and death.1187

Patients treated with dabigatran may experience dyspepsia (about 11% in the RE-LY trial, and 2% discontinued the drug because of gastrointestinal symptoms419). After-meal ingestion of dabigatran and/or the addition of proton-pump inhibitors improves symptoms.1188

Management of AF patients with liver disease is challenging, owing to increased bleeding risk (associated with decreased hepatic synthetic function in advanced liver disease, thrombocytopenia, and gastrointestinal variceal lesions), as well as increased ischaemic risk1189,1190). Patients with hepatic dysfunction were generally excluded from the RCTs,1191 especially those with abnormal clotting tests, as such patients may be at higher risk of bleeding on VKA, possibly less so on NOACs. Despite the paucity of data, observational studies did not raise concerns regarding the use of NOACs in advanced hepatic disease.1192 In a recent study, AF patients with liver fibrosis had no increase in bleeding on NOACs compared with VKAs.470 Other reassuring data for NOACs come from a large nationwide cohort.472 A number of patients may be started on a NOAC while having unrecognized significant liver damage and, in cirrhotic patients, ischaemic stroke reduction may outweigh bleeding risk.471 NOACs are contraindicated in patients within Child-Turcotte-Pugh C hepatic dysfunction, and rivaroxaban is not recommended for patients in the Child-Turcotte-Pugh B or C category.1193

11.12 Atrial fibrillation and haematological disorders

Anaemia is an independent predictor of OAC-related major bleeding.393,402 In a population-based AF cohort, anaemia was associated with major bleeding and lower TTR, whereas OAC use in AF patients with moderate or severe anaemia was associated with more major bleeding but no reduction in thrombo-embolic risk.1194 Thrombocytopenia is also associated with increased bleeding risk. Before and during anticoagulation treatment, both anaemia and thrombocytopenia should be investigated and corrected, if possible. Decision making on OAC use in patients with platelet counts <100/µL requires a multidisciplinary approach including haematologists, balancing thrombotic and bleeding risks and addressing modifiable bleeding risk factors. Some chemotherapeutic drugs may increase the risk of incident AF (e.g. ibrutinib, melphalan, anthracyclines)1195–1197 or impair platelet function, thus increasing the risk of bleeding (e.g. ibrutinib).1198,1199

11.13 The elderly and frail with atrial fibrillation

The prevalence of AF increases progressively with age67,1200–1206, and age is an independent risk factor for adverse outcomes in AF.372,1200,1207,1208 Older people are less likely to receive OAC1209–1216 despite sufficient evidence supporting the use of OAC in this population. Frailty, comorbidities, and increased risk of falls1217–1219 do not outweigh the benefits of OAC given the small absolute risk of bleeding in anticoagulated elderly patients.339,390,391,1220–1223 Evidence from RCTs,441,1224 meta-analyses423,1225 and large registries339,433,1209,1226 support the use of OAC in this age group. Antiplatelets are neither more effective nor safer than warfarin and may even be harmful,433 whereas NOACs appear to have a better overall risk–benefit profile compared with warfarin.423,433,441,1035,1225,1227–1236 Prescribing a reduced dose of OAC is less effective in preventing AF adverse outcomes.1107,1211,1237,1238

Rate control is traditionally the preferred strategy, but evidence informing the choice between rate and rhythm control in the elderly is insufficient.1239–1242 Limited evidence on other AF treatments supports the use of all rate and rhythm control options, including cardioversion, pacemaker implantation, and AF catheter ablation without any age discrimination. AF catheter ablation may be an effective and safe option in selected older individuals with success rates comparable to younger patients1243–1255 and acceptable complication rates.1243,1245–1247,1249–1260 Nevertheless, age was a predictor of complications in AF catheter ablation in some studies1261–1263 and longer follow-up studies suggested an age-related increase in multivariable-adjusted risk for AF/AFL recurrence, death, and major adverse cardiac events.1257

11.14 Patients with cognitive impairment/dementia

Evidence regarding effective prevention of cognitive impairment in AF is derived mainly from observational studies, suggesting that OAC could play a protective role in AF patients with stroke risk factors, not only for stroke prevention but also for prevention of cognitive decline.1264 The quality of anticoagulation with VKAs (i.e. TTR) seems to play an additional role: low TTR and supratherapeutic INR values were associated with higher risk of dementia.1265,1266 Limited evidence suggests that NOACs may be superior to VKA for preventing cognitive impairment in some,1267,1268 but not all, studies.1269 Recent observational data indicate a protective effect of OAC even in low-risk AF patients who do not need OAC for stroke prevention.1270 A number of RCTs with cognitive function as an endpoint are ongoing and will provide more insights into the role of anticoagulation (NOACs and VKAs) for prevention of cognitive impairment in AF.86

Conversely, cognitive impairment can influence treatment adherence,1271,1272 thus affecting outcomes in AF patients. After AF catheter ablation, silent brain lesions are detected by MRI, but this has not led to cognitive impairment in the AXAFA–AFNET 5 trial, although underpowered.880

11.15 Atrial fibrillation and congenital heart disease

Survival of patients with congenital heart disease has increased over time, but robust data on the management of AF are missing and available evidence is derived mainly from observational studies and/or extrapolation from large clinical trials.

In patients with AF (or AFL or intra-atrial re-entrant tachycardia) and congenital heart disease, OAC treatment is recommended for all patients with intracardiac repair, cyanotic congenital heart disease, Fontan palliation, or systemic right ventricle.1273 Patients with AF and other congenital heart diseases should follow the general risk stratification for OAC use in AF. Notably, NOACs are contraindicated in patients with mechanical heart valves,1165 whereas they seem safe in those with a valvular bioprosthesis.1274,1275

Rate control drugs such as beta-blockers, verapamil, diltiazem, and digitalis can be used with caution due to the risk of bradycardia and hypotension. Rhythm control strategies (i.e. amiodarone) may be effective. In Fontan patients, sodium-channel blockers suppress half of the atrial arrhythmias, but caution is needed for proarrhythmia. When cardioversion is planned, both 3 weeks of anticoagulation and TOE may be considered as thrombi are common in patients with congenital heart disease and atrial tachyarrhythmias.1276,1277

In patients with atrial septal defect, closure may be considered before the fourth decade of life to decrease the risk of AF or AFL.1278 Patients with stroke who underwent closure of the patent foramen ovale may have an increased risk of AF,1279 but in patients with patent foramen ovale and AF, closure is not recommended for stroke prevention; and OAC use should be decided using the conventional stroke risk assessment tool. In patients with a history of AF, AF surgery or AF catheter ablation should be considered at the time of closure of the septal defect.1280–1282 AF catheter ablation of late atrial arrhythmias is likely to be effective after surgical atrial septal defect closure.1283

Recommendations for the management of AF in patients with congenital heart disease

graphic
graphic

AF = atrial fibrillation; AFL = atrial flutter; TOE = transoesophageal echocardiography.

a

Class of recommendation.

b

Level of evidence.

Recommendations for the management of AF in patients with congenital heart disease

graphic
graphic

AF = atrial fibrillation; AFL = atrial flutter; TOE = transoesophageal echocardiography.

a

Class of recommendation.

b

Level of evidence.

11.16 Atrial fibrillation in inherited cardiomyopathies and primary arrhythmia syndromes

A higher incidence and prevalence of AF have been described in patients with inherited cardiomyopathies and primary arrhythmia syndromes.1284–1318 Sometimes AF is the presenting or only clinically overt feature,1319–1323 is often associated with adverse clinical outcomes,1292,1299,1301,1307,1308,1310,1324–1329 and has important implications:

  • The use of AADs may be challenging. In congenital long QT syndrome, many drugs are contraindicated owing to increased risk of QT prolongation and torsade de pointes (http://www.crediblemeds.org/); in Brugada syndrome, class I drugs are contraindicated (http://www.brugadadrugs.org/). Owing to its long-term adverse effects, chronic use of amiodarone is problematic in these typically young individuals.

  • In patients with an implantable cardioverter defibrillator, AF is a common cause of inappropriate shocks.1307,1311,1330–1333 Programming a single high-rate ventricular fibrillation zone ≥210 − 220 bpm with long detection time is safe,1295,1296,1334 and is recommended in patients without documented slow monomorphic ventricular tachycardia. Implantation of an atrial lead may be considered in case of significant bradycardia under beta-blocker treatment.

Supplementary Table 14 summarizes the main clinical features of AF in patients with inherited cardiac diseases.

Patients with Wolff−Parkinson−White syndrome and AF are at risk of fast ventricular rates resulting from rapid conduction of atrial electrical activity to the ventricles via the accessory pathway, and at increased risk of ventricular fibrillation and sudden death.1335,1336 Electrical cardioversion should be readily available for haemodynamically compromised patients with pre-excited AF, and atrioventricular node-modulating drugs (e.g. verapamil, beta-blockers, digoxin) should be avoided.1337,1338 Pharmacological cardioversion can be attempted using ibutilide,1339 whereas AADs class Ia (procainamide) and Ic (propafenone, flecainide) should be used with caution owing to their effect on the atrioventricular node.1340–1343 Amiodarone may not be safe in pre-excited AF as it may enhance pathway conduction.1343

11.17 Atrial fibrillation during pregnancy

AF is one of the most frequent arrhythmias during pregnancy,1344 especially in women with congenital heart disease1345,1346 and in older gravidae,1344,1347,1348 and is associated with increased risk of death.1344 Rapid atrioventricular conduction may have serious haemodynamic consequences for mother and foetus.

Pregnancy is associated with a hypercoagulable state and increased thrombo-embolic risk. Given the lack of specific data, the same rules for stroke risk assessment should be used as in non-pregnant women.1349 Detailed practical recommendations on oral and parenteral anticoagulation regimens depending on the pregnancy trimester, such as low- and high-dose VKA use during the second and third trimesters, timing of low-molecular-weight heparin (LMWH) to unfractionated heparin (UFH) relative delivery, and control of therapeutic effects are given in the recent ESC Pregnancy Guidelines.1349 Immediate anticoagulation is required in clinically significant mitral stenosis, using LMWH at therapeutic doses in the first and last trimesters, and VKA with the usual INR targets or LMWH for the second trimester. Use of NOACs is prohibited during pregnancy. Vaginal delivery should be advised for most women but is contraindicated while the mother is on VKAs because of the risk of foetal intracranial bleeding.1349

Intravenous beta-blockers are recommended for acute rate control. Beta-1 selective blockers (e.g. metoprolol and bisoprolol) are generally safe and are recommended as the first choice.1349 If beta-blockers fail, digoxin and verapamil should be considered for rate control.

Rhythm control should be considered the preferred strategy during pregnancy. Electrical cardioversion is recommended if there is haemodynamic instability or considerable risk for mother or foetus. It can be performed safely without compromising foetal blood flow1350 and the consequent risk for foetal arrhythmias or preterm labour is low.1351,1352 The fetal heart rate should routinely be controlled after cardioversion.1353 Cardioversion should generally be preceded by anticoagulation (section 10.2.2.6).1349 In haemodynamically stable patients without structural heart disease, i.v. ibutilide or flecainide may be considered for termination of AF but experience is limited.1354,1355 Flecainide, propafenone, or sotalol should be considered to prevent AF if atrioventricular nodal-blocking drugs fail. AF catheter ablation has no role during pregnancy.

Recommendations for the management of AF during pregnancy

graphic
graphic

AF = atrial fibrillation; ECG = electrocardiogram; US FDA = United States Food and Drug Administration; i.v. = intravenous; LV = left ventricular; HCM = hypertrophic cardiomyopathy; QTc = corrected QT interval; VKA = vitamin K antagonist.

a

Class of recommendation.

b

Level of evidence.

c

Cardioversion of AF should generally be preceded by anticoagulation.

d

Atenolol has been associated with higher rates of foetal growth retardation and is not recommended.1356

e

Flecainide and propafenone should be combined with atrioventricular nodal-blocking drugs, but structural heart disease, reduced LV function, and bundle branch block should be excluded.

f

Class III drugs should not be used in prolonged QTc.

g

Atrioventricular nodal-blocking drugs should not be used in patients with pre-excitation on resting ECG or pre-excited AF.

Note that the former A to X categories of drugs—the classification system for counselling of pregnant women requiring drug therapy—was replaced by the Pregnancy and Lactation Labelling Rule, which provides a descriptive risk summary and detailed information on animal and clinical data, by the US FDA in June 2015.

Recommendations for the management of AF during pregnancy

graphic
graphic

AF = atrial fibrillation; ECG = electrocardiogram; US FDA = United States Food and Drug Administration; i.v. = intravenous; LV = left ventricular; HCM = hypertrophic cardiomyopathy; QTc = corrected QT interval; VKA = vitamin K antagonist.

a

Class of recommendation.

b

Level of evidence.

c

Cardioversion of AF should generally be preceded by anticoagulation.

d

Atenolol has been associated with higher rates of foetal growth retardation and is not recommended.1356

e

Flecainide and propafenone should be combined with atrioventricular nodal-blocking drugs, but structural heart disease, reduced LV function, and bundle branch block should be excluded.

f

Class III drugs should not be used in prolonged QTc.

g

Atrioventricular nodal-blocking drugs should not be used in patients with pre-excitation on resting ECG or pre-excited AF.

Note that the former A to X categories of drugs—the classification system for counselling of pregnant women requiring drug therapy—was replaced by the Pregnancy and Lactation Labelling Rule, which provides a descriptive risk summary and detailed information on animal and clinical data, by the US FDA in June 2015.

11.18 Atrial fibrillation in professional athletes

Moderate physical activity improves cardiovascular health and prevents AF, whereas intense sports activity increases the risk of AF.35,1357 Athletes have an approximate five-fold increased lifetime risk of AF compared with sedentary individuals despite a lower prevalence of conventional AF risk factors.35,1020 Risk factors for AF in athletes include male sex, middle age, endurance sports, tall stature, and total lifetime exercise dose exceeding 1500 − 2000 hours.1020,1358–1361 Endurance sports such as running, cycling, and cross-country skiing35,1362 carry the highest risk.

In the absence of RCTs, recommendations for AF management in athletes are based largely on evidence in non-athletes, observational data, and expert consensus.143 The need for anticoagulation is determined by clinical risk factors. Sports with direct bodily contact or prone to trauma should be avoided in patients on OAC. As athletes have a high prevalence of sinus bradycardia and sinus pauses, medical therapy is frequently contraindicated or poorly tolerated.1021,1363 Digoxin and verapamil are often ineffective for rate control during exertional AF, whereas beta-blockers may not be well tolerated or are sometimes prohibited. Pill-in-the-pocket therapy has been used, but sports activity should be avoided after ingestion of flecainide or propafenone until AF ceases and two half-lives of the drug have elapsed.586 AF catheter ablation is often preferred by athletes and was similarly efficacious in both the athletic and non-athletic populations in small studies.1364,1365

Recommendations for sports activity in patients with AF

graphic
graphic

AF = atrial fibrillation.

a

Class of recommendation.

b

Level of evidence.

Recommendations for sports activity in patients with AF

graphic
graphic

AF = atrial fibrillation.

a

Class of recommendation.

b

Level of evidence.

11.19 Postoperative atrial fibrillation

Perioperative AF describes the onset of the arrhythmia during an ongoing intervention. This is most relevant in patients undergoing cardiac surgery. While multiple strategies to reduce the incidence of perioperative AF with pretreatment or acute drug treatment have been described, there is lack of evidence from large RCTs. Amiodarone is the most frequently used drug for prevention of perioperative AF.1369

Postoperative AF, defined as new-onset AF in the immediate postoperative period, is a clinically relevant problem,1370,1371 occurring in 20 − 50% of patients after cardiac surgery,1372,1373 10 − 30% after non-cardiac thoracic surgery,1374 and in 5 − 10% after vascular or large colorectal surgery,1375 with peak incidence between postoperative day 2 and 4.1376 Intra- and postoperative changes affecting AF triggers and pre-existing atrial substrate may increase atrial vulnerability to AF. Many episodes of postoperative AF are self-terminating and some are asymptomatic, but postoperative AF has been associated with a four- to five-fold risk of recurrent AF in the next 5 years.1377,1378 It has also been shown to be a risk factor for stroke, myocardial infarction, and death compared with non-postoperative AF patients.1379,1380

Other adverse consequences of postoperative AF include haemodynamic instability, prolonged hospital stay, infections, renal complications, bleeding, increased in-hospital death, and greater healthcare costs.1371,1381,1382 Management of postoperative AF is shown in Figure 23.

Management of postoperative AF. AAD = antiarrhythmic drug; bpm = beats per minute; CCB = calcium channel blocker; ECV = electrical cardioversion; LVEF = left ventricular ejection fraction; Mg2+ magnesium; OAC = oral anticoagulation; PCV = pharmacological cardioversion; PUFA=polyunsaturated fatty acid.
Figure 23

Management of postoperative AF. AAD = antiarrhythmic drug; bpm = beats per minute; CCB = calcium channel blocker; ECV = electrical cardioversion; LVEF = left ventricular ejection fraction; Mg2+ magnesium; OAC = oral anticoagulation; PCV = pharmacological cardioversion; PUFA=polyunsaturated fatty acid.

11.19.1 Prevention of postoperative AF

Preoperative beta-blocker (propranolol, carvedilol plus N-acetyl cysteine) use in cardiac and non-cardiac surgery is associated with a reduced incidence of postoperative AF,1383–1386 but not major adverse events such as death, stroke, or acute kidney injury.1387 Notably, in non-cardiac surgery, perioperative metoprolol was associated with increased risk of death in a large RCT.1388 In a meta-analysis, amiodarone (oral or i.v.), and beta-blockers were equally effective in reducing postoperative AF,1389 but their combination was better than beta-blockers alone.1390 Lower cumulative doses of amiodarone (<3000 mg) could be effective, with fewer adverse events.1391–1393 Data for other interventions such as statins974,,1394 magnesium,1395 sotalol,1385 colchicine,1396 posterior pericardiotomy,1397,1398 (bi)atrial pacing,1385 and corticosteroids1399 are not robust. Two large RCTs showed no significant effect of i.v. steroids on the incidence of postoperative AF after cardiac surgery,1400,1401 and colchicine is currently being investigated in the prevention of postoperative AF [COP-AF (Colchicine For The Prevention Of Perioperative Atrial Fibrillation In Patients Undergoing Thoracic Surgery): NCT03310125].

11.19.2 Prevention of thrombo-embolic events

In a large meta-analysis, patients with postoperative AF had a 62% higher odds of early and 37% higher risk of long-term stroke compared with those without postoperative AF (≥1-year stroke rates were 2.4% vs. 0.4%, respectively), as well as 44% higher odds of early and 37% higher risk of long-term mortality; long-term stroke risk was substantially higher with non-cardiac than cardiac postoperative AF (HR 2.00; 95% CI 1.70–2.35 for non-cardiac vs. HR 1.20; 95% CI 1.07–1.34 for cardiac postoperative AF; P for subgroup difference <0.0001).1379

Nevertheless, the evidence on OAC effects in patients with postoperative AF is not very robust.1382,1402–1407 Observational data1408 suggest that although coronary artery bypass graft-related postoperative AF might not be equivalent to non-surgery AF regarding the long-term risk of adverse outcomes, OAC use during follow-up was associated with a significantly lower risk of thrombo-embolic events in both postoperative AF and non-surgery AF compared with no OAC.1408 Reportedly, postoperative AF occurring after non-cardiac surgery was associated with a similar long-term thrombo-embolic risk to non-surgery AF, and OAC therapy was associated with comparably lower risk of thrombo-embolic events and all-cause death in both groups.1409 Ongoing RCTs in cardiac [PACES (Anticoagulation for New-Onset Post-Operative Atrial Fibrillation After CABG); NCT04045665] and non-cardiac (ASPIRE-AF; NCT03968393) surgery will inform optimal long-term OAC use among patients developing postoperative AF.

In haemodynamically unstable patients with postoperative AF, emergency electrical cardioversion (or i.v. administration of amiodarone1385 or vernakalant,583 if consistent with the clinical situation) is indicated. In a recent RCT of postoperative AF patients after cardiac surgery, neither rate nor rhythm control showed net clinical advantage over each other.1373 Hence, rate or rhythm control treatment decisions should be based on symptoms, and non-emergency cardioversion should follow the principles of peri-cardioversion anticoagulation outlined in section 10.2.

Recommendations for postoperative AF

graphic
graphic

AF = atrial fibrillation; OAC = oral anticoagulant.

a

Class of recommendation.

b

Level of evidence.

Recommendations for postoperative AF

graphic
graphic

AF = atrial fibrillation; OAC = oral anticoagulant.

a

Class of recommendation.

b

Level of evidence.

12 Prevention of atrial fibrillation

12.1 Primary prevention of atrial fibrillation

Primary prevention of AF refers to the implementation of preventive measures in patients at risk but without previous documentation of AF. This strategy relies on the identification and management of risk factors and comorbidities predisposing to AF, before the development of atrial remodelling and fibrosis964,.1411 Upstream therapy refers to the use of non-AADs that modify the atrial substrate or target-specific mechanisms of AF to prevent the occurrence or recurrence of the arrhythmia. The key targets of upstream therapy are structural changes in the atria (e.g. fibrosis, hypertrophy, inflammation, oxidative stress), but effects on atrial ion channels, gap junctions, and calcium handling are also evident.964

Adequate management of hypertension and HF may prevent AF by reducing atrial stretch, but inhibition of the renin-angiotensin-aldosterone system may exert an additional protective role by suppressing electrical and structural cardiac remodelling.964,1411,1412 Large RCTs and meta-analyses have yielded equivocal results, either in favour1413–1416 or against1417–1421 statin use for primary prevention of AF. Controversial results have also been reported for the effects of fish oils on primary prevention of AF.1422

For primary prevention of postoperative AF after cardiac and non-cardiac surgery, see section 11.19.

12.2 Secondary prevention of atrial fibrillation

For secondary AF prevention see section 11.3 and Supplementary section 12.

13 Sex-related differences in atrial fibrillation

Female patients are generally under-represented in RCTs, including AF trials. Sex-related differences in the epidemiology, pathophysiology, clinical presentation, and prognosis of AF that are consistently reported19,107,124,1423,1424 may influence the effectiveness of AF treatment, and hence should be considered in a personalized, individual patient-centred approach to AF management in clinical practice.1425 Understanding the underlying pathophysiological mechanisms and biology may help to improve personalized treatments. Adequate representation of women in future AF trials is recommended, as well as the identification and resolution of sex-specific barriers to implementation of guideline-recommended treatments for AF.

Women presenting with AF are older, have a higher prevalence of hypertension, VHD, and HFpEF, and a lower prevalence of CAD compared with men. Women with AF are more often symptomatic than men with AF, with greater symptom severity.1423,1426

Female sex is a stroke risk modifier that increases the risk of AF-associated stroke in the presence of other stroke risk factors.353 Women with AF have a greater stroke severity and permanent disability than men with AF.1427 Anticoagulation with warfarin may be less well controlled in women, and they have a greater residual stroke risk even with well-controlled VKAs.1428 The efficacy and safety of NOACs in landmark RCTs were consistent in both sexes, but women were largely under-represented.423

In women with AF, the use of AADs for rhythm control is associated with significantly higher rates of life-threatening adverse events (e.g. acquired long QT syndrome with class Ia or III AADs)1429,1430 or sinus-node disease/bradyarrhythmia requiring pacemaker implantation19 compared with male patients. Women with AF are less likely to undergo electrical cardioversion,1426 and are referred for AF catheter ablation later than men, possibly reflecting AF occurrence later in life among women.107,1431,1432 The result of PVI may be less favourable in women,1431,1432 with higher rates of procedure-related complications.1431 Women are more likely to undergo atrioventricular nodal ablation for AF than men.124 Sex-specific data on cardiovascular risk management in women with AF are lacking. Principles outlined in section 11.3 apply to women with AF.

Recommendations pertaining to sex-related differences in AF

graphic
graphic

AF = atrial fibrillation.

a

Class of recommendation.

b

Level of evidence.

Recommendations pertaining to sex-related differences in AF

graphic
graphic

AF = atrial fibrillation.

a

Class of recommendation.

b

Level of evidence.

14 Implementation of the atrial fibrillation guidelines

Guideline-adherent care (i.e. the implementation of guideline-recommended management to individual AF patients) aims to improve patient outcomes and reduce healthcare costs,1238,1434,1435 but adherence to guidelines is modest worldwide.124,1436–1439,1440,1441 Reportedly, the adoption of NOACs as first-line therapy has been associated with increasing guideline-adherent stroke prevention.1442,1443

Guideline non-adherence is multifactorial,1215,1444,1445 including physician/healthcare professional- and healthcare system-related factors.1446 Integrated AF management may facilitate adherence to guidelines. Various educational interventions280,284,290,1447,1448 based on guideline-provided recommendations284 and tailored to close specific knowledge gaps among healthcare professionals and/or AF patients1446 may facilitate the implementation of guideline-based AF management to improve patient outcomes.277,1449–1452 Further research is needed to identify the cost-effective intervention type(s) that would more effectively improve patient clinical outcomes, medication adherence, and QoL.

15 Quality measures and clinical performance indicators in the management of atrial fibrillation

Measurable service quality has been identified as a cornerstone for optimal AF management and is a mandatory step towards value-based healthcare. Quality and performance indicator sets should provide practitioners and institutions with the tools to measure the quality of care (e.g. adherence to guideline class I recommendations upon discharge/end of visit, complications after procedures, access/waiting list times) and identify opportunities for improvement. They should capture important aspects of care quality, including structure, process, outcome measures, and patient-centrednes, while the reporting burden for hospitals, practices, and practitioners should be kept to a minimum.658,1453–1455

A collaborative effort involving the ESC, EHRA, Asia Pacific Heart Rhythm Society, Heart Rhythm Society, and Latin American Heart Rhythm Society was put in place to develop quality indicators for the diagnosis and management of AF; a summary form of these quality indicators is provided in Table 22, with the full set published separately.317 The ESC quality indicators are intended for quality improvement and performance measurement through meaningful surveillance, as well as for integration within registries that specifically aim to identify areas for improvement in clinical practice and are not intended for ranking healthcare professionals/providers or payment incentives.

Table 22

Summary of quality indicators for the diagnosis and management of AF

Domain: Patient assessment (at baseline and follow-up)
Main quality indicator: CHA2DS2-VASc cardioembolic risk assessment.
Main quality indicator: bleeding risk assessment using a validated method such as the HAS-BLED score.
Numerator: Number of AF patients who have their respective score documented at the time of diagnosis and at every follow-up appointment.
Denominator: Number of AF patients.
Domain: Anticoagulation
Main quality indicator: inappropriate prescription of anticoagulation to patients with a CHA2DS2-VASc score of 0 for men and 1 for women.
Numerator: number of AF patients with CHA2DS2-VASc score of 0 for men and 1 for women, who are inappropriately prescribed anticoagulation.
Denominator: number of AF patients with CHA2DS2-VASc score of 0 for men and 1 for women who do not have other indication for anticoagulation.
Main quality indicator: proportion of patients with a CHA2DS2-VASc score of ≥1 for men and ≥2 for women who are prescribed anticoagulation.
Numerator: Number of AF patients with CHA2DS2-VASc score of ≥1 for men and ≥2 for women who are prescribed anticoagulation.
Denominator: Number of AF patients with CHA2DS2-VASc score of ≥1 for men and ≥2 for women who are eligible for anticoagulation with no contraindication or refusal.
Domain: rate control
Main quality indicator: inappropriate prescription of AADsa to patients with permanent AF (i.e. where no attempt to restore sinus rhythm is planned).
Numerator: Number of patients with permanent AF who are prescribed one or more AADsa for rhythm control.
Denominator: Number of patients with permanent AF.
Domain: rhythm control
Main quality indicator: inappropriate prescription of class IC AADs to patients with structural heart disease.
Numerator: number of AF patients with structural heart disease who are inappropriately prescribed class IC AADs.
Denominator: number of AF patients with structural heart disease.
Main quality indicator: proportion of patients with symptomatic paroxysmal or persistent AF who are offered AF catheter ablation after failure of/intolerance to one class I or class III AAD.
Numerator: Number of patients with paroxysmal or persistent AF who are offered catheter ablation after the failure of, or intolerance to, at least one class I or class III AAD.
Denominator: Number of patients with paroxysmal or persistent AF with no contraindications (or refusal) to catheter ablation who remain symptomatic on, or intolerant to at least one class I or class III AAD.
Domain: risk factor management
Main quality indicator: Proportion of patients who have their modifiable risk factors identified.
Numerator: number of AF patients who have their modifiable risk factors (e.g. BP, obesity, OSA, alcohol excess, lack of exercise, poor glycaemic control and smoking) identified
Denominator: number of AF patients.
Domain: outcomes
Main quality indicator: ischaemic stroke or TIA.
Main quality indicator: life-threatening or major bleeding events.b
Numerator: number of AF patients who have a documented ischaemic or bleeding event
Denominator: number of AF patients or number of patients prescribed an OAC, respectively.
Domain: Patient assessment (at baseline and follow-up)
Main quality indicator: CHA2DS2-VASc cardioembolic risk assessment.
Main quality indicator: bleeding risk assessment using a validated method such as the HAS-BLED score.
Numerator: Number of AF patients who have their respective score documented at the time of diagnosis and at every follow-up appointment.
Denominator: Number of AF patients.
Domain: Anticoagulation
Main quality indicator: inappropriate prescription of anticoagulation to patients with a CHA2DS2-VASc score of 0 for men and 1 for women.
Numerator: number of AF patients with CHA2DS2-VASc score of 0 for men and 1 for women, who are inappropriately prescribed anticoagulation.
Denominator: number of AF patients with CHA2DS2-VASc score of 0 for men and 1 for women who do not have other indication for anticoagulation.
Main quality indicator: proportion of patients with a CHA2DS2-VASc score of ≥1 for men and ≥2 for women who are prescribed anticoagulation.
Numerator: Number of AF patients with CHA2DS2-VASc score of ≥1 for men and ≥2 for women who are prescribed anticoagulation.
Denominator: Number of AF patients with CHA2DS2-VASc score of ≥1 for men and ≥2 for women who are eligible for anticoagulation with no contraindication or refusal.
Domain: rate control
Main quality indicator: inappropriate prescription of AADsa to patients with permanent AF (i.e. where no attempt to restore sinus rhythm is planned).
Numerator: Number of patients with permanent AF who are prescribed one or more AADsa for rhythm control.
Denominator: Number of patients with permanent AF.
Domain: rhythm control
Main quality indicator: inappropriate prescription of class IC AADs to patients with structural heart disease.
Numerator: number of AF patients with structural heart disease who are inappropriately prescribed class IC AADs.
Denominator: number of AF patients with structural heart disease.
Main quality indicator: proportion of patients with symptomatic paroxysmal or persistent AF who are offered AF catheter ablation after failure of/intolerance to one class I or class III AAD.
Numerator: Number of patients with paroxysmal or persistent AF who are offered catheter ablation after the failure of, or intolerance to, at least one class I or class III AAD.
Denominator: Number of patients with paroxysmal or persistent AF with no contraindications (or refusal) to catheter ablation who remain symptomatic on, or intolerant to at least one class I or class III AAD.
Domain: risk factor management
Main quality indicator: Proportion of patients who have their modifiable risk factors identified.
Numerator: number of AF patients who have their modifiable risk factors (e.g. BP, obesity, OSA, alcohol excess, lack of exercise, poor glycaemic control and smoking) identified
Denominator: number of AF patients.
Domain: outcomes
Main quality indicator: ischaemic stroke or TIA.
Main quality indicator: life-threatening or major bleeding events.b
Numerator: number of AF patients who have a documented ischaemic or bleeding event
Denominator: number of AF patients or number of patients prescribed an OAC, respectively.

AAD = antiarrhythmic drug; AF = atrial fibrillation; BP = blood pressure; CHA2DS2-VASc = Congestive heart failure, Hypertension, Age ≥75 years, Diabetes mellitus, Stroke, Vascular disease, Age 65-74 years, Sex category (female); HAS-BLED = Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile INR, Elderly (>65 years), Drugs/alcohol concomitantly; OAC = oral anticoagulant; OSA = obstructive sleep apnoea; TIA = transient ischaemic attack.

a

Flecainide, propafenone, amiodarone, dronedarone, sotalol and disopyramide.

b

Using the definitions of the International Society of Thrombosis and Haemostasis.1456,1457

Table 22

Summary of quality indicators for the diagnosis and management of AF

Domain: Patient assessment (at baseline and follow-up)
Main quality indicator: CHA2DS2-VASc cardioembolic risk assessment.
Main quality indicator: bleeding risk assessment using a validated method such as the HAS-BLED score.
Numerator: Number of AF patients who have their respective score documented at the time of diagnosis and at every follow-up appointment.
Denominator: Number of AF patients.
Domain: Anticoagulation
Main quality indicator: inappropriate prescription of anticoagulation to patients with a CHA2DS2-VASc score of 0 for men and 1 for women.
Numerator: number of AF patients with CHA2DS2-VASc score of 0 for men and 1 for women, who are inappropriately prescribed anticoagulation.
Denominator: number of AF patients with CHA2DS2-VASc score of 0 for men and 1 for women who do not have other indication for anticoagulation.
Main quality indicator: proportion of patients with a CHA2DS2-VASc score of ≥1 for men and ≥2 for women who are prescribed anticoagulation.
Numerator: Number of AF patients with CHA2DS2-VASc score of ≥1 for men and ≥2 for women who are prescribed anticoagulation.
Denominator: Number of AF patients with CHA2DS2-VASc score of ≥1 for men and ≥2 for women who are eligible for anticoagulation with no contraindication or refusal.
Domain: rate control
Main quality indicator: inappropriate prescription of AADsa to patients with permanent AF (i.e. where no attempt to restore sinus rhythm is planned).
Numerator: Number of patients with permanent AF who are prescribed one or more AADsa for rhythm control.
Denominator: Number of patients with permanent AF.
Domain: rhythm control
Main quality indicator: inappropriate prescription of class IC AADs to patients with structural heart disease.
Numerator: number of AF patients with structural heart disease who are inappropriately prescribed class IC AADs.
Denominator: number of AF patients with structural heart disease.
Main quality indicator: proportion of patients with symptomatic paroxysmal or persistent AF who are offered AF catheter ablation after failure of/intolerance to one class I or class III AAD.
Numerator: Number of patients with paroxysmal or persistent AF who are offered catheter ablation after the failure of, or intolerance to, at least one class I or class III AAD.
Denominator: Number of patients with paroxysmal or persistent AF with no contraindications (or refusal) to catheter ablation who remain symptomatic on, or intolerant to at least one class I or class III AAD.
Domain: risk factor management
Main quality indicator: Proportion of patients who have their modifiable risk factors identified.
Numerator: number of AF patients who have their modifiable risk factors (e.g. BP, obesity, OSA, alcohol excess, lack of exercise, poor glycaemic control and smoking) identified
Denominator: number of AF patients.
Domain: outcomes
Main quality indicator: ischaemic stroke or TIA.
Main quality indicator: life-threatening or major bleeding events.b
Numerator: number of AF patients who have a documented ischaemic or bleeding event
Denominator: number of AF patients or number of patients prescribed an OAC, respectively.
Domain: Patient assessment (at baseline and follow-up)
Main quality indicator: CHA2DS2-VASc cardioembolic risk assessment.
Main quality indicator: bleeding risk assessment using a validated method such as the HAS-BLED score.
Numerator: Number of AF patients who have their respective score documented at the time of diagnosis and at every follow-up appointment.
Denominator: Number of AF patients.
Domain: Anticoagulation
Main quality indicator: inappropriate prescription of anticoagulation to patients with a CHA2DS2-VASc score of 0 for men and 1 for women.
Numerator: number of AF patients with CHA2DS2-VASc score of 0 for men and 1 for women, who are inappropriately prescribed anticoagulation.
Denominator: number of AF patients with CHA2DS2-VASc score of 0 for men and 1 for women who do not have other indication for anticoagulation.
Main quality indicator: proportion of patients with a CHA2DS2-VASc score of ≥1 for men and ≥2 for women who are prescribed anticoagulation.
Numerator: Number of AF patients with CHA2DS2-VASc score of ≥1 for men and ≥2 for women who are prescribed anticoagulation.
Denominator: Number of AF patients with CHA2DS2-VASc score of ≥1 for men and ≥2 for women who are eligible for anticoagulation with no contraindication or refusal.
Domain: rate control
Main quality indicator: inappropriate prescription of AADsa to patients with permanent AF (i.e. where no attempt to restore sinus rhythm is planned).
Numerator: Number of patients with permanent AF who are prescribed one or more AADsa for rhythm control.
Denominator: Number of patients with permanent AF.
Domain: rhythm control
Main quality indicator: inappropriate prescription of class IC AADs to patients with structural heart disease.
Numerator: number of AF patients with structural heart disease who are inappropriately prescribed class IC AADs.
Denominator: number of AF patients with structural heart disease.
Main quality indicator: proportion of patients with symptomatic paroxysmal or persistent AF who are offered AF catheter ablation after failure of/intolerance to one class I or class III AAD.
Numerator: Number of patients with paroxysmal or persistent AF who are offered catheter ablation after the failure of, or intolerance to, at least one class I or class III AAD.
Denominator: Number of patients with paroxysmal or persistent AF with no contraindications (or refusal) to catheter ablation who remain symptomatic on, or intolerant to at least one class I or class III AAD.
Domain: risk factor management
Main quality indicator: Proportion of patients who have their modifiable risk factors identified.
Numerator: number of AF patients who have their modifiable risk factors (e.g. BP, obesity, OSA, alcohol excess, lack of exercise, poor glycaemic control and smoking) identified
Denominator: number of AF patients.
Domain: outcomes
Main quality indicator: ischaemic stroke or TIA.
Main quality indicator: life-threatening or major bleeding events.b
Numerator: number of AF patients who have a documented ischaemic or bleeding event
Denominator: number of AF patients or number of patients prescribed an OAC, respectively.

AAD = antiarrhythmic drug; AF = atrial fibrillation; BP = blood pressure; CHA2DS2-VASc = Congestive heart failure, Hypertension, Age ≥75 years, Diabetes mellitus, Stroke, Vascular disease, Age 65-74 years, Sex category (female); HAS-BLED = Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile INR, Elderly (>65 years), Drugs/alcohol concomitantly; OAC = oral anticoagulant; OSA = obstructive sleep apnoea; TIA = transient ischaemic attack.

a

Flecainide, propafenone, amiodarone, dronedarone, sotalol and disopyramide.

b

Using the definitions of the International Society of Thrombosis and Haemostasis.1456,1457

Recommendations for quality measures in patients with AF

graphic
graphic

AF = atrial fibrillation.

a

Class of recommendation.

b

Level of evidence.

Recommendations for quality measures in patients with AF

graphic
graphic

AF = atrial fibrillation.

a

Class of recommendation.

b

Level of evidence.

16 Epidemiology, clinical implications, and management of atrial high-rate episodes/ subclinical atrial fibrillation

The incidence of AHRE/subclinical AF in patients with a pacemaker/implanted device is 30–70%, but it may be lower in the general population.1458 Very short episodes (≤10 − 20 s/day) are considered clinically irrelevant, as they are not significantly associated with longer episodes or an increased risk of stroke or systemic embolism.1459 However, longer episodes of AHRE/subclinical AF (minimum of 5 − 6 min) are associated with an increased risk of clinical AF,467,469 ischaemic stroke,168,467 major adverse cardiovascular events,1460 and cardiovascular death.1461

Overall, the absolute risk of stroke associated with AHRE/subclinical AF may be lower than with clinical AF.160,168,226,467 The temporal dissociation from acute stroke suggests that AHRE/subclinical AF may represent a marker rather than a risk factor for stroke4,7,1462 (Supplementary Box 6).

Whereas current data were obtained mostly from pacemakers/implantable cardioverter defibrillators or post-stroke patients, AHRE/subclinical AF is increasingly reported in a variety of patients undergoing cardiac monitoring. Clinical AF will reportedly develop in 1 in 5 - 6 of patients within 2.5 years after diagnosing AHRE/subclinical AF.168 Notwithstanding that more high-quality evidence is needed to inform optimal management of these patients, more intense follow-up and monitoring to detect clinical AF early is prudent (preferably with the support of remote monitoring). Notably, the AHRE/subclinical AF burden is not static but may change on daily basis,469 hence should be regularly reassessed—the greater the AHRE/subclinical AF burden at diagnosis, the higher the risk of subsequent progression to longer episodes469 (Figure 24).

Progression of atrial high-rate episode burden (left panel) and stroke rates according to AHRE daily burden and CHA2DS2-VASc score (right panel). AHRE = atrial high-rate episodes; CHA2DS2-VASc = Congestive heart failure, Hypertension, Age ≥75 years, Diabetes mellitus, Stroke, Vascular disease, Age 65 − 74 years, Sex category (female); OAC = oral anticoagulant. aThe higher the burden at diagnosis, the greater the incidence of progression in the next 6 months and thereafter. bStroke rates above the threshold for OAC are shown in red.
Figure 24

Progression of atrial high-rate episode burden (left panel) and stroke rates according to AHRE daily burden and CHA2DS2-VASc score (right panel). AHRE = atrial high-rate episodes; CHA2DS2-VASc = Congestive heart failure, Hypertension, Age ≥75 years, Diabetes mellitus, Stroke, Vascular disease, Age 65 − 74 years, Sex category (female); OAC = oral anticoagulant. aThe higher the burden at diagnosis, the greater the incidence of progression in the next 6 months and thereafter. bStroke rates above the threshold for OAC are shown in red.

Whereas available evidence is insufficient to justify routine OAC use in patients with AHRE/subclinical AF, modifiable stroke risk factors should be identified and managed in each patient.

The use of OAC may be considered in selected patients with longer durations of AHRE/subclinical AF (≥24 h) and an estimated high individual risk of stroke,4,1462 accounting for the anticipated net clinical benefit and informed patient’s preferences (Figures 24 and25). In the recent trials, OAC was initiated in 76.4% and 56.3% of patients with ≥2 clinical stroke risk factors and insertable cardiac monitor-detected physician-confirmed AF≥6 min, but follow-up bleeding rates were not reported.1463,1464 In a large retrospective cohort study using remote monitoring data about daily AF burden, there was large practice variation in OAC initiation. Across increasing AF burden strata (from >6 min to >24 h) the risk of stroke in untreated patients increased numerically, and the strongest association of OAC with reduction in stroke was observed among patients with device-detected AF episodes of >24 h.5

Proposed management of AHRE/subclinical AF. AF = atrial fibrillation; AHRE = atrial high-rate episode; CKD = chronic kidney disease; CHA2DS2-VASc = Congestive heart failure, Hypertension, Age ≥75 years, Diabetes mellitus, Stroke, Vascular disease, Age 65 − 74 years, Sex category (female); f = female; LA = left atrium; LoE = level of evidence; m = male; OAC = oral anticoagulant; SCAF = subclinical atrial fibrillation. aHighly selected patients (e.g. with previous stroke and/or age ≥75 years, or ≥3 CHA2DS2-VASc risk factors, and additional non-CHA2DS2-VASc stroke factors such as CKD, elevated blood biomarkers, spontaneous echo contrast in dilated LA, etc); selected patients (e.g. with previous stroke and/or age ≥75 years, or ≥3 CHA2DS2-VASc risk factors , etc).
Figure 25

Proposed management of AHRE/subclinical AF. AF = atrial fibrillation; AHRE = atrial high-rate episode; CKD = chronic kidney disease; CHA2DS2-VASc = Congestive heart failure, Hypertension, Age ≥75 years, Diabetes mellitus, Stroke, Vascular disease, Age 65 − 74 years, Sex category (female); f = female; LA = left atrium; LoE = level of evidence; m = male; OAC = oral anticoagulant; SCAF = subclinical atrial fibrillation. aHighly selected patients (e.g. with previous stroke and/or age ≥75 years, or ≥3 CHA2DS2-VASc risk factors, and additional non-CHA2DS2-VASc stroke factors such as CKD, elevated blood biomarkers, spontaneous echo contrast in dilated LA, etc); selected patients (e.g. with previous stroke and/or age ≥75 years, or ≥3 CHA2DS2-VASc risk factors , etc).

Recommendations for management of patients with AHRE

graphic
graphic

AF = atrial fibrillation; AHRE = atrial high-rate episode; CIED = cardiac implantable electronic device; ECG = electrocardiogram.

a

Class of recommendation.

b

Level of evidence.

Recommendations for management of patients with AHRE

graphic
graphic

AF = atrial fibrillation; AHRE = atrial high-rate episode; CIED = cardiac implantable electronic device; ECG = electrocardiogram.

a

Class of recommendation.

b

Level of evidence.

17 Atrial fibrillation and other atrial tachyarrhythmias (atrial flutter and atrial tachycardias)

Although AFL may exist as a solitary atrial arrhythmia, a significant proportion of patients will subsequently develop AF.1466–1470 Typical AFL may occur in those taking class IC AADs or amiodarone.1467,1468,1471 The ABC pathway for integrated AF management largely applies to patients with AFL. It is recommended that stroke-prevention strategies in patients with solitary AFL, including periprocedural management of stroke risk, follow the same principles as in patients with AF.1472

Rate control should be the first step in symptom management. However, cardioversion to sinus rhythm may be more effective, especially electrical cardioversion or (where feasible) high-rate stimulation.1473,1474 Of note, the class III AADs dofetilide and ibutilide i.v. are very effective in interrupting AFL, whereas the class Ic drugs flecainide and propafenone1475–1478 should not be used in the absence of atrioventricular-blocking drugs as they may slow the atrial rate, thus facilitating 1 : 1 atrioventricular conduction with a rapid ventricular rate.1479,1480 AF catheter ablation of the CTI is the most effective rhythm control treatment for CTI-dependent AFL.732,1481,1482 When typical AFL develops in AF patients during treatment with class Ic drugs or amiodarone, CTI ablation should be considered to ensure that AADs can be continued for AF rhythm control.732,1481

Atypical AFL (i.e. macro re-entrant atrial tachycardia) most commonly occurs in diseased or scarred atrial myocardium. Clinical management of atypical AFL/macro re-entrant atrial tachycardia broadly follows the principles of typical AFL management, but the use of AADs is often limited by significant structural heart disease, and ablation is more complex.1336

Notably, the intervention to treat atrial tachycardias (AFL/macro re-entrant atrial tachycardia) occurring early after AF catheter ablation (or surgery) should be delayed, and initial rate control or the use of AADs should be considered instead, as some of these tachyarrhythmias are transient and cease after maturation of the lesions deployed by the index procedure.1483–1485 For additional details about AFL, see Supplementary Box 7 and the 2019 ESC Guidelines on supraventricular tachycardias.1336

18 Key messages

  1. The diagnosis of AF needs to be confirmed by a conventional 12-lead ECG tracing or rhythm strip showing AF for ≥30 s.

  2. Structured characterization of AF, including stroke risk, symptom severity, severity of AF burden, and AF substrate, helps improve personalized treatment of AF patients.

  3. Novel tools and technologies for screening and detection of AF such as (micro-)implants and wearables substantially add to the diagnostic opportunities in patients at risk for AF. However, appropriate management pathways based on such tools are still incompletely defined.

  4. Integrated holistic management of AF patients is essential to improving their outcomes.

  5. Patient values need to be considered in treatment decision making and incorporated into the AF management pathways; the structured assessment of PRO measures is an important element to document and measure treatment success.

  6. The ABC pathway streamlines integrated care of AF patients across healthcare levels and among different specialties.

  7. Structured, clinical, risk-score−based assessment of individual thrombo-embolic risk, using the CHA2DS2-VASc score, should be performed as the first step in optimal thrombo-embolic risk management in AF patients.

  8. Patients with AF and risk factors for stroke need to be treated with OAC for stroke prevention. In NOAC-eligible patients, NOACs are preferred over VKAs.

  9. A formal structured risk-score−based bleeding risk assessment using, for example, the HAS-BLED score, helps to identify non-modifiable and address modifiable bleeding risk factors in AF patients.

  10. An elevated bleeding risk should not automatically lead to withholding OAC in patients with AF and stroke risk. Instead, modifiable bleeding risk factors should be addressed, and high-risk patients scheduled for a more frequent clinical review and follow-up.

  11. Rate control is an integral part of AF management and is often sufficient to improve AF-related symptoms.

  12. The primary indication for rhythm control using cardioversion, AADs, and/or catheter ablation is reduction in AF-related symptoms and improvement of QoL.

  13. The decision to initiate long-term AAD therapy needs to balance symptom burden, possible adverse drug reactions, particularly drug-induced proarrhythmia or extracardiac side-effects, and patient preferences.

  14. Catheter ablation is a well-established treatment for prevention of AF recurrences. When performed by appropriately trained operators, catheter ablation is a safe and superior alternative to AADs for maintenance of sinus rhythm and symptom improvement.

  15. Major risk factors for AF recurrence should be assessed and considered in the decision making for interventional therapy.

  16. In patients with AF and normal LVEF, catheter ablation has not been shown to reduce total mortality or stroke. In patients with AF and tachycardia-induced cardiomyopathy, catheter ablation reverses LV dysfunction in most cases.

  17. Weight loss, strict control of risk factors, and avoidance of triggers for AF are important strategies to improve outcome of rhythm control.

  18. Identification and management of risk factors and concomitant diseases is an integral part of the treatment of AF patients.

  19. In AF patients with ACS undergoing uncomplicated PCI, an early discontinuation of aspirin and switch to dual antithrombotic therapy with OAC and a P2Y12 inhibitor should be considered.

  20. Patients with AHRE should be regularly monitored for progression to clinical AF and changes in the individual thrombo-embolic risk (i.e. change in CHA2DS2-VASc score). In patients with longer AHRE (especially >24 h) and a high CHA2DS2-VASc score, it is reasonable to consider the use of OAC when a positive net clinical benefit from OAC is anticipated in a shared, informed, treatment decision-making process.

19 Gaps in evidence

Whereas some progress has been made since publication of the 2016 ESC AF Guidelines, major gaps identified in those guidelines persist in 2020, calling for more intense research. In 2019, the EHRA published a white paper that covers major gaps in the field of AF in detail.1486 The following bullet-list gives the most important knowledge gaps:

□ Major health modifiers causing atrial fibrillation

Mechanisms of AF are not yet fully understood. Improvement in understanding of these mechanisms in individual patients, e.g. patients with cardiac structural remodelling or HF, would allow better selection of treatments including the best rate and rhythm control strategies and OAC.

It is uncertain how educational interventions translate into actual behavioural change (patients and physicians) that leads to improvements in clinical management and outcomes, especially in the multimorbid AF patient.

□ Implementation of digital technologies for screening, diagnosis, and risk stratification in the atrial fibrillation patient

New techniques for digital ECG analysis (e.g. machine learning and artificial intelligence) and new technologies (e.g. wearables and injectables) have opened up potentially significant opportunities for the detection and diagnosis of AF. These innovations may help to personalize therapy and risk stratification. Studies are needed to evaluate such opportunities and to define for which groups of patients this is worthwhile.

□ Type of atrial fibrillation

There is a gap in knowledge regarding classification of AF. Recent data suggest that paroxysmal AF is not one entity. According to the pattern, type of therapy and outcome may differ.1487 More studies are needed.

□ How much atrial fibrillation constitutes a mandate for therapy?

The threshold of AF burden at which to initiate OAC therapy needs to be defined more clearly. This knowledge gap has resulted in substantial variation in physician attitudes and practice patterns.5

We are still waiting for the results of two ongoing RCTs in subclinical AF patients who are detected with cardiac implantable electronic device (CIED) [(Apixaban for the Reduction of Thrombo-Embolism in Patients With Device-Detected Sub-Clinical Atrial Fibrillation) (NCT 01938248) and NOAH (Non-vitamin K Antagonist Oral Anticoagulants in Patients With Atrial High Rate Episodes) (NCT 02618577)].

□ Role of biomarkers in atrial fibrillation management

Although some studies have demonstrated an effective role of biomarkers (including natriuretic peptides and troponin) in AF risk assessment, there is uncertainty over the exact time point of biomarker assessment, optimal cut-offs, and the effect on management decision making based on changes in biomarker levels over time, especially with increasing age and incident comorbidities.

□ Stroke risk in specific populations

Some studies have tested the effect of biomarkers in predicting risk of AF-related complications, including stroke, in specific populations. However, it is unknown if biomarkers and biomarker-based scores practically help physicians in refining stroke risk, especially in prospective non-anticoagulated cohorts, particularly given the dynamic nature of stroke risk and how many current biomarkers are non-specific for AF or AF-related outcomes.

There is uncertainty of actual stroke risk in AHRE, compared with actual stroke risk in overt AF, in properly matched cohorts in similar settings, and the effect of appropriate management pathways.

The effect of sex in AF patients has been more investigated. Men with AF are less likely to have hypertension or VHD vs. women.1488 Women often present with atypical symptoms related to AF. Further comparative studies are needed in different settings and ethnic groups on the effect of different stroke risk factors and female sex on stroke and bleeding risks.

□ Anticoagulant therapy in specific patients

There is a gap in knowledge regarding optimal NOAC dosing in specific groups, including those with mild-to-moderate CKD, with very low/high body mass index, and patients receiving medications with a high risk of metabolic interaction.1489

In patients with CrCl 25 mL/min, RCT-derived data on the effect of VKA or NOACs is still lacking, due to the exclusion of these patients from the major RCTs. However, two RCTs (NCT02933697, NCT03987711) are currently assessing OAC use and comparing NOACs with VKAs in patients with end-stage renal disease.

□ Anticoagulation in patients with heart valve diseases

There are gaps in evidence on NOAC use in AF patients with rheumatic mitral valve disease and during the first 3 months after surgical or transcatheter implantation of a bioprosthesis; observational data regarding the use of NOACs after transcatheter aortic valve implantation are conflicting.1163

□ Anticoagulation in atrial fibrillation patients after a bleeding or stroke event

As high-quality RCT-derived evidence to inform optimal timing of anticoagulation after acute ischaemic stroke is lacking, OAC use in the early post-stroke period is currently based on expert consensus. Several ongoing RCTs [ELAN (NCT03148457), OPTIMAS (EudraCT, 2018-003859-3), TIMING (NCT02961348), and START (NCT03021928)] will try to assess the differences between the two approaches, including early (<1 week) vs. late NOAC initiation in patients with AF-related ischaemic stroke.

□ Left atrial appendage occlusion for stroke prevention

More studies have been conducted in this field. There is clearer evidence of the safety and possible complications of the LAA closure procedure.450–454 However, there are still knowledge gaps to be addressed: (i) antithrombotic management after LAA occlusion has not been evaluated in a randomized manner; and (ii) the efficacy and safety of LAA closure vs. OAC therapy needs to be assessed in randomized trials.

LAA occluders have not been compared with NOAC therapy in patients at risk for bleeding, or with surgical LAA occlusion/exclusion.

□ Surgical exclusion of Left atrial appendage

Only limited RCT data are available457–459 on surgical exclusion of the LAA. Although a large RCT in patients with an associated cardiac surgical procedure is ongoing,462 adequately powered RCTs are needed.

There is the need for adequately powered trials to define the best indications for LAA occlusion/exclusion compared with NOAC therapy in patients with relative or absolute contraindications for anticoagulation, in those with an ischaemic stroke on anticoagulant therapy, and for assessment of the appropriate antithrombotic therapy after LAA occlusion.

□ Atrial fibrillation catheter ablation technique

The best approach to safely and expeditiously achieve permanent PVI in a single procedure is still one of the knowledge gaps in relation to emerging technologies for catheter ablation of AF. Moreover, it remains unknown if ablating additional targets will improve the outcomes of AF catheter ablation.1490

□ Outcome of atrial fibrillation catheter ablation

The following issues need to be addressed in further studies:

  • The value of early AF ablation to prevent AF progression.

  • The optimal outcome measure (AF 30 s, AF burden, etc.) for AF-related outcome.

  • How much reduction in AF burden is needed to achieve an effect on hard endpoints, including survival, stroke, and comorbidity.

  • The main mechanism of PVI translating into freedom of AF.

  • The potential effect of cardiac structure and function on the likelihood of success of AF ablation.

Despite the publication of CABANA and CASTLE-AF, more data are needed on the effect of AF catheter ablation on clinical outcomes, including death, stroke, serious bleeding, AF recurrence, QoL, and cardiac arrest.

The relationship between the degree of atrial dilation/fibrosis and successful ablation of AF needs to be addressed. Additionally, the impact of specific components of structural heart disease, including LA structure/function, LV structure, etc., on the success of AF catheter ablation and the likelihood of recurrence requires further investigation.

□ Who may benefit less from atrial fibrillation catheter ablation

There are gaps in knowledge about subgroups of patients who may benefit less from AF catheter ablation, including (i) persistent and long-standing persistent AF; (ii) patients with enlarged atrial size and/or atrial fibrosis; (iii) patients with atypical AFL; and (iv) patients with risk factors for AF recurrence, including obesity or sleep apnoea.

□ Thoracoscopic ‘stand-alone’ atrial fibrillation surgery

There are no convincing data on the effects on stroke of surgical ablation as a stand-alone procedure or in combination with LAA occlusion or exclusion on various outcomes including QoL, stroke, and death.

□ Personalized therapy

The arrhythmia phenotype may differ among patients. Improved assessment of the pathophysiological process involved in the individual patient by using clinical characteristics, blood biomarkers, and non-invasive substrate determination (echo/MRI/CT) may improve personalized therapy (e.g. selection of rhythm control, yes or no; treatment of risk factors and comorbidities; type of antiarrhythmic drug; atrial ablation; and which type/techniques used for AF).

Management of AF. AAD = antiarrhythmic drug; AF = atrial fibrillation; ECG = electrocardiogram; EHRA = European Heart Rhythm Association; CHA2DS2-VASc = Congestive HF, Hypertension, Age ≥75 years, diabetes mellitus, Stroke, Vascular disease, Age 65 − 74 years, Sex category (female); CV = cardioversion; NOAC = non-vitamin K antagonist oral anticoagulant; OAC = oral anticoagulant; TTR = time in therapeutic range; VKA = vitamin K antagonist.
Central Illustration

Management of AF. AAD = antiarrhythmic drug; AF = atrial fibrillation; ECG = electrocardiogram; EHRA = European Heart Rhythm Association; CHA2DS2-VASc = Congestive HF, Hypertension, Age ≥75 years, diabetes mellitus, Stroke, Vascular disease, Age 65 − 74 years, Sex category (female); CV = cardioversion; NOAC = non-vitamin K antagonist oral anticoagulant; OAC = oral anticoagulant; TTR = time in therapeutic range; VKA = vitamin K antagonist.

20 ‘What to do’ and ‘what not to do’ messages from the Guidelines

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AAD = antiarrhythmic drug; ACS = acute coronary syndrome; AF = atrial fibrillation; AFL = atrial flutter; AHRE = atrial high-rate episodes; BP = blood pressure; CCS = chronic coronary syndrome; CHA2DS2-VASc = Congestive heart failure, Hypertension, Age ≥75 years, Diabetes mellitus, Stroke, Vascular disease, Age 65–74 years, Sex category (female); CIED = cardiac implantable electronic device; CrCl = creatinine clearance; ECG = electrocardiogram; HF = heart failure; HFpEF = heart failure with preserved ejection fraction; HFrEF = heart failure with reduced ejection fraction; i.v. = intravenous; INR = international normalized ratio; LMWH = low-molecular-weight heparin; LV = left ventricular; LVEF = left ventricular ejection fraction; LVH = left ventricular hypertrophy; NOAC = non-vitamin K antagonist oral anticoagulant; OAC = oral anticoagulant; PCI = percutaneous coronary intervention; PRO = patient-reported outcome; PVI = pulmonary vein isolation; QoL = quality of life; TIA = transient ischaemic attack; TOE = transoesophageal echocardiography; TTR = time in therapeutic range; UFH = unfractionated heparin; VHD = Valvular heart disease; VKA = vitamin K antagonist.

graphic
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AAD = antiarrhythmic drug; ACS = acute coronary syndrome; AF = atrial fibrillation; AFL = atrial flutter; AHRE = atrial high-rate episodes; BP = blood pressure; CCS = chronic coronary syndrome; CHA2DS2-VASc = Congestive heart failure, Hypertension, Age ≥75 years, Diabetes mellitus, Stroke, Vascular disease, Age 65–74 years, Sex category (female); CIED = cardiac implantable electronic device; CrCl = creatinine clearance; ECG = electrocardiogram; HF = heart failure; HFpEF = heart failure with preserved ejection fraction; HFrEF = heart failure with reduced ejection fraction; i.v. = intravenous; INR = international normalized ratio; LMWH = low-molecular-weight heparin; LV = left ventricular; LVEF = left ventricular ejection fraction; LVH = left ventricular hypertrophy; NOAC = non-vitamin K antagonist oral anticoagulant; OAC = oral anticoagulant; PCI = percutaneous coronary intervention; PRO = patient-reported outcome; PVI = pulmonary vein isolation; QoL = quality of life; TIA = transient ischaemic attack; TOE = transoesophageal echocardiography; TTR = time in therapeutic range; UFH = unfractionated heparin; VHD = Valvular heart disease; VKA = vitamin K antagonist.

21 Supplementary data

Supplementary Data with additional Supplementary Figures, Tables, and text complementing the full text are available on the European Heart Journal website and via the ESC website at www.escardio.org/guidelines.

The disclosure forms of all experts involved in the development of these guidelines are available on the ESC website www.escardio.org/guidelines

ESC Committee for Practice Guidelines (CPG) and National Cardiac Societies document reviewers, and Author/Task Force Member affiliations: listed in the Appendix.

1Representing the European Association for Cardio-Thoracic Surgery (EACTS)

ESC entities having participated in the development of this document:

Associations: Association for Acute CardioVascular Care (ACVC), Association of Cardiovascular Nursing & Allied Professions (ACNAP), European Association of Cardiovascular Imaging (EACVI), European Association of Preventive Cardiology (EAPC), European Association of Percutaneous Cardiovascular Interventions (EAPCI), European Heart Rhythm Association (EHRA), Heart Failure Association (HFA).

Councils: Council on Stroke, Council on Valvular Heart Disease.

Working Groups: Cardiac Cellular Electrophysiology, Cardiovascular Pharmacotherapy, Cardiovascular Surgery, e-Cardiology, Thrombosis.

The content of these European Society of Cardiology (ESC) Guidelines has been published for personal and educational use only. No commercial use is authorized. No part of the ESC Guidelines may be translated or reproduced in any form without written permission from the ESC. Permission can be obtained upon submission of a written request to Oxford University Press, the publisher of the European Heart Journal and the party authorized to handle such permissions on behalf of the ESC ([email protected]).

Disclaimer The ESC Guidelines represent the views of the ESC and were produced after careful consideration of the scientific and medical knowledge and the evidence available at the time of their publication. The ESC is not responsible in the event of any contradiction, discrepancy and/or ambiguity between the ESC Guidelines and any other official recommendations or guidelines issued by the relevant public health authorities, in particular in relation to good use of healthcare or therapeutic strategies. Health professionals are encouraged to take the ESC Guidelines fully into account when exercising their clinical judgment, as well as in the determination and the implementation of preventive, diagnostic or therapeutic medical strategies; however, the ESC Guidelines do not override, in any way whatsoever, the individual responsibility of health professionals to make appropriate and accurate decisions in consideration of each patient’s health condition and in consultation with that patient and, where appropriate and/or necessary, the patient’s caregiver. Nor do the ESC Guidelines exempt health professionals from taking into full and careful consideration the relevant official updated recommendations or guidelines issued by the competent public health authorities, in order to manage each patient’s case in light of the scientifically accepted data pursuant to their respective ethical and professional obligations. It is also the health professional’s responsibility to verify the applicable rules and regulations relating to drugs and medical devices at the time of prescription.

22 Appendix

Author/Task Force Member Affiliations:Nikolaos Dagres, Department of Electrophysiology, Heart Center Leipzig at the University of Leipzig, Leipzig, Germany; Elena Arbelo, Arrhythmia Department, Cardiovascular Institute, Hospital Clinic de Barcelona, Barcelona, Catalonia, Spain; Jeroen J. Bax, Cardiology, Leiden University Medical Center, Leiden, Netherlands; Carina Blomström-Lundqvist, Department of Medical Science and Cardiology, Medicine, Uppsala, Sweden; Giuseppe Boriani, Cardiology Division, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Policlinico di Modena, Modena, Italy; Manuel Castella,1 Cardiovascular Surgery, Hospital Clínic, University of Barcelona, Barcelona, Spain; Gheorghe-Andrei Dan, Cardiology Department, Internal Medicine Clinic, ‘Carol Davila’ University of Medicine, Colentina University Hospital, Bucharest, Romania; Polychronis E. Dilaveris, 1st University Department of Cardiology, National & Kapodistrian University of Athens School of Medicine, Athens, Attica, Greece; Laurent Fauchier, Department of Cardiology, Centre Hospitalier Universitaire Trousseau and University of Tours, Tours, France; Gerasimos Filippatos, Department of Cardiology, Attikon University Hospital, National and Kapodistrian University of Athens, Athens, Greece; Jonathan M. Kalman, Department of Cardiology, Royal Melbourne Hospital and University of Melbourne, Melbourne, Australia; Mark La Meir,1 Cardiac surgery, UZ Brussel, Brussels, Belgium; Deirdre A. Lane, Liverpool Centre for Cardiovascular Science, University of Liverpool and Liverpool Heart & Chest Hospital, Liverpool, United Kingdom, and Department of Clinical Medicine, Aalborg University, Aalborg, Denmark; Jean-Pierre Lebeau, Department of General Practice, University of Tours, Tours, France; Maddalena Lettino, Cardiovascular, San Gerardo Hospital, ASST-Monza, Monza, Italy; Gregory Y. H. Lip, Liverpool Centre for Cardiovascular Science, University of Liverpool and Liverpool Heart & Chest Hospital, Liverpool, United Kingdom, and Department of Clinical Medicine, Aalborg University, Aalborg, Denmark; Fausto J. Pinto, Cardiology, CCUL, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal; G. Neil Thomas, Institute of Applied Health Research, University of Birmingham, Birmingham, United Kingdom; Marco Valgimigli, Cardiocentro Ticino, Lugano, Switzerland; Isabelle C. Van Gelder, Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands; Bart P. Van Putte,1 Cardiothoracic Surgery, St Antonius Hospital, Nieuwegein, Netherlands; Caroline L. Watkins, Faculty of Health and Wellbeing, University of Central Lancashire, Preston, United Kingdom.

ESC Committee for Practice Guidelines (CPG): Stephan Windecker (Chairperson Switzerland), Victor Aboyans (France), Colin Baigent (United Kingdom), Jean-Philippe Collet (France), Veronica Dean (France), Victoria Delgado (Netherlands), Donna Fitzsimons (United Kingdom), Chris P. Gale (United Kingdom), Diederick E. Grobbee (Netherlands), Sigrun Halvorsen (Norway), Gerhard Hindricks (Germany), Bernard Iung (France), Peter Jüni (Canada), Hugo A. Katus (Germany), Ulf Landmesser (Germany), Christophe Leclercq (France), Maddalena Lettino (Italy), Basil S. Lewis (Israel), Béla Merkely (Hungary), Christian Mueller (Switzerland), Steffen E. Petersen (United Kingdom), Anna Sonia Petronio (Italy), Dimitrios J. Richter (Greece), Marco Roffi (Switzerland), Evgeny Shlyakhto (Russian Federation), Iain A. Simpson (United Kingdom), Miguel Sousa-Uva (Portugal), Rhian M. Touyz (United Kingdom).

ESC National Cardiac Societies actively involved in the review process of the 2020 ESC Guidelines for the diagnosis and management of atrial fibrillation.

Algeria: Algerian Society of Cardiology, Tahar Delassi; Armenia: Armenian Cardiologists Association, Hamayak S. Sisakian; Austria: Austrian Society of Cardiology, Daniel Scherr; Belarus: Belorussian Scientific Society of Cardiologists, Alexandr Chasnoits; Belgium: Belgian Society of Cardiology, Michel De Pauw; Bosnia and Herzegovina: Association of Cardiologists of Bosnia and Herzegovina, Elnur Smajić; Bulgaria: Bulgarian Society of Cardiology, Tchavdar Shalganov; Cyprus: Cyprus Society of Cardiology, Panayiotis Avraamides; Czech Republic: Czech Society of Cardiology, Josef Kautzner; Denmark: Danish Society of Cardiology, Christian Gerdes; Egypt: Egyptian Society of Cardiology, Ahmad Abd Alaziz; Estonia: Estonian Society of Cardiology, Priit Kampus; Finland: Finnish Cardiac Society, Pekka Raatikainen; France: French Society of Cardiology, Serge Boveda; Georgia: Georgian Society of Cardiology, Giorgi Papiashvili; Germany: German Cardiac Society, Lars Eckardt; Greece: Hellenic Society of Cardiology, Vassilios P. Vassilikos; Hungary: Hungarian Society of Cardiology, Zoltán Csanádi; Iceland: Icelandic Society of Cardiology, David O. Arnar; Ireland: Irish Cardiac Society, Joseph Galvin; Israel: Israel Heart Society, Alon Barsheshet; Italy: Italian Federation of Cardiology, Pasquale Caldarola; Kazakhstan: Association of Cardiologists of Kazakhstan, Amina Rakisheva; Kosovo (Republic of): Kosovo Society of Cardiology, Ibadete Bytyçi; Kyrgyzstan: Kyrgyz Society of Cardiology, Alina Kerimkulova; Latvia: Latvian Society of Cardiology, Oskars Kalejs; Lebanon: Lebanese Society of Cardiology, Mario Njeim; Lithuania: Lithuanian Society of Cardiology, Aras Puodziukynas; Luxembourg: Luxembourg Society of Cardiology, Laurent Groben; Malta: Maltese Cardiac Society, Mark A. Sammut; Moldova (Republic of): Moldavian Society of Cardiology, Aurel Grosu; Montenegro: Montenegro Society of Cardiology, Aneta Boskovic; Morocco: Moroccan Society of Cardiology, Abdelhamid Moustaghfir; Netherlands: Netherlands Society of Cardiology, Natasja de Groot; North Macedonia: North Macedonian Society of Cardiology, Lidija Poposka; Norway: Norwegian Society of Cardiology, Ole-Gunnar Anfinsen; Poland: Polish Cardiac Society, Przemyslaw P. Mitkowski; Portugal: Portuguese Society of Cardiology, Diogo Magalhães Cavaco; Romania: Romanian Society of Cardiology, Calin Siliste; Russian Federation: Russian Society of Cardiology, Evgeny N. Mikhaylov; San Marino: San Marino Society of Cardiology, Luca Bertelli; Serbia: Cardiology Society of Serbia, Dejan Kojic; Slovakia: Slovak Society of Cardiology, Robert Hatala; Slovenia: Slovenian Society of Cardiology, Zlatko Fras; Spain: Spanish Society of Cardiology, Fernando Arribas; Sweden: Swedish Society of Cardiology, Tord Juhlin; Switzerland: Swiss Society of Cardiology, Christian Sticherling; Tunisia: Tunisian Society of Cardiology and Cardio-Vascular Surgery, Leila Abid; Turkey: Turkish Society of Cardiology, Ilyas Atar; Ukraine: Ukrainian Association of Cardiology, Oleg Sychov; United Kingdom of Great Britain and Northern Ireland: British Cardiovascular Society, Matthew G. D. Bates; Uzbekistan: Association of Cardiologists of Uzbekistan, Nodir U. Zakirov.

23 References

1

Calkins
H
,
Hindricks
G
,
Cappato
R
,
Kim
YH
,
Saad
EB
,
Aguinaga
L
,
Akar
JG
,
Badhwar
V
,
Brugada
J
,
Camm
J
,
Chen
PS
,
Chen
SA
,
Chung
MK
,
Nielsen
JC
,
Curtis
AB,
,
Davies
DW
,
Day
JD
,
d'Avila
A
,
de Groot
N
,
Di Biase
L
,
Duytschaever
M
,
Edgerton
JR
,
Ellenbogen
KA
,
Ellinor
PT
,
Ernst
S
,
Fenelon
G
,
Gerstenfeld
EP
,
Haines
DE
,
Haissaguerre
M
,
Helm
RH
,
Hylek
E
,
Jackman
WM
,
Jalife
J
,
Kalman
JM,
,
Kautzner
J
,
Kottkamp
H
,
Kuck
KH
,
Kumagai
K
,
Lee
R
,
Lewalter
T
,
Lindsay
BD
,
Macle
L
,
Mansour
M
,
Marchlinski
FE
,
Michaud
GF
,
Nakagawa
H
,
Natale
A
,
Nattel
S
,
Okumura
K
,
Packer
D
,
Pokushalov
E
,
Reynolds
MR
,
Sanders
P,
,
Scanavacca
M
,
Schilling
R
,
Tondo
C
,
Tsao
HM
,
Verma
A
,
Wilber
DJ
,
Yamane
T.
2017 HRS/EHRA/ECAS/APHRS/SOLAECE expert consensus statement on catheter and surgical ablation of atrial fibrillation: executive summary
.
Europace
2018
;
20
:
157
208
.

2

Charitos
EI
,
Stierle
U
,
Ziegler
PD
,
Baldewig
M
,
Robinson
DR
,
Sievers
HH
,
Hanke
T
.
A comprehensive evaluation of rhythm monitoring strategies for the detection of atrial fibrillation recurrence: insights from 647 continuously monitored patients and implications for monitoring after therapeutic interventions
.
Circulation
2012
;
126
:
806
814
.

3

Gorenek
B
,
Boriani
G
,
Dan
GA
,
Fauchier
L
,
Fenelon
G
,
Huang
H
,
Kudaiberdieva
G
,
Lip
GYH
,
Mahajan
R
,
Potpara
T
,
Ramirez
JD
,
Vos
MA
,
Marin
F
, ESC Scientific Document Group.
European Heart Rhythm Association (EHRA) position paper on arrhythmia management and device therapies in endocrine disorders, endorsed by Asia Pacific Heart Rhythm Society (APHRS) and Latin American Heart Rhythm Society (LAHRS
).
Europace
2018
;
20
:
895
896
.

4

Freedman
B
,
Boriani
G
,
Glotzer
TV
,
Healey
JS
,
Kirchhof
P
,
Potpara
TS.
Management of atrial high-rate episodes detected by cardiac implanted electronic devices
.
Nat Rev Cardiol
2017
;
14
:
701
714
.

5

Perino
AC
,
Fan
J
,
Askari
M,
,
Heidenreich
PA
,
Keung
E
,
Raitt
MH
,
Piccini
JP
,
Ziegler
PD
,
Turakhia
MP.
Practice variation in anticoagulation prescription and outcomes after device-detected atrial fibrillation
.
Circulation
2019
;
139
:
2502
2512
.

6

Steinberg
JS
,
O'Connell
H
,
Li
S
,
Ziegler
PD.
Thirty-second gold standard definition of atrial fibrillation and its relationship with subsequent arrhythmia patterns: analysis of a large prospective device database
.
Circ Arrhythm Electrophysiol
2018
;
11
:
e006274
.

7

Camm
AJ
,
Simantirakis
E
,
Goette
A
,
Lip
GY
,
Vardas
P
,
Calvert
M
,
Chlouverakis
G
,
Diener
HC
,
Kirchhof
P.
Atrial high-rate episodes and stroke prevention
.
Europace
2017
;
19
:
169
179
.

8

Pollak
WM
,
Simmons
JD
,
Interian
A
Jr.
,
Atapattu
SA
,
Castellanos
A
,
Myerburg
RJ
,
Mitrani
RD.
Clinical utility of intraatrial pacemaker stored electrograms to diagnose atrial fibrillation and flutter
.
Pacing Clin Electrophysiol
2001
;
24
:
424
429
.

9

Kaufman
ES
,
Israel
CW
,
Nair
GM
,
Armaganijan
L
,
Divakaramenon
S
,
Mairesse
GH
,
Brandes
A
,
Crystal
E
,
Costantini
O
,
Sandhu
RK
,
Parkash
R
,
Connolly
SJ
,
Hohnloser
SH
,
Healey
JS
; ASSERT Steering Committee and Investigators.
Positive predictive value of device-detected atrial high-rate episodes at different rates and durations: an analysis from ASSERT
.
Heart Rhythm
2012
;
9
:
1241
1246
.

10

Benjamin
EJ
,
Muntner
P
,
Alonso
A
,
Bittencourt
MS
,
Callaway
CW
,
Carson
AP
,
Chamberlain
AM
,
Chang
AR
,
Cheng
S
,
Das
SR
,
Delling
FN
,
Djousse
L
,
Elkind
MSV
,
Ferguson
JF
,
Fornage
M
,
Jordan
LC
,
Khan
SS
,
Kissela
BM
,
Knutson
KL
,
Kwan
TW
,
Lackland
DT
,
Lewis
TT
,
Lichtman
JH
,
Longenecker
CT
,
Loop
MS
,
Lutsey
PL
,
Martin
SS
,
Matsushita
K
,
Moran
AE
,
Mussolino
ME
,
O’Flaherty
M,
,
Pandey
A,
,
Perak
AM
,
Rosamond
WD
,
Roth
GA
,
Sampson
UKA
,
Satou
GM,
,
Schroeder
EB
,
Shah
SH
,
Spartano
NL
,
Stokes
A
,
Tirschwell
DL
,
Tsao
CW
,
Turakhia
MP
,
VanWagner
LB
,
Wilkins
JT,
,
Wong
SS
,
Virani
SS
, American Heart Association Council on Epidemiology and Prevention Statistics Committee and Stroke Statistics Subcommittee.
Heart disease and stroke statistics – 2019 update: a report from the American Heart Association
.
Circulation
2019
;
139
:
e56
e528
.

11

Chugh
SS
,
Havmoeller
R
,
Narayanan
K
,
Singh
D
,
Rienstra
M
,
Benjamin
EJ
,
Gillum
RF
,
Kim
YH
,
McAnulty
JH
Jr
,
Zheng
ZJ
,
Forouzanfar
MH
,
Naghavi
M
,
Mensah
GA
,
Ezzati
M
,
Murray
CJ.
Worldwide epidemiology of atrial fibrillation: a Global Burden of Disease 2010 Study
.
Circulation
2014
;
129
:
837
847
.

12

Colilla
S
,
Crow
A
,
Petkun
W
,
Singer
DE
,
Simon
T
,
Liu
X.
Estimates of current and future incidence and prevalence of atrial fibrillation in the US adult population
.
Am J Cardiol
2013
;
112
:
1142
1147
.

13

Krijthe
BP
,
Kunst
A
,
Benjamin
EJ
,
Lip
GY
,
Franco
OH
,
Hofman
A
,
Witteman
JC
,
Stricker
BH
,
Heeringa
J.
Projections on the number of individuals with atrial fibrillation in the European Union, from 2000 to 2060
.
Eur Heart J
2013
;
34
:
2746
2751
.

14

Dewland
TA
,
Olgin
JE
,
Vittinghoff
E
,
Marcus
GM.
Incident atrial fibrillation among Asians, Hispanics, blacks, and whites
.
Circulation
2013
;
128
:
2470
2477
.

15

Staerk
L
,
Sherer
JA
,
Ko
D
,
Benjamin
EJ
,
Helm
RH.
Atrial fibrillation: epidemiology, pathophysiology, and clinical outcomes
.
Circ Res
2017
;
120
:
1501
1517
.

16

Alonso
A
,
Agarwal
SK
,
Soliman
EZ
,
Ambrose
M
,
Chamberlain
AM
,
Prineas
RJ
,
Folsom
AR.
Incidence of atrial fibrillation in whites and African Americans: the Atherosclerosis Risk in Communities (ARIC) study
.
Am Heart J
2009
;
158
:
111
117
.

17

Chao
TF
,
Liu
CJ
,
Tuan
TC
,
Chen
TJ
,
Hsieh
MH
,
Lip
GYH
,
Chen
SA.
Lifetime risks, projected numbers, and adverse outcomes in Asian patients with atrial fibrillation: a report from the Taiwan Nationwide AF Cohort Study
.
Chest
2018
;
153
:
453
466
.

18

Guo
Y
,
Tian
Y
,
Wang
H
,
Si
Q
,
Wang
Y
,
Lip
GYH.
Prevalence, incidence, and lifetime risk of atrial fibrillation in China: new insights into the global burden of atrial fibrillation
.
Chest
2015
;
147
:
109
119
.

19

Di Carlo
A
,
Bellino
L
,
Consoli
D
,
Mori
F
,
Zaninelli
A
,
Baldereschi
M
,
Baldereschi
M
,
Cattarinussi
A
,
D'Alfonso
MG
,
Gradia
C
,
Sgherzi
B
,
Pracucci
G
,
Piccardi
B
,
Polizzi
B
,
Inzitari
D
, National Research Program: Progetto FAI. La Fibrillazione Atriale in Italia.
Prevalence of atrial fibrillation in the Italian elderly population and projections from 2020 to 2060 for Italy and the European Union: the FAI Project
.
Europace
2019
;
21
:
1468
1475
.

20

Mou
L
,
Norby
FL
,
Chen
LY
,
O'Neal
WT
,
Lewis
TT
,
Loehr
LR
,
Soliman
EZ
,
Alonso
A.
Lifetime risk of atrial fibrillation by race and socioeconomic status: ARIC study (Atherosclerosis Risk in Communities
).
Circ Arrhythm Electrophysiol
2018
;
11
:
e006350
.

21

Boriani
G
,
Savelieva
I
,
Dan
GA
,
Deharo
JC
,
Ferro
C
,
Israel
CW
,
Lane
DA
,
La Manna
G
,
Morton
J
,
Mitjans
AM
,
Vos
MA
,
Turakhia
MP
,
Lip
GY.
Chronic kidney disease in patients with cardiac rhythm disturbances or implantable electrical devices: clinical significance and implications for decision making – a position paper of the European Heart Rhythm Association endorsed by the Heart Rhythm Society and the Asia Pacific Heart Rhythm Society
.
Europace
2015
;
17
:
1169
1196
.

22

Aune
D
,
Feng
T
,
Schlesinger
S
,
Janszky
I
,
Norat
T
,
Riboli
E.
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
.

23

Cadby
G
,
McArdle
N
,
Briffa
T
,
Hillman
DR
,
Simpson
L
,
Knuiman
M
,
Hung
J.
Severity of OSA is an independent predictor of incident atrial fibrillation hospitalization in a large sleep-clinic cohort
.
Chest
2015
;
148
:
945
952
.

24

Hobbelt
AH
,
Siland
JE
,
Geelhoed
B
,
Van Der Harst
P
,
Hillege
HL
,
Van Gelder
IC
,
Rienstra
M.
Clinical, biomarker, and genetic predictors of specific types of atrial fibrillation in a community-based cohort: data of the PREVEND study
.
Europace
2017
;
19
:
226
232
.

25

Nalliah
CJ
,
Sanders
P
,
Kalman
JM.
The impact of diet and lifestyle on atrial fibrillation
.
Curr Cardiol Rep
2018
;
20
:
137
.

26

Lip
GYH
,
Coca
A
,
Kahan
T
,
Boriani
G
,
Manolis
AS
,
Olsen
MH
,
Oto
A
,
Potpara
TS
,
Steffel
J
,
Marin
F
,
de Oliveira Figueiredo
MJ
,
de Simone
G
,
Tzou
WS
,
Chiang
CE
,
Williams
B
Reviewers
Dan
GA
,
Gorenek
B
,
Fauchier
L
,
Savelieva
I
,
Hatala
R
,
van Gelder
I
,
Brguljan-Hitij
J
,
Erdine
S
,
Lovic
D
,
Kim
YH
,
Salinas-Arce
J
,
Field
M.
Hypertension and cardiac arrhythmias: a consensus document from the European Heart Rhythm Association (EHRA) and ESC Council on Hypertension, endorsed by the Heart Rhythm Society (HRS), Asia-Pacific Heart Rhythm Society (APHRS) and Sociedad Latinoamericana de Estimulacion Cardiaca y Electrofisiologia (SOLEACE)
.
Europace
2017
;
19
:
891
911
.

27

Gallagher
C
,
Hendriks
JML
,
Elliott
AD
,
Wong
CX
,
Rangnekar
G
,
Middeldorp
ME
,
Mahajan
R
,
Lau
DH
,
Sanders
P.
Alcohol and incident atrial fibrillation – a systematic review and meta-analysis
.
Int J Cardiol
2017
;
246
:
46
52
.

28

Ricci
C
,
Gervasi
F
,
Gaeta
M
,
Smuts
CM
,
Schutte
AE
,
Leitzmann
MF.
Physical activity volume in relation to risk of atrial fibrillation. A non-linear meta-regression analysis
.
Eur J Prev Cardiol
2018
;
25
:
857
866
.

29

Heeringa
J
,
van der Kuip
DA
,
Hofman
A
,
Kors
JA
,
van Herpen
G
,
Stricker
BH
,
Stijnen
T
,
Lip
GY
,
Witteman
JC.
Prevalence, incidence and lifetime risk of atrial fibrillation: the Rotterdam Study
.
Eur Heart J
2006
;
27
:
949
953
.

30

Lloyd-Jones
DM
,
Wang
TJ
,
Leip
EP
,
Larson
MG
,
Levy
D
,
Vasan
RS
,
D’Agostino
RB
,
Massaro
JM
,
Beiser
A
,
Wolf
PA
,
Benjamin
EJ.
Lifetime risk for development of atrial fibrillation: the Framingham Heart Study
.
Circulation
2004
;
110
:
1042
-
1046
.

31

Magnussen
C
,
Niiranen
TJ
,
Ojeda
FM
,
Gianfagna
F
,
Blankenberg
S
,
Njolstad
I
,
Vartiainen
E
,
Sans
S
,
Pasterkamp
G
,
Hughes
M
,
Costanzo
S
,
Donati
MB
,
Jousilahti
P
,
Linneberg
A
,
Palosaari
T
,
de Gaetano
G
,
Bobak
M
,
den Ruijter
HM
,
Mathiesen
E
,
Jorgensen
T
,
Soderberg
S
,
Kuulasmaa
K
,
Zeller
T
,
Iacoviello
L
,
Salomaa
V
,
Schnabel
RB
,
BiomarCaRE
Consortium.
Sex differences and similarities in atrial fibrillation epidemiology, risk factors, and mortality in community cohorts: results from the BiomarCaRE Consortium (
Biomarker for Cardiovascular Risk Assessment in Europe). Circulation
2017
;
136
:
1588
1597
.

32

Staerk
L
,
Wang
B
,
Preis
SR
,
Larson
MG
,
Lubitz
SA
,
Ellinor
PT
,
McManus
DD
,
Ko
D
,
Weng
LC
,
Lunetta
KL
,
Frost
L
,
Benjamin
EJ
,
Trinquart
L.
Lifetime risk of atrial fibrillation according to optimal, borderline, or elevated levels of risk factors: cohort study based on longitudinal data from the Framingham Heart Study
.
BMJ
2018
;
361
:
k1453
.

33

Allan
V
,
Honarbakhsh
S
,
Casas
JP
,
Wallace
J
,
Hunter
R
,
Schilling
R
,
Perel
P
,
Morley
K
,
Banerjee
A
,
Hemingway
H.
Are cardiovascular risk factors also associated with the incidence of atrial fibrillation? A systematic review and field synopsis of 23 factors in 32 population-based cohorts of 20 million participants
.
Thromb Haemost
2017
;
117
:
837
850
.

34

Feghaly
J
,
Zakka
P
,
London
B
,
MacRae
CA
,
Refaat
MM.
Genetics of atrial fibrillation
.
J Am Heart Assoc
2018
;
7
:
e009884
.

35

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
.

36

Alonso
A
,
Jensen
PN
,
Lopez
FL
,
Chen
LY
,
Psaty
BM
,
Folsom
AR
,
Heckbert
SR.
Association of sick sinus syndrome with incident cardiovascular disease and mortality: the Atherosclerosis Risk in Communities Study and Cardiovascular Health Study
.
PLoS One
2014
;
9
:
e109662
.

37

Alonso
A
,
Lopez
FL
,
Matsushita
K
,
Loehr
LR
,
Agarwal
SK
,
Chen
LY
,
Soliman
EZ
,
Astor
BC
,
Coresh
J.
Chronic kidney disease is associated with the incidence of atrial fibrillation: the Atherosclerosis Risk in Communities (ARIC) study
.
Circulation
2011
;
123
:
2946
2953
.

38

Andersen
K
,
Farahmand
B
,
Ahlbom
A
,
Held
C
,
Ljunghall
S
,
Michaelsson
K
,
Sundstrom
J.
Risk of arrhythmias in 52 755 long-distance cross-country skiers: a cohort study
.
Eur Heart J
2013
;
34
:
3624
3631
.

39

Asad
Z
,
Abbas
M
,
Javed
I
,
Korantzopoulos
P
,
Stavrakis
S.
Obesity is associated with incident atrial fibrillation independent of gender: a meta-analysis
.
J Cardiovasc Electrophysiol
2018
;
29
:
725
732
.

40

Aune
D
,
Sen
A
,
Schlesinger
S
,
Norat
T
,
Janszky
I
,
Romundstad
P
,
Tonstad
S
,
Riboli
E
,
Vatten
LJ.
Body mass index, abdominal fatness, fat mass and the risk of atrial fibrillation: a systematic review and dose-response meta-analysis of prospective studies
.
Eur J Epidemiol
2017
;
32
:
181
192
.

41

Bansal
N
,
Zelnick
LR
,
Alonso
A
,
Benjamin
EJ
,
de Boer
IH
,
Deo
R
,
Katz
R
,
Kestenbaum
B
,
Mathew
J
,
Robinson-Cohen
C
,
Sarnak
MJ
,
Shlipak
MG
,
Sotoodehnia
N
,
Young
B
,
Heckbert
SR.
eGFR and albuminuria in relation to risk of incident atrial fibrillation: a meta-analysis of the Jackson Heart Study, the Multi-Ethnic Study of Atherosclerosis, and the Cardiovascular Health Study
.
Clin J Am Soc Nephrol
2017
;
12
:
1386
1398
.

42

Baumgartner
C
,
da Costa
BR
,
Collet
TH
,
Feller
M
,
Floriani
C
,
Bauer
DC
,
Cappola
AR
,
Heckbert
SR
,
Ceresini
G
,
Gussekloo
J
,
den Elzen
WPJ
,
Peeters
RP
,
Luben
R
,
Volzke
H
,
Dorr
M
,
Walsh
JP
,
Bremner
A
,
Iacoviello
M
,
Macfarlane
P
,
Heeringa
J
,
Stott
DJ,
,
Westendorp
RGJ
,
Khaw
KT
,
Magnani
JW
,
Aujesky
D
,
Rodondi
N
,
Thyroid Studies Collaboration. Thyroid function within the normal range, subclinical hypothyroidism, and the risk of atrial fibrillation
.
Circulation
2017
;
136
:
2100
2116
.

43

Benjamin
EJ
,
Levy
D
,
Vaziri
SM
,
D'Agostino
RB
,
Belanger
AJ
,
Wolf
PA.
Independent risk factors for atrial fibrillation in a population-based cohort. The Framingham Heart Study
.
JAMA
1994
;
271
:
840
844
.

44

Bunch
TJ
,
May
HT
,
Bair
TL
,
Anderson
JL
,
Crandall
BG
,
Cutler
MJ
,
Jacobs
V
,
Mallender
C
,
Muhlestein
JB
,
Osborn
JS
,
Weiss
JP
,
Day
JD.
Long-term natural history of adult Wolff-Parkinson-White syndrome patients treated with and without catheter ablation
.
Circ Arrhythm Electrophysiol
2015
;
8
:
1465
1471
.

45

Chang
SH
,
Kuo
CF
,
Chou
IJ
,
See
LC
,
Yu
KH
,
Luo
SF
,
Huang
LH
,
Zhang
W
,
Doherty
M
,
Wen
MS
,
Kuo
CT
,
Yeh
YH.
Association of a family history of atrial fibrillation with incidence and outcomes of atrial fibrillation: a population-based family cohort study
.
JAMA Cardiol
2017
;
2
:
863
870
.

46

Chen
LY
,
Leening
MJ
,
Norby
FL
,
Roetker
NS
,
Hofman
A
,
Franco
OH
,
Pan
W
,
Polak
JF
,
Witteman
JC
,
Kronmal
RA
,
Folsom
AR
,
Nazarian
S
,
Stricker
BH
,
Heckbert
SR
,
Alonso
A.
Carotid intima-media thickness and arterial stiffness and the risk of atrial fibrillation: the Atherosclerosis Risk in Communities (ARIC) study, Multi-Ethnic Study of Atherosclerosis (MESA), and the Rotterdam Study
.
J Am Heart Assoc
2016
;
5
.

47

Cheng
M
,
Hu
Z
,
Lu
X
,
Huang
J
,
Gu
D.
Caffeine intake and atrial fibrillation incidence: dose response meta-analysis of prospective cohort studies
.
Can J Cardiol
2014
;
30
:
448
454
.

48

Cheng
S
,
Keyes
MJ
,
Larson
MG
,
McCabe
EL
,
Newton-Cheh
C
,
Levy
D
,
Benjamin
EJ
,
Vasan
RS
,
Wang
TJ.
Long-term outcomes in individuals with prolonged PR interval or first-degree atrioventricular block
.
JAMA
2009
;
301
:
2571
2577
.

49

Conen
D
,
Chiuve
SE
,
Everett
BM
,
Zhang
SM
,
Buring
JE
,
Albert
CM.
Caffeine consumption and incident atrial fibrillation in women
.
Am J Clin Nutr
2010
;
92
:
509
514
.

50

Desai
R
,
Patel
U
,
Singh
S
,
Bhuva
R
,
Fong
HK
,
Nunna
P
,
Zalavadia
D
,
Dave
H
,
Savani
S
,
Doshi
R.
The burden and impact of arrhythmia in chronic obstructive pulmonary disease: insights from the National Inpatient Sample
.
Int J Cardiol
2019
;
281
:
49
55
.

51

Eaker
ED
,
Sullivan
LM
,
Kelly-Hayes
M
,
D’Agostino
RB
Sr
,
Benjamin
EJ.
Anger and hostility predict the development of atrial fibrillation in men in the Framingham Offspring Study
.
Circulation
2004
;
109
:
1267
1271
.

52

Fox
CS
,
Parise
H
,
D’Agostino
RB
Sr
,
Lloyd
Jones DM
,
Vasan
RS
,
Wang
TJ
,
Levy
D
,
Wolf
PA
,
Benjamin
EJ.
Parental atrial fibrillation as a risk factor for atrial fibrillation in offspring
.
JAMA
2004
;
291
:
2851
2855
.

53

Furberg
CD
,
Psaty
BM
,
Manolio
TA
,
Gardin
JM
,
Smith
VE
,
Rautaharju
PM.
Prevalence of atrial fibrillation in elderly subjects (the Cardiovascular Health Study)
.
Am J Cardiol
1994
;
74
:
236
241
.

54

Giacomantonio
NB
,
Bredin
SS
,
Foulds
HJ
,
Warburton
DE.
A systematic review of the health benefits of exercise rehabilitation in persons living with atrial fibrillation
.
Can J Cardiol
2013
;
29
:
483
491
.

55

Kirchhof
P
,
Lip
GY
,
Van Gelder
IC
,
Bax
J
,
Hylek
E
,
Kaab
S
,
Schotten
U
,
Wegscheider
K
,
Boriani
G
,
Brandes
A
,
Ezekowitz
M
,
Diener
H
,
Haegeli
L
,
Heidbuchel
H
,
Lane
D
,
Mont
L
,
Willems
S
,
Dorian
P
,
Aunes-Jansson
M
,
Blomstrom-Lundqvist
C
,
Borentain
M
,
Breitenstein
S
,
Brueckmann
M
,
Cater
N
,
Clemens
A
,
Dobrev
D
,
Dubner
S
,
Edvardsson
NG
,
Friberg
L
,
Goette
A
,
Gulizia
M
,
Hatala
R
,
Horwood
J
,
Szumowski
L
,
Kappenberger
L
,
Kautzner
J
,
Leute
A
,
Lobban
T
,
Meyer
R
,
Millerhagen
J
,
Morgan
J
,
Muenzel
F
,
Nabauer
M
,
Baertels
C
,
Oeff
M
,
Paar
D
,
Polifka
J
,
Ravens
U
,
Rosin
L
,
Stegink
W
,
Steinbeck
G
,
Vardas
P
,
Vincent
A
,
Walter
M
,
Breithardt
G
,
Camm
AJ.
Comprehensive risk reduction in patients with atrial fibrillation: emerging diagnostic and therapeutic options – a report from the 3rd Atrial Fibrillation Competence NETwork/European Heart Rhythm Association consensus conference
.
Europace
2012
;
14
:
8
27
.

56

Ko
D
,
Benson
MD
,
Ngo
D
,
Yang
Q
,
Larson
MG
,
Wang
TJ
,
Trinquart
L
,
McManus
DD
,
Lubitz
SA
,
Ellinor
PT
,
Vasan
RS
,
Gerszten
RE
,
Benjamin
EJ
,
Lin
H.
Proteomics profiling and risk of new-onset atrial fibrillation: Framingham Heart Study
.
J Am Heart Assoc
2019
;
8
:
e010976
.

57

Kwok
CS
,
Anderson
SG
,
Myint
PK
,
Mamas
MA
,
Loke
YK.
Physical activity and incidence of atrial fibrillation: a systematic review and meta-analysis
.
Int J Cardiol
2014
;
177
:
467
476
.

58

Lip
GYH
,
Collet
JP
,
de Caterina
R
,
Fauchier
L
,
Lane
DA
,
Larsen
TB
,
Marin
F
,
Morais
J
,
Narasimhan
C
,
Olshansky
B
,
Pierard
L
,
Potpara
T
,
Sarrafzadegan
N
,
Sliwa
K
,
Varela
G
,
Vilahur
G
,
Weiss
T,
,
Boriani
G
,
Rocca
B.
Antithrombotic therapy in atrial fibrillation associated with valvular heart disease: executive summary of a joint consensus document from the European Heart Rhythm Association (EHRA) and European Society of Cardiology Working Group on Thrombosis, Endorsed by the ESC Working Group on Valvular Heart Disease, Cardiac Arrhythmia Society of Southern Africa (CASSA), Heart Rhythm Society (HRS), Asia Pacific Heart Rhythm Society (APHRS), South African Heart (SA Heart) Association and Sociedad Latinoamericana de Estimulacion Cardiaca y Electrofisiologia (SOLEACE)
.
Thromb Haemost
2017
;
117
:
2215
2236
.

59

Loomba
RS
,
Buelow
MW
,
Aggarwal
S
,
Arora
RR
,
Kovach
J
,
Ginde
S.
Arrhythmias in adults with congenital heart disease: what are risk factors for specific arrhythmias?
Pacing Clin Electrophysiol
2017
;
40
:
353
361
.

60

Lubitz
SA
,
Yin
X
,
Fontes
JD
,
Magnani
JW
,
Rienstra
M
,
Pai
M
,
Villalon
ML
,
Vasan
RS
,
Pencina
MJ
,
Levy
D
,
Larson
MG
,
Ellinor
PT
,
Benjamin
EJ.
Association between familial atrial fibrillation and risk of new-onset atrial fibrillation
.
JAMA
2010
;
304
:
2263
2269
.

61

May
AM
,
Blackwell
T
,
Stone
PH
,
Stone
KL
,
Cawthon
PM
,
Sauer
WH
,
Varosy
PD
,
Redline
S
,
Mehra
R
,
Sleep
MrOS
(
Outcomes of Sleep Disorders in Older Men) Study Group. Central sleep-disordered breathing predicts incident atrial fibrillation in older men
.
Am J Respir Crit Care Med
2016
;
193
:
783
791
.

62

Michniewicz
E
,
Mlodawska
E
,
Lopatowska
P
,
Tomaszuk-Kazberuk
A
,
Malyszko
J.
Patients with atrial fibrillation and coronary artery disease – double trouble
.
Adv Med Sci
2018
;
63
:
30
35
.

63

Monrad
M
,
Sajadieh
A
,
Christensen
JS
,
Ketzel
M
,
Raaschou-Nielsen
O
,
Tjonneland
A
,
Overvad
K
,
Loft
S
,
Sorensen
M.
Long-term exposure to traffic-related air pollution and risk of incident atrial fibrillation: a cohort study
.
Environ Health Perspect
2017
;
125
:
422
427
.

64

O'Neal
WT
,
Efird
JT
,
Qureshi
WT
,
Yeboah
J
,
Alonso
A
,
Heckbert
SR
,
Nazarian
S
,
Soliman
EZ.
Coronary artery calcium progression and atrial fibrillation: the Multi-Ethnic Study of Atherosclerosis
.
Circ Cardiovasc Imaging
2015
;
8
:pii: e003786.

65

Qureshi
WT
,
Alirhayim
Z
,
Blaha
MJ
,
Juraschek
SP
,
Keteyian
SJ
,
Brawner
CA
,
Al-Mallah MH. Cardiorespiratory fitness and risk of incident atrial fibrillation: results from the Henry Ford Exercise Testing (FIT) Project
.
Circulation
2015
;
131
:
1827
1834
.

66

Santhanakrishnan
R
,
Wang
N
,
Larson
MG
,
Magnani
JW
,
McManus
DD
,
Lubitz
SA
,
Ellinor
PT
,
Cheng
S
,
Vasan
RS
,
Lee
DS
,
Wang
TJ
,
Levy
D
,
Benjamin
EJ
,
Ho
JE.
Atrial fibrillation begets heart failure and vice versa: temporal associations and differences in preserved versus reduced ejection fraction
.
Circulation
2016
;
133
:
484
492
.

67

Schnabel
RB
,
Yin
X
,
Gona
P
,
Larson
MG
,
Beiser
AS
,
McManus
DD
,
Newton-Cheh
C
,
Lubitz
SA
,
Magnani
JW
,
Ellinor
PT
,
Seshadri
S
,
Wolf
PA
,
Vasan
RS
,
Benjamin
EJ
,
Levy
D.
50-Year trends in atrial fibrillation prevalence, incidence, risk factors, and mortality in the Framingham Heart Study: a cohort study
.
Lancet
2015
;
386
:
154
162
.

68

Shen
J
,
Johnson
VM
,
Sullivan
LM
,
Jacques
PF
,
Magnani
JW
,
Lubitz
SA
,
Pandey
S
,
Levy
D
,
Vasan
RS
,
Quatromoni
PA
,
Junyent
M
,
Ordovas
JM
,
Benjamin
EJ.
Dietary factors and incident atrial fibrillation: the Framingham Heart Study
.
Am J Clin Nutr
2011
;
93
:
261
266
.

69

Svensson
T
,
Kitlinski
M
,
Engstrom
G
,
Melander
O.
Psychological stress and risk of incident atrial fibrillation in men and women with known atrial fibrillation genetic risk scores
.
Sci Rep
2017
;
7
:
42613
.

70

Tung
P
,
Levitzky
YS
,
Wang
R
,
Weng
J
,
Quan
SF
,
Gottlieb
DJ
,
Rueschman
M
,
Punjabi
NM
,
Mehra
R
,
Bertisch
S
,
Benjamin
EJ
,
Redline
S.
Obstructive and central sleep apnea and the risk of incident atrial fibrillation in a community cohort of men and women
.
J Am Heart Assoc
2017
;
6
:pii.

71

Walkey
AJ
,
Greiner
MA
,
Heckbert
SR
,
Jensen
PN
,
Piccini
JP
,
Sinner
MF
,
Curtis
LH
,
Benjamin
EJ.
Atrial fibrillation among Medicare beneficiaries hospitalized with sepsis: incidence and risk factors
.
Am Heart J
2013
;
165
:
949
955.e3
.

72

Zoller
B
,
Ohlsson
H
,
Sundquist
J
,
Sundquist
K.
High familial risk of atrial fibrillation/atrial flutter in multiplex families: a nationwide family study in Sweden
.
J Am Heart Assoc
2012
;
2
:
e003384
.

73

Lip
GYH
,
Skjoth
F
,
Nielsen
PB
,
Larsen
TB.
Evaluation of the C2HEST risk score as a possible opportunistic screening tool for incident atrial fibrillation in a healthy population (from a nationwide Danish cohort study)
.
Am J Cardiol
2020
;
125
:
48
54
.

74

Yiin
GSC
,
Li
L
,
Bejot
Y
,
Rothwell
PM.
Time trends in atrial fibrillation-associated stroke and premorbid anticoagulation
.
Stroke
2018
:
STROKEAHA118022249
.

75

Akao
M
,
Chun
YH
,
Wada
H
,
Esato
M
,
Hashimoto
T
,
Abe
M
,
Hasegawa
K
,
Tsuji
H
,
Furuke
K
,
Fushimi
AF
Registry Investigators.
Current status of clinical background of patients with atrial fibrillation in a community-based survey: the Fushimi AF Registry
.
J Cardiol
2013
;
61
:
260
266
.

76

An
Y
,
Ogawa
H
,
Yamashita
Y
,
Ishii
M
,
Iguchi
M
,
Masunaga
N
,
Esato
M
,
Tsuji
H
,
Wada
H
,
Hasegawa
K
,
Abe
M
,
Lip
GYH
,
Akao
M.
Causes of death in Japanese patients with atrial fibrillation: the Fushimi Atrial Fibrillation Registry
.
Eur Heart J Qual Care Clin Outcomes
2019
;
5
:
35
42
.

77

Andersson
T
,
Magnuson
A
,
Bryngelsson
IL
,
Frobert
O
,
Henriksson
KM
,
Edvardsson
N
,
Poci
D.
All-cause mortality in 272,186 patients hospitalized with incident atrial fibrillation 1995–2008: a Swedish nationwide long-term case-control study
.
Eur Heart J
2013
;
34
:
1061
1067
.

78

Andrew
NE
,
Thrift
AG
,
Cadilhac
DA.
The prevalence, impact and economic implications of atrial fibrillation in stroke: what progress has been made?
Neuroepidemiology
2013
;
40
:
227
239
.

79

Bakhai
A
,
Darius
H
,
De Caterina
R
,
Smart
A
,
Le Heuzey
JY
,
Schilling
RJ
,
Zamorano
JL
,
Shah
M
,
Bramlage
P
,
Kirchhof
P.
Characteristics and outcomes of atrial fibrillation patients with or without specific symptoms: results from the PREFER in AF registry
.
Eur Heart J Qual Care Clin Outcomes
2016
;
2
:
299
305
.

80

Benjamin
EJ
,
Wolf
PA
,
D’Agostino
RB
,
Silbershatz
H
,
Kannel
WB
,
Levy
D.
Impact of atrial fibrillation on the risk of death: the Framingham Heart Study
.
Circulation
1998
;
98
:
946
952
.

81

Blum
S
,
Muff
C
,
Aeschbacher
S
,
Ammann
P
,
Erne
P
,
Moschovitis
G
,
Di Valentino
M
,
Shah
D
,
Schlapfer
J
,
Fischer
A
,
Merkel
T
,
Kuhne
M
,
Sticherling
C
,
Osswald
S
,
Conen
D.
Prospective assessment of sex-related differences in symptom status and health perception among patients with atrial fibrillation
.
J Am Heart Assoc
2017
;
6
:
e005401
.

82

Boriani
G
,
Laroche
C
,
Diemberger
I
,
Fantecchi
E
,
Popescu
MI
,
Rasmussen
LH
,
Sinagra
G
,
Petrescu
L
,
Tavazzi
L
,
Maggioni
AP
,
Lip
GY.
Asymptomatic atrial fibrillation: clinical correlates, management, and outcomes in the EORP-AF Pilot General Registry
.
Am J Med
2015
;
128
:
509
518.e2
.

83

Ceornodolea
AD
,
Bal
R
,
Severens
JL.
Epidemiology and management of atrial fibrillation and stroke: review of data from four European countries
.
Stroke Res Treat
2017
;
2017
:
8593207
.

84

Chao
TF
,
Lip
GY
,
Liu
CJ
,
Tuan
TC
,
Chen
SJ
,
Wang
KL
,
Lin
YJ
,
Chang
SL
,
Lo
LW
,
Hu
YF
,
Chen
TJ
,
Chiang
CE
,
Chen
SA.
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
.

85

Chao
T-F
,
Liu
C-J
,
Wang
K-L
,
Lin
Y-J
,
Chang
S-L
,
Lo
L-W
,
Hu
Y-F
,
Tuan
T-C
,
Chen
T-J
,
Lip
GY.
Should atrial fibrillation patients with 1 additional risk factor of the CHA2DS2-VASc score (beyond sex) receive oral anticoagulation?
J Am Coll Cardiol
2015
;
65
:
635
642
.

86

Dagres
N
,
Chao
T-F
,
Fenelon
G
,
Aguinaga
L
,
Benhayon
D
,
Benjamin
EJ
,
Bunch
TJ
,
Chen
LY
,
Chen
S-A
,
Darrieux
F
,
de Paola
A
,
Fauchier
L
,
Goette
A
,
Kalman
J
,
Kalra
L
,
Kim
Y-H
,
Lane
DA
,
Lip
GYH
,
Lubitz
SA
,
Márquez
MF
,
Potpara
T
,
Pozzer
DL
,
Ruskin
JN
,
Savelieva
I
,
Teo
WS
,
Tse
H-F
,
Verma
A
,
Zhang
S
,
Chung
MK
,
Bautista-Vargas
W-F
,
Chiang
C-E
,
Cuesta
A
,
Dan
G-A
,
Frankel
DS
,
Guo
Y
,
Hatala
R
,
Lee
YS
,
Murakawa
Y
,
Pellegrini
CN
,
Pinho
C
,
Milan
DJ
,
Morin
DP
,
Nadalin
E
,
Ntaios
G
,
Prabhu
MA
,
Proietti
M
,
Rivard
L
,
Valentino
M
,
Shantsila
A.
European Heart Rhythm Association (EHRA)/Heart Rhythm Society (HRS)/Asia Pacific Heart Rhythm Society (APHRS)/Latin American Heart Rhythm Society (LAHRS) expert consensus on arrhythmias and cognitive function: what is the best practice?
EP Europace
2018
;
20
:
1399
1421
.

87

Esato
M
,
Chun
YH
,
An
Y
,
Ogawa
H
,
Wada
H
,
Hasegawa
K
,
Tsuji
H
,
Abe
M
,
Lip
GYH
,
Akao
M.
Clinical impact of asymptomatic presentation status in patients with paroxysmal and sustained atrial fibrillation: the Fushimi AF Registry
.
Chest
2017
;
152
:
1266
1275
.

88

Freeman
JV
,
Simon
DN
,
Go
AS
,
Spertus
J
,
Fonarow
GC
,
Gersh
BJ
,
Hylek
EM
,
Kowey
PR
,
Mahaffey
KW
,
Thomas
LE
,
Chang
P
,
Peterson
ED
,
Piccini
JP
; Outcomes Registry for Better Informed Treatment of Atrial Fibrillation Investigators.
Association between atrial fibrillation symptoms, quality of life, and patient outcomes: results from the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF)
.
Circ Cardiovasc Qual Outcomes
2015
;
8
:
393
402
.

89

Frost
L
,
Engholm
G
,
Johnsen
S
,
Moller
H
,
Henneberg
EW
,
Husted
S.
Incident thromboembolism in the aorta and the renal, mesenteric, pelvic, and extremity arteries after discharge from the hospital with a diagnosis of atrial fibrillation
.
Arch Intern Med
2001
;
161
:
272
276
.

90

Gaita
F
,
Corsinovi
L
,
Anselmino
M
,
Raimondo
C
,
Pianelli
M
,
Toso
E
,
Bergamasco
L
,
Boffano
C
,
Valentini
MC
,
Cesarani
F
,
Scaglione
M.
Prevalence of silent cerebral ischemia in paroxysmal and persistent atrial fibrillation and correlation with cognitive function
.
J Am Coll Cardiol
2013
;
62
:
1990
1997
.

91

Garcia-Fernandez
A
,
Roldan
V
,
Rivera-Caravaca
JM
,
Lip
GYH
,
Marin
F.
Applicability of the modified CHA2DS2-VASc score for stroke risk stratification in Caucasian atrial fibrillation patients
.
Eur J Intern Med
2017
;
38
:
e21
e22
.

92

Gleason
KT
,
Nazarian
S
,
Dennison Himmelfarb
CR.
Atrial fibrillation symptoms and sex, race, and psychological distress: a literature review
.
J Cardiovasc Nurs
2018
;
33
:
137
143
.

93

Gomez-Outes
A
,
Lagunar-Ruiz
J
,
Terleira-Fernandez
AI
,
Calvo-Rojas
G
,
Suarez-Gea
ML
,
Vargas-Castrillon
E.
Causes of death in anticoagulated patients with atrial fibrillation
.
J Am Coll Cardiol
2016
;
68
:
2508
2521
.

94

Graves
KG
,
May
HT
,
Jacobs
V
,
Bair
TL
,
Stevens
SM
,
Woller
SC
,
Crandall
BG
,
Cutler
MJ
,
Day
JD
,
Mallender
C
,
Osborn
JS
,
Peter Weiss
J
,
Jared Bunch
T.
Atrial fibrillation incrementally increases dementia risk across all CHADS2 and CHA2DS2VASc strata in patients receiving long-term warfarin
.
Am Heart J
2017
;
188
:
93
98
.

95

John
RM
,
Michaud
GF
,
Stevenson
WG.
Atrial fibrillation hospitalization, mortality, and therapy
.
Eur Heart J
2018
;
39
:
3958
3960
.

96

Kalantarian
S
,
Ruskin
JN.
Atrial fibrillation and cognitive decline: phenomenon or epiphenomenon?
Cardiol Clin
2016
;
34
:
279
285
.

97

Kalantarian
S
,
Stern
TA
,
Mansour
M
,
Ruskin
JN.
Cognitive impairment associated with atrial fibrillation: a meta-analysis
.
Ann Intern Med
2013
;
158
:
338
46
.

98

Kim
MH
,
Johnston
SS
,
Chu
BC
,
Dalal
MR
,
Schulman
KL.
Estimation of total incremental health care costs in patients with atrial fibrillation in the United States
.
Circ Cardiovasc Qual Outcomes
2011
;
4
:
313
320
.

99

Kirchhof
P
,
Schmalowsky
J
,
Pittrow
D
,
Rosin
L
,
Kirch
W
,
Wegscheider
K
,
Meinertz
T
, ATRIUM Study Group.
Management of patients with atrial fibrillation by primary-care physicians in Germany: 1-year results of the ATRIUM registry
.
Clin Cardiol
2014
;
37
:
277
284
.

100

Kochhauser
S
,
Joza
J
,
Essebag
V
,
Proietti
R
,
Koehler
J
,
Tsang
B
,
Wulffhart
Z
,
Pantano
A
,
Khaykin
Y
,
Ziegler
PD
,
Verma
A.
The impact of duration of atrial fibrillation recurrences on measures of health-related quality of life and symptoms
.
Pacing Clin Electrophysiol
2016
;
39
:
166
72
.

101

Konig
S
,
Ueberham
L
,
Schuler
E
,
Wiedemann
M
,
Reithmann
C
,
Seyfarth
M
,
Sause
A
,
Tebbenjohanns
J
,
Schade
A
,
Shin
DI
,
Staudt
A
,
Zacharzowsky
U
,
Andrie
R
,
Wetzel
U
,
Neuser
H
,
Wunderlich
C
,
Kuhlen
R
,
Tijssen
JGP
,
Hindricks
G
,
Bollmann
A.
In-hospital mortality of patients with atrial arrhythmias: insights from the German-wide Helios hospital network of 161 502 patients and 34 025 arrhythmia-related procedures
.
Eur Heart J
2018
;
39
:
3947
3957
.

102

Kotecha
D
,
Lam
CS
,
Van Veldhuisen
DJ
,
Van Gelder
IC
,
Voors
AA
,
Rienstra
M.
Heart failure with preserved ejection fraction and atrial fibrillation: vicious twins
.
J Am Coll Cardiol
2016
;
68
:
2217
2228
.

103

Kupper
N
,
van den Broek
K
,
Haagh
E
,
van der Voort
P
,
Widdershoven
J
,
Denollet
J.
Type D personality affects health-related quality of life in patients with lone atrial fibrillation by increasing symptoms related to sympathetic activation
.
J Psychosom Res
2018
;
115
:
44
52
.

104

Kwok
CS
,
Loke
YK
,
Hale
R
,
Potter
JF
,
Myint
PK.
Atrial fibrillation and incidence of dementia: a systematic review and meta-analysis
.
Neurology
2011
;
76
:
914
922
.

105

Levy
S
,
Maarek
M
,
Coumel
P
,
Guize
L
,
Lekieffre
J
,
Medvedowsky
JL
,
Sebaoun
A.
Characterization of different subsets of atrial fibrillation in general practice in France: the ALFA study. The College of French Cardiologists
.
Circulation
1999
;
99
:
3028
3035
.

106

Lin
HJ
,
Wolf
PA
,
Kelly-Hayes
M
,
Beiser
AS
,
Kase
CS
,
Benjamin
EJ
,
D’Agostino
RB.
Stroke severity in atrial fibrillation. The Framingham Study
.
Stroke
1996
;
27
:
1760
1764
.

107

Lip
GY
,
Laroche
C
,
Boriani
G
,
Cimaglia
P
,
Dan
GA
,
Santini
M
,
Kalarus
Z
,
Rasmussen
LH
,
Popescu
MI
,
Tica
O
,
Hellum
CF
,
Mortensen
B
,
Tavazzi
L
,
Maggioni
AP.
Sex-related differences in presentation, treatment, and outcome of patients with atrial fibrillation in Europe: a report from the Euro Observational Research Programme Pilot Survey on Atrial Fibrillation
.
Europace
2015
;
17
:
24
31
.

108

McCabe
PJ
,
Rhudy
LM
,
DeVon
HA.
Patients’ experiences from symptom onset to initial treatment for atrial fibrillation
.
J Clin Nurs
2015
;
24
:
786
796
.

109

McCabe
PJ
,
Schumacher
K
,
Barnason
SA.
Living with atrial fibrillation: a qualitative study
.
J Cardiovasc Nurs
2011
;
26
:
336
344
.

110

Meyre
P
,
Blum
S
,
Berger
S
,
Aeschbacher
S
,
Schoepfer
H
,
Briel
M
,
Osswald
S
,
Conen
D.
Risk of hospital admissions in patients with atrial fibrillation: a systematic review and meta-analysis
.
Can J Cardiol
2019
;
35
:
1332
1343
.

111

Nieuwlaat
R
,
Capucci
A
,
Camm
AJ
,
Olsson
SB
,
Andresen
D
,
Davies
DW
,
Cobbe
S,
,
Breithardt
G
,
Le Heuzey
JY
,
Prins
MH
,
Levy
S
,
Crijns
HJ
; European Heart Survey Investigators.
Atrial fibrillation management: a prospective survey in ESC member countries: the Euro Heart Survey on Atrial Fibrillation
.
Eur Heart J
2005
;
26
:
2422
2434
.

112

Overvad
TF
,
Nielsen
PB
,
Lip
GY.
Treatment thresholds for stroke prevention in atrial fibrillation: observations on the CHA2DS2-VASc score
.
Eur Heart J Cardiovasc Pharmacother
2017
;
3
:
37
41
.

113

Page
RL
,
Wilkinson
WE
,
Clair
WK
,
McCarthy
EA
,
Pritchett
EL.
Asymptomatic arrhythmias in patients with symptomatic paroxysmal atrial fibrillation and paroxysmal supraventricular tachycardia
.
Circulation
1994
;
89
:
224
227
.

114

Piccini
JP
,
Fauchier
L.
Rhythm control in atrial fibrillation
.
Lancet
2016
;
388
:
829
840
.

115

Pistoia
F
,
Sacco
S
,
Tiseo
C
,
Degan
D
,
Ornello
R
,
Carolei
A.
The epidemiology of atrial fibrillation and stroke
.
Cardiol Clin
2016
;
34
:
255
268
.

116

Pokorney
SD
,
Piccini
JP
,
Stevens
SR
,
Patel
MR
,
Pieper
KS
,
Halperin
JL
,
Breithardt
G
,
Singer
DE
,
Hankey
GJ
,
Hacke
W
,
Becker
RC
,
Berkowitz
SD
,
Nessel
CC
,
Mahaffey
KW
,
Fox
KA
,
Califf
RM
; ROCKET AF Steering Committee Investigators.
Cause of death and predictors of all-cause mortality in anticoagulated patients with nonvalvular atrial fibrillation: data from ROCKET AF
.
J Am Heart Assoc
2016
;
5
:
e002197
.

117

Potpara
TS
,
Polovina
MM,
,
Marinkovic
JM
,
Lip
GY.
A comparison of clinical characteristics and long-term prognosis in asymptomatic and symptomatic patients with first-diagnosed atrial fibrillation: the Belgrade Atrial Fibrillation Study
.
Int J Cardiol
2013
;
168
:
4744
4749
.

118

Randolph
TC
,
Simon
DN
,
Thomas
L,
,
Allen
LA
,
Fonarow
GC
,
Gersh
BJ
,
Kowey
PR
,
Reiffel
JA
,
Naccarelli
GV
,
Chan
PS
,
Spertus
JA
,
Peterson
ED
,
Piccini
JP
; ORBIT AF Investigators.
Patient factors associated with quality of life in atrial fibrillation
.
Am Heart J
2016
;
182
:
135
143
.

119

Rienstra
M
,
Lubitz
SA
,
Mahida
S
,
Magnani
JW
,
Fontes
JD
,
Sinner
MF
,
Van Gelder
IC
,
Ellinor
PT
,
Benjamin
EJ.
Symptoms and functional status of patients with atrial fibrillation: state-of-the-art and future research opportunities
.
Circulation
2012
;
125
:
2933
2943
.

120

Rienstra
M
,
Vermond
RA
,
Crijns
HJ
,
Tijssen
JG
,
Van Gelder
IC
; RACE Investigators.
Asymptomatic persistent atrial fibrillation and outcome: results of the RACE study
.
Heart Rhythm
2014
;
11
:
939
945
.

121

Rivard
L
,
Khairy
P.
Mechanisms, clinical significance, and prevention of cognitive impairment in patients with atrial fibrillation
.
Can J Cardiol
2017
;
33
:
1556
1564
.

122

Santangeli
P
,
Di Biase
L
,
Bai
R
,
Mohanty
S
,
Pump
A
,
Cereceda Brantes
M
,
Horton
R
,
Burkhardt
JD
,
Lakkireddy
D
,
Reddy
YM
,
Casella
M
,
Dello Russo
A
,
Tondo
C
,
Natale
A.
Atrial fibrillation and the risk of incident dementia: a meta-analysis
.
Heart Rhythm
2012
;
9
:
1761
1768
.

123

Schnabel
RB
,
Michal
M
,
Wilde
S
,
Wiltink
J
,
Wild
PS
,
Sinning
CR
,
Lubos
E
,
Ojeda
FM
,
Zeller
T
,
Munzel
T
,
Blankenberg
S
,
Beutel
ME.
Depression in atrial fibrillation in the general population
.
PLoS One
2013
;
8
:
e79109
.

124

Schnabel
RB
,
Pecen
L
,
Ojeda
FM
,
Lucerna
M
,
Rzayeva
N
,
Blankenberg
S
,
Darius
H
,
Kotecha
D
,
Caterina
R
,
Kirchhof
P.
Gender differences in clinical presentation and 1-year outcomes in atrial fibrillation
.
Heart
2017
;
103
:
1024
1030
.

125

Senoo
K
,
Suzuki
S
,
Sagara
K
,
Otsuka
T
,
Matsuno
S
,
Funada
R
,
Uejima
T
,
Oikawa
Y
,
Yajima
J
,
Koike
A
,
Nagashima
K
,
Kirigaya
H
,
Sawada
H
,
Aizawa
T
,
Yamashita
T.
Distribution of first-detected atrial fibrillation patients without structural heart diseases in symptom classifications
.
Circ J
2012
;
76
:
1020
1023
.

126

Serpytis
R
,
Navickaite
A
,
Serpytiene
E
,
Barysiene
J
,
Marinskis
G
,
Jatuzis
D
,
Petrulioniene
Z
,
Laucevicius
A
,
Serpytis
P.
Impact of atrial fibrillation on cognitive function, psychological distress, quality of life, and impulsiveness
.
Am J Med
2018
;
131
:
703.e1-703
e5
.

127

Siontis
KC
,
Gersh
BJ
,
Killian
JM
,
Noseworthy
PA,
,
McCabe
P
,
Weston
SA
,
Roger
VL
,
Chamberlain
AM.
Typical, atypical, and asymptomatic presentations of new-onset atrial fibrillation in the community: characteristics and prognostic implications
.
Heart Rhythm
2016
;
13
:
1418
1424
.

128

Steg
PG
,
Alam
S
,
Chiang
CE
,
Gamra
H
,
Goethals
M
,
Inoue
H
,
Krapf
L
,
Lewalter
T
,
Merioua
I
,
Murin
J
,
Naditch-Brule
L
,
Ponikowski
P
,
Rosenqvist
M
,
Silva-Cardoso
J
,
Zharinov
O
,
Brette
S
,
Neill
JO
; RealiseAF investigators.
Symptoms, functional status and quality of life in patients with controlled and uncontrolled atrial fibrillation: data from the RealiseAF cross-sectional international registry
.
Heart
2012
;
98
:
195
201
.

129

Steinberg
BA
,
Kim
S
,
Fonarow
GC
,
Thomas
L
,
Ansell
J
,
Kowey
PR
,
Mahaffey
KW
,
Gersh
BJ
,
Hylek
E
,
Naccarelli
G
,
Go
AS
,
Reiffel
J
,
Chang
P
,
Peterson
ED
,
Piccini
JP.
Drivers of hospitalization for patients with atrial fibrillation: results from the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF)
.
Am Heart J
2014
;
167
:
735
742.e2
.

130

Stewart
S
,
Hart
CL
,
Hole
DJ
,
McMurray
JJ.
A population-based study of the long-term risks associated with atrial fibrillation: 20-year follow-up of the Renfrew/Paisley study
.
Am J Med
2002
;
113
:
359
364
.

131

Streur
M
,
Ratcliffe
SJ
,
Ball
J
,
Stewart
S
,
Riegel
B.
Symptom clusters in adults with chronic atrial fibrillation
.
J Cardiovasc Nurs
2017
;
32
:
296
303
.

132

Thrall
G
,
Lip
GY
,
Carroll
D
,
Lane
D.
Depression, anxiety, and quality of life in patients with atrial fibrillation
.
Chest
2007
;
132
:
1259
1264
.

133

Ugowe
FE
,
Jackson LRn. Atrial fibrillation and mortality risk: seeing the big picture
.
Eur Heart J Qual Care Clin Outcomes
2019
;
5
:
6
7
.

134

Vermond
RA
,
Crijns
HJ
,
Tijssen
JG
,
Alings
AM
,
Van den Berg
MP
,
Hillege
HL
,
Van Veldhuisen
DJ
,
Van Gelder
IC
,
Rienstra
M
; RACE II investigators.
Symptom severity is associated with cardiovascular outcome in patients with permanent atrial fibrillation in the RACE II study
.
Europace
2014
;
16
:
1417
1425
.

135

Walters
TE
,
Wick
K
,
Tan
G
,
Mearns
M
,
Joseph
SA
,
Morton
JB
,
Sanders
P
,
Bryant
C
,
Kistler
PM
,
Kalman
JM.
Psychological distress and suicidal ideation in patients with atrial fibrillation: prevalence and response to management strategy
.
J Am Heart Assoc
2018
;
7
:
e005502
.

136

Walters
TE
,
Wick
K
,
Tan
G
,
Mearns
M
,
Joseph
SA
,
Morton
JB
,
Sanders
P
,
Bryant
C
,
Kistler
PM
,
Kalman
JM.
Symptom severity and quality of life in patients with atrial fibrillation: psychological function outweighs clinical predictors
.
Int J Cardiol
2019
;
279
:
84
89
.

137

Wang
TJ,
,
Massaro
JM
,
Levy
D
,
Vasan
RS
,
Wolf
PA
,
D’Agostino
RB
,
Larson
MG
,
Kannel
WB
,
Benjamin
EJ.
A risk score for predicting stroke or death in individuals with new-onset atrial fibrillation in the community: the Framingham Heart Study
.
JAMA
2003
;
290
:
1049
1056
.

138

Wijesurendra
RS
,
Casadei
B.
Atrial fibrillation: effects beyond the atrium?
Cardiovasc Res
2015
;
105
:
238
247
.

139

Xiong
Q
,
Proietti
M
,
Senoo
K
,
Lip
GY.
Asymptomatic versus symptomatic atrial fibrillation: a systematic review of age/gender differences and cardiovascular outcomes
.
Int J Cardiol
2015
;
191
:
172
177
.

140

Ziff
OJ
,
Carter
PR
,
McGowan
J
,
Uppal
H
,
Chandran
S
,
Russell
S
,
Bainey
KR
,
Potluri
R.
The interplay between atrial fibrillation and heart failure on long-term mortality and length of stay: insights from the United Kingdom ACALM registry
.
Int J Cardiol
2018
;
252
:
117
121
.

141

Sepehri Shamloo
A
,
Dagres
N
,
Mussigbrodt
A
,
Stauber
A
,
Kircher
S
,
Richter
S
,
Dinov
B
,
Bertagnolli
L
,
Husser-Bollmann
D
,
Bollmann
A
,
Hindricks
G
,
Arya
A.
Atrial fibrillation and cognitive impairment: new insights and future directions
.
Heart Lung Circ
2020
;
29
:
69
85
.

142

Conen
D
,
Rodondi
N
,
Muller
A
,
Beer
JH
,
Ammann
P
,
Moschovitis
G
,
Auricchio
A
,
Hayoz
D
,
Kobza
R
,
Shah
D
,
Novak
J
,
Schlapfer
J
,
Di Valentino
M
,
Aeschbacher
S
,
Blum
S
,
Meyre
P
,
Sticherling
C
,
Bonati
LH
,
Ehret
G
,
Moutzouri
E
,
Fischer
U
,
Monsch
AU
,
Stippich
C
,
Wuerfel
J
,
Sinnecker
T
,
Coslovsky
M
,
Schwenkglenks
M
,
Kuhne
M
,
Osswald
S
,
Swiss
AFSI.
Relationships of overt and silent brain lesions with cognitive function in patients with atrial fibrillation
.
J Am Coll Cardiol
2019
;
73
:
989
999
.

143

Kirchhof
P
,
Benussi
S
,
Kotecha
D
,
Ahlsson
A
,
Atar
D
,
Casadei
B
,
Castella
M
,
Diener
HC
,
Heidbuchel
H
,
Hendriks
J
,
Hindricks
G
,
Manolis
AS
,
Oldgren
J
,
Popescu
BA
,
Schotten
U
,
Van Putte
B
,
Vardas
P
, ESC Scientific Document Group.
2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS
.
Eur Heart J
2016
;
37
:
2893
2962
.

144

Boriani
G
,
Diemberger
I
,
Ziacchi
M
,
Valzania
C
,
Gardini
B
,
Cimaglia
P
,
Martignani
C
,
Biffi
M.
AF burden is important – fact or fiction?
Int J Clin Pract
2014
;
68
:
444
452
.

145

Boriani
G
,
Pettorelli
D.
Atrial fibrillation burden and atrial fibrillation type: clinical significance and impact on the risk of stroke and decision making for long-term anticoagulation
.
Vascul Pharmacol
2016
;
83
:
26
35
.

146

Charitos
EI
,
Purerfellner
H
,
Glotzer
TV
,
Ziegler
PD.
Clinical classifications of atrial fibrillation poorly reflect its temporal persistence: insights from 1,195 patients continuously monitored with implantable devices
.
J Am Coll Cardiol
2014
;
63
:
2840
2848
.

147

Wyse
DG
,
Van Gelder
IC
,
Ellinor
PT
,
Go
AS
,
Kalman
JM
,
Narayan
SM
,
Nattel
S
,
Schotten
U
,
Rienstra
M.
Lone atrial fibrillation: does it exist?
J Am Coll Cardiol
2014
;
63
:
1715
1723
.

148

Lip
GYH
,
Collet
JP
,
Caterina
R
,
Fauchier
L
,
Lane
DA
,
Larsen
TB
,
Marin
F
,
Morais
J
,
Narasimhan
C
,
Olshansky
B
,
Pierard
L
,
Potpara
T
,
Sarrafzadegan
N
,
Sliwa
K
,
Varela
G
,
Vilahur
G
,
Weiss
T
,
Boriani
G
,
Rocca
B
, ESC Scientific Document Group.
Antithrombotic therapy in atrial fibrillation associated with valvular heart disease: a joint consensus document from the European Heart Rhythm Association (EHRA) and European Society of Cardiology Working Group on Thrombosis, endorsed by the ESC Working Group on Valvular Heart Disease, Cardiac Arrhythmia Society of Southern Africa (CASSA), Heart Rhythm Society (HRS), Asia Pacific Heart Rhythm Society (APHRS), South African Heart (SA Heart) Association and Sociedad Latinoamericana de Estimulacion Cardiaca y Electrofisiologia (SOLEACE)
.
Europace
2017
;
19
:
1757
1758
.

149

January
CT
,
Wann
LS
,
Calkins
H
,
Chen
LY
,
Cigarroa
JE
,
Cleveland
JC
Jr.
,
Ellinor
PT
,
Ezekowitz
MD
,
Field
ME
,
Furie
KL
,
Heidenreich
PA
,
Murray
KT
,
Shea
JB
,
Tracy
CM
,
Yancy
CW.
2019 AHA/ACC/HRS focused update of the 2014 AHA/ACC/HRS Guideline for the management of patients with atrial fibrillation
.
Circulation
2019
;;
140
:
e125
e151
.

150

NHFA CSANZ Atrial Fibrillation Guideline Working Group,

Brieger
D
,
Amerena
J
,
Attia
J
,
Bajorek
B
,
Chan
KH
,
Connell
C
,
Freedman
B
,
Ferguson
C
,
Hall
T
,
Haqqani
H
,
Hendriks
J
,
Hespe
C
,
Hung
J
,
Kalman
JM
,
Sanders
P
,
Worthington
J
,
Yan
TD
,
Zwar
N.
National Heart Foundation of Australia and the Cardiac Society of Australia and New Zealand: Australian Clinical Guidelines for the diagnosis and management of atrial fibrillation 2018
.
Heart Lung Circ
2018
;
27
:
1209
1266
.

151

Potpara TS, Lip GYH, Blomstrom-Lundqvist C, Boriani G, Van Gelder IC, Heidbuchel H, Hindricks G, Camm AJ. The 4S-AF scheme (Stroke Risk; Symptoms; Severity of Burden; Substrate): A novel approach to in-depth characterization (rather than Classification) of atrial fibrillation. Thromb Haemost 2020; doi: 10.1055/s-0040-1716408.

152

Chen
LY
,
Chung
MK
,
Allen
LA
,
Ezekowitz
M
,
Furie
KL
,
McCabe
P
,
Noseworthy
PA
,
Perez
MV
,
Turakhia
MP,
American Heart Association Council on Clinical Cardiology, Council on Cardiovascular and Stroke Nursing, Council on Quality of Care and Outcomes Research, and Stroke Council.
Atrial fibrillation burden: moving beyond atrial fibrillation as a binary entity: a scientific statement from the American Heart Association
.
Circulation
2018
;
137
:
e623
e644
.

153

Ziegler
PD
,
Koehler
JL
,
Mehra
R.
Comparison of continuous versus intermittent monitoring of atrial arrhythmias
.
Heart Rhythm
2006
;
3
:
1445
1452
.

154

Boriani
G
,
Proietti
M
,
Laroche
C
,
Fauchier
L
,
Marin
F
,
Nabauer
M
,
Potpara
T
,
Dan
GA
,
Kalarus
Z
,
Diemberger
I
,
Tavazzi
L
,
Maggioni
AP
,
Lip
GYH
; EORP-AF Long-Term General Registry Investigators Steering Committee (National Coordinators.
Contemporary stroke prevention strategies in 11 096 European patients with atrial fibrillation: a report from the EURObservational Research Programme on Atrial Fibrillation (EORP-AF) long-term general registry
.
Europace
2018
;
20
:
747
757
.

155

Pandey
A
,
Kim
S
,
Moore
C
,
Thomas
L
,
Gersh
B
,
Allen
LA
,
Kowey
PR
,
Mahaffey
KW
,
Hylek
E
,
Peterson
ED
,
Piccini
JP
,
Fonarow
GC
; ORBIT-AF Investigators and Patients.
Predictors and prognostic implications of incident heart failure in patients with prevalent atrial fibrillation
.
JACC Heart Fail
2017
;
5
:
44
52
.

156

Ganesan
AN
,
Chew
DP
,
Hartshorne
T
,
Selvanayagam
JB
,
Aylward
PE
,
Sanders
P
,
McGavigan
AD.
The impact of atrial fibrillation type on the risk of thromboembolism, mortality, and bleeding: a systematic review and meta-analysis
.
Eur Heart J
2016
;
37
:
1591
1602
.

157

Al-Khatib
SM
,
Thomas
L
,
Wallentin
L
,
Lopes
RD
,
Gersh
B
,
Garcia
D
,
Ezekowitz
J
,
Alings
M
,
Yang
H
,
Alexander
JH
,
Flaker
G
,
Hanna
M
,
Granger
CB.
Outcomes of apixaban vs. warfarin by type and duration of atrial fibrillation: results from the ARISTOTLE trial
.
Eur Heart J
2013
;
34
:
2464
2471
.

158

Link
MS
,
Giugliano
RP
,
Ruff
CT
,
Scirica
BM
,
Huikuri
H
,
Oto
A
,
Crompton
AE,
,
Murphy
SA
,
Lanz
H
,
Mercuri
MF
,
Antman
EM
,
Braunwald
E
; ENGAGE AF-TIMI 48 Investigators.
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 Electrophysiol
2017
;
10
:
e004267
.

159

Steinberg
BA
,
Hellkamp
AS
,
Lokhnygina
Y
,
Patel
MR
,
Breithardt
G
,
Hankey
GJ
,
Becker
RC
,
Singer
DE
,
Halperin
JL
,
Hacke
W
,
Nessel
CC
,
Berkowitz
SD
,
Mahaffey
KW
,
Fox
KA
,
Califf
RM
,
Piccini
JP
; ROCKET-AF Steering Committee and Investigators.
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
.

160

Hart
RG
,
Pearce
LA
,
Rothbart
RM
,
McAnulty
JH
,
Asinger
RW
,
Halperin
JL.
Stroke with intermittent atrial fibrillation: incidence and predictors during aspirin therapy. Stroke Prevention in Atrial Fibrillation Investigators
.
J Am Coll Cardiol
2000
;
35
:
183
187
.

161

Takabayashi
K
,
Hamatani
Y
,
Yamashita
Y
,
Takagi
D
,
Unoki
T
,
Ishii
M
,
Iguchi
M
,
Masunaga
N
,
Ogawa
H
,
Esato
M
,
Chun
YH
,
Tsuji
H
,
Wada
H
,
Hasegawa
K
,
Abe
M
,
Lip
GY
,
Akao
M.
Incidence of stroke or systemic embolism in paroxysmal versus sustained atrial fibrillation: the Fushimi Atrial Fibrillation Registry
.
Stroke
2015
;
46
:
3354
3361
.

162

Nieuwlaat
R
,
Dinh
T
,
Olsson
SB
,
Camm
AJ
,
Capucci
A
,
Tieleman
RG
,
Lip
GY
,
Crijns
HJ
; Euro Heart Survey Investigators.
Should we abandon the common practice of withholding oral anticoagulation in paroxysmal atrial fibrillation?
Eur Heart J
2008
;
29
:
915
922
.

163

Go
AS
,
Reynolds
K
,
Yang
J
,
Gupta
N
,
Lenane
J
,
Sung
SH
,
Harrison
TN
,
Liu
TI
,
Solomon
MD.
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
.

164

Ecker
V
,
Knoery
C
,
Rushworth
G
,
Rudd
I
,
Ortner
A
,
Begley
D
,
Leslie
SJ.
A review of factors associated with maintenance of sinus rhythm after elective electrical cardioversion for atrial fibrillation
.
Clin Cardiol
2018
;
41
:
862
870
.

165

Nyong
J
,
Amit
G
,
Adler
AJ
,
Owolabi
OO
,
Perel
P
,
Prieto-Merino
D
,
Lambiase
P
,
Casas
JP
,
Morillo
CA.
Efficacy and safety of ablation for people with non-paroxysmal atrial fibrillation
.
Cochrane Database Syst Rev
2016
;
11
:
CD012088
.

166

Piccini
JP
,
Passman
R
,
Turakhia
M
,
Connolly
AT
,
Nabutovsky
Y
,
Varma
N.
Atrial fibrillation burden, progression, and the risk of death: a case-crossover analysis in patients with cardiac implantable electronic devices
.
Europace
2019
;
21
:
404
413
.

167

Deng
H
,
Bai
Y
,
Shantsila
A
,
Fauchier
L
,
Potpara
TS
,
Lip
GYH.
Clinical scores for outcomes of rhythm control or arrhythmia progression in patients with atrial fibrillation: a systematic review
.
Clin Res Cardiol
2017
;
106
:
813
823
.

168

Healey
JS
,
Connolly
SJ
,
Gold
MR
,
Israel
CW
,
Van Gelder
IC
,
Capucci
A
,
Lau
CP
,
Fain
E
,
Yang
S
,
Bailleul
C
,
Morillo
CA
,
Carlson
M
,
Themeles
E
,
Kaufman
ES
,
Hohnloser
SH
; ASSERT Investigators.
Subclinical atrial fibrillation and the risk of stroke
.
N Engl J Med
2012
;
366
:
120
129
.

169

Potpara
TS
,
Stankovic
GR
,
Beleslin
BD
,
Polovina
MM,
,
Marinkovic
JM
,
Ostojic
MC
,
Lip
GYH.
A 12-year follow-up study of patients with newly diagnosed lone atrial fibrillation: implications of arrhythmia progression on prognosis: the Belgrade Atrial Fibrillation Study
.
Chest
2012
;
141
:
339
347
.

170

Goette
A
,
Kalman
JM
,
Aguinaga
L
,
Akar
J
,
Cabrera
JA
,
Chen
SA
,
Chugh
SS
,
Corradi
D
,
D'Avila
A
,
Dobrev
D
,
Fenelon
G
,
Gonzalez
M
,
Hatem
SN
,
Helm
R
,
Hindricks
G
,
Ho
SY
,
Hoit
B
,
Jalife
J
,
Kim
YH
,
Lip
GY
,
Ma
CS
,
Marcus
GM
,
Murray
K
,
Nogami
A
,
Sanders
P
,
Uribe
W
,
Van Wagoner
DR
,
Nattel
S.
EHRA/HRS/APHRS/SOLAECE expert consensus on atrial cardiomyopathies: definition, characterization, and clinical implication
.
Europace
2016
;
18
:
1455
1490
.

171

Nattel
S
,
Guasch
E
,
Savelieva
I
,
Cosio
FG
,
Valverde
I
,
Halperin
JL
,
Conroy
JM
,
Al-Khatib
SM
,
Hess
PL
,
Kirchhof
P
,
De Bono
J,
,
Lip
GY
,
Banerjee
A
,
Ruskin
J
,
Blendea
D
,
Camm
AJ.
Early management of atrial fibrillation to prevent cardiovascular complications
.
Eur Heart J
2014
;
35
:
1448
1456
.

172

Freedman
B
,
Camm
J
,
Calkins
H
,
Healey
JS
,
Rosenqvist
M
,
Wang
J
,
Albert
CM
,
Anderson
CS
,
Antoniou
S,
,
Benjamin
EJ
,
Boriani
G
,
Brachmann
J
,
Brandes
A
,
Chao
TF
,
Conen
D
,
Engdahl
J
,
Fauchier
L
,
Fitzmaurice
DA
,
Friberg
L
,
Gersh
BJ
,
Gladstone
DJ
,
Glotzer
TV
,
Gwynne
K
,
Hankey
GJ
,
Harbison
J
,
Hillis
GS
,
Hills
MT
,
Kamel
H
,
Kirchhof
P
,
Kowey
PR,
,
Krieger
D
,
Lee
VWY
,
Levin
LA
,
Lip
GYH
,
Lobban
T
,
Lowres
N
,
Mairesse
GH
,
Martinez
C
,
Neubeck
L
,
Orchard
J,
,
Piccini
JP
,
Poppe
K
,
Potpara
TS
,
Puererfellner
H
,
Rienstra
M
,
Sandhu
RK
,
Schnabel
RB
,
Siu
CW
,
Steinhubl
S
,
Svendsen
JH
,
Svennberg
E
,
Themistoclakis
S
,
Tieleman
RG
,
Turakhia
MP
,
Tveit
A
,
Uittenbogaart
SB
,
Van Gelder
IC
,
Verma
A
,
Wachter
R
,
Yan
BP
,
SCREEN Collaborators
AF-
.
Screening for atrial fibrillation: a report of the AF-SCREEN International Collaboration
.
Circulation
2017
;
135
:
1851
1867
.

173

Mairesse
GH
,
Moran
P
,
Van Gelder
IC
,
Elsner
C
,
Rosenqvist
M
,
Mant
J
,
Banerjee
A
,
Gorenek
B
,
Brachmann
J
,
Varma
N
,
Glotz de Lima
G
,
Kalman
J
,
Claes
N
,
Lobban
T
,
Lane
D
,
Lip
GYH
,
Boriani
G
, ESC Scientific Document Group.
Screening for atrial fibrillation: a European Heart Rhythm Association (EHRA) consensus document endorsed by the Heart Rhythm Society (HRS), Asia Pacific Heart Rhythm Society (APHRS), and Sociedad Latinoamericana de Estimulacion Cardiaca y Electrofisiologia (SOLAECE
).
Europace
2017
;
19
:
1589
1623
.

174

Padfield
GJ
,
Steinberg
C
,
Swampillai
J
,
Qian
H
,
Connolly
SJ
,
Dorian
P
,
Green
MS
,
Humphries
KH
,
Klein
GJ
,
Sheldon
R
,
Talajic
M
,
Kerr
CR.
Progression of paroxysmal to persistent atrial fibrillation: 10-year follow-up in the Canadian Registry of Atrial Fibrillation
.
Heart Rhythm
2017
;
14
:
801
807
.

175

Vidal-Perez
R
,
Otero-Ravina
F
,
Lado-Lopez
M
,
Turrado-Turrado
V
,
Rodriguez-Moldes
E
,
Gomez-Vazquez
JL
,
de Frutos-de Marcos
C
,
de Blas-Abad
P
,
Besada-Gesto
R
,
Gonzalez-Juanatey
JR
; BARBANZA Investigators.
The change in the atrial fibrillation type as a prognosis marker in a community study: long-term data from AFBAR (Atrial Fibrillation in the BARbanza) study
.
Int J Cardiol
2013
;
168
:
2146
2152
.

176

de Vos
CB
,
Pisters
R
,
Nieuwlaat
R
,
Prins
MH
,
Tieleman
RG
,
Coelen
RJ
,
van den Heijkant
AC
,
Allessie
MA,
,
Crijns
HJ
.
Progression from paroxysmal to persistent atrial fibrillation clinical correlates and prognosis
.
J Am Coll Cardiol
2010
;
55
:
725
731
.

177

Hobbelt
AH
,
Spronk
HM
,
Crijns
H
,
Ten Cate
H
,
Rienstra
M
,
Van Gelder
IC.
Prethrombotic state in young very low-risk patients with atrial fibrillation
.
J Am Coll Cardiol
2017
;
69
:
1990
1992
.

178

Habibi
M
,
Samiei
S
,
Ambale Venkatesh
B
,
Opdahl
A
,
Helle-Valle
TM
,
Zareian
M
,
Almeida
AL
,
Choi
EY
,
Wu
C
,
Alonso
A
,
Heckbert
SR
,
Bluemke
DA
,
Lima
JA
.
Cardiac magnetic resonance-measured left atrial volume and function and incident atrial fibrillation: results from MESA (Multi-Ethnic Study of Atherosclerosis)
.
Circ Cardiovasc Imaging
2016
;
9
:
e004299
.

179

Brambatti
M
,
Connolly
SJ
,
Gold
MR
,
Morillo
CA
,
Capucci
A
,
Muto
C
,
Lau
CP
,
Van Gelder
IC
,
Hohnloser
SH
,
Carlson
M
,
Fain
E
,
Nakamya
J
,
Mairesse
GH
,
Halytska
M
,
Deng
WQ
,
Israel
CW
,
Healey
JS
; ASSERT Investigators.
Temporal relationship between subclinical atrial fibrillation and embolic events
.
Circulation
2014
;
129
:
2094
2099
.

180

Guichard
JB
,
Nattel
S.
Atrial Cardiomyopathy: A useful notion in cardiac disease management or a passing fad?
J Am Coll Cardiol
2017
;
70
:
756
765
.

181

Hirsh
BJ
,
Copeland-Halperin
RS
,
Halperin
JL.
Fibrotic atrial cardiomyopathy, atrial fibrillation, and thromboembolism: mechanistic links and clinical inferences
.
J Am Coll Cardiol
2015
;
65
:
2239
2251
.

182

Freedman
B
,
Potpara
TS
,
Lip
GY.
Stroke prevention in atrial fibrillation
.
Lancet
2016
;
388
:
806
817
.

183

Martinez
C
,
Katholing
A
,
Freedman
SB.
Adverse prognosis of incidentally detected ambulatory atrial fibrillation. A cohort study
.
Thromb Haemost
2014
;
112
:
276
286
.

184

Wilson
JM
,
Jungner
YG.
[Principles and practice of mass screening for disease]
.
Bol Oficina Sanit Panam
1968
;
65
:
281
393
.

185

Welton
NJ
,
McAleenan
A
,
Thom
HH
,
Davies
P
,
Hollingworth
W
,
Higgins
JP
,
Okoli
G
,
Sterne
JA
,
Feder
G
,
Eaton
D
,
Hingorani
A
,
Fawsitt
C
,
Lobban
T
,
Bryden
P
,
Richards
A
,
Sofat
R.
Screening strategies for atrial fibrillation: a systematic review and cost-effectiveness analysis
.
Health Technol Assess
2017
;
21
:
1
236
.

186

Steinhubl
SR
,
Waalen
J
,
Edwards
AM
,
Ariniello
LM
,
Mehta
RR
,
Ebner
GS
,
Carter
C
,
Baca-Motes
K
,
Felicione
E
,
Sarich
T
,
Topol
EJ.
Effect of a home-based wearable continuous ECG monitoring patch on detection of undiagnosed atrial fibrillation: the mSToPS randomized clinical trial
.
JAMA
2018
;
320
:
146
155
.

187

Schnabel
RB
,
Haeusler
KG,
,
Healey
JS
,
Freedman
B
,
Boriani
G
,
Brachmann
J
,
Brandes
A
,
Bustamante
A
,
Casadei
B
,
Crijns
H
,
Doehner
W
,
Engstrom
G
,
Fauchier
L
,
Friberg
L
,
Gladstone
DJ
,
Glotzer
TV
,
Goto
S
,
Hankey
GJ,
,
Harbison
JA
,
Hobbs
FDR
,
Johnson
LSB
,
Kamel
H
,
Kirchhof
P
,
Korompoki
E
,
Krieger
DW
,
Lip
GYH
,
Lochen
ML
,
Mairesse
GH
,
Montaner
J
,
Neubeck
L
,
Ntaios
G
,
Piccini
JP
,
Potpara
TS
,
Quinn
TJ
,
Reiffel
JA
,
Ribeiro
ALP
,
Rienstra
M
,
Rosenqvist
M
,
Sakis
T,
,
Sinner
MF
,
Svendsen
JH
,
Van Gelder
IC
,
Wachter
R
,
Wijeratne
T
,
Yan
B.
Searching for atrial fibrillation poststroke: a white paper of the AF-SCREEN International Collaboration
.
Circulation
2019
;
140
:
1834
1850
.

188

Yan
BP
,
Lai
WHS
,
Chan
CKY
,
Chan
SC
,
Chan
LH
,
Lam
KM
,
Lau
HW
,
Ng
CM
,
Tai
LY
,
Yip
KW
,
To
OTL
,
Freedman
B,
,
Poh
YC
,
Poh
MZ.
Contact-free screening of atrial fibrillation by a smartphone using facial pulsatile photoplethysmographic signals
.
J Am Heart Assoc
2018
;
7
.

189

Orchard
J
,
Lowres
N
,
Freedman
SB
,
Ladak
L
,
Lee
W
,
Zwar
N
,
Peiris
D
,
Kamaladasa
Y
,
Li
J
,
Neubeck
L.
Screening for atrial fibrillation during influenza vaccinations by primary care nurses using a smartphone electrocardiograph (iECG): a feasibility study
.
Eur J Prev Cardiol
2016
;
23
:
13
20
.

190

Lampert
R.
Screening for atrial fibrillation using smartphone-based technology and layperson volunteers: high-tech meets community participatory research for the best of both worlds
.
Heart Rhythm
2018
;
15
:
1312
1313
.

191

Lahdenoja
O
,
Hurnanen
T
,
Iftikhar
Z
,
Nieminen
S
,
Knuutila
T
,
Saraste
A
,
Kiviniemi
T
,
Vasankari
T
,
Airaksinen
J
,
Pankaala
M
,
Koivisto
T.
Atrial fibrillation detection via accelerometer and gyroscope of a smartphone
.
IEEE J Biomed Health Inform
2018
;
22
:
108
118
.

192

Freedman
B.
Screening for atrial fibrillation using a smartphone: is there an app for that?
J Am Heart Assoc
2016
;
5
.

193

Chan
NY
,
Choy
CC.
Screening for atrial fibrillation in 13 122 Hong Kong citizens with smartphone electrocardiogram
.
Heart
2017
;
103
:
24
31
.

194

Chan
PH
,
Wong
CK
,
Poh
YC
,
Pun
L
,
Leung
WW,
,
Wong
YF
,
Wong
MM
,
Poh
MZ
,
Chu
DW
,
Siu
CW.
Diagnostic performance of a smartphone-based photoplethysmographic application for atrial fibrillation screening in a primary care setting
.
J Am Heart Assoc
2016
;
5
.

195

Brasier
N
,
Raichle
CJ
,
Dorr
M
,
Becke
A
,
Nohturfft
V
,
Weber
S
,
Bulacher
F
,
Salomon
L
,
Noah
T
,
Birkemeyer
R
,
Eckstein
J.
Detection of atrial fibrillation with a smartphone camera: first prospective, international, two-centre, clinical validation study (DETECT AF PRO)
.
Europace
2019
;
21
:
41
47
.

196

Tison
GH
,
Sanchez
JM
,
Ballinger
B
,
Singh
A
,
Olgin
JE
,
Pletcher
MJ
,
Vittinghoff
E
,
Lee
ES
,
Fan
SM
,
Gladstone
RA
,
Mikell
C
,
Sohoni
N
,
Hsieh
J
,
Marcus
GM
.
Passive detection of atrial fibrillation using a commercially available smartwatch
.
JAMA Cardiol
2018
;
3
:
409
416
.

197

Li
KHC
,
White
FA
,
Tipoe
T
,
Liu
T
,
Wong
MC
,
Jesuthasan
A
,
Baranchuk
A
,
Tse
G
,
Yan
BP.
The current state of mobile phone apps for monitoring heart rate, heart rate variability, and atrial fibrillation: narrative review
.
JMIR Mhealth Uhealth
2019
;
7
:
e11606
.

198

Bumgarner
JM
,
Lambert
CT
,
Hussein
AA
,
Cantillon
DJ
,
Baranowski
B
,
Wolski
K
,
Lindsay
BD
,
Wazni
OM
,
Tarakji
KG.
Smartwatch algorithm for automated detection of atrial fibrillation
.
J Am Coll Cardiol
2018
;
71
:
2381
2388
.

199

Wasserlauf
J
,
You
C
,
Patel
R
,
Valys
A
,
Albert
D
,
Passman
R.
Smartwatch performance for the detection and quantification of atrial fibrillation
.
Circ Arrhythm Electrophysiol
2019
;
12
:
e006834
.

200

Attia
ZI
,
Noseworthy
PA
,
Lopez-Jimenez
F
,
Asirvatham
SJ
,
Deshmukh
AJ
,
Gersh
BJ
,
Carter
RE
,
Yao
X
,
Rabinstein
AA
,
Erickson
BJ
,
Kapa
S
,
Friedman
PA.
Anartificial intelligence-enabled ECG algorithm for the identification of patients with atrial fibrillation during sinus rhythm: a retrospective analysis of outcome prediction
.
Lancet
2019
;
394
:
861
867
.

201

Turakhia
MP
,
Desai
M
,
Hedlin
H
,
Rajmane
A
,
Talati
N
,
Ferris
T
,
Desai
S
,
Nag
D
,
Patel
M
,
Kowey
P
,
Rumsfeld
JS
,
Russo
AM
,
Hills
MT
,
Granger
CB
,
Mahaffey
KW
,
Perez
MV.
Rationale and design of a large-scale, app-based study to identify cardiac arrhythmias using a smartwatch: the Apple Heart Study
.
Am Heart J
2019
;
207
:
66
75
.

202

Guo
Y
,
Wang
H
,
Zhang
H
,
Liu
T
,
Liang
Z
,
Xia
Y
,
Yan
L
,
Xing
Y
,
Shi
H
,
Li
S
,
Liu
Y
,
Liu
F
,
Feng
M
,
Chen
Y
,
Lip
GYH
; MAFA II Investigators.
Mobile photoplethysmographic technology to detect atrial fibrillation
.
J Am Coll Cardiol
2019
;
74
:
2365
2375
.

203

Harris
K
,
Edwards
D
,
Mant
J.
How can we best detect atrial fibrillation?
J R Coll Physicians Edinb
2012
;
42 Suppl 18
:
5
22
.

204

Wiesel
J
,
Wiesel
D
,
Suri
R
,
Messineo
FC.
The use of a modified sphygmomanometer to detect atrial fibrillation in outpatients
.
Pacing Clin Electrophysiol
2004
;
27
:
639
643
.

205

Wiesel
J
,
Fitzig
L
,
Herschman
Y
,
Messineo
FC.
Detection of atrial fibrillation using a modified microlife blood pressure monitor
.
Am J Hypertens
2009
;
22
:
848
852
.

206

Stergiou
GS
,
Karpettas
N
,
Protogerou
A
,
Nasothimiou
EG
,
Kyriakidis
M.
Diagnostic accuracy of a home blood pressure monitor to detect atrial fibrillation
.
J Hum Hypertens
2009
;
23
:
654
658
.

207

Willits
I
,
Keltie
K
,
Craig
J
,
Sims
A.
WatchBP Home A for opportunistically detecting atrial fibrillation during diagnosis and monitoring of hypertension: a
NICE Medical Technology Guidance. Appl Health Econ Health Policy
2014
;
12
:
255
265
.

208

Desteghe
L
,
Raymaekers
Z
,
Lutin
M
,
Vijgen
J
,
Dilling-Boer
D
,
Koopman
P
,
Schurmans
J
,
Vanduynhoven
P
,
Dendale
P
,
Heidbuchel
H.
Performance of handheld electrocardiogram devices to detect atrial fibrillation in a cardiology and geriatric ward setting
.
Europace
2017
;
19
:
29
39
.

209

Kaasenbrood
F,
,
Hollander
M
,
Rutten
FH
,
Gerhards
LJ
,
Hoes
AW
,
Tieleman
RG.
Yield of screening for atrial fibrillation in primary care with a hand-held, single-lead electrocardiogram device during influenza vaccination
.
Europace
2016
;
18
:
1514
1520
.

210

Wiesel
J
,
Abraham
S
,
Messineo
FC.
Screening for asymptomatic atrial fibrillation while monitoring the blood pressure at home: trial of regular versus irregular pulse for prevention of stroke (TRIPPS 2.0)
.
Am J Cardiol
2013
;
111
:
1598
1601
.

211

Jacobs
MS
,
Kaasenbrood
F
,
Postma
MJ
,
van Hulst
M
,
Tieleman
RG.
Cost-effectiveness of screening for atrial fibrillation in primary care with a handheld, single-lead electrocardiogram device in the Netherlands
.
Europace
2018
;
20
:
12
18
.

212

Lowres
N
,
Neubeck
L
,
Salkeld
G
,
Krass
I
,
McLachlan
AJ
,
Redfern
J
,
Bennett
AA
,
Briffa
T
,
Bauman
A
,
Martinez
C
,
Wallenhorst
C
,
Lau
JK
,
Brieger
DB
,
Sy
RW
,
Freedman
SB.
Feasibility and cost-effectiveness of stroke prevention through community screening for atrial fibrillation using iPhone ECG in pharmacies. The SEARCH-AF study
.
Thromb Haemost
2014
;
111
:
1167
1176
.

213

William
AD
,
Kanbour
M
,
Callahan
T
,
Bhargava
M
,
Varma
N
,
Rickard
J
,
Saliba
W
,
Wolski
K
,
Hussein
A
,
Lindsay
BD
,
Wazni
OM
,
Tarakji
KG.
Assessing the accuracy of an automated atrial fibrillation detection algorithm using smartphone technology: the iREAD Study
.
Heart Rhythm
2018
;
15
:
1561
1565
.

214

Nemati
S
,
Ghassemi
MM
,
Ambai
V
,
Isakadze
N
,
Levantsevych
O
,
Shah
A
,
Clifford
GD.
Monitoring and detecting atrial fibrillation using wearable technology
.
Conf Proc IEEE Eng Med Biol Soc
2016
;
2016
:
3394
3397
.

215

Petryszyn
P
,
Niewinski
P
,
Staniak
A
,
Piotrowski
P
,
Well
A
,
Well
M
,
Jeskowiak
I
,
Lip
G
,
Ponikowski
P.
Effectiveness of screening for atrial fibrillation and its determinants. A meta-analysis
.
PLoS One
2019
;
14
:
e0213198
.

216

Orchard
J
,
Lowres
N
,
Neubeck
L
,
Freedman
B.
Atrial fibrillation: is there enough evidence to recommend opportunistic or systematic screening?
Int J Epidemiol
2018
;
47
:
1361
.

217

Svennberg
E
,
Engdahl
J
,
Al-Khalili
F
,
Friberg
L
,
Frykman
V
,
Rosenqvist
M.
Mass screening for untreated atrial fibrillation: the STROKESTOP Study
.
Circulation
2015
;
131
:
2176
2184
.

218

Halcox
JPJ
,
Wareham
K
,
Cardew
A
,
Gilmore
M,
,
Barry
JP
,
Phillips
C
,
Gravenor
MB.
Assessment of remote heart rhythm sampling using the AliveCor heart monitor to screen for atrial fibrillation: the REHEARSE-AF Study
.
Circulation
2017
;
136
:
1784
1794
.

219

Turakhia
MP
,
Shafrin
J
,
Bognar
K
,
Goldman
DP,
,
Mendys
PM
,
Abdulsattar
Y
,
Wiederkehr
D
,
Trocio
J.
Economic burden of undiagnosed nonvalvular atrial fibrillation in the United States
.
Am J Cardiol
2015
;
116
:
733
739
.

220

Fay
MR
,
Fitzmaurice
DA
,
Freedman
B.
Screening of older patients for atrial fibrillation in general practice: current evidence and its implications for future practice
.
Eur J Gen Pract
2017
;
23
:
246
253
.

221

Boriani
G
,
Valzania
C
,
Biffi
M
,
Diemberger
I
,
Ziacchi
M
,
Martignani
C.
Asymptomatic lone atrial fibrillation – how can we detect the arrhythmia?
Curr Pharm Des
2015
;
21
:
659
666
.

222

Hobbs
FD
,
Fitzmaurice
DA
,
Mant
J
,
Murray
E
,
Jowett
S
,
Bryan
S
,
Raftery
J
,
Davies
M
,
Lip
G.
A randomised controlled trial and cost-effectiveness study of systematic screening (targeted and total population screening) versus routine practice for the detection of atrial fibrillation in people aged 65 and over. The SAFE study
.
Health Technol Assess
2005
;
9
:iii-iv, ix-x,
1
74
.

223

Aronsson
M
,
Svennberg
E
,
Rosenqvist
M
,
Engdahl
J
,
Al-Khalili
F
,
Friberg
L
,
Frykman-Kull
V
,
Levin
LA.
Cost-effectiveness of mass screening for untreated atrial fibrillation using intermittent ECG recording
.
Europace
2015
;
17
:
1023
1029
.

224

Lowres
N
,
Neubeck
L
,
Redfern
J
,
Freedman
SB.
Screening to identify unknown atrial fibrillation. A systematic review
.
Thromb Haemost
2013
;
110
:
213
222
.

225

Engdahl
J
,
Andersson
L
,
Mirskaya
M
,
Rosenqvist
M.
Stepwise screening of atrial fibrillation in a 75-year-old population: implications for stroke prevention
.
Circulation
2013
;
127
:
930
937
.

226

Boriani
G
,
Glotzer
TV
,
Santini
M
,
West
TM
,
De Melis
M
,
Sepsi
M
,
Gasparini
M
,
Lewalter
T
,
Camm
JA
,
Singer
DE.
Device-detected atrial fibrillation and risk for stroke: an analysis of >10,000 patients from the SOS AF project (Stroke preventiOn Strategies based on Atrial Fibrillation information from implanted devices)
.
Eur Heart J
2014
;
35
:
508
516
.

227

Lowres
N
,
Krass
I
,
Neubeck
L
,
Redfern
J
,
McLachlan
AJ
,
Bennett
AA
,
Freedman
SB.
Atrial fibrillation screening in pharmacies using an iPhone ECG: a qualitative review of implementation
.
Int J Clin Pharm
2015
;
37
:
1111
1120
.

228

Wynn
GJ
,
Todd
DM
,
Webber
M
,
Bonnett
L
,
McShane
J
,
Kirchhof
P
,
Gupta
D.
The European Heart Rhythm Association symptom classification for atrial fibrillation: validation and improvement through a simple modification
.
Europace
2014
;
16
:
965
972
.

229

De With
RR
,
Rienstra
M
,
Smit
MD
,
Weijs
B
,
Zwartkruis
VW
,
Hobbelt
AH
,
Alings
M
,
Tijssen
JGP
,
Brugemann
J
,
Geelhoed
B
,
Hillege
HL
,
Tukkie
R
,
Hemels
ME
,
Tieleman
RG
,
Ranchor
AV
,
Van Veldhuisen
DJ
,
Crijns
H
,
Van Gelder
IC.
Targeted therapy of underlying conditions improves quality of life in patients with persistent atrial fibrillation: results of the RACE 3 study
.
Europace
2019
;
21
:
563
571
.

230

Schnabel
RB
,
Pecen
L
,
Rzayeva
N
,
Lucerna
M
,
Purmah
Y
,
Ojeda
FM
,
De Caterina
R
,
Kirchhof
P.
Symptom burden of atrial fibrillation and its relation to interventions and outcome in Europe
.
J Am Heart Assoc
2018
;
7
.

231

Björkenheim
A
,
Brandes
A
,
Magnuson
A
,
Chemnitz
A
,
Svedberg
L
,
Edvardsson
N
,
Poçi
D.
Assessment of atrial fibrillation – specific symptoms before and 2 years after atrial fibrillation ablation: do patients and physicians differ in their perception of symptom relief?
JACC: Clinical Electrophysiology
2017
;
3
:
1168
1176
.

232

Sandhu
RK
,
Smigorowsky
M
,
Lockwood
E
,
Savu
A
,
Kaul
P
,
McAlister
FA.
Impact of electrical cardioversion on quality of life for the treatment of atrial fibrillation
.
Can J Cardiol
2017
;
33
:
450
455
.

233

Singh
BN
,
Singh
SN
,
Reda
DJ
,
Tang
XC,
,
Lopez
B
,
Harris
CL
,
Fletcher
RD
,
Sharma
SC
,
Atwood
JE
,
Jacobson
AK
,
Lewis
HD,
Jr.
,
Raisch
DW
,
Ezekowitz
MD
; Sotalol Amiodarone Atrial Fibrillation Efficacy Trial Investigators.
Amiodarone versus sotalol for atrial fibrillation
.
N Engl J Med
2005
;
352
:
1861
1872
.

234

Gilbert
KA
,
Hogarth
AJ
,
MacDonald
W
,
Lewis
NT
,
Tan
LB
,
Tayebjee
MH.
Restoration of sinus rhythm results in early and late improvements in the functional reserve of the heart following direct current cardioversion of persistent AF: FRESH-AF
.
Int J Cardiol
2015
;
199
:
121
125
.

235

Jais
P
,
Cauchemez
B
,
Macle
L
,
Daoud
E
,
Khairy
P
,
Subbiah
R
,
Hocini
M
,
Extramiana
F
,
Sacher
F
,
Bordachar
P
,
Klein
G
,
Weerasooriya
R
,
Clementy
J
,
Haissaguerre
M.
Catheter ablation versus antiarrhythmic drugs for atrial fibrillation: the A4 study
.
Circulation
2008
;
118
:
2498
2505
.

236

Oral
H
,
Pappone
C
,
Chugh
A
,
Good
E
,
Bogun
F
,
Pelosi
F
Jr.
,
Bates
ER
,
Lehmann
MH
,
Vicedomini
G
,
Augello
G
,
Agricola
E
,
Sala
S
,
Santinelli
V
,
Morady
F.
Circumferential pulmonary-vein ablation for chronic atrial fibrillation
.
N Engl J Med
2006
;
354
:
934
941
.

237

Mont
L
,
Bisbal
F
,
Hernandez-Madrid
A
,
Perez-Castellano
N
,
Vinolas
X
,
Arenal
A
,
Arribas
F
,
Fernandez-Lozano
I
,
Bodegas
A
,
Cobos
A
,
Matia
R
,
Perez-Villacastin
J
,
Guerra
JM
,
Avila
P
,
Lopez-Gil
M
,
Castro
V
,
Arana
JI
,
Brugada
J
; SARA investigators.
Catheter ablation vs. antiarrhythmic drug treatment of persistent atrial fibrillation: a multicentre, randomized, controlled trial (SARA study
).
Eur Heart J
2014
;
35
:
501
507
.

238

Forleo
GB
,
Mantica
M
,
De Luca
L
,
Leo
R
,
Santini
L
,
Panigada
S
,
De Sanctis
V
,
Pappalardo
A
,
Laurenzi
F
,
Avella
A
,
Casella
M
,
Dello Russo
A
,
Romeo
F
,
Pelargonio
G
,
Tondo
C.
Catheter ablation of atrial fibrillation in patients with diabetes mellitus type 2: results from a randomized study comparing pulmonary vein isolation versus antiarrhythmic drug therapy
.
J Cardiovasc Electrophysiol
2009
;
20
:
22
28
.

239

Wilber
DJ
,
Pappone
C
,
Neuzil
P
,
De Paola
A
,
Marchlinski
F
,
Natale
A
,
Macle
L
,
Daoud
EG
,
Calkins
H
,
Hall
B
,
Reddy
V
,
Augello
G
,
Reynolds
MR
,
Vinekar
C
,
Liu
CY
,
Berry
SM
,
Berry
DA
; ThermoCool AF Trial Investigators.
Comparison of antiarrhythmic drug therapy and radiofrequency catheter ablation in patients with paroxysmal atrial fibrillation: a randomized controlled trial
.
JAMA
2010
;
303
:
333
340
.

240

Wazni
OM
,
Marrouche
NF
,
Martin
DO
,
Verma
A
,
Bhargava
M
,
Saliba
W
,
Bash
D
,
Schweikert
R
,
Brachmann
J
,
Gunther
J
,
Gutleben
K
,
Pisano
E
,
Potenza
D
,
Fanelli
R
,
Raviele
A
,
Themistoclakis
S
,
Rossillo
A
,
Bonso
A
,
Natale
A.
Radiofrequency ablation vs antiarrhythmic drugs as first-line treatment of symptomatic atrial fibrillation: a randomized trial
.
JAMA
2005
;
293
:
2634
2640
.

241

Morillo
CA
,
Verma
A
,
Connolly
SJ
,
Kuck
KH
,
Nair
GM
,
Champagne
J
,
Sterns
LD
,
Beresh
H
,
Healey
JS
,
Natale
A
; RAAFT Investigators.
Radiofrequency ablation vs antiarrhythmic drugs as first-line treatment of paroxysmal atrial fibrillation (RAAFT-2): a randomized trial
.
JAMA
2014
;
311
:
692
700
.

242

Cosedis Nielsen
J
,
Johannessen
A
,
Raatikainen
P
,
Hindricks
G
,
Walfridsson
H
,
Kongstad
O
,
Pehrson
S
,
Englund
A
,
Hartikainen
J
,
Mortensen
LS
,
Hansen
PS.
Radiofrequency ablation as initial therapy in paroxysmal atrial fibrillation
.
N Engl J Med
2012
;
367
:
1587
1595
.

243

Pokorney
SD
,
Kim
S
,
Thomas
L
,
Fonarow
GC
,
Kowey
PR
,
Gersh
BJ
,
Mahaffey
KW
,
Peterson
ED
,
Piccini
JP
; Outcomes Registry for Better Informed Treatment of Atrial Fibrillation Investigators.
Cardioversion and subsequent quality of life and natural history of atrial fibrillation
.
Am Heart J
2017
;
185
:
59
66
.

244

Mantovan
R
,
Macle
L
,
De Martino
G
,
Chen
J
,
Morillo
CA
,
Novak
P
,
Calzolari
V
,
Khaykin
Y
,
Guerra
PG
,
Nair
G
,
Torrecilla
EG
,
Verma
A.
Relationship of quality of life with procedural success of atrial fibrillation (AF) ablation and postablation AF burden: substudy of the STAR AF randomized trial
.
Can J Cardiol
2013
;
29
:
1211
1217
.

245

Rienstra
M
,
Hobbelt
AH
,
Alings
M
,
Tijssen
JGP
,
Smit
MD
,
Brugemann
J
,
Geelhoed
B
,
Tieleman
RG
,
Hillege
HL
,
Tukkie
R
,
Van Veldhuisen
DJ
,
Crijns
H
,
Van Gelder
IC
; RACE Investigators.
Targeted therapy of underlying conditions improves sinus rhythm maintenance in patients with persistent atrial fibrillation: results of the RACE 3 trial
.
Eur Heart J
2018
;
39
:
2987
2996
.

246

Blomstrom-Lundqvist
C
,
Gizurarson
S
,
Schwieler
J
,
Jensen
SM
,
Bergfeldt
L
,
Kenneback
G
,
Rubulis
A
,
Malmborg
H
,
Raatikainen
P
,
Lonnerholm
S
,
Hoglund
N
,
Mortsell
D.
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
.

247

Mark
DB
,
Anstrom
KJ
,
Sheng
S
,
Piccini
JP
,
Baloch
KN
,
Monahan
KH
,
Daniels
MR
,
Bahnson
TD
,
Poole
JE
,
Rosenberg
Y
,
Lee
KL
,
Packer
DL
; CABANA Investigators.
Effect of catheter ablation vs medical therapy on quality of life among patients with atrial fibrillation: the CABANA randomized clinical trial
.
JAMA
2019
.

248

Gaita
F
,
Scaglione
M
,
Battaglia
A
,
Matta
M
,
Gallo
C
,
Galata
M
,
Caponi
D
,
Di Donna
P
,
Anselmino
M.
Very long-term outcome following transcatheter ablation of atrial fibrillation. Are results maintained after 10 years of follow-up?
Europace
2018
;
20
:
443
450
.

249

Donal
E
,
Lip
GY
,
Galderisi
M
,
Goette
A
,
Shah
D
,
Marwan
M
,
Lederlin
M
,
Mondillo
S
,
Edvardsen
T,
,
Sitges
M
,
Grapsa
J
,
Garbi
M
,
Senior
R
,
Gimelli
A
,
Potpara
TS
,
Van Gelder
IC
,
Gorenek
B
,
Mabo
P
,
Lancellotti
P
,
Kuck
KH
,
Popescu
BA
,
Hindricks
G
,
Habib
G
,
Cardim
NM
,
Cosyns
B
,
Delgado
V
,
Haugaa
KH
,
Muraru
D
,
Nieman
K
,
Boriani
G
,
Cohen
A.
EACVI/EHRA Expert Consensus Document on the role of multi-modality imaging for the evaluation of patients with atrial fibrillation
.
Eur Heart J Cardiovasc Imaging
2016
;
17
:
355
383
.

250

Delgado
V
,
Di Biase
L
,
Leung
M
,
Romero
J
,
Tops
LF
,
Casadei
B
,
Marrouche
N
,
Bax
JJ.
Structure and function of the left atrium and left atrial appendage: AF and stroke implications
.
J Am Coll Cardiol
2017
;
70
:
3157
3172
.

251

Oakes
RS
,
Badger
TJ
,
Kholmovski
EG
,
Akoum
N
,
Burgon
NS
,
Fish
EN
,
Blauer
JJ
,
Rao
SN
,
DiBella
EV
,
Segerson
NM
,
Daccarett
M
,
Windfelder
J
,
McGann
CJ
,
Parker
D
,
MacLeod
RS
,
Marrouche
NF.
Detection and quantification of left atrial structural remodeling with delayed-enhancement magnetic resonance imaging in patients with atrial fibrillation
.
Circulation
2009
;
119
:
1758
1767
.

252

Cameli
M
,
Lisi
M
,
Righini
FM
,
Massoni
A
,
Natali
BM
,
Focardi
M
,
Tacchini
D
,
Geyer
A
,
Curci
V
,
Di Tommaso
C
,
Lisi
G
,
Maccherini
M
,
Chiavarelli
M
,
Massetti
M
,
Tanganelli
P
,
Mondillo
S.
Usefulness of atrial deformation analysis to predict left atrial fibrosis and endocardial thickness in patients undergoing mitral valve operations for severe mitral regurgitation secondary to mitral valve prolapse
.
Am J Cardiol
2013
;
111
:
595
601
.

253

Nakamori
S
,
Nezafat
M
,
Ngo
LH
,
Manning
WJ
,
Nezafat
R.
Left atrial epicardial fat volume is associated with atrial fibrillation: a prospective cardiovascular magnetic resonance 3D Dixon Study
.
J Am Heart Assoc
2018
;
7
.

254

Murphy
A
,
Banerjee
A
,
Breithardt
G
,
Camm
AJ
,
Commerford
P
,
Freedman
B
,
Gonzalez-Hermosillo
JA
,
Halperin
JL
,
Lau
CP
,
Perel
P
,
Xavier
D
,
Wood
D
,
Jouven
X
,
Morillo
CA.
The World Heart Federation roadmap for nonvalvular atrial fibrillation
.
Glob Heart
2017
;
12
:
273
284
.

255

Timmis
A
,
Townsend
N
,
Gale
CP
,
Torbica
A
,
Lettino
M
,
Petersen
SE
,
Mossialos
EA
,
Maggioni
AP
,
Kazakiewicz
D
,
May
HT
,
De Smedt
D
,
Flather
M
,
Zuhlke
L
,
Beltrame
JF
,
Huculeci
R
,
Tavazzi
L
,
Hindricks
G
,
Bax
J
,
Casadei
B
,
Achenbach
S
,
Wright
L
,
Vardas
P.
European Society of Cardiology: Cardiovascular Disease Statistics 2019
.
Eur Heart J
2020
;
41
:
12
85
.

256

Charles
C
,
Whelan
T
,
Gafni
A.
What do we mean by partnership in making decisions about treatment?
BMJ
1999
;
319
:
780
782
.

257

Lane
DA
,
Aguinaga
L
,
Blomstrom-Lundqvist
C
,
Boriani
G
,
Dan
GA
,
Hills
MT
,
Hylek
EM
,
LaHaye
SA
,
Lip
GY
,
Lobban
T
,
Mandrola
J
,
McCabe
PJ
,
Pedersen
SS
,
Pisters
R
,
Stewart
S
,
Wood
K
,
Potpara
TS
,
Gorenek
B
,
Conti
JB
,
Keegan
R
,
Power
S
,
Hendriks
J
,
Ritter
P
,
Calkins
H
,
Violi
F
,
Hurwitz
J.
Cardiac tachyarrhythmias and patient values and preferences for their management: the European Heart Rhythm Association (EHRA) consensus document endorsed by the Heart Rhythm Society (HRS), Asia Pacific Heart Rhythm Society (APHRS), and Sociedad Latinoamericana de Estimulacion Cardiaca y Electrofisiologia (SOLEACE)
.
Europace
2015
;
17
:
1747
1769
.

258

Bergtun
S
,
Oterhals
K
,
Fridlund
B.
Patients’ experiences 1-6 months after atrial fibrillation ablation: an holistic perspective
.
J Adv Nurs
2019
;
75
:
150
160
.

259

Borg Xuereb
C
,
Shaw
RL
,
Lane
DA.
Patients’ and physicians’ experiences of atrial fibrillation consultations and anticoagulation decision-making: a multi-perspective IPA design
.
Psychol Health
2016
;
31
:
436
455
.

260

Loewen
PS
,
Ji
AT
,
Kapanen
A
,
McClean
A.
Patient values and preferences for antithrombotic therapy in atrial fibrillation. A narrative systematic review
.
Thromb Haemost
2017
;
117
:
1007
1022
.

261

Seaburg
L
,
Hess
EP
,
Coylewright
M
,
Ting
HH
,
McLeod
CJ
,
Montori
VM.
Shared decision making in atrial fibrillation: where we are and where we should be going
.
Circulation
2014
;
129
:
704
710
.

262

Bajorek
BV
,
Ogle
SJ
,
Duguid
MJ
,
Shenfield
GM
,
Krass
I.
Management of warfarin in atrial fibrillation: views of health professionals, older patients and their carers
.
Med J Aust
2007
;
186
:
175
180
.

263

Hess
EP
,
Knoedler
MA
,
Shah
ND
,
Kline
JA
,
Breslin
M
,
Branda
ME,
,
Pencille
LJ,
,
Asplin
BR
,
Nestler
DM
,
Sadosty
AT
,
Stiell
IG
,
Ting
HH
,
Montori
VM.
The chest pain choice decision aid: a randomized trial
.
Circ Cardiovasc Qual Outcomes
2012
;
5
:
251
259
.

264

Lane
DA
,
Meyerhoff
J
,
Rohner
U
,
Lip
GYH.
Atrial fibrillation patient preferences for oral anticoagulation and stroke knowledge: results of a conjoint analysis
.
Clin Cardiol
2018
;
41
:
855
861
.

265

Lindberg
T
,
Sanmartin Berglund
J
,
Elmstahl
S
,
Bohman
DM.
Older individuals’ need for knowledge and follow-up about their chronic atrial fibrillation, lifelong medical treatment and medical controls
.
Scand J Caring Sci
2017
;
31
:
1022
1030
.

266

Palacio
AM
,
Kirolos
I
,
Tamariz
L.
Patient values and preferences when choosing anticoagulants
.
Patient Prefer Adherence
2015
;
9
:
133
138
.

267

Lane
DA
,
Lip
GY.
Patient’s values and preferences for stroke prevention in atrial fibrillation: balancing stroke and bleeding risk with oral anticoagulation
.
Thromb Haemost
2014
;
111
:
381
383
.

268

MacLean
S
,
Mulla
S
,
Akl
EA
,
Jankowski
M
,
Vandvik
PO
,
Ebrahim
S
,
McLeod
S
,
Bhatnagar
N
,
Guyatt
GH.
Patient values and preferences in decision making for antithrombotic therapy: a systematic review: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines
.
Chest
2012
;
141
:
e1S
e23S
.

269

Desteghe
L
,
Engelhard
L
,
Raymaekers
Z
,
Kluts
K
,
Vijgen
J
,
Dilling-Boer
D
,
Koopman
P
,
Schurmans
J
,
Dendale
P
,
Heidbuchel
H.
Knowledge gaps in patients with atrial fibrillation revealed by a new validated knowledge questionnaire
.
Int J Cardiol
2016
;
223
:
906
914
.

270

Frankel
DS
,
Parker
SE
,
Rosenfeld
LE
,
Gorelick
PB.
HRS/NSA 2014 Survey of atrial fibrillation and stroke: gaps in knowledge and perspective, opportunities for improvement
.
J Stroke Cerebrovasc Dis
2015
;
24
:
1691
700
.

271

Lane
DA
,
Ponsford
J
,
Shelley
A
,
Sirpal
A
,
Lip
GY.
Patient knowledge and perceptions of atrial fibrillation and anticoagulant therapy: effects of an educational intervention programme. The West Birmingham Atrial Fibrillation Project
.
Int J Cardiol
2006
;
110
:
354
358
.

272

McCabe
PJ
,
Schad
S
,
Hampton
A
,
Holland
DE.
Knowledge and self-management behaviors of patients with recently detected atrial fibrillation
.
Heart Lung
2008
;
37
:
79
90
.

273

Ihara
M
,
Washida
K.
Linking atrial fibrillation with Alzheimer’s disease: epidemiological, pathological, and mechanistic evidence
.
J Alzheimers Dis
2018
;
62
:
61
72
.

274

Lip
GYH
,
Lane
DA
,
Sarwar
S.
Streamlining primary and secondary care management pathways for stroke prevention in atrial fibrillation
.
Eur Heart J
2017
;
38
:
2980
2982
.

275

Guo
Y
,
Lane
DA
,
Wang
L
,
Chen
Y
,
Lip
GYH
; mAF-App II Trial investigators.
Mobile Health (mHealth) technology for improved screening, patient involvement and optimising integrated care in atrial fibrillation: the mAFA (mAF-App) II randomised trial
.
Int J Clin Pract
2019
:
e13352
.

276

Franchi
C
,
Antoniazzi
S
,
Ardoino
I
,
Proietti
M
,
Marcucci
M
,
Santalucia
P
,
Monzani
V
,
Mannucci
PM
,
Nobili
A
,
Collaborators
S-A.
Simulation-based education for physicians to increase oral anticoagulants in hospitalized elderly patients with atrial fibrillation
.
Am J Med
2019
;132:e634–e647.

277

Vinereanu
D
,
Lopes
RD
,
Bahit
MC
,
Xavier
D
,
Jiang
J
,
Al-Khalidi
HR
,
He
W
,
Xian
Y
,
Ciobanu
AO
,
Kamath
DY
,
Fox
KA
,
Rao
MP
,
Pokorney
SD
,
Berwanger
O
,
Tajer
C
,
de Barros
ESPGM
,
Roettig
ML
,
Huo
Y
,
Granger
CB
; IMPACT-AF Investigators.
A multifaceted intervention to improve treatment with oral anticoagulants in atrial fibrillation (IMPACT-AF): an international, cluster-randomised trial
.
Lancet
2017
;
390
:
1737
1746
.

278

Raparelli
V
,
Proietti
M
,
Cangemi
R
,
Lip
GY
,
Lane
DA
,
Basili
S.
Adherence to oral anticoagulant therapy in patients with atrial fibrillation. Focus on non-vitamin K antagonist oral anticoagulants
.
Thromb Haemost
2017
;
117
:
209
218
.

279

Parimbelli
E
,
Sacchi
L
,
Budasu
R
,
Napolitano
C
,
Peleg
M
,
Quaglini
S.
The role of nurses in e-health: the MobiGuide project experience
.
Stud Health Technol Inform
2016
;
225
:
153
157
.

280

Guo
Y
,
Chen
Y
,
Lane
DA
,
Liu
L
,
Wang
Y
,
Lip
GYH.
Mobile health technology for atrial fibrillation management integrating decision support, education, and patient involvement: mAF App trial
.
Am J Med
2017
;
130
:
1388
1396.e6
.

281

Kotecha
D
,
Chua
WWL
,
Fabritz
L
,
Hendriks
J
,
Casadei
B
,
Schotten
U
,
Vardas
P
,
Heidbuchel
H
,
Dean
V
,
Kirchhof
P
,
European Society of Cardiology (ESC) Atrial Fibrillation Guidelines Taskforce, the CATCH ME consortium, and the European Heart Rhythm Association (EHRA). European Society of Cardiology smartphone and tablet applications for patients with atrial fibrillation and their health care providers
.
Europace
2018
;
20
:
225
233
.

282

Lee
J-A
,
Evangelista
LS
,
Moore
AA
,
Juth
V
,
Guo
Y
,
Gago-Masague
S
,
Lem
CG
,
Nguyen
M
,
Khatibi
P
,
Baje
M
,
Amin
AN.
Feasibility study of a mobile health intervention for older adults on oral anticoagulation therapy
.
Gerontol Geriatr Med
2016
;
2
. doi:10.1177/2333721416672970. Published 2016 Oct 7.

283

Stephan
LS
,
Dytz Almeida
E
,
Guimaraes
RB
,
Ley
AG
,
Mathias
RG
,
Assis
MV
,
Leiria
TL.
Processes and recommendations for creating mHealth apps for low-income populations
.
JMIR Mhealth Uhealth
2017
;
5
:
e41
.

284

Clarkesmith
DE
,
Pattison
HM
,
Khaing
PH
,
Lane
DA.
Educational and behavioural interventions for anticoagulant therapy in patients with atrial fibrillation
.
Cochrane Database Syst Rev
2017
;
4
:
CD008600
.

285

Man-Son-Hing
M
,
Laupacis
A
,
O’Connor
AM
,
Biggs
J
,
Drake
E
,
Yetisir
E
,
Hart
RG.
A patient decision aid regarding antithrombotic therapy for stroke prevention in atrial fibrillation: a randomized controlled trial
.
JAMA
1999
;
282
:
737
743
.

286

McAlister
FA
,
Man-Son-Hing
M
,
Straus
SE
,
Ghali
WA
,
Anderson
D
,
Majumdar
SR
,
Gibson
P
,
Cox
JL
,
Fradette
M
; Decision Aid in Atrial Fibrillation Investigators.
Impact of a patient decision aid on care among patients with nonvalvular atrial fibrillation: a cluster randomized trial
.
CMAJ
2005
;
173
:
496
501
.

287

Thomson
RG
,
Eccles
MP
,
Steen
IN
,
Greenaway
J
,
Stobbart
L
,
Murtagh
MJ
,
May
CR.
A patient decision aid to support shared decision-making on anti-thrombotic treatment of patients with atrial fibrillation: randomised controlled trial
.
Qual Saf Health Care
2007
;
16
:
216
223
.

288

Eckman
MH
,
Costea
A
,
Attari
M
,
Munjal
J
,
Wise
RE
,
Knochelmann
C
,
Flaherty
ML
,
Baker
P
,
Ireton
R
,
Harnett
BM,
,
Leonard
AC
,
Steen
D
,
Rose
A
,
Kues
J.
Shared decision-making tool for thromboprophylaxis in atrial fibrillation – a feasibility study
.
Am Heart J
2018
;
199
:
13
21
.

289

Eckman
MH
,
Lip
GY
,
Wise
RE
,
Speer
B
,
Sullivan
M
,
Walker
N
,
Kissela
B
,
Flaherty
ML
,
Kleindorfer
D
,
Baker
P
,
Ireton
R
,
Hoskins
D
,
Harnett
BM
,
Aguilar
C
,
Leonard
AC
,
Arduser
L
,
Steen
D
,
Costea
A
,
Kues
J.
Impact of an atrial fibrillation decision support tool on thromboprophylaxis for atrial fibrillation
.
Am Heart J
2016
;
176
:
17
27
.

290

Karlsson
LO
,
Nilsson
S
,
Bang
M
,
Nilsson
L
,
Charitakis
E
,
Janzon
M.
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
.

291

Vinereanu
D
,
Lopes
RD
,
Mulder
H
,
Gersh
BJ
,
Hanna
M
,
de Barros
ESPGM
,
Atar
D
,
Wallentin
L
,
Granger
CB
,
Alexander
JH
; ARISTOTLE Investigators.
Echocardiographic risk factors for stroke and outcomes in patients with atrial fibrillation anticoagulated with apixaban or warfarin
.
Stroke
2017
;
48
:
3266
3273
.

292

Hendriks
JM
,
de Wit
R
,
Crijns
HJ
,
Vrijhoef
HJ
,
Prins
MH
,
Pisters
R
,
Pison
LA
,
Blaauw
Y
,
Tieleman
RG.
Nurse-led care vs. usual care for patients 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
.

293

Stewart
S
,
Ball
J
,
Horowitz
JD
,
Marwick
TH
,
Mahadevan
G
,
Wong
C
,
Abhayaratna
WP
,
Chan
YK
,
Esterman
A
,
Thompson
DR
,
Scuffham
PA
,
Carrington
MJ.
Standard versus atrial fibrillation-specific management strategy (SAFETY) to reduce recurrent admission and prolong survival: pragmatic, multicentre, randomised controlled trial
.
Lancet
2015
;
385
:
775
784
.

294

Carter
L
,
Gardner
M
,
Magee
K
,
Fearon
A
,
Morgulis
I
,
Doucette
S
,
Sapp
JL
,
Gray
C
,
Abdelwahab
A
,
Parkash
R.
An integrated management approach to atrial fibrillation
.
J Am Heart Assoc
2016
;
5
.

295

Wijtvliet
E
,
Tieleman
RG
,
van Gelder
IC
,
Pluymaekers
NAHA
,
Rienstra
M
,
Folkeringa
RJ
,
Bronzwaer
P
,
Elvan
A
,
Elders
J
,
Tukkie
R
,
Luermans
JGLM
,
Van Asselt
ADIT
,
Van Kuijk
SMJ
,
Tijssen
JG
,
Crijns
HJGM
; RACE Investigators.
Nurse-led vs. usual-care for atrial fibrillation
.
Eur Heart J
2020
;
41
:
634
641
.

296

Gallagher
C
,
Elliott
AD
,
Wong
CX
,
Rangnekar
G
,
Middeldorp
ME
,
Mahajan
R
,
Lau
DH
,
Sanders
P
,
Hendriks
JML.
Integrated care in atrial fibrillation: a systematic review and meta-analysis
.
Heart
2017
;
103
:
1947
1953
.

297

Michie
S
,
van Stralen
MM
,
West
R.
The behaviour change wheel: a new method for characterising and designing behaviour change interventions
.
Implement Sci
2011
;
6
:
42
.

298

Lip
GYH
,
Lane
DA
,
Potpara
TS.
Innovative strategies to improve adherence to non-vitamin K antagonist oral anticoagulants for stroke prevention in atrial fibrillation
.
Eur Heart J
2018
;
39
:
1404
1406
.

299

Seligman
WH
,
Das-Gupta
Z
,
Jobi-Odeneye
AO
,
Arbelo
E
,
Banerjee
A
,
Bollmann
A
,
Caffrey-Armstrong
B
,
Cehic
DA
,
Corbalan
R
,
Collins
M
,
Dandamudi
G
,
Dorairaj
P
,
Fay
M
,
Van Gelder
IC
,
Goto
S
,
Granger
CB
,
Gyorgy
B
,
Healey
JS
,
Hendriks
JM
,
Hills
MT
,
Hobbs
FDR
,
Huisman
MV
,
Koplan
KE
,
Lane
DA
,
Lewis
WR
,
Lobban
T
,
Steinberg
BA
,
McLeod
CJ
,
Moseley
S
,
Timmis
A
,
Yutao
G
,
Camm
AJ.
Development of an international standard set of outcome measures for patients with atrial fibrillation: a report of the International Consortium for Health Outcomes Measurement (ICHOM) atrial fibrillation working group
.
Eur Heart J
2020
;41:1132–1140.

300

Dobler
CC
,
Harb
N
,
Maguire
CA
,
Armour
CL
,
Coleman
C
,
Murad
MH.
Treatment burden should be included in clinical practice guidelines
.
BMJ
2018
;
363
:
k4065
.

301

Eton
DT
,
Ramalho de Oliveira
D
,
Egginton
JS
,
Ridgeway
JL
,
Odell
L
,
May
CR
,
Montori
VM.
Building a measurement framework of burden of treatment in complex patients with chronic conditions: a qualitative study
.
Patient Relat Outcome Meas
2012
;
3
:
39
49
.

302

Tran
VT
,
Montori
VM
,
Eton
DT
,
Baruch
D
,
Falissard
B
,
Ravaud
P.
Development and description of measurement properties of an instrument to assess treatment burden among patients with multiple chronic conditions
.
BMC Med
2012
;
10
:
68
.

303

Vijan
S
,
Hayward
RA
,
Ronis
DL
,
Hofer
TP.
Brief report: the burden of diabetes therapy: implications for the design of effective patient-centered treatment regimens
.
J Gen Intern Med
2005
;
20
:
479
482
.

304

Vermeire
E
,
Hearnshaw
H
,
Van Royen
P
,
Denekens
J.
Patient adherence to treatment: three decades of research. A comprehensive review
.
J Clin Pharm Ther
2001
;
26
:
331
342
.

305

Ho
PM
,
Rumsfeld
JS
,
Masoudi
FA
,
McClure
DL
,
Plomondon
ME
,
Steiner
JF
,
Magid
DJ.
Effect of medication nonadherence on hospitalization and mortality among patients with diabetes mellitus
.
Arch Intern Med
2006
;
166
:
1836
1841
.

306

Rasmussen
JN
,
Chong
A
,
Alter
DA.
Relationship between adherence to evidence-based pharmacotherapy and long-term mortality after acute myocardial infarction
.
JAMA
2007
;
297
:
177
186
.

307

May
C
,
Montori
VM
,
Mair
FS.
We need minimally disruptive medicine
.
BMJ
2009
;
339
:
b2803
.

308

Wilcox
AR
,
Dragnev
MC
,
Darcey
CJ
,
Siegel
CA.
A new tool to measure the burden of Crohn’s disease and its treatment: do patient and physician perceptions match?
Inflamm Bowel Dis
2010
;
16
:
645
650
.

309

Bohlen
K
,
Scoville
E
,
Shippee
ND
,
May
CR
,
Montori
VM.
Overwhelmed patients: a videographic analysis of how patients with type 2 diabetes and clinicians articulate and address treatment burden during clinical encounters
.
Diabetes Care
2012
;
35
:
47
49
.

310

Buffel du Vaure
C
,
Ravaud
P
,
Baron
G
,
Barnes
C
,
Gilberg
S
,
Boutron
I.
Potential workload in applying clinical practice guidelines for patients with chronic conditions and multimorbidity: a systematic analysis
.
BMJ Open
2016
;
6
:
e010119
.

311

Potpara
TS
,
Mihajlovic
M
,
Zec
N
,
Marinkovic
M
,
Kovacevic
V
,
Simic
J
,
Kocijancic
A
,
Vajagic
L
,
Jotic
A
,
Mujovic
N
,
Stankovic
G.
Self-reported treatment burden in patients with atrial fibrillation: quantification, major determinants and implications for integrated holistic management of the arrhythmia
.
Europace
2020
; doi:10.1093/europace/euaa210.

312

Tran
VT
,
Harrington
M
,
Montori
VM
,
Barnes
C
,
Wicks
P
,
Ravaud
P.
Adaptation and validation of the Treatment Burden Questionnaire (TBQ) in English using an internet platform
.
BMC Med
2014
;
12
:
109
.

313

Steinberg
BA
,
Dorian
P,
,
Anstrom
KJ
,
Hess
R
,
Mark
DB
,
Noseworthy
PA
,
Spertus
JA
,
Piccini
JP.
Patient-reported outcomes in atrial fibrillation research: results of a Clinicaltrials.gov analysis
.
JACC Clin Electrophysiol
2019
;
5
:
599
605
.

314

Calvert
M
,
Kyte
D
,
Price
G
,
Valderas
JM
,
Hjollund
NH.
Maximising the impact of patient reported outcome assessment for patients and society
.
BMJ
2019
;
364
:
k5267
.

315

Rotenstein
LS
,
Huckman
RS
,
Wagle
NW.
Making patients and doctors happier – the potential of patient-reported outcomes
.
N Engl J Med
2017
;
377
:
1309
1312
.

316

Van Der Wees
PJ
,
Nijhuis-Van Der Sanden
MW
,
Ayanian
JZ
,
Black
N
,
Westert
GP
,
Schneider
EC.
Integrating the use of patient-reported outcomes for both clinical practice and performance measurement: views of experts from 3 countries
.
Milbank Q
2014
;
92
:
754
775
.

317

Arbelo
E
,
Aktaa
S
,
Bollmann
A
,
D’Avila
A
,
Drossart
I
,
Dwight
J
,
Hills
MT
,
Hindricks
G
,
Kusumoto
FM
,
Lane
DA
,
Lau
DH
,
Lettino
M
,
Lip
GYH
,
Lobban
T
,
Pak
H-N
,
Potpara
T
,
Saenz
LC
,
Van Gelder
IC
,
Varosy
P
,
Gale
CP
,
Dagres
N.
Quality indicators for the care and outcomes of adults with atrial fibrillation. Task Force for the development of quality indicators in Atrial Fibrillation of the European Heart Rhythm Association (EHRA) and of the European Society of Cardiology (ESC): Developed in collaboration with the Heart Rhythm Society (HRS), the Asia Pacific Heart Rhythm Society (APHRS) and the Latin-American Heart Rhythm Society (LAHRS)
.
Europace
2020
;doi:10.1093/europace/euaa253.

318

Lip
GYH.
The ABC pathway: an integrated approach to improve AF management
.
Nat Rev Cardiol
2017
;
14
:
627
628
.

319

Proietti
M
,
Romiti
GF
,
Olshansky
B
,
Lane
DA
,
Lip
GYH.
Improved outcomes by integrated care of anticoagulated patients with atrial fibrillation using the simple ABC (Atrial Fibrillation Better Care) Pathway
.
Am J Med
2018
;
131
:
1359
1366.e6
.

320

Yoon
M
,
Yang
PS
,
Jang
E
,
Yu
HT
,
Kim
TH
,
Uhm
JS
,
Kim
JY
,
Sung
JH
,
Pak
HN
,
Lee
MH
,
Joung
B
,
Lip
GYH.
Improved population-based clinical outcomes of patients with atrial fibrillation by compliance with the simple ABC (Atrial Fibrillation Better Care) pathway for integrated care management: a nationwide cohort study
.
Thromb Haemost
2019
;
19
:
1695
1703
.

321

Pastori
D
,
Pignatelli
P
,
Menichelli
D
,
Violi
F
,
Lip
GYH.
Integrated care management of patients with atrial fibrillation and risk of cardiovascular events: the ABC (Atrial fibrillation Better Care) pathway in the ATHERO-AF study cohort
.
Mayo Clin Proc
2019;94:1261–1267

322

Pastori
D
,
Farcomeni
A
,
Pignatelli
P
,
Violi
F
,
Lip
GY.
ABC (Atrial fibrillation Better Care) pathway and healthcare costs in atrial fibrillation: the ATHERO-AF study
.
Am J Med
2019
;132:856–861.

323

Guo
Y
,
Lane
DA
,
Wang
L
,
Zhang
H
,
Wang
H
,
Zhang
W
,
Wen
J
,
Xing
Y
,
Wu
F
,
Xia
Y
,
Liu
T
,
Wu
F
,
Liang
Z
,
Liu
F
,
Zhao
Y
,
Li
R
,
Li
X
,
Zhang
L
,
Guo
J
,
Burnside
G
,
Chen
Y
,
Lip GYH; mAF-App II Trial Investigators. Mobile health technology to improve care for patients with atrial fibrillation
.
J Am Coll Cardiol
2020
;
75
:
1523
1534
.

324

Pisters
R
,
Lane
DA
,
Marin
F
,
Camm
AJ
,
Lip
GY.
Stroke and thromboembolism in atrial fibrillation
.
Circ J
2012
;
76
:
2289
2304
.

325

Szymanski
FM
,
Lip
GY
,
Filipiak
KJ
,
Platek
AE
,
Hrynkiewicz-Szymanska
A
,
Opolski
G.
Stroke risk factors beyond the CHA(2)DS(2)-VASc score: can we improve our identification of ‘high stroke risk’ patients with atrial fibrillation?
Am J Cardiol
2015
;
116
:
1781
1788
.

326

Atrial Fibrillation Investigators.

Echocardiographic predictors of stroke in patients with atrial fibrillation: a prospective study of 1066 patients from 3 clinical trials
.
Arch Intern Med
1998
;
158
:
1316
1320
.

327

Ntaios
G
,
Lip
GY
,
Lambrou
D
,
Papavasileiou
V
,
Manios
E
,
Milionis
H
,
Spengos
K
,
Makaritsis
K
,
Vemmos
K.
Leukoaraiosis and stroke recurrence risk in patients with and without atrial fibrillation
.
Neurology
2015
;
84
:
1213
1219
.

328

Esteve-Pastor
MA
,
Roldan
V
,
Rivera-Caravaca
JM
,
Ramirez-Macias
I
,
Lip
GYH
,
Marin
F.
The use of biomarkers in clinical management guidelines: a critical appraisal
.
Thromb Haemost
2019
;
119
:
1901
1919
.

329

Hijazi
Z
,
Oldgren
J
,
Siegbahn
A
,
Wallentin
L.
Application of biomarkers for risk stratification in patients with atrial fibrillation
.
Clin Chem
2017
;
63
:
152
164
.

330

Yaghi
S
,
Kamel
H.
Stratifying stroke risk in atrial fibrillation: beyond clinical risk scores
.
Stroke
2017
;
48
:
2665
2670
.

331

Ioannou
A
,
Papageorgiou
N
,
Falconer
D
,
Rehal
O
,
Sewart
E
,
Zacharia
E
,
Toutouzas
K
,
Vlachopoulos
C
,
Siasos
G
,
Tsioufis
C
,
Tousoulis
D.
Biomarkers associated with stroke risk in atrial fibrillation
.
Curr Med Chem
2019
;
26
:
803
823
.

332

Sepehri Shamloo
A
,
Bollmann
A
,
Dagres
N
,
Hindricks
G
,
Arya
A.
Natriuretic peptides: biomarkers for atrial fibrillation management
.
Clin Res Cardiol
2020
;109:957–966.

333

Decker
JJ
,
Norby
FL
,
Rooney
MR
,
Soliman
EZ
,
Lutsey
PL
,
Pankow
JS
,
Alonso
A
,
Chen
LY.
Metabolic syndrome and risk of ischemic stroke in atrial fibrillation: ARIC Study
.
Stroke
2019
;
50
:
3045
3050
.

334

Lip
GY
,
Nieuwlaat
R
,
Pisters
R
,
Lane
DA
,
Crijns
HJ.
Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: the Euro Heart Survey on atrial fibrillation
.
Chest
2010
;
137
:
263
272
.

335

Banerjee
A
,
Taillandier
S
,
Olesen
JB
,
Lane
DA
,
Lallemand
B
,
Lip
GY
,
Fauchier
L.
Ejection fraction and outcomes in patients with atrial fibrillation and heart failure: the Loire Valley Atrial Fibrillation Project
.
Eur J Heart Fail
2012
;
14
:
295
301
.

336

Jung
H
,
Sung
JH
,
Yang
PS
,
Jang
E
,
Yu
HT
,
Kim
TH
,
Pak
HN
,
Lee
MH
,
Joung
B
,
Lip
GYH.
Stroke risk stratification for atrial fibrillation patients with hypertrophic cardiomyopathy
.
J Am Coll Cardiol
2018
;
72
:
2409
2411
.

337

Jung
H
,
Yang
PS
,
Jang
E
,
Yu
HT
,
Kim
TH
,
Uhm
JS
,
Kim
JY
,
Pak
HN
,
Lee
MH
,
Joung
B
,
Lip
GYH.
Effectiveness and safety of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation with hypertrophic cardiomyopathy: a nationwide cohort study
.
Chest
2019
;
155
:
354
363
.

338

Kim
D
,
Yang
PS
,
Kim
TH
,
Jang
E
,
Shin
H
,
Kim
HY
,
Yu
HT
,
Uhm
JS
,
Kim
JY
,
Pak
HN
,
Lee
MH
,
Joung
B
,
Lip
GYH.
Ideal blood pressure in patients with atrial fibrillation
.
J Am Coll Cardiol
2018
;
72
:
1233
1245
.

339

Lip
GY
,
Clementy
N
,
Pericart
L
,
Banerjee
A
,
Fauchier
L.
Stroke and major bleeding risk in elderly patients aged >/=75 years with atrial fibrillation: the Loire Valley Atrial Fibrillation Project
.
Stroke
2015
;
46
:
143
50
.

340

Overvad
TF
,
Skjoth
F
,
Lip
GY
,
Lane
DA
,
Albertsen
IE
,
Rasmussen
LH
,
Larsen
TB.
Duration of diabetes mellitus and risk of thromboembolism and bleeding in atrial fibrillation: nationwide cohort study
.
Stroke
2015
;
46
:
2168
74
.

341

Lip
GYH
,
Clementy
N
,
Pierre
B
,
Boyer
M
,
Fauchier
L.
The impact of associated diabetic retinopathy on stroke and severe bleeding risk in diabetic patients with atrial fibrillation: the Loire Valley Atrial Fibrillation Project
.
Chest
2015
;
147
:
1103
1110
.

342

Fangel
MV
,
Nielsen
PB
,
Larsen
TB
,
Christensen
B
,
Overvad
TF
,
Lip
GYH
,
Goldhaber
SZ
,
Jensen
MB.
Type 1 versus type 2 diabetes and thromboembolic risk in patients with atrial fibrillation: a Danish nationwide cohort study
.
Int J Cardiol
2018
;
268
:
137
142
.

343

Chao
TF
,
Liu
CJ
,
Liao
JN
,
Wang
KL
,
Lin
YJ
,
Chang
SL
,
Lo
LW
,
Hu
YF
,
Tuan
TC
,
Chung
FP
,
Chen
TJ
,
Lip
GY
,
Chen
SA.
Use of oral anticoagulants for stroke prevention in patients with atrial fibrillation who have a history of intracranial hemorrhage
.
Circulation
2016
;
133
:
1540
1547
.

344

Bronnum Nielsen
P
,
Larsen
TB
,
Gorst-Rasmussen
A
,
Skjoth
F
,
Rasmussen
LH
,
Lip
GYH.
Intracranial hemorrhage and subsequent ischemic stroke in patients with atrial fibrillation: a nationwide cohort study
.
Chest
2015
;
147
:
1651
1658
.

345

Nielsen
PB
,
Larsen
TB
,
Skjoth
F
,
Gorst-Rasmussen
A
,
Rasmussen
LH
,
Lip
GY.
Restarting anticoagulant treatment after intracranial hemorrhage in patients with atrial fibrillation and the impact on recurrent stroke, mortality, and bleeding: a nationwide cohort study
.
Circulation
2015
;
132
:
517
525
.

346

Lin
LY
,
Lee
CH
,
Yu
CC,
,
Tsai
CT
,
Lai
LP
,
Hwang
JJ
,
Chen
PC
,
Lin
JL.
Risk factors and incidence of ischemic stroke in Taiwanese with nonvalvular atrial fibrillation – a nation-wide database analysis
.
Atherosclerosis
2011
;
217
:
292
295
.

347

Anandasundaram
B
,
Lane
DA
,
Apostolakis
S
,
Lip
GY.
The impact of atherosclerotic vascular disease in predicting a stroke, thromboembolism and mortality in atrial fibrillation patients: a systematic review
.
J Thromb Haemost
2013
;
11
:
975
987
.

348

Friberg
L
,
Rosenqvist
M
,
Lip
GY.
Evaluation of risk stratification schemes for ischaemic stroke and bleeding in 182 678 patients with atrial fibrillation: the Swedish Atrial Fibrillation cohort study
.
Eur Heart J
2012
;
33
:
1500
1510
.

349

Steensig
K
,
Olesen
KKW
,
Thim
T
,
Nielsen
JC
,
Jensen
SE
,
Jensen
LO
,
Kristensen
SD
,
Botker
HE
,
Lip
GYH
,
Maeng
M.
Should the presence or extent of coronary artery disease be quantified in the CHA2DS2-VASc score in atrial fibrillation? A report from the Western Denmark Heart Registry
.
Thromb Haemost
2018
;
118
:
2162
2170
.

350

Zabalgoitia
M
,
Halperin
JL
,
Pearce
LA
,
Blackshear
JL,
,
Asinger
RW
,
Hart
RG.
Transesophageal echocardiographic correlates of clinical risk of thromboembolism in nonvalvular atrial fibrillation
. Stroke Prevention in Atrial Fibrillation III Investigators.
J Am Coll Cardiol
1998
;
31
:
1622
1626
.

351

Kim
TH
,
Yang
PS
,
Yu
HT
,
Jang
E
,
Uhm
JS
,
Kim
JY
,
Pak
HN
,
Lee
MH
,
Joung
B
,
Lip
GYH.
Age threshold for ischemic stroke risk in atrial fibrillation
.
Stroke
2018
;
49
:
1872
1879
.

352

Chao
TF
,
Wang
KL
,
Liu
CJ
,
Lin
YJ
,
Chang
SL
,
Lo
LW
,
Hu
YF
,
Tuan
TC
,
Chung
FP
,
Liao
JN
,
Chen
TJ
,
Chiang
CE
,
Lip
GY
,
Chen
SA.
Age threshold for increased stroke risk among patients with atrial fibrillation: a nationwide cohort study from Taiwan
.
J Am Coll Cardiol
2015
;
66
:
1339
1347
.

353

Nielsen
PB
,
Skjoth
F
,
Overvad
TF
,
Larsen
TB
,
Lip
GYH.
Female sex is a risk modifier rather than a risk factor for stroke in atrial fibrillation: should we use a CHA2DS2-VA score rather than CHA2DS2-VASc?
Circulation
2018
;
137
:
832
840
.

354

Killu
AM
,
Granger
CB
,
Gersh
BJ.
Risk stratification for stroke in atrial fibrillation: a critique
.
Eur Heart J
2019
;
40
:
1294
1302
.

355

Rivera-Caravaca
JM
,
Roldan
V
,
Esteve-Pastor
MA
,
Valdes
M
,
Vicente
V
,
Lip
GYH
,
Marin
F.
Long-term stroke risk prediction in patients with atrial fibrillation: comparison of the ABC-Stroke and CHA2DS2-VASc scores
.
J Am Heart Assoc
2017
;
6
: pii: JAHA.117.006490. doi: 10.1161/JAHA.117.006490.

356

Alkhouli
M
,
Friedman
PA.
Ischemic stroke risk in patients with nonvalvular atrial fibrillation: JACC review topic of the week
.
J Am Coll Cardiol
2019
;
74
:
3050
3065
.

357

Wu
VC
,
Wu
M
,
Aboyans
V,
,
Chang
SH
,
Chen
SW
,
Chen
MC
,
Wang
CL
,
Hsieh
IC
,
Chu
PH
,
Lin
YS.
Female sex as a risk factor for ischaemic stroke varies with age in patients with atrial fibrillation
.
Heart
2020
;106:534–540.

358

Tomasdottir
M
,
Friberg
L
,
Hijazi
Z
,
Lindback
J
,
Oldgren
J.
Risk of ischemic stroke and utility of CHA2 DS2 -VASc score in women and men with atrial fibrillation
.
Clin Cardiol
2019
;
42
:
1003
1009
.

359

Friberg
L
,
Benson
L
,
Rosenqvist
M
,
Lip
GY.
Assessment of female sex as a risk factor in atrial fibrillation in Sweden: nationwide retrospective cohort study
.
BMJ
2012
;
344
:
e3522
.

360

Overvad
TF
,
Potpara
TS
,
Nielsen
PB.
Stroke risk stratification: CHA2DS2-VA or CHA2DS2-VASc?
Heart Lung Circ
2019
;
28
:
e14
e15
.

361

Nielsen
PB
,
Overvad
TF.
Female sex as a risk modifier for stroke risk in atrial fibrillation: using CHA2DS2-VASc versus CHA2DS2-VA for stroke risk stratification in atrial fibrillation: a note of caution
.
Thromb Haemost
2020
. doi: 10.1055/s-0040-1710014. Epub ahead of print.

362

Marzona
I
,
Proietti
M
,
Farcomeni
A
,
Romiti
GF
,
Romanazzi
I
,
Raparelli
V
,
Basili
S
,
Lip
GYH
,
Nobili
A
,
Roncaglioni
MC.
Sex differences in stroke and major adverse clinical events in patients with atrial fibrillation: a systematic review and meta-analysis of 993,600 patients
.
Int J Cardiol
2018
;
269
:
182
191
.

363

Friberg
L
,
Benson
L
,
Lip
GY.
Balancing stroke and bleeding risks in patients with atrial fibrillation and renal failure: the Swedish Atrial Fibrillation Cohort study
.
Eur Heart J
2015
;
36
:
297
306
.

364

Poli
M
,
Philip
P
,
Taillard
J
,
Debruxelles
S
,
Renou
P
,
Orgogozo
JM
,
Rouanet
F
,
Sibon
I.
Atrial fibrillation is a major cause of stroke in apneic patients: a prospective study
.
Sleep Med
2017
;
30
:
251
254
.

365

Bassand
JP
,
Accetta
G
,
Al Mahmeed
W
,
Corbalan
R
,
Eikelboom
J
,
Fitzmaurice
DA
,
Fox
KAA
,
Gao
H
,
Goldhaber
SZ
,
Goto
S
,
Haas
S
,
Kayani
G
,
Pieper
K
,
Turpie
AGG
,
van Eickels
M
,
Verheugt
FWA
,
Kakkar
AK
; GARFIELD-AF Investigators.
Risk factors for death, stroke, and bleeding in 28,628 patients from the GARFIELD-AF registry: rationale for comprehensive management of atrial fibrillation
.
PLoS One
2018
;
13
:
e0191592
.

366

Overvad
TF
,
Rasmussen
LH
,
Skjoth
F
,
Overvad
K
,
Lip
GY
,
Larsen
TB.
Body mass index and adverse events in patients with incident atrial fibrillation
.
Am J Med
2013
;
126
:
640.e9-17
.

367

Lip
GY
,
Lane
D
,
Van Walraven
C
,
Hart
RG.
Additive role of plasma von Willebrand factor levels to clinical factors for risk stratification of patients with atrial fibrillation
.
Stroke
2006
;
37
:
2294
2300
.

368

Fox
KAA
,
Lucas
JE
,
Pieper
KS
,
Bassand
JP
,
Camm
AJ
,
Fitzmaurice
DA
,
Goldhaber
SZ
,
Goto
S
,
Haas
S
,
Hacke
W
,
Kayani
G
,
Oto
A
,
Mantovani
LG
,
Misselwitz
F
,
Piccini
JP
,
Turpie
AGG
,
Verheugt
FWA
,
Kakkar
AK
; GARFIELD-AF Investigators.
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
.

369

Zhu
W
,
Fu
L
,
Ding
Y
,
Huang
L
,
Xu
Z
,
Hu
J
,
Hong
K.
Meta-analysis of ATRIA versus CHA2DS2-VASc for predicting stroke and thromboembolism in patients with atrial fibrillation
.
Int J Cardiol
2017
;
227
:
436
442
.

370

Singer
DE
,
Chang
Y
,
Borowsky
LH
,
Fang
MC
,
Pomernacki
NK
,
Udaltsova
N
,
Reynolds
K
,
Go
AS.
A new risk scheme to predict ischemic stroke and other thromboembolism in atrial fibrillation: the ATRIA study stroke risk score
.
J Am Heart Assoc
2013
;
2
:
e000250
.

371

Graves
KG
,
May
HT
,
Knowlton
KU
,
Muhlestein
JB
,
Jacobs
V
,
Lappe
DL
,
Anderson
JL
,
Horne
BD
,
Bunch
TJ.
Improving CHA2DS2-VASc stratification of non-fatal stroke and mortality risk using the Intermountain Mortality Risk Score among patients with atrial fibrillation
.
Open Heart
2018
;
5
:
e000907
.

372

Hijazi
Z
,
Lindback
J
,
Alexander
JH
,
Hanna
M
,
Held
C
,
Hylek
EM
,
Lopes
RD
,
Oldgren
J
,
Siegbahn
A
,
Stewart
RA
,
White
HD
,
Granger
CB
,
Wallentin
L
; ARISTOTLE and STABILITY Investigators.
The ABC (age, biomarkers, clinical history) stroke risk score: a biomarker-based risk score for predicting stroke in atrial fibrillation
.
Eur Heart J
2016
;
37
:
1582
90
.

373

Hijazi
Z
,
Lindahl
B
,
Oldgren
J
,
Andersson
U
,
Lindback
J
,
Granger
CB
,
Alexander
JH
,
Gersh
BJ,
,
Hanna
M
,
Harjola
VP
,
Hylek
EM
,
Lopes
RD
,
Siegbahn
A
,
Wallentin
L.
Repeated measurements of cardiac biomarkers in atrial fibrillation and validation of the ABC stroke score over time
.
J Am Heart Assoc
2017
;
6
.

374

Oldgren
J
,
Hijazi
Z
,
Lindback
J
,
Alexander
JH
,
Connolly
SJ
,
Eikelboom
JW
,
Ezekowitz
MD
,
Granger
CB
,
Hylek
EM
,
Lopes
RD
,
Siegbahn
A
,
Yusuf
S
,
Wallentin
L
; RE-LY and ARISTOTLE Investigators.
Performance and validation of a novel biomarker-based stroke risk score for atrial fibrillation
.
Circulation
2016
;
134
:
1697
1707
.

375

Berg
DD
,
Ruff
CT
,
Jarolim
P
,
Giugliano
RP
,
Nordio
F
,
Lanz
HJ
,
Mercuri
MF
,
Antman
EM
,
Braunwald
E
,
Morrow
DA
.
Performance of the ABC scores for assessing the risk of stroke or systemic embolism and bleeding in patients with atrial fibrillation in ENGAGE AF-TIMI 48
.
Circulation
2019
;
139
:
760
771
.

376

Rivera-Caravaca
JM
,
Marin
F
,
Vilchez
JA
,
Galvez
J
,
Esteve-Pastor
MA
,
Vicente
V
,
Lip
GYH
,
Roldan
V.
Refining stroke and bleeding prediction in atrial fibrillation by adding consecutive biomarkers to clinical risk scores
.
Stroke
2019
;
50
:
1372
1379
.

377

Esteve-Pastor
MA
,
Rivera-Caravaca
JM
,
Roldan
V
,
Vicente
V
,
Valdes
M
,
Marin
F
,
Lip
GY.
Long-term bleeding risk prediction in ‘real world’patients with atrial fibrillation: comparison of the HAS-BLED and ABC-Bleeding risk scores
.
Thromb Haemost
2017
;
117
:
1848
1858
.

378

Shin
SY
,
Han
SJ
,
Kim
JS,
,
Im
SI
,
Shim
J
,
Ahn
J
,
Lee
EM
,
Park
YM
,
Kim
JH
,
Lip
GYH
,
Lim
HE.
Identification of markers associated with development of stroke in ‘clinically low-risk’ atrial fibrillation patients
.
J Am Heart Assoc
2019
;
8
:
e012697
.

379

Chao
TF
,
Lip
GYH
,
Lin
YJ
,
Chang
SL
,
Lo
LW
,
Hu
YF
,
Tuan
TC
,
Liao
JN
,
Chung
FP
,
Chen
TJ
,
Chen
SA.
Age threshold for the use of non-vitamin K antagonist oral anticoagulants for stroke prevention in patients with atrial fibrillation: insights into the optimal assessment of age and incident comorbidities
.
Eur Heart J
2019
;
40
:
1504
1514
.

380

Nielsen
PB
,
Larsen
TB
,
Skjoth
F
,
Overvad
TF
,
Lip
GY.
Stroke and thromboembolic event rates in atrial fibrillation according to different guideline treatment thresholds: a nationwide cohort study
.
Sci Rep
2016
;
6
:
27410
.

381

Fauchier
L
,
Clementy
N
,
Bisson
A
,
Ivanes
F
,
Angoulvant
D
,
Babuty
D
,
Lip
GY.
Should atrial fibrillation patients with only 1 nongender-related CHA2DS2-VASc risk factor be anticoagulated?
Stroke
2016
;
47
:
1831
1836
.

382

Chao
TF
,
Lip
GYH
,
Liu
CJ
,
Lin
YJ
,
Chang
SL
,
Lo
LW
,
Hu
YF
,
Tuan
TC
,
Liao
JN
,
Chung
FP
,
Chen
TJ
,
Chen
SA.
Relationship of aging and incident comorbidities to stroke risk in patients with atrial fibrillation
.
J Am Coll Cardiol
2018
;
71
:
122
132
.

383

Yoon
M
,
Yang
PS
,
Jang
E
,
Yu
HT
,
Kim
TH
,
Uhm
JS
,
Kim
JY
,
Pak
HN
,
Lee
MH
,
Lip
GYH
,
Joung
B.
Dynamic changes of CHA2DS2-VASc score and the risk of ischaemic stroke in Asian patients with atrial fibrillation: a nationwide cohort study
.
Thromb Haemost
2018
;
118
:
1296
1304
.

384

Chao
TF
,
Chiang
CE
,
Chen
TJ
,
Lip
GYH
,
Chen
SA.
Reassessment of risk for stroke during follow-up of patients with atrial fibrillation
.
Ann Intern Med
2019
;
170
:
663
664
.

385

Potpara
TS
,
Polovina
MM
,
Licina
MM,
,
Marinkovic
JM
,
Prostran
MS
,
Lip
GY.
Reliable identification of ‘truly low’ thromboembolic risk in patients initially diagnosed with ‘lone’ atrial fibrillation: the Belgrade Atrial Fibrillation Study
.
Circ Arrhythm Electrophysiol
2012
;
5
:
319
326
.

386

Weijs
B
,
Dudink
E
,
de Vos
CB
,
Limantoro
I
,
Tieleman
RG
,
Pisters
R
,
Cheriex
EC
,
Luermans
J
,
Crijns
H.
Idiopathic atrial fibrillation patients rapidly outgrow their low thromboembolic risk: a 10-year follow-up study
.
Neth Heart J
2019
;
27
:
487
497
.

387

Chao
TF
,
Liao
JN
,
Tuan
TC
,
Lin
YJ
,
Chang
SL
,
Lo
LW
,
Hu
YF
,
Chung
FP
,
Chen
TJ
,
Lip
GYH
,
Chen
SA.
Incident co-morbidities in patients with atrial fibrillation initially with a CHA2DS2-VASc score of 0 (males) or 1 (females): implications for reassessment of stroke risk in initially ‘low-risk’ patients
.
Thromb Haemost
2019
;
119
:
1162
1170
.

388

Borre
ED
,
Goode
A
,
Raitz
G
,
Shah
B
,
Lowenstern
A
,
Chatterjee
R
,
Sharan
L
,
Allen LaPointe
NM
,
Yapa
R
,
Davis
JK
,
Lallinger
K
,
Schmidt
R
,
Kosinski
A
,
Al-Khatib
SM
,
Sanders
GD.
Predicting thromboembolic and bleeding event risk in patients with non-valvular atrial fibrillation: a systematic review
.
Thromb Haemost
2018
;
118
:
2171
2187
.

389

Chao
TF
,
Lip
GYH
,
Lin
YJ
,
Chang
SL
,
Lo
LW
,
Hu
YF
,
Tuan
TC
,
Liao
JN
,
Chung
FP
,
Chen
TJ
,
Chen
SA.
Incident risk factors and major bleeding 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
.

390

Man-Son-Hing
M
,
Nichol
G
,
Lau
A
,
Laupacis
A.
Choosing antithrombotic therapy for elderly patients with atrial fibrillation who are at risk for falls
.
Arch Intern Med
1999
;
159
:
677
685
.

391

Gage
BF
,
Yan
Y
,
Milligan
PE
,
Waterman
AD
,
Culverhouse
R
,
Rich
MW
,
Radford
MJ.
Clinical classification schemes for predicting hemorrhage: results from the National Registry of Atrial Fibrillation (NRAF)
.
Am Heart J
2006
;
151
:
713
719
.

392

Fang
MC
,
Go
AS
,
Chang
Y
,
Borowsky
LH
,
Pomernacki
NK
,
Udaltsova
N
,
Singer
DE.
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
.

393

O'Brien
EC
,
Simon
DN
,
Thomas
LE
,
Hylek
EM
,
Gersh
BJ
,
Ansell
JE
,
Kowey
PR
,
Mahaffey
KW
,
Chang
P
,
Fonarow
GC
,
Pencina
MJ,
,
Piccini
JP
,
Peterson
ED
.
The ORBIT bleeding score: a simple bedside score to assess bleeding risk in atrial fibrillation
.
Eur Heart J
2015
;
36
:
3258
3264
.

394

Rohla
M
,
Weiss
TW
,
Pecen
L
,
Patti
G
,
Siller-Matula
JM
,
Schnabel
RB
,
Schilling
R
,
Kotecha
D
,
Lucerna
M
,
Huber
K
,
De Caterina
R
,
Kirchhof
P.
Risk factors for thromboembolic and bleeding events in anticoagulated patients with atrial fibrillation: the prospective, multicentre observational PREvention oF thromboembolic events – European Registry in Atrial Fibrillation (PREFER in AF
).
BMJ Open
2019
;
9
:
e022478
.

395

Pisters
R
,
Lane
DA
,
Nieuwlaat
R
,
de Vos
CB
,
Crijns
HJ
,
Lip
GY.
A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey
.
Chest
2010
;
138
:
1093
1100
.

396

Mori
N
,
Sotomi
Y
,
Hirata
A
,
Hirayama
A
,
Sakata
Y
,
Higuchi
Y.
External validation of the ORBIT bleeding score and the HAS-BLED score in nonvalvular atrial fibrillation patients using direct oral anticoagulants (Asian data from the DIRECT registry)
.
Am J Cardiol
2019
;
124
:
1044
1048
.

397

Yao
X
,
Gersh
BJ
,
Sangaralingham
LR
,
Kent
DM
,
Shah
ND
,
Abraham
NS
,
Noseworthy
PA.
Comparison of the CHA2DS2-VASc, CHADS2, HAS-BLED, ORBIT, and ATRIA risk scores in predicting non-vitamin K antagonist oral anticoagulants-associated bleeding in patients with atrial fibrillation
.
Am J Cardiol
2017
;
120
:
1549
1556
.

398

Rutherford
OW
,
Jonasson
C
,
Ghanima
W
,
Holst
R
,
Halvorsen
S.
New score for assessing bleeding risk in patients with atrial fibrillation treated with NOACs
.
Open Heart
2018
;
5
:
e000931
.

399

Thomas
MR
,
Lip
GY.
Novel risk markers and risk assessments for cardiovascular disease
.
Circ Res
2017
;
120
:
133
149
.

400

Khan
AA
,
Lip
GYH.
The prothrombotic state in atrial fibrillation: pathophysiological and management implications
.
Cardiovasc Res
2019
;
115
:
31
45
.

401

Ban
N
,
Siegfried
CJ
,
Lin
JB
,
Shui
YB
,
Sein
J
,
Pita-Thomas
W
,
Sene
A
,
Santeford
A
,
Gordon
M
,
Lamb
R
,
Dong
Z
,
Kelly
SC
,
Cavalli
V
,
Yoshino
J
,
Apte
RS.
GDF15 is elevated in mice following retinal ganglion cell death and in glaucoma patients
.
JCI Insight
2017
;
2
:pii: 91455. doi: 10.1172/jci.insight.91455.

402

Hijazi
Z
,
Oldgren
J
,
Lindback
J
,
Alexander
JH
,
Connolly
SJ
,
Eikelboom
JW
,
Ezekowitz
MD
,
Held
C
,
Hylek
EM
,
Lopes
RD
,
Siegbahn
A
,
Yusuf
S
,
Granger
CB
,
Wallentin
L
; ARISTOTLE and RE-LY Investigators.
The novel biomarker-based ABC (age, biomarkers, clinical history)-bleeding risk score for patients with atrial fibrillation: a derivation and validation study
.
Lancet
2016
;
387
:
2302
2311
.

403

Esteve-Pastor
MA
,
Rivera-Caravaca
JM
,
Roldan
V
,
Vicente
V
,
Valdes
M
,
Marin
F
,
Lip
GYH.
Long-term bleeding risk prediction in ‘real world’ patients with atrial fibrillation: comparison of the HAS-BLED and ABC-Bleeding risk scores. The Murcia Atrial Fibrillation Project
.
Thromb Haemost
2017
;
117
:
1848
1858
.

404

Caldeira
D
,
Costa
J
,
Fernandes
RM
,
Pinto
FJ
,
Ferreira
JJ.
Performance of the HAS-BLED high bleeding-risk category, compared to ATRIA and HEMORR2HAGES in patients with atrial fibrillation: a systematic review and meta-analysis
.
J Interv Card Electrophysiol
2014
;
40
:
277
284
.

405

Zhu
W
,
He
W
,
Guo
L
,
Wang
X
,
Hong
K.
The HAS-BLED score for predicting major bleeding risk in anticoagulated patients with atrial fibrillation: a systematic review and meta-analysis
.
Clin Cardiol
2015
;
38
:
555
561
.

406

Chang
G
,
Xie
Q
,
Ma
L
,
Hu
K
,
Zhang
Z
,
Mu
G
,
Cui
Y.
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.

407

Lip
GY
,
Lane
DA.
Bleeding risk assessment in atrial fibrillation: observations on the use and misuse of bleeding risk scores
.
J Thromb Haemost
2016
;
14
:
1711
1714
.

408

Chao
TF
,
Lip
GYH
,
Lin
YJ
,
Chang
SL
,
Lo
LW
,
Hu
YF
,
Tuan
TC
,
Liao
JN
,
Chung
FP
,
Chen
TJ
,
Chen
SA.
Major bleeding and intracranial hemorrhage risk prediction in patients with atrial fibrillation: attention to modifiable bleeding risk factors or use of a bleeding risk stratification score? A nationwide cohort study
.
Int J Cardiol
2018
;
254
:
157
161
.

409

Guo
Y
,
Zhu
H
,
Chen
Y
,
Lip
GYH.
Comparing bleeding risk assessment focused on modifiable risk factors only versus validated bleeding risk scores in atrial fibrillation
.
Am J Med
2018
;
131
:
185
192
.

410

Esteve-Pastor
MA
,
Rivera-Caravaca
JM
,
Shantsila
A
,
Roldan
V
,
Lip
GYH
,
Marin
F.
Assessing bleeding risk in atrial fibrillation patients: comparing a bleeding risk score based only on modifiable bleeding risk factors against the HAS-BLED score. The AMADEUS trial
.
Thromb Haemost
2017
;
117
:
2261
2266
.

411

Guo
Y
,
Lane
DA
,
Chen
Y
,
Lip
GYH
; mAF-App II Trial investigators.
Regular bleeding risk assessment associated with reduction in bleeding outcomes: the mAFA-II randomized trial
.
Am J Med
2020
:pii: S0002-9343(20)30274-6.

412

Hart
RG
,
Pearce
LA
,
Aguilar
MI.
Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation
.
Ann Intern Med
2007
;
146
:
857
867
.

413

De Caterina
R
,
Husted
S
,
Wallentin
L
,
Andreotti
F
,
Arnesen
H
,
Bachmann
F
,
Baigent
C
,
Huber
K
,
Jespersen
J
,
Kristensen
SD
,
Lip
GY
,
Morais
J
,
Rasmussen
LH
,
Siegbahn
A
,
Verheugt
FW
,
Weitz
JI.
Vitamin K antagonists in heart disease: current status and perspectives (Section III). Position paper of the ESC working group on thrombosis – Task Force on anticoagulants in heart disease
.
Thromb Haemost
2013
;
110
:
1087
1107
.

414

Wan
Y
,
Heneghan
C
,
Perera
R
,
Roberts
N
,
Hollowell
J
,
Glasziou
P
,
Bankhead
C
,
Xu
Y.
Anticoagulation control and prediction of adverse events in patients with atrial fibrillation: a systematic review
.
Circ Cardiovasc Qual Outcomes
2008
;
1
:
84
91
.

415

Sjalander
S
,
Sjogren
V
,
Renlund
H
,
Norrving
B
,
Sjalander
A.
Dabigatran, rivaroxaban and apixaban vs. high TTR warfarin in atrial fibrillation
.
Thromb Res
2018
;
167
:
113
118
.

416

Amin
A
,
Deitelzweig
S
,
Jing
Y
,
Makenbaeva
D
,
Wiederkehr
D
,
Lin
J
,
Graham
J.
Estimation of the impact of warfarin’s time-in-therapeutic range on stroke and major bleeding rates and its influence on the medical cost avoidance associated with novel oral anticoagulant use-learnings from ARISTOTLE, ROCKET-AF, and RE-LY trials
.
J Thromb Thrombolysis
2014
;
38
:
150
159
.

417

Apostolakis
S
,
Sullivan
RM
,
Olshansky
B
,
Lip
GYH.
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
.

418

Proietti
M
,
Lip
GY.
Simple decision-making between a vitamin K antagonist and a non-vitamin K antagonist oral anticoagulant: using the SAMe-TT2R2 score
.
Eur Heart J Cardiovasc Pharmacother
2015
;
1
:
150
152
.

419

Connolly
SJ
,
Ezekowitz
MD
,
Yusuf
S
,
Eikelboom
J
,
Oldgren
J
,
Parekh
A
,
Pogue
J
,
Reilly
PA
,
Themeles
E
,
Varrone
J
,
Wang
S
,
Alings
M
,
Xavier
D
,
Zhu
J
,
Diaz
R
,
Lewis
BS
,
Darius
H
,
Diener
HC
,
Joyner
CD
,
Wallentin
L
; RE-LY Steering Committee Investigators.
Dabigatran versus warfarin in patients with atrial fibrillation
.
N Engl J Med
2009
;
361
:
1139
1151
.

420

Patel
MR
,
Mahaffey
KW
,
Garg
J
,
Pan
G
,
Singer
DE
,
Hacke
W
,
Breithardt
G
,
Halperin
JL
,
Hankey
GJ
,
Piccini
JP
,
Becker
RC
,
Nessel
CC
,
Paolini
JF
,
Berkowitz
SD
,
Fox
KA
,
Califf
RM
; ROCKET AF Investigators.
Rivaroxaban versus warfarin in nonvalvular atrial fibrillation
.
N Engl J Med
2011
;
365
:
883
891
.

421

Granger
CB
,
Alexander
JH
,
McMurray
JJ
,
Lopes
RD
,
Hylek
EM
,
Hanna
M
,
Al-Khalidi
HR
,
Ansell
J
,
Atar
D
,
Avezum
A
,
Bahit
MC
,
Diaz
R
,
Easton
JD
,
Ezekowitz
JA
,
Flaker
G
,
Garcia
D
,
Geraldes
M
,
Gersh
BJ
,
Golitsyn
S
,
Goto
S
,
Hermosillo
AG
,
Hohnloser
SH
,
Horowitz
J
,
Mohan
P
,
Jansky
P
,
Lewis
BS
,
Lopez-Sendon
JL
,
Pais
P
,
Parkhomenko
A
,
Verheugt
FW
,
Zhu
J
,
Wallentin
L
; ARISTOTLE Committees and Investigators.
Apixaban versus warfarin in patients with atrial fibrillation
.
N Engl J Med
2011
;
365
:
981
992
.

422

Giugliano
RP
,
Ruff
CT
,
Braunwald
E
,
Murphy
SA
,
Wiviott
SD
,
Halperin
JL
,
Waldo
AL
,
Ezekowitz
MD
,
Weitz
JI
,
Spinar
J
,
Ruzyllo
W
,
Ruda
M
,
Koretsune
Y
,
Betcher
J
,
Shi
M
,
Grip
LT
,
Patel
SP
,
Patel
I
,
Hanyok
JJ
,
Mercuri
M
,
Antman
EM
; ENGAGE AF-TIMI Investigators.
Edoxaban versus warfarin in patients with atrial fibrillation
.
N Engl J Med
2013
;
369
:
2093
2104
.

423

Ruff
CT
,
Giugliano
RP
,
Braunwald
E
,
Hoffman
EB
,
Deenadayalu
N
,
Ezekowitz
MD
,
Camm
AJ
,
Weitz
JI
,
Lewis
BS
,
Parkhomenko
A
,
Yamashita
T
,
Antman
EM.
Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials
.
Lancet
2014
;
383
:
955
962
.

424

Wang
KL
,
Lip
GY
,
Lin
SJ
,
Chiang
CE.
Non-vitamin K antagonist oral anticoagulants for stroke prevention in Asian patients with nonvalvular atrial fibrillation: meta-analysis
.
Stroke
2015
;
46
:
2555
2561
.

425

Connolly
SJ
,
Eikelboom
J
,
Joyner
C
,
Diener
HC
,
Hart
R
,
Golitsyn
S
,
Flaker
G
,
Avezum
A
,
Hohnloser
SH
,
Diaz
R
,
Talajic
M
,
Zhu
J
,
Pais
P
,
Budaj
A
,
Parkhomenko
A
,
Jansky
P
,
Commerford
P
,
Tan
RS
,
Sim
KH
,
Lewis
BS
,
Van Mieghem
W
,
Lip
GY
,
Kim
JH
,
Lanas-Zanetti
F
,
Gonzalez-Hermosillo
A
,
Dans
AL
,
Munawar
M
,
O'Donnell
M
,
Lawrence
J
,
Lewis
G
,
Afzal
R
,
Yusuf
S
; AVERROES Steering Committee Investigators.
Apixaban in patients with atrial fibrillation
.
N Engl J Med
2011
;
364
:
806
817
.

426

Carmo
J
,
Moscoso Costa
F
,
Ferreira
J
,
Mendes
M.
Dabigatran in real-world atrial fibrillation. Meta-analysis of observational comparison studies with vitamin K antagonists
.
Thromb Haemost
2016
;
116
:
754
763
.

427

Huisman
MV
,
Rothman
KJ
,
Paquette
M
,
Teutsch
C
,
Diener
HC
,
Dubner
SJ
,
Halperin
JL
,
Ma
CS
,
Zint
K
,
Elsaesser
A
,
Lu
S
,
Bartels
DB
,
Lip
GYH
; GLORIA-AF Investigators.
Two-year follow-up of patients treated with dabigatran for stroke prevention in atrial fibrillation: Global Registry on Long-Term Antithrombotic Treatment in Patients with Atrial Fibrillation (GLORIA-AF) registry
.
Am Heart J
2018
;
198
:
55
63
.

428

Camm
AJ
,
Amarenco
P
,
Haas
S
,
Hess
S
,
Kirchhof
P
,
Kuhls
S
,
van Eickels
M
,
Turpie
AG
; XANTUS Investigators.
XANTUS: a real-world, prospective, observational study of patients treated with rivaroxaban for stroke prevention in atrial fibrillation
.
Eur Heart J
2016
;
37
:
1145
1153
.

429

Martinez
CAA
,
Lanas
F
,
Radaideh
G
,
Kharabsheh
SM
,
Lambelet
M
,
Viaud
MAL
,
Ziadeh
NS
,
Turpie
AGG
; XANTUS Investigators.
XANTUS-EL: a real-world, prospective, observational study of patients treated with rivaroxaban for stroke prevention in atrial fibrillation in Eastern Europe, Middle East, Africa and Latin America
.
Egypt Heart J
2018
;
70
:
307
313
.

430

Li
XS
,
Deitelzweig
S
,
Keshishian
A
,
Hamilton
M
,
Horblyuk
R
,
Gupta
K
,
Luo
X
,
Mardekian
J
,
Friend
K
,
Nadkarni
A
,
Pan
X
,
Lip
GYH.
Effectiveness and safety of apixaban versus warfarin in non-valvular atrial fibrillation patients in ‘real-world’ clinical practice. A propensity-matched analysis of 76,940 patients
.
Thromb Haemost
2017
;
117
:
1072
1082
.

431

Lee
SR
,
Choi
EK
,
Han
KD
,
Jung
JH
,
Oh
S
,
Lip
GYH.
Edoxaban in Asian patients with atrial fibrillation: effectiveness and safety
.
J Am Coll Cardiol
2018
;
72
:
838
853
.

432

Ingrasciotta
Y
,
Crisafulli
S
,
Pizzimenti
V
,
Marciano
I
,
Mancuso
A
,
Ando
G
,
Corrao
S
,
Capranzano
P
,
Trifiro
G.
Pharmacokinetics of new oral anticoagulants: implications for use in routine care
.
Expert Opin Drug Metab Toxicol
2018
;
14
:
1057
1069
.

433

Chao
TF
,
Liu
CJ
,
Lin
YJ
,
Chang
SL
,
Lo
LW
,
Hu
YF
,
Tuan
TC
,
Liao
JN
,
Chung
FP
,
Chen
TJ
,
Lip
GYH
,
Chen
SA.
Oral anticoagulation in very elderly patients with atrial fibrillation: a nationwide cohort study
.
Circulation
2018
;
138
:
37
47
.

434

Stanton
BE
,
Barasch
NS
,
Tellor
KB.
Comparison of the safety and effectiveness of apixaban versus warfarin in patients with severe renal impairment
.
Pharmacotherapy
2017
;
37
:
412
419
.

435

Siontis
KC
,
Zhang
X
,
Eckard
A
,
Bhave
N
,
Schaubel
DE
,
He
K
,
Tilea
A
,
Stack
AG
,
Balkrishnan
R
,
Yao
X
,
Noseworthy
PA
,
Shah
ND
,
Saran
R
,
Nallamothu
BK.
Outcomes associated with apixaban use in patients with end-stage kidney disease and atrial fibrillation in the United States
.
Circulation
2018
;
138
:
1519
1529
.

436

Steinberg
BA
,
Shrader
P
,
Thomas
L
,
Ansell
J
,
Fonarow
GC
,
Gersh
BJ
,
Kowey
PR
,
Mahaffey
KW
,
Naccarelli
G
,
Reiffel
J
,
Singer
DE
,
Peterson
ED
,
Piccini
JP
; ORBIT-AF Investigators and Patients.
Off-label dosing of non-vitamin K antagonist oral anticoagulants and adverse outcomes: the ORBIT-AF II registry
.
J Am Coll Cardiol
2016
;
68
:
2597
2604
.

437

Yao
X
,
Shah
ND
,
Sangaralingham
LR
,
Gersh
BJ
,
Noseworthy
PA.
Non-vitamin K antagonist oral anticoagulant dosing in patients with atrial fibrillation and renal dysfunction
.
J Am Coll Cardiol
2017
;
69
:
2779
2790
.

438

ACTIVE Writing Group of the ACTIVE Investigators,

Connolly
S
,
Pogue
J
,
Hart
R
,
Pfeffer
M
,
Hohnloser
S
,
Chrolavicius
S
,
Pfeffer
M
,
Hohnloser
S
,
Yusuf
S.
Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE W): a randomised controlled trial
.
Lancet
2006
;
367
:
1903
1912
.

439

ACTIVE Investigators,

Connolly
SJ
,
Pogue
J
,
Hart
RG
,
Hohnloser
SH
,
Pfeffer
M
,
Chrolavicius
S
,
Yusuf
S.
Effect of clopidogrel added to aspirin in patients with atrial fibrillation
.
N Engl J Med
2009
;
360
:
2066
2078
.

440

Sjalander
S
,
Sjalander
A
,
Svensson
PJ
,
Friberg
L.
Atrial fibrillation patients do not benefit from acetylsalicylic acid
.
Europace
2014
;
16
:
631
638
.

441

Mant
J
,
Hobbs
FD
,
Fletcher
K
,
Roalfe
A
,
Fitzmaurice
D
,
Lip
GY
,
Murray
E
; BAFTA investigators, Midland Research Practices Network (MidReC.
Warfarin versus aspirin for stroke prevention in an elderly community population with atrial fibrillation (the Birmingham Atrial Fibrillation Treatment of the Aged Study, BAFTA): a randomised controlled trial
.
Lancet
2007
;
370
:
493
503
.

442

Lip
GY.
The role of aspirin for stroke prevention in atrial fibrillation
.
Nat Rev Cardiol
2011
;
8
:
602
606
.

443

Verheugt
FWA
,
Gao
H
,
Al Mahmeed
W
,
Ambrosio
G
,
Angchaisuksiri
P
,
Atar
D
,
Bassand
JP
,
Camm
AJ
,
Cools
F
,
Eikelboom
J
,
Kayani
G
,
Lim
TW
,
Misselwitz
F
,
Pieper
KS
,
van Eickels
M
,
Kakkar
AK
; GARFIELD-AF Investigators.
Characteristics of patients with atrial fibrillation prescribed antiplatelet monotherapy compared with those on anticoagulants: insights from the GARFIELD-AF registry
.
Eur Heart J
2018
;
39
:
464
473
.

444

Holmes
DR
,
Reddy
VY
,
Turi
ZG
,
Doshi
SK
,
Sievert
H
,
Buchbinder
M
,
Mullin
CM
,
Sick
P
; PROTECT AF Investigators.
Percutaneous closure of the left atrial appendage versus warfarin therapy for prevention of stroke in patients with atrial fibrillation: a randomised non-inferiority trial
.
Lancet
2009
;
374
:
534
542
.

445

Reddy
VY
,
Doshi
SK
,
Sievert
H
,
Buchbinder
M
,
Neuzil
P
,
Huber
K
,
Halperin
JL
,
Holmes
D
; PROTECT AF Investigators.
Percutaneous left atrial appendage closure for stroke prophylaxis in patients with atrial fibrillation: 2.3-year follow-up of the PROTECT AF (Watchman Left Atrial Appendage System for Embolic Protection in Patients with Atrial Fibrillation) trial
.
Circulation
2013
;
127
:
720
729
.

446

Holmes
DR
Jr ,
Kar
S
,
Price
MJ
,
Whisenant
B
,
Sievert
H
,
Doshi
SK
,
Huber
K
,
Reddy
VY.
Prospective randomized evaluation of the Watchman left atrial appendage closure device in patients with atrial fibrillation versus long-term warfarin therapy: the PREVAIL trial
.
J Am Coll Cardiol
2014
;
64
:
1
12
.

447

Holmes
DR
Jr. ,
Doshi
SK
,
Kar
S
,
Price
MJ
,
Sanchez
JM
,
Sievert
H
,
Valderrabano
M
,
Reddy
VY.
Left atrial appendage closure as an alternative to warfarin for stroke prevention in atrial fibrillation: a patient-level meta-analysis
.
J Am Coll Cardiol
2015
;
65
:
2614
2623
.

448

Reddy
VY
,
Mobius-Winkler
S
,
Miller
MA
,
Neuzil
P
,
Schuler
G
,
Wiebe
J
,
Sick
P
,
Sievert
H.
Left atrial appendage closure with the Watchman device in patients with a contraindication for oral anticoagulation: the ASAP study (ASA Plavix Feasibility Study With Watchman Left Atrial Appendage Closure Technology)
.
J Am Coll Cardiol
2013
;
61
:
2551
2556
.

449

Boersma
LV
,
Schmidt
B
,
Betts
TR
,
Sievert
H
,
Tamburino
C
,
Teiger
E
,
Pokushalov
E
,
Kische
S
,
Schmitz
T
,
Stein
KM
,
Bergmann
MW
, on behalf of the EWOLUTION investigators.
Implant success and safety of left atrial appendage closure with the WATCHMAN device: peri-procedural outcomes from the EWOLUTION registry
.
Eur Heart J
2016
;
37
:
2465
2474
.

450

Boersma
LV
,
Ince
H
,
Kische
S
,
Pokushalov
E
,
Schmitz
T
,
Schmidt
B
,
Gori
T
,
Meincke
F
,
Protopopov
AV
,
Betts
T
,
Foley
D
,
Sievert
H
,
Mazzone
P
,
De Potter
T
,
Vireca
E
,
Stein
K
,
Bergmann
MW
, for the EWOLUTION Investigators.
Efficacy and safety of left atrial appendage closure with WATCHMAN in patients with or without contraindication to oral anticoagulation: 1-year follow-up outcome data of the EWOLUTION trial
.
Heart Rhythm
2017
;
14
:
1302
1308
.

451

Badheka
AO
,
Chothani
A
,
Mehta
K
,
Patel
NJ
,
Deshmukh
A
,
Hoosien
M
,
Shah
N
,
Singh
V
,
Grover
P
,
Savani
GT
,
Panaich
SS
,
Rathod
A
,
Patel
N
,
Arora
S
,
Bhalara
V
,
Coffey
JO
,
O’Neill
W
,
Makkar
R
,
Grines
CL
,
Schreiber
T
,
Di Biase
L
,
Natale
A
,
Viles-Gonzalez
JF.
Utilization and adverse outcomes of percutaneous left atrial appendage closure for stroke prevention in atrial fibrillation in the United States: influence of hospital
volume.
Circ Arrhythm Electrophysiol
2015
;
8
:
42
48
.

452

Pison
L
,
Potpara
TS
,
Chen
J
,
Larsen
TB
,
Bongiorni
MG
,
Blomstrom-Lundqvist
C
; Scientific Initiative Committee EHRA.
Left atrial appendage closure-indications, techniques, and outcomes: results of the European Heart Rhythm Association Survey
.
Europace
2015
;
17
:
642
646
.

453

Price
MJ
,
Gibson
DN
,
Yakubov
SJ
,
Schultz
JC
,
Di Biase
L
,
Natale
A
,
Burkhardt
JD
,
Pershad
A
,
Byrne
TJ
,
Gidney
B
,
Aragon
JR
,
Goldstein
J
,
Moulton
K
,
Patel
T
,
Knight
B
,
Lin
AC
,
Valderrabano
M.
Early safety and efficacy of percutaneous left atrial appendage suture ligation: results from the US transcatheter LAA ligation consortium
.
J Am Coll Cardiol
2014
;
64
:
565
572
.

454

Fauchier
L
,
Cinaud
A
,
Brigadeau
F
,
Lepillier
A
,
Pierre
B
,
Abbey
S
,
Fatemi
M
,
Franceschi
F
,
Guedeney
P
,
Jacon
P
,
Paziaud
O
,
Venier
S
,
Deharo
JC
,
Gras
D
,
Klug
D
,
Mansourati
J
,
Montalescot
G
,
Piot
O
,
Defaye
P.
Device-related thrombosis after percutaneous left atrial appendage occlusion for atrial fibrillation
.
J Am Coll Cardiol
2018
;
71
:
1528
1536
.

455

Lakkireddy
D
,
Afzal
MR
,
Lee
RJ
,
Nagaraj
H
,
Tschopp
D
,
Gidney
B
,
Ellis
C
,
Altman
E
,
Lee
B
,
Kar
S
,
Bhadwar
N
,
Sanchez
M
,
Gadiyaram
V
,
Evonich
R
,
Rasekh
A
,
Cheng
J
,
Cuoco
F
,
Chandhok
S
,
Gunda
S
,
Reddy
M
,
Atkins
D
,
Bommana
S
,
Cuculich
P
,
Gibson
D
,
Nath
J
,
Ferrell
R
,
Matthew
E
,
Wilber
D.
Short and long-term outcomes of percutaneous left atrial appendage suture ligation: results from a US multicenter evaluation
.
Heart Rhythm
2016
;
13
:
1030
1036
.

456

van Laar
C
,
Verberkmoes
NJ
,
van Es
HW
,
Lewalter
T
,
Dunnington
G
,
Stark
S
,
Longoria
J
,
Hofman
FH
,
Pierce
CM
,
Kotecha
D
,
van Putte
BP.
Thoracoscopic left atrial appendage clipping: a multicenter cohort analysis
.
JACC Clin Electrophysiol
2018
;
4
:
893
901
.

457

Healey
JS
,
Crystal
E
,
Lamy
A
,
Teoh
K
,
Semelhago
L
,
Hohnloser
SH
,
Cybulsky
I
,
Abouzahr
L
,
Sawchuck
C
,
Carroll
S
,
Morillo
C
,
Kleine
P
,
Chu
V
,
Lonn
E
,
Connolly
SJ.
Left Atrial Appendage Occlusion Study (LAAOS): results of a randomized controlled pilot study of left atrial appendage occlusion during coronary bypass surgery in patients at risk for stroke
.
Am Heart J
2005
;
150
:
288
293
.

458

Whitlock
RP
,
Vincent
J
,
Blackall
MH
,
Hirsh
J
,
Fremes
S
,
Novick
R
,
Devereaux
PJ
,
Teoh
K
,
Lamy
A
,
Connolly
SJ
,
Yusuf
S
,
Carrier
M
,
Healey
JS
.
Left Atrial Appendage Occlusion Study II (LAAOS II)
.
Can J Cardiol
2013
;
29
:
1443
1447
.

459

Tsai
YC
,
Phan
K
,
Munkholm-Larsen
S
,
Tian
DH
,
La Meir
M
,
Yan
TD.
Surgical left atrial appendage occlusion during cardiac surgery for patients with atrial fibrillation: a meta-analysis
.
Eur J Cardiothorac Surg
2015
;
47
:
847
854
.

460

Aryana
A
,
Singh
SK
,
Singh
SM
,
O’Neill
PG
,
Bowers
MR
,
Allen
SL
,
Lewandowski
SL
,
Vierra
EC
,
d’Avila
A.
Association between incomplete surgical ligation of left atrial appendage and stroke and systemic embolization
.
Heart Rhythm
2015
;
12
:
1431
1437
.

461

Gillinov
AM
,
Gelijns
AC
,
Parides
MK
,
DeRose
JJ
Jr
,
Moskowitz
AJ
,
Voisine
P
,
Ailawadi
G
,
Bouchard
D
,
Smith
PK
,
Mack
MJ
,
Acker
MA,
,
Mullen
JC
,
Rose
EA,
,
Chang
HL
,
Puskas
JD
,
Couderc
JP
,
Gardner
TJ
,
Varghese
R
,
Horvath
KA
,
Bolling
SF
,
Michler
RE,
,
Geller
NL
,
Ascheim
DD
,
Miller
MA
,
Bagiella
E
,
Moquete
EG
,
Williams
P,
,
Taddei-Peters
WC
,
O'Gara
PT
,
Blackstone
EH
,
Argenziano
M
; CTSN Investigators.
Surgical ablation of atrial fibrillation during mitral-valve surgery
.
N Engl J Med
2015
;
372
:
1399
1409
.

462

Whitlock
R
,
Healey
J
,
Vincent
J
,
Brady
K
,
Teoh
K
,
Royse
A
,
Shah
P
,
Guo
Y
,
Alings
M
,
Folkeringa
RJ
,
Paparella
D
,
Colli
A
,
Meyer
SR
,
Legare
JF
,
Lamontagne
F
,
Reents
W
,
Boning
A
,
Connolly
S.
Rationale and design of the Left Atrial Appendage Occlusion Study (LAAOS) III
.
Ann Cardiothorac Surg
2014
;
3
:
45
54
.

463

Nielsen
PB
,
Skjoth
F
,
Sogaard
M
,
Kjaeldgaard
JN
,
Lip
GY
,
Larsen
TB.
Effectiveness and safety of reduced dose non-vitamin K antagonist oral anticoagulants and warfarin in patients with atrial fibrillation: propensity weighted nationwide cohort study
.
BMJ
2017
;
356
:
j510
.

464

Larsen
TB
,
Skjoth
F
,
Nielsen
PB
,
Kjaeldgaard
JN
,
Lip
GY.
Comparative effectiveness and safety of non-vitamin K antagonist oral anticoagulants and warfarin in patients with atrial fibrillation: propensity weighted nationwide cohort study
.
BMJ
2016
;
353
:
i3189
.

465

Tilz
RR
,
Potpara
T
,
Chen
J
,
Dobreanu
D
,
Larsen
TB
,
Haugaa
KH
,
Dagres
N.
Left atrial appendage occluder implantation in Europe: indications and anticoagulation post-implantation. Results of the European Heart Rhythm Association Survey
.
Europace
2017
;
19
:
1737
1742
.

466

Ogawa
H
,
An
Y
,
Ikeda
S
,
Aono
Y
,
Doi
K
,
Ishii
M
,
Iguchi
M
,
Masunaga
N
,
Esato
M
,
Tsuji
H
,
Wada
H
,
Hasegawa
K
,
Abe
M
,
Lip
GYH
,
Akao
M
; Fushimi AF Registry Investigators.
Progression from paroxysmal to sustained atrial fibrillation is associated with increased adverse events
.
Stroke
2018
;
49
:
2301
2308
.

467

Mahajan
R
,
Perera
T
,
Elliott
AD
,
Twomey
DJ
,
Kumar
S
,
Munwar
DA
,
Khokhar
KB
,
Thiyagarajah
A
,
Middeldorp
ME
,
Nalliah
CJ
,
Hendriks
JML
,
Kalman
JM
,
Lau
DH
,
Sanders
P.
Subclinical device-detected atrial fibrillation and stroke risk: a systematic review and meta-analysis
.
Eur Heart J
2018
;
39
:
1407
1415
.

468

Van Gelder
IC
,
Healey
JS
,
Crijns
H
,
Wang
J
,
Hohnloser
SH
,
Gold
MR
,
Capucci
A
,
Lau
CP
,
Morillo
CA,
,
Hobbelt
AH
,
Rienstra
M
,
Connolly
SJ.
Duration of device-detected subclinical atrial fibrillation and occurrence of stroke in ASSERT
.
Eur Heart J
2017
;
38
:
1339
1344
.

469

Boriani
G
,
Glotzer
TV
,
Ziegler
PD
,
De Melis
M
,
Mangoni di
SSL
,
Sepsi
M
,
Landolina
M
,
Lunati
M
,
Lewalter
T
,
Camm
AJ.
Detection of new atrial fibrillation in patients with cardiac implanted electronic devices and factors associated with transition to higher device-detected atrial fibrillation burden
.
Heart Rhythm
2018
;
15
:
376
383
.

470

Pastori
D
,
Lip
GYH
,
Farcomeni
A
,
Del Sole
F
,
Sciacqua
A
,
Perticone
F
,
Marcucci
R
,
Grifoni
E
,
Pignatelli
P
,
Violi
F
, ATHERO-AF study group.
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
.

471

Kuo
L
,
Chao
TF
,
Liu
CJ
,
Lin
YJ
,
Chang
SL
,
Lo
LW
,
Hu
YF
,
Tuan
TC
,
Liao
JN
,
Chung
FP
,
Chen
TJ
,
Lip
GYH
,
Chen
SA.
Liver cirrhosis in patients with atrial fibrillation: would oral anticoagulation have a net clinical benefit for stroke prevention?
J Am Heart Assoc
2017
;
6
.

472

Lee
SR
,
Lee
HJ
,
Choi
EK
,
Han
KD
,
Jung
JH
,
Cha
MJ
,
Oh
S
,
Lip
GYH.
Direct oral anticoagulants in patients with atrial fibrillation and liver disease
.
J Am Coll Cardiol
2019
;
73
:
3295
3308
.

473

Staerk
L
,
Lip
GY
,
Olesen
JB
,
Fosbol
EL
,
Pallisgaard
JL
,
Bonde
AN
,
Gundlund
A
,
Lindhardt
TB
,
Hansen
ML
,
Torp-Pedersen
C
,
Gislason
GH.
Stroke and recurrent haemorrhage associated with antithrombotic treatment after gastrointestinal bleeding in patients with atrial fibrillation: nationwide cohort study
.
BMJ
2015
;
351
:
h5876
.

474

Eckman
MH
,
Singer
DE
,
Rosand
J
,
Greenberg
SM.
Moving the tipping point: the decision to anticoagulate patients with atrial fibrillation
.
Circ Cardiovasc Qual Outcomes
2011
;
4
:
14
21
.

475

Proietti
M
,
Lip
GY.
Major outcomes in atrial fibrillation patients with one risk factor: impact of time in therapeutic range observations from the SPORTIF trials
.
Am J Med
2016
;
129
:
1110
1116
.

476

Lip
GY
,
Nielsen
PB.
Should patients with atrial fibrillation and 1 stroke risk factor (CHA2DS2-VASc Score 1 in Men, 2 in Women) be anticoagulated? Yes: even 1 stroke risk factor confers a real risk of stroke
.
Circulation
2016
;
133
:
1498
1503; discussion 1503
.

477

Lip
GY
,
Lane
DA.
Stroke prevention in atrial fibrillation: a systematic review
.
JAMA
2015
;
313
:
1950
1962
.

478

Hijazi
Z
,
Hohnloser
SH
,
Andersson
U
,
Alexander
JH
,
Hanna
M
,
Keltai
M
,
Parkhomenko
A
,
Lopez-Sendon
JL
,
Lopes
RD
,
Siegbahn
A
,
Granger
CB
,
Wallentin
L.
Efficacy and safety of apixaban compared with warfarin in patients with atrial fibrillation in relation to renal function over time: insights from the ARISTOTLE randomized clinical trial
.
JAMA Cardiol
2016
;
1
:
451
460
.

479

Bohm
M
,
Ezekowitz
MD
,
Connolly
SJ
,
Eikelboom
JW
,
Hohnloser
SH
,
Reilly
PA
,
Schumacher
H
,
Brueckmann
M
,
Schirmer
SH
,
Kratz
MT
,
Yusuf
S
,
Diener
HC
,
Hijazi
Z
,
Wallentin
L.
Changes in renal function in patients with atrial fibrillation: an analysis from the RE-LY trial
.
J Am Coll Cardiol
2015
;
65
:
2481
2493
.

480

Clarkesmith
DE
,
Pattison
HM
,
Lip
GY
,
Lane
DA.
Educational intervention improves anticoagulation control in atrial fibrillation patients: the TREAT randomised trial
.
PLoS One
2013
;
8
:
e74037
.

481

Teiger
E
,
Thambo
JB
,
Defaye
P
,
Hermida
JS
,
Abbey
S
,
Klug
D
,
Juliard
JM
,
Pasquie
JL
,
Rioufol
G
,
Lepillier
A
,
Elbaz
M
,
Horvilleur
J
,
Brenot
P
,
Pierre
B
,
Le Corvoisier
P.
Percutaneous left atrial appendage closure is a reasonable option for patients with atrial fibrillation at high risk for cerebrovascular events
.
Circ Cardiovasc Interv
2018
;
11
:e
005841
.

482

Saw
J,
,
Fahmy
P
,
Azzalini
L
,
Marquis
JF
,
Hibbert
B
,
Morillo
C
,
Carrizo
A
,
Ibrahim
R.
Early Canadian multicenter experience with WATCHMAN for percutaneous left atrial appendage closure
.
J Cardiovasc Electrophysiol
2017
;
28
:
396
401
.

483

Martin Gutierrez
E
,
Castano
M
,
Gualis
J
,
Martinez-Comendador
JM
,
Maiorano
P
,
Castillo
L
,
Laguna
G
.
Beneficial effect of left atrial appendage closure during cardiac surgery: a meta-analysis of 280 585 patients
.
Eur J Cardiothorac Surg
2020
;
57
:
252
262
.

484

Al-Khatib
SM
,
Allen LaPointe
NM
,
Chatterjee
R
,
Crowley
MJ
,
Dupre
ME
,
Kong
DF
,
Lopes
RD
,
Povsic
TJ
,
Raju
SS,
,
Shah
B
,
Kosinski
AS,
,
McBroom
AJ
,
Sanders
GD.
Rate- and rhythm-control therapies in patients with atrial fibrillation: a systematic review
.
Ann Intern Med
2014
;
160
:
760
773
.

485

Tamariz
LJ
,
Bass
EB.
Pharmacological rate control of atrial fibrillation
.
Cardiol Clin
2004
;
22
:
35
45
.

486

Nikolaidou
T
,
Channer
KS.
Chronic atrial fibrillation: a systematic review of medical heart rate control management
.
Postgrad Med J
2009
;
85
:
303
312
.

487

Groenveld
HF
,
Crijns
HJ
,
Van den Berg
MP
,
Van Sonderen
E
,
Alings
AM
,
Tijssen
JG
,
Hillege
HL
,
Tuininga
YS
,
Van Veldhuisen
DJ
,
Ranchor
AV
,
Van Gelder
IC
; RACE II Investigators.
The effect of rate control on quality of life in patients with permanent atrial fibrillation: data from the RACE II (Rate Control Efficacy in Permanent Atrial Fibrillation II) study
.
J Am Coll Cardiol
2011
;
58
:
1795
1803
.

488

Van Gelder
IC
,
Groenveld
HF
,
Crijns
HJ
,
Tuininga
YS
,
Tijssen
JG
,
Alings
AM
,
Hillege
HL
,
Bergsma-Kadijk
JA
,
Cornel
JH
,
Kamp
O
,
Tukkie
R
,
Bosker
HA
,
Van Veldhuisen
DJ
,
Van den Berg
MP
; RACE II Investigators.
Lenient versus strict rate control in patients with atrial fibrillation
.
N Engl J Med
2010
;
362
:
1363
1373
.

489

Van Gelder
IC
,
Wyse
DG
,
Chandler
ML
,
Cooper
HA
,
Olshansky
B
,
Hagens
VE
,
Crijns
HJ
; RACE and AFFIRM Investigators.
Does intensity of rate-control influence outcome in atrial fibrillation? An analysis of pooled data from the RACE and AFFIRM studies
.
Europace
2006
;
8
:
935
942
.

490

Van Gelder
IC
,
Rienstra
M
,
Crijns
HJ
,
Olshansky
B.
Rate control in atrial fibrillation
.
Lancet
2016
;
388
:
818
828
.

491

Kotecha
D
,
Holmes
J
,
Krum
H
,
Altman
DG
,
Manzano
L
,
Cleland
JG
,
Lip
GY
,
Coats
AJ
,
Andersson
B
,
Kirchhof
P
,
von Lueder
TG
,
Wedel
H
,
Rosano
G
,
Shibata
MC
,
Rigby
A
,
Flather
MD.
Efficacy of beta blockers in patients with heart failure plus atrial fibrillation: an individual-patient data meta-analysis
.
Lancet
2014
;
384
:
2235
2243
.

492

Ulimoen
SR
,
Enger
S
,
Carlson
J
,
Platonov
PG
,
Pripp
AH
,
Abdelnoor
M
,
Arnesen
H
,
Gjesdal
K
,
Tveit
A.
Comparison of four single-drug regimens on ventricular rate and arrhythmia-related symptoms in patients with permanent atrial fibrillation
.
Am J Cardiol
2013
;
111
:
225
230
.

493

Ulimoen
SR
,
Enger
S
,
Pripp
AH
,
Abdelnoor
M
,
Arnesen
H
,
Gjesdal
K
,
Tveit
A.
Calcium channel blockers improve exercise capacity and reduce N-terminal Pro-B-type natriuretic peptide levels compared with beta-blockers in patients with permanent atrial fibrillation
.
Eur Heart J
2014
;
35
:
517
524
.

494

Figulla
HR
,
Gietzen
F
,
Zeymer
U
,
Raiber
M
,
Hegselmann
J
,
Soballa
R
,
Hilgers
R.
Diltiazem improves cardiac function and exercise capacity in patients with idiopathic dilated cardiomyopathy. Results of the Diltiazem in Dilated Cardiomyopathy trial
.
Circulation
1996
;
94
:
346
352
.

495

Hallberg
P
,
Lindback
J
,
Lindahl
B
,
Stenestrand
U
,
Melhus
H
, group R-H.
Digoxin and mortality in atrial fibrillation: a prospective cohort study
.
Eur J Clin Pharmacol
2007
;
63
:
959
971
.

496

Turakhia
MP
,
Santangeli
P
,
Winkelmayer
WC
,
Xu
X
,
Ullal
AJ
,
Than
CT
,
Schmitt
S
,
Holmes
TH
,
Frayne
SM,
,
Phibbs
CS
,
Yang
F
,
Hoang
DD
,
Ho
PM
,
Heidenreich
PA.
Increased mortality associated with digoxin in contemporary patients with atrial fibrillation: findings from the TREAT-AF study
.
J Am Coll Cardiol
2014
;
64
:
660
668
.

497

Whitbeck
MG
,
Charnigo
RJ
,
Khairy
P
,
Ziada
K
,
Bailey
AL
,
Zegarra
MM
,
Shah
J
,
Morales
G
,
Macaulay
T
,
Sorrell
VL
,
Campbell
CL
,
Gurley
J
,
Anaya
P
,
Nasr
H
,
Bai
R
,
Di Biase
L
,
Booth
DC
,
Jondeau
G
,
Natale
A
,
Roy
D
,
Smyth
S
,
Moliterno
DJ
,
Elayi
CS.
Increased mortality among patients taking digoxin – analysis from the AFFIRM study
.
Eur Heart J
2013
;
34
:
1481
1488
.

498

Andrey
JL
,
Romero
S
,
Garcia-Egido
A
,
Escobar
MA
,
Corzo
R
,
Garcia-Dominguez
G
,
Lechuga
V
,
Gomez
F.
Mortality and morbidity of heart failure treated with digoxin. A propensity-matched study
.
Int J Clin Pract
2011
;
65
:
1250
1258
.

499

Flory
JH
,
Ky
B
,
Haynes
K
,
S
MB
,
Munson
J
,
Rowan
C
,
Strom
BL
,
Hennessy
S
.
Observational cohort study of the safety of digoxin use in women with heart failure
.
BMJ Open
2012
;
2
:
e000888
.

500

Gheorghiade
M
,
Fonarow
GC
,
van Veldhuisen
DJ
,
Cleland
JG
,
Butler
J
,
Epstein
AE
,
Patel
K
,
Aban
IB
,
Aronow
WS
,
Anker
SD
,
Ahmed
A.
Lack of evidence of increased mortality among patients with atrial fibrillation taking digoxin: findings from post hoc propensity-matched analysis of the AFFIRM trial
.
Eur Heart J
2013
;
34
:
1489
1497
.

501

Aguirre Davila
L
,
Weber
K
,
Bavendiek
U
,
Bauersachs
J
,
Wittes
J
,
Yusuf
S
,
Koch
A.
Digoxin-mortality: randomized vs. observational comparison in the DIG trial
.
Eur Heart J
2019
;
40
:
3336
3341
.

502

Ziff
OJ
,
Lane
DA
,
Samra
M
,
Griffith
M
,
Kirchhof
P
,
Lip
GY
,
Steeds
RP
,
Townend
J
,
Kotecha
D.
Safety and efficacy of digoxin: systematic review and meta-analysis of observational and controlled trial data
.
BMJ
2015
;
351
:
h4451
.

503

Bavendiek
U
,
Berliner
D
,
Davila
LA
,
Schwab
J
,
Maier
L
,
Philipp
SA
,
Rieth
A
,
Westenfeld
R
,
Piorkowski
C
,
Weber
K
,
Hanselmann
A
,
Oldhafer
M
,
Schallhorn
S
,
von der Leyen
H
,
Schroder
C
,
Veltmann
C
,
Stork
S
,
Bohm
M
,
Koch
A
,
Bauersachs
J
; DIGIT-HF Investigators and Committees.
Rationale and design of the DIGIT-HF trial (DIGitoxin to Improve ouTcomes in patients with advanced chronic Heart Failure): a randomized, double-blind, placebo-controlled study
.
Eur J Heart Fail
2019
;
21
:
676
684
.

504

Clemo
HF
,
Wood
MA
,
Gilligan
DM
,
Ellenbogen
KA.
Intravenous amiodarone for acute heart rate control in the critically ill patient with atrial tachyarrhythmias
.
Am J Cardiol
1998
;
81
:
594
598
.

505

Klijn
CJ
,
Paciaroni
M
,
Berge
E
,
Korompoki
E
,
Korv
J
,
Lal
A
,
Putaala
J
,
Werring
DJ.
Antithrombotic treatment for secondary prevention of stroke and other thromboembolic events in patients with stroke or transient ischemic attack and non-valvular atrial fibrillation: a European Stroke Organisation guideline
.
Eur Stroke J
2019
;
4
:
198
223
.

506

Gosselink
AT
,
Crijns
HJ
,
Van Gelder
IC
,
Hillige
H
,
Wiesfeld
AC
,
Lie
KI.
Low-dose amiodarone for maintenance of sinus rhythm after cardioversion of atrial fibrillation or flutter
.
JAMA
1992
;
267
:
3289
3293
.

507

Scheuermeyer
FX
,
Grafstein
E
,
Stenstrom
R
,
Christenson
J
,
Heslop
C
,
Heilbron
B
,
McGrath
L
,
Innes
G.
Safety and efficiency of calcium channel blockers versus beta-blockers for rate control in patients with atrial fibrillation and no acute underlying medical illness
.
Acad Emerg Med
2013
;
20
:
222
230
.

508

Schreck
DM
,
Rivera
AR
,
Tricarico
VJ.
Emergency management of atrial fibrillation and flutter: intravenous diltiazem versus intravenous digoxin
.
Ann Emerg Med
1997
;
29
:
135
140
.

509

Segal
JB
,
McNamara
RL
,
Miller
MR
,
Kim
N
,
Goodman
SN
,
Powe
NR
,
Robinson
K
,
Yu
D
,
Bass
EB.
The evidence regarding the drugs used for ventricular rate control
.
J Fam Pract
2000
;
49
:
47
59
.

510

Siu
CW,
,
Lau
CP
,
Lee
WL
,
Lam
KF
,
Tse
HF.
Intravenous diltiazem is superior to intravenous amiodarone or digoxin for achieving ventricular rate control in patients with acute uncomplicated atrial fibrillation
.
Crit Care Med
2009
;
37
:
2174
2179
; quiz 2180.

511

Tisdale
JE
,
Padhi
ID
,
Goldberg
AD
,
Silverman
NA
,
Webb
CR
,
Higgins
RS
,
Paone
G
,
Frank
DM
,
Borzak
S.
A randomized, double-blind comparison of intravenous diltiazem and digoxin for atrial fibrillation after coronary artery bypass surgery
.
Am Heart J
1998
;
135
:
739
747
.

512

Darby
AE
,
Dimarco
JP.
Management of atrial fibrillation in patients with structural heart disease
.
Circulation
2012
;
125
:
945
957
.

513

Kotecha
D
,
Piccini
JP.
Atrial fibrillation in heart failure: what should we do?
Eur Heart J
2015
;
36
:
3250
3257
.

514

Delle Karth
G
,
Geppert
A
,
Neunteufl
T
,
Priglinger
U
,
Haumer
M
,
Gschwandtner
M
,
Siostrzonek
P
,
Heinz
G.
Amiodarone versus diltiazem for rate control in critically ill patients with atrial tachyarrhythmias
.
Crit Care Med
2001
;
29
:
1149
1153
.

515

Hou
ZY
,
Chang
MS
,
Chen
CY
,
Tu
MS,
,
Lin
SL
,
Chiang
HT
,
Woosley
RL.
Acute treatment of recent-onset atrial fibrillation and flutter with a tailored dosing regimen of intravenous amiodarone. A randomized, digoxin-controlled study
.
Eur Heart J
1995
;
16
:
521
528
.

516

Lim
KT
,
Davis
MJ
,
Powell
A
,
Arnolda
L
,
Moulden
K
,
Bulsara
M
,
Weerasooriya
R.
Ablate and pace strategy for atrial fibrillation: long-term outcome of AIRCRAFT trial
.
Europace
2007
;
9
:
498
505
.

517

Queiroga
A
,
Marshall
HJ
,
Clune
M
,
Gammage
MD.
Ablate and pace revisited: long term survival and predictors of permanent atrial fibrillation
.
Heart
2003
;
89
:
1035
1038
.

518

Geelen
P
,
Brugada
J
,
Andries
E
,
Brugada
P
.
Ventricular fibrillation and sudden death after radiofrequency catheter ablation of the atrioventricular junction
.
Pacing Clin Electrophysiol
1997
;
20
:
343
348
.

519

Wang
RX
,
Lee
HC
,
Hodge
DO
,
Cha
YM
,
Friedman
PA
,
Rea
RF
,
Munger
TM
,
Jahangir
A
,
Srivathsan
K
,
Shen
WK.
Effect of pacing method on risk of sudden death after atrioventricular node ablation and pacemaker implantation in patients with atrial fibrillation
.
Heart Rhythm
2013
;
10
:
696
701
.

520

Chatterjee
NA
,
Upadhyay
GA
,
Ellenbogen
KA
,
McAlister
FA
,
Choudhry
NK
,
Singh
JP.
Atrioventricular nodal ablation in atrial fibrillation: a meta-analysis and systematic review
.
Circ Arrhythm Electrophysiol
2012
;
5
:
68
76
.

521

Bradley
DJ
,
Shen
WK.
Overview of management of atrial fibrillation in symptomatic elderly patients: pharmacologic therapy versus AV node ablation
.
Clin Pharmacol Ther
2007
;
81
:
284
287
.

522

Ozcan
C
,
Jahangir
A
,
Friedman
PA
,
Patel
PJ
,
Munger
TM
,
Rea
RF
,
Lloyd
MA
,
Packer
DL
,
Hodge
DO
,
Gersh
BJ
,
Hammill
SC
,
Shen
WK.
Long-term survival after ablation of the atrioventricular node and implantation of a permanent pacemaker in patients with atrial fibrillation
.
N Engl J Med
2001
;
344
:
1043
1051
.

523

Wood
MA
,
Brown-Mahoney
C
,
Kay
GN
,
Ellenbogen
KA.
Clinical outcomes after ablation and pacing therapy for atrial fibrillation: a meta-analysis
.
Circulation
2000
;
101
:
1138
1144
.

524

Brignole
M
,
Auricchio
A
,
Baron-Esquivias
G
,
Bordachar
P
,
Boriani
G
,
Breithardt
OA
,
Cleland
J
,
Deharo
JC
,
Delgado
V
,
Elliott
PM
,
Gorenek
B
,
Israel
CW
,
Leclercq
C
,
Linde
C
,
Mont
L
,
Padeletti
L
,
Sutton
R
,
Vardas
PE
ESC Committee for Practice Guidelines
Zamorano
JL
,
Achenbach
S
,
Baumgartner
H
,
Bax
JJ
,
Bueno
H
,
Dean
V
,
Deaton
C
,
Erol
C
,
Fagard
R
,
Ferrari
R
,
Hasdai
D
,
Hoes
AW
,
Kirchhof
P
,
Knuuti
J
,
Kolh
P
,
Lancellotti
P
,
Linhart
A
,
Nihoyannopoulos
P
,
Piepoli
MF
,
Ponikowski
P
,
Sirnes
PA
,
Tamargo
JL
,
Tendera
M
,
Torbicki
A
,
Wijns
W
,
Windecker
S
,
Document
R
,
Kirchhof
P
,
Blomstrom-Lundqvist
C
,
Badano
LP
,
Aliyev
F
,
Bansch
D
,
Baumgartner
H
,
Bsata
W
,
Buser
P
,
Charron
P
,
Daubert
JC
,
Dobreanu
D
,
Faerestrand
S
,
Hasdai
D
,
Hoes
AW
,
Le Heuzey
JY
,
Mavrakis
H
,
McDonagh
T
,
Merino
JL
,
Nawar
MM
,
Nielsen
JC
,
Pieske
B
,
Poposka
L
,
Ruschitzka
F
,
Tendera
M
,
Van Gelder
IC
,
Wilson
CM.
2013 ESC Guidelines on cardiac pacing and cardiac resynchronization therapy: the Task Force on cardiac pacing and resynchronization therapy of the European Society of Cardiology (ESC). Developed in collaboration with the European Heart Rhythm Association (EHRA)
.
Eur Heart J
2013
;
34
:
2281
2329
.

525

Chatterjee
NA
,
Upadhyay
GA
,
Ellenbogen
KA
,
Hayes
DL
,
Singh
JP.
Atrioventricular nodal ablation in atrial fibrillation: a meta-analysis of biventricular vs. right ventricular pacing mode
.
Eur J Heart Fail
2012
;
14
:
661
667
.

526

Huang
W
,
Su
L
,
Wu
S.
Pacing treatment of atrial fibrillation patients with heart failure: His bundle pacing combined with atrioventricular node ablation
.
Card Electrophysiol Clin
2018
;
10
:
519
535
.

527

Brignole
M
,
Pokushalov
E
,
Pentimalli
F
,
Palmisano
P
,
Chieffo
E
,
Occhetta
E
,
Quartieri
F
,
Calo
L
,
Ungar
A
,
Mont
L
; APAF-CRT Investigators.
A randomized controlled trial of atrioventricular junction ablation and cardiac resynchronization therapy in patients with permanent atrial fibrillation and narrow QRS
.
Eur Heart J
2018
;
39
:
3999
4008
.

528

Huang
W
,
Su
L
,
Wu
S
,
Xu
L
,
Xiao
F
,
Zhou
X
,
Ellenbogen
KA.
Benefits of permanent His bundle pacing combined with atrioventricular node ablation in atrial fibrillation patients with heart failure with both preserved and reduced left ventricular ejection fraction
.
J Am Heart Assoc
2017
;
6
.

529

Farshi
R
,
Kistner
D
,
Sarma
JS
,
Longmate
JA
,
Singh
BN.
Ventricular rate control in chronic atrial fibrillation during daily activity and programmed exercise: a crossover open-label study of five drug regimens
.
J Am Coll Cardiol
1999
;
33
:
304
310
.

530

Khand
AU
,
Rankin
AC
,
Martin
W
,
Taylor
J,
,
Gemmell
I
,
Cleland
JG.
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
.

531

Lewis
RV
,
Irvine
N
,
McDevitt
DG.
Relationships between heart rate, exercise tolerance and cardiac output in atrial fibrillation: the effects of treatment with digoxin, verapamil and diltiazem
.
Eur Heart J
1988
;
9
:
777
781
.

532

Mulder
BA
,
Van Veldhuisen
DJ
,
Crijns
HJ
,
Tijssen
JG
,
Hillege
HL
,
Alings
M
,
Rienstra
M
,
Van den Berg
MP
,
Van Gelder
IC.
Digoxin in patients with permanent atrial fibrillation: data from the RACE II study
.
Heart Rhythm
2014
;
11
:
1543
1550
.

533

Roth
A
,
Harrison
E
,
Mitani
G
,
Cohen
J
,
Rahimtoola
SH
,
Elkayam
U.
Efficacy and safety of medium- and high-dose diltiazem alone and in combination with digoxin for control of heart rate at rest and during exercise in patients with chronic atrial fibrillation
.
Circulation
1986
;
73
:
316
324
.

534

David
D
,
Segni
ED
,
Klein
HO
,
Kaplinsky
E.
Inefficacy of digitalis in the control of heart rate in patients with chronic atrial fibrillation: beneficial effect of an added beta adrenergic blocking agent
.
Am J Cardiol
1979
;
44
:
1378
1382
.

535

Weerasooriya
R
,
Davis
M
,
Powell
A
,
Szili-Torok
T
,
Shah
C
,
Whalley
D
,
Kanagaratnam
L
,
Heddle
W
,
Leitch
J
,
Perks
A
,
Ferguson
L
,
Bulsara
M.
The Australian Intervention Randomized Control of Rate in Atrial Fibrillation Trial (AIRCRAFT)
.
J Am Coll Cardiol
2003
;
41
:
1697
1702
.

536

Vijayaraman
P
,
Subzposh
FA
,
Naperkowski
A.
Atrioventricular node ablation and His bundle pacing
.
Europace
2017
;
19
:
iv10
iv16
.

537

Shiga
T
,
Yoshioka
K
,
Watanabe
E
,
Omori
H
,
Yagi
M
,
Okumura
Y
,
Matsumoto
N
,
Kusano
K
,
Oshiro
C
,
Ikeda
T
,
Takahashi
N
,
Komatsu
T
,
Suzuki
A
,
Suzuki
T
,
Sato
Y
,
Yamashita
T
; AF-QOL study investigators.
Paroxysmal atrial fibrillation recurrences and quality of life in symptomatic patients: a crossover study of flecainide and pilsicainide
.
J Arrhythm
2017
;
33
:
310
317
.

538

Capucci
A
,
Piangerelli
L
,
Ricciotti
J
,
Gabrielli
D
,
Guerra
F.
Flecainide-metoprolol combination reduces atrial fibrillation clinical recurrences and improves tolerability at 1-year follow-up in persistent symptomatic atrial fibrillation
.
Europace
2016
;
18
:
1698
1704
.

539

Shi
LZ
,
Heng
R
,
Liu
SM
,
Leng
FY.
Effect of catheter ablation versus antiarrhythmic drugs on atrial fibrillation: a meta-analysis of randomized controlled trials
.
Exp Ther Med
2015
;
10
:
816
822
.

540

Siontis
KC
,
Ioannidis
JPA
,
Katritsis
GD
,
Noseworthy
PA
,
Packer
DL
,
Hummel
JD,
,
Jais
P
,
Krittayaphong
R
,
Mont
L
,
Morillo
CA
,
Nielsen
JC
,
Oral
H
,
Pappone
C
,
Santinelli
V
,
Weerasooriya
R
,
Wilber
DJ
,
Gersh
BJ
,
Josephson
ME
,
Katritsis
DG.
Radiofrequency ablation versus antiarrhythmic drug therapy for atrial fibrillation: meta-analysis of quality of life, morbidity, and mortality
.
JACC Clin Electrophysiol
2016
;
2
:
170
180
.

541

Kim
YG
,
Shim
J
,
Choi
JI
,
Kim
YH.
Radiofrequency catheter ablation improves the quality of life measured with a short form-36 questionnaire in atrial fibrillation patients: a systematic review and meta-analysis
.
PLoS One
2016
;
11
:
e0163755
.

542

Bayes de Luna
A
,
Platonov
P
,
Cosio
FG
,
Cygankiewicz
I
,
Pastore
C
,
Baranowski
R
,
Bayes-Genis
A
,
Guindo
J
,
Vinolas
X
,
Garcia-Niebla
J
,
Barbosa
R
,
Stern
S
,
Spodick
D.
Interatrial blocks. A separate entity from left atrial enlargement: a consensus report
.
J Electrocardiol
2012
;
45
:
445
451
.

543

Jadidi
A
,
Muller-Edenborn
B
,
Chen
J
,
Keyl
C
,
Weber
R
,
Allgeier
J
,
Moreno-Weidmann
Z
,
Trenk
D
,
Neumann
FJ
,
Lehrmann
H
,
Arentz
T.
The duration of the amplified sinus-p-wave identifies presence of left atrial low voltage substrate and predicts outcome after pulmonary vein isolation in patients with persistent atrial fibrillation
.
JACC Clin Electrophysiol
2018
;
4
:
531
543
.

544

Dudink
E
,
Erkuner
O
,
Berg
J
,
Nieuwlaat
R
,
de Vos
CB
,
Weijs
B
,
Capucci
A
,
Camm
AJ
,
Breithardt
G
,
Le Heuzey
JY
,
Luermans
J
,
Crijns
H.
The influence of progression of atrial fibrillation on quality of life: a report from the Euro Heart Survey
.
Europace
2018
;
20
:
929
934
.

545

Zhang
YY
,
Qiu
C
,
Davis
PJ
,
Jhaveri
M
,
Prystowsky
EN
,
Kowey
P
,
Weintraub
WS.
Predictors of progression of recently diagnosed atrial fibrillation in REgistry on Cardiac Rhythm DisORDers Assessing the Control of Atrial Fibrillation (RecordAF) – United States cohort
.
Am J Cardiol
2013
;
112
:
79
84
.

546

Bunch
TJ
,
May
HT
,
Bair
TL
,
Johnson
DL
,
Weiss
JP
,
Crandall
BG
,
Osborn
JS
,
Anderson
JL
,
Muhlestein
JB
,
Lappe
DL
,
Day
JD.
Increasing time between first diagnosis of atrial fibrillation and catheter ablation adversely affects long-term outcomes
.
Heart Rhythm
2013
;
10
:
1257
1262
.

547

Andrade
JG
,
Champagne
J
,
Deyell
MW
,
Essebag
V
,
Lauck
S
,
Morillo
C
,
Sapp
J
,
Skanes
A
,
Theoret-Patrick
P
,
Wells
GA
,
Verma
A
; EARLY-AF Study Investigators.
A randomized clinical trial of early invasive intervention for atrial fibrillation (EARLY-AF) – methods and rationale
.
Am Heart J
2018
;
206
:
94
104
.

548

Teh
AW
,
Kistler
PM
,
Lee
G
,
Medi
C
,
Heck
PM
,
Spence
SJ,
,
Morton
JB
,
Sanders
P
,
Kalman
JM.
Long-term effects of catheter ablation for lone atrial fibrillation: progressive atrial electroanatomic substrate remodeling despite successful ablation
.
Heart Rhythm
2012
;
9
:
473
480
.

549

Aliot
E
,
Brandes
A
,
Eckardt
L
,
Elvan
A
,
Gulizia
M
,
Heidbuchel
H
,
Kautzner
J
,
Mont
L
,
Morgan
J
,
Ng
A
,
Szumowski
L
,
Themistoclakis
S
,
Van Gelder
IC
,
Willems
S
,
Kirchhof
P.
The EAST study: redefining the role of rhythmcontrol therapy in atrial fibrillation: EAST, the Early treatment of Atrial fibrillation for Stroke prevention Trial
.
Eur Heart J
2015
;
36
:
255
256
.

550

Michelena
HI
,
Powell
BD
,
Brady
PA
,
Friedman
PA
,
Ezekowitz
MD.
Gender in atrial fibrillation: ten years later
.
Gend Med
2010
;
7
:
206
217
.

551

Sethi
NJ
,
Feinberg
J
,
Nielsen
EE
,
Safi
S
,
Gluud
C
,
Jakobsen
JC.
The effects of rhythm control strategies versus rate control strategies for atrial fibrillation and atrial flutter: a systematic review with meta-analysis and trial sequential analysis
.
PLoS One
2017
;
12
:
e0186856
.

552

Ha
AC
,
Breithardt
G
,
Camm
AJ
,
Crijns
HJ
,
Fitzmaurice
GM
,
Kowey
PR
,
Le Heuzey
JY
,
Naditch-Brule
L
,
Prystowsky
EN
,
Schwartz
PJ
,
Torp-Pedersen
C
,
Weintraub
WS
,
Dorian
P.
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 Disorders Assessing the Control of Atrial Fibrillation: RECORD-AF)
.
Circ Cardiovasc Qual Outcomes
2014
;
7
:
896
904
.

553

Bulkova
V
,
Fiala
M
,
Havranek
S
,
Simek
J
,
Sknouril
L
,
Januska
J
,
Spinar
J
,
Wichterle
D.
Improvement in quality of life after catheter ablation for paroxysmal versus long-standing persistent atrial fibrillation: a prospective study with 3-year follow-up
.
J Am Heart Assoc
2014
;
3
.

554

Kirchhof
P
,
Monnig
G
,
Wasmer
K
,
Heinecke
A
,
Breithardt
G
,
Eckardt
L
,
Bocker
D.
A trial of self-adhesive patch electrodes and hand-held paddle electrodes for external cardioversion of atrial fibrillation (MOBIPAPA)
.
Eur Heart J
2005
;
26
:
1292
1297
.

555

Kirchhof
P
,
Eckardt
L
,
Loh
P
,
Weber
K
,
Fischer
RJ
,
Seidl
KH
,
Bocker
D
,
Breithardt
G
,
Haverkamp
W
,
Borggrefe
M.
Anterior-posterior versus anterior-lateral electrode positions for external cardioversion of atrial fibrillation: a randomised trial
.
Lancet
2002
;
360
:
1275
1279
.

556

Um
KJ
,
McIntyre
WF
,
Healey
JS
,
Mendoza
PA
,
Koziarz
A
,
Amit
G
,
Chu
VA
,
Whitlock
RP
,
Belley-Cote
EP.
Pre- and post-treatment with amiodarone for elective electrical cardioversion of atrial fibrillation: a systematic review and meta-analysis
.
Europace
2019
;
21
:
856
863
.

557

Schmidt
AS
,
Lauridsen
KG
,
Torp
P
,
Bach
LF
,
Rickers
H
,
Lofgren
B.
Maximum-fixed energy shocks for cardioverting atrial fibrillation
.
Eur Heart J
2020
;
41
:
626
631
.

558

Pluymaekers
N
,
Dudink
E
,
Luermans
J
,
Meeder
JG
,
Lenderink
T
,
Widdershoven
J
,
Bucx
JJJ
,
Rienstra
M
,
Kamp
O
,
Van Opstal
JM
,
Alings
M
,
Oomen
A
,
Kirchhof
CJ
,
Van Dijk
VF
,
Ramanna
H
,
Liem
A
,
Dekker
LR
,
Essers
BAB
,
Tijssen
JGP
,
Van Gelder
IC
,
Crijns
H
; RACE ACWAS Investigators.
Early or delayed cardioversion in recent-onset atrial fibrillation
.
N Engl J Med
2019
;
380
:
1499
1508
.

559

Baranchuk
A
,
Yeung
C.
Advanced interatrial block predicts atrial fibrillation recurrence across different populations: learning Bayes syndrome
.
Int J Cardiol
2018
;
272
:
221
222
.

560

Toufan
M
,
Kazemi
B
,
Molazadeh
N.
The significance of the left atrial volume index in prediction of atrial fibrillation recurrence after electrical cardioversion
.
J Cardiovasc Thorac Res
2017
;
9
:
54
59
.

561

Voskoboinik
A
,
Kalman
E
,
Plunkett
G
,
Knott
J,
,
Moskovitch
J
,
Sanders
P
,
Kistler
PM
,
Kalman
JM.
A comparison of early versus delayed elective electrical cardioversion for recurrent episodes of persistent atrial fibrillation: a multi-center study
.
Int J Cardiol
2019
;
284
:
33
37
.

562

Furniss
SS
,
Sneyd
JR
.
Safe sedation in modern cardiological practice
.
Heart
2015
;
101
:
1526
1530
.

563

Mittal
S
,
Ayati
S
,
Stein
KM
,
Schwartzman
D
,
Cavlovich
D
,
Tchou
PJ
,
Markowitz
SM
,
Slotwiner
DJ
,
Scheiner
MA
,
Lerman
BB.
Transthoracic cardioversion of atrial fibrillation: comparison of rectilinear biphasic versus damped sine wave monophasic shocks
.
Circulation
2000
;
101
:
1282
1287
.

564

Inacio
JF
,
da Rosa Mdos
S
,
Shah
J,
,
Rosario
J
,
Vissoci
JR
,
Manica
AL
,
Rodrigues
CG.
Monophasic and biphasic shock for transthoracic conversion of atrial fibrillation: systematic review and network meta-analysis
.
Resuscitation
2016
;
100
:
66
75
.

565

Kirkland
S
,
Stiell
I
,
AlShawabkeh
T
,
Campbell
S
,
Dickinson
G
,
Rowe
BH.
The efficacy of pad placement for electrical cardioversion of atrial fibrillation/flutter: a systematic review
.
Acad Emerg Med
2014
;
21
:
717
726
.

566

Boriani
G
,
Diemberger
I
,
Biffi
M
,
Martignani
C
,
Branzi
A.
Pharmacological cardioversion of atrial fibrillation: current management and treatment options
.
Drugs
2004
;
64
:
2741
2762
.

567

Danias
PG
,
Caulfield
TA
,
Weigner
MJ
,
Silverman
DI
,
Manning
WJ.
Likelihood of spontaneous conversion of atrial fibrillation to sinus rhythm
.
J Am Coll Cardiol
1998
;
31
:
588
592
.

568

Dan
GA
,
Martinez-Rubio
A
,
Agewall
S
,
Boriani
G
,
Borggrefe
M
,
Gaita
F
,
van Gelder
I
,
Gorenek
B
,
Kaski
JC
,
Kjeldsen
K
,
Lip
GYH
,
Merkely
B
,
Okumura
K
,
Piccini
JP
,
Potpara
T
,
Poulsen
BK
,
Saba
M
,
Savelieva
I
,
Tamargo
JL
,
Wolpert
C
, ESC Scientific Document Group.
Antiarrhythmic drugs-clinical use and clinical decision making: a consensus document from the European Heart Rhythm Association (EHRA) and European Society of Cardiology (ESC) Working Group on Cardiovascular Pharmacology, endorsed by the Heart Rhythm Society (HRS), Asia-Pacific Heart Rhythm Society (APHRS) and International Society of Cardiovascular Pharmacotherapy (ISCP)
.
Europace
2018
;
20
:
731
732
.

569

Markey
GC
,
Salter
N
,
Ryan
J.
Intravenous flecainide for emergency department management of acute atrial fibrillation
.
J Emerg Med
2018
;
54
:
320
327
.

570

Chevalier
P
,
Durand-Dubief
A
,
Burri
H
,
Cucherat
M
,
Kirkorian
G
,
Touboul
P.
Amiodarone versus placebo and class Ic drugs for cardioversion of recent-onset atrial fibrillation: a meta-analysis
.
J Am Coll Cardiol
2003
;
41
:
255
262
.

571

Capucci
A
,
Lenzi
T
,
Boriani
G
,
Trisolino
G
,
Binetti
N
,
Cavazza
M
,
Fontana
G
,
Magnani
B.
Effectiveness of loading oral flecainide for converting recent-onset atrial fibrillation to sinus rhythm in patients without organic heart disease or with only systemic hypertension
.
Am J Cardiol
1992
;
70
:
69
72
.

572

Donovan
KD
,
Dobb
GJ
,
Coombs
LJ
,
Lee
KY
,
Weekes
JN
,
Murdock
CJ
,
Clarke
GM.
Efficacy of flecainide for the reversion of acute onset atrial fibrillation
.
Am J Cardiol
1992
;
70
:50A-54A; discussion 54A-55A.

573

Reisinger
J
,
Gatterer
E
,
Lang
W
,
Vanicek
T
,
Eisserer
G
,
Bachleitner
T
,
Niemeth
C
,
Aicher
F
,
Grander
W
,
Heinze
G
,
Kuhn
P
,
Siostrzonek
P.
Flecainide versus ibutilide for immediate cardioversion of atrial fibrillation of recent onset
.
Eur Heart J
2004
;
25
:
1318
1324
.

574

Khan
IA.
Oral loading single dose flecainide for pharmacological cardioversion of recent-onset atrial fibrillation
.
Int J Cardiol
2003
;
87
:
121
128
.

575

Galve
E
,
Rius
T
,
Ballester
R
,
Artaza
MA
,
Arnau
JM
,
Garcia-Dorado
D
,
Soler-Soler
J.
Intravenous amiodarone in treatment of recent-onset atrial fibrillation: results of a randomized, controlled study
.
J Am Coll Cardiol
1996
;
27
:
1079
1082
.

576

Vardas
PE
,
Kochiadakis
GE
,
Igoumenidis
NE
,
Tsatsakis
AM
,
Simantirakis
EN
,
Chlouverakis
GI.
Amiodarone as a first-choice drug for restoring sinus rhythm in patients with atrial fibrillation: a randomized, controlled study
.
Chest
2000
;
117
:
1538
1545
.

577

Letelier
LM
,
Udol
K
,
Ena
J
,
Weaver
B
,
Guyatt
GH.
Effectiveness of amiodarone for conversion of atrial fibrillation to sinus rhythm: a meta-analysis
.
Arch Intern Med
2003
;
163
:
777
785
.

578

Bash
LD
,
Buono
JL,
,
Davies
GM
,
Martin
A
,
Fahrbach
K
,
Phatak
H
,
Avetisyan
R
,
Mwamburi
M.
Systematic review and meta-analysis of the efficacy of cardioversion by vernakalant and comparators in patients with atrial fibrillation
.
Cardiovasc Drugs Ther
2012
;
26
:
167
179
.

579

Camm
AJ
,
Capucci
A
,
Hohnloser
SH
,
Torp-Pedersen
C
,
Van Gelder
IC
,
Mangal
B
,
Beatch
G
; AVRO Investigators.
A randomized active-controlled study comparing the efficacy and safety of vernakalant to amiodarone in recent-onset atrial fibrillation
.
J Am Coll Cardiol
2011
;
57
:
313
321
.

580

Akel
T
,
Lafferty
J.
Efficacy and safety of intravenous vernakalant for the rapid conversion of recent-onset atrial fibrillation: a meta-analysis
.
Ann Noninvasive Electrocardiol
2018
;
23
:
e12508
.

581

Beatch
GN
,
Mangal
B.
Safety and efficacy of vernakalant for the conversion of atrial fibrillation to sinus rhythm; a phase 3b randomized controlled trial
.
BMC Cardiovasc Disord
2016
;
16
:
113
.

582

Roy
D
,
Pratt
CM
,
Torp-Pedersen
C
,
Wyse
DG
,
Toft
E
,
Juul-Moller
S
,
Nielsen
T
,
Rasmussen
SL
,
Stiell
IG
,
Coutu
B
,
Ip
JH
,
Pritchett
EL
,
Camm
AJ
; Atrial Arrhythmia Conversion Trial Investigators.
Vernakalant hydrochloride for rapid conversion of atrial fibrillation: a phase 3, randomized, placebo-controlled trial
.
Circulation
2008
;
117
:
1518
1525
.

583

Kowey
PR
,
Dorian
P
,
Mitchell
LB
,
Pratt
CM
,
Roy
D
,
Schwartz
PJ
,
Sadowski
J
,
Sobczyk
D
,
Bochenek
A
,
Toft
E
; Atrial Arrhythmia Conversion Trial Investigators.
Vernakalant hydrochloride for the rapid conversion of atrial fibrillation after cardiac surgery: a randomized, double-blind, placebo-controlled trial
.
Circ Arrhythm Electrophysiol
2009
;
2
:
652
659
.

584

Pohjantahti-Maaroos
H
,
Hyppola
H
,
Lekkala
M
,
Sinisalo
E
,
Heikkola
A
,
Hartikainen
J.
Intravenous vernakalant in comparison with intravenous flecainide in the cardioversion of recent-onset atrial fibrillation
.
Eur Heart J Acute Cardiovasc Care
2019
;
8
:
114
120
.

585

Vos
MA
,
Golitsyn
SR
,
Stangl
K
,
Ruda
MY
,
Van Wijk
LV
,
Harry
JD
,
Perry
KT
,
Touboul
P
,
Steinbeck
G
,
Wellens
HJ.
Superiority of ibutilide (a new class III agent) over DL-sotalol in converting atrial flutter and atrial fibrillation. The Ibutilide/Sotalol Comparator Study Group
.
Heart
1998
;
79
:
568
575
.

586

Alboni
P
,
Botto
GL
,
Baldi
N
,
Luzi
M
,
Russo
V
,
Gianfranchi
L
,
Marchi
P
,
Calzolari
M
,
Solano
A
,
Baroffio
R
,
Gaggioli
G.
Outpatient treatment of recent-onset atrial fibrillation with the ‘pill-in-the-pocket’ approach
.
N Engl J Med
2004
;
351
:
2384
2391
.

587

Brembilla-Perrot
B
,
Houriez
P
,
Beurrier
D
,
Claudon
O
,
Terrier de la Chaise
A
,
Louis
P.
Predictors of atrial flutter with 1:1 conduction in patients treated with class I antiarrhythmic drugs for atrial tachyarrhythmias
.
Int J Cardiol
2001
;
80
:
7
15
.

588

Zhang
N
,
Guo
JH
,
Zhang
H
,
Li
XB
,
Zhang
P
,
Xn
Y.
Comparison of intravenous ibutilide vs. propafenone for rapid termination of recent onset atrial fibrillation
.
Int J Clin Pract
2005
;
59
:
1395
1400
.

589

Conde
D
,
Costabel
JP
,
Caro
M
,
Ferro
A
,
Lambardi
F
,
Corrales Barboza
A
,
Lavalle Cobo
A
,
Trivi
M.
Flecainide versus vernakalant for conversion of recent-onset atrial fibrillation
.
Int J Cardiol
2013
;
168
:
2423
2425
.

590

Martinez-Marcos
FJ
,
Garcia-Garmendia
JL
,
Ortega-Carpio
A
,
Fernandez-Gomez
JM
,
Santos
JM
,
Camacho
C.
Comparison of intravenous flecainide, propafenone, and amiodarone for conversion of acute atrial fibrillation to sinus rhythm
.
Am J Cardiol
2000
;
86
:
950
953
.

591

Deedwania
PC
,
Singh
BN
,
Ellenbogen
K
,
Fisher
S
,
Fletcher
R
,
Singh
SN.
Spontaneous conversion and maintenance of sinus rhythm by amiodarone in patients with heart failure and atrial fibrillation: observations from the veterans affairs congestive heart failure survival trial of antiarrhythmic therapy (CHF-STAT). The Department of Veterans Affairs CHF-STAT Investigators
.
Circulation
1998
;
98
:
2574
2579
.

592

Hofmann
R
,
Steinwender
C
,
Kammler
J
,
Kypta
A
,
Wimmer
G
,
Leisch
F.
Intravenous amiodarone bolus for treatment of atrial fibrillation in patients with advanced congestive heart failure or cardiogenic shock
.
Wien Klin Wochenschr
2004
;
116
:
744
749
.

593

Crijns
HJ
,
Weijs
B
,
Fairley
AM
,
Lewalter
T
,
Maggioni
AP
,
Martin
A,
,
Ponikowski
P
,
Rosenqvist
M
,
Sanders
P
,
Scanavacca
M
,
Bash
LD
,
Chazelle
F
,
Bernhardt
A
,
Gitt
AK
,
Lip
GY
,
Le Heuzey
JY.
Contemporary real life cardioversion of atrial fibrillation: results from the multinational RHYTHM-AF study
.
Int J Cardiol
2014
;
172
:
588
594
.

594

Kirchhof
P
,
Andresen
D
,
Bosch
R
,
Borggrefe
M
,
Meinertz
T
,
Parade
U
,
Ravens
U
,
Samol
A
,
Steinbeck
G
,
Treszl
A
,
Wegscheider
K
,
Breithardt
G.
Short-term versus long-term antiarrhythmic drug treatment after cardioversion of atrial fibrillation (Flec-SL): a prospective, randomised, open-label, blinded endpoint assessment trial
.
Lancet
2012
;
380
:
238
246
.

595

Van Gelder
IC
,
Tuinenburg
AE
,
Schoonderwoerd
BS
,
Tieleman
RG
,
Crijns
HJ.
Pharmacologic versus direct-current electrical cardioversion of atrial flutter and fibrillation
.
Am J Cardiol
1999
;
84
:
147R
151R
.

596

Climent
VE
,
Marin
F
,
Mainar
L
,
Gomez-Aldaravi
R
,
Martinez
JG
,
Chorro
FJ
,
Roman
P
,
Sogorb
F.
Effects of pretreatment with intravenous flecainide on efficacy of external cardioversion of persistent atrial fibrillation
.
Pacing Clin Electrophysiol
2004
;
27
:
368
372
.

597

Mussigbrodt
A
,
John
S
,
Kosiuk
J
,
Richter
S
,
Hindricks
G
,
Bollmann
A.
Vernakalant-facilitated electrical cardioversion: comparison of intravenous vernakalant and amiodarone for drug-enhanced electrical cardioversion of atrial fibrillation after failed electrical cardioversion
.
Europace
2016
;
18
:
51
56
.

598

Singh
SN
,
Tang
XC
,
Reda
D
,
Singh
BN.
Systematic electrocardioversion for atrial fibrillation and role of antiarrhythmic drugs: a substudy of the SAFE-T trial
.
Heart Rhythm
2009
;
6
:
152
155
.

599

Oral
H
,
Souza
JJ
,
Michaud
GF
,
Knight
BP
,
Goyal
R
,
Strickberger
SA
,
Morady
F.
Facilitating transthoracic cardioversion of atrial fibrillation with ibutilide pretreatment
.
N Engl J Med
1999
;
340
:
1849
1854
.

600

Khan
IA.
Single oral loading dose of propafenone for pharmacological cardioversion of recent-onset atrial fibrillation
.
J Am Coll Cardiol
2001
;
37
:
542
547
.

601

Alboni
P
,
Botto
GL
,
Boriani
G
,
Russo
G
,
Pacchioni
F
,
Iori
M
,
Pasanisi
G
,
Mancini
M
,
Mariconti
B
,
Capucci
A.
Intravenous administration of flecainide or propafenone in patients with recent-onset atrial fibrillation does not predict adverse effects during ‘pill-in-the-pocket’ treatment
.
Heart
2010
;
96
:
546
549
.

602

Arbelo
E
,
Brugada
J
,
Hindricks
G
,
Maggioni
A
,
Tavazzi
L
,
Vardas
P
,
Anselme
F
,
Inama
G
,
Jais
P
,
Kalarus
Z
,
Kautzner
J
,
Lewalter
T
,
Mairesse
G
,
Perez-Villacastin
J
,
Riahi
S
,
Taborsky
M
,
Theodorakis
G
,
Trines
S
; Atrial Fibrillation Ablation Pilot Study Investigators.
ESC-EURObservational Research Programme: the Atrial Fibrillation Ablation Pilot Study, conducted by the European Heart Rhythm Association
.
Europace
2012
;
14
:
1094
1103
.

603

Arbelo
E
,
Brugada
J
,
Hindricks
G
,
Maggioni
AP
,
Tavazzi
L
,
Vardas
P
,
Laroche
C
,
Anselme
F
,
Inama
G
,
Jais
P
,
Kalarus
Z
,
Kautzner
J
,
Lewalter
T
,
Mairesse
GH
,
Perez-Villacastin
J
,
Riahi
S
,
Taborsky
M
,
Theodorakis
G
,
Trines
SA
; Atrial Fibrillation Ablation Pilot Study Investigators.
The atrial fibrillation ablation pilot study: a European Survey on Methodology and results of catheter ablation for atrial fibrillation conducted by the European Heart Rhythm Association
.
Eur Heart J
2014
;
35
:
1466
1478
.

604

Arbelo
E
,
Brugada
J
,
Blomstrom-Lundqvist
C
,
Laroche
C
,
Kautzner
J
,
Pokushalov
E
,
Raatikainen
P
,
Efremidis
M
,
Hindricks
G
,
Barrera
A
,
Maggioni
A
,
Tavazzi
L
,
Dagres
N
, on the behalf of the ESC EHRA Atrial Fibrillation Ablation Long-term Registry Investigators.
Contemporary management of patients undergoing atrial fibrillation ablation: in-hospital and 1-year follow-up findings from the ESC-EHRA atrial fibrillation ablation long-term registry
.
Eur Heart J
2017
;
38
:
1303
1316
.

605

Krittayaphong
R
,
Raungrattanaamporn
O
,
Bhuripanyo
K
,
Sriratanasathavorn
C
,
Pooranawattanakul
S
,
Punlee
K
,
Kangkagate
C.
A randomized clinical trial of the efficacy of radiofrequency catheter ablation and amiodarone in the treatment of symptomatic atrial fibrillation
.
J Med Assoc Thai
2003
;
86 Suppl 1
:
S8
16
.

606

Stabile
G
,
Bertaglia
E
,
Senatore
G
,
De Simone
A
,
Zoppo
F
,
Donnici
G
,
Turco
P
,
Pascotto
P
,
Fazzari
M
,
Vitale
DF.
Catheter ablation treatment in patients with drug-refractory atrial fibrillation: a prospective, multi-centre, randomized, controlled study (Catheter Ablation For The Cure Of Atrial Fibrillation Study)
.
Eur Heart J
2006
;
27
:
216
221
.

607

Pappone
C
,
Augello
G
,
Sala
S
,
Gugliotta
F
,
Vicedomini
G
,
Gulletta
S
,
Paglino
G
,
Mazzone
P
,
Sora
N
,
Greiss
I
,
Santagostino
A
,
LiVolsi
L
,
Pappone
N
,
Radinovic
A
,
Manguso
F
,
Santinelli
V.
A randomized trial of circumferential pulmonary vein ablation versus antiarrhythmic drug therapy in paroxysmal atrial fibrillation: the APAF Study
.
J Am Coll Cardiol
2006
;
48
:
2340
2347
.

608

Calkins
H
,
Reynolds
MR
,
Spector
P
,
Sondhi
M
,
Xu
Y
,
Martin
A
,
Williams
CJ
,
Sledge
I.
Treatment of atrial fibrillation with antiarrhythmic drugs or radiofrequency ablation: two systematic literature reviews and meta-analyses
.
Circ Arrhythm Electrophysiol
2009
;
2
:
349
361
.

609

Packer
DL
,
Kowal
RC
,
Wheelan
KR
,
Irwin
JM
,
Champagne
J
,
Guerra
PG
,
Dubuc
M
,
Reddy
V
,
Nelson
L
,
Holcomb
RG
,
Lehmann
JW
,
Ruskin
JN
; STOP AF Cryoablation Investigators.
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
.

610

Ganesan
AN
,
Shipp
NJ
,
Brooks
AG
,
Kuklik
P
,
Lau
DH
,
Lim
HS
,
Sullivan
T
,
Roberts-Thomson
KC
,
Sanders
P.
Long-term outcomes of catheter ablation of atrial fibrillation: a systematic review and meta-analysis
.
J Am Heart Assoc
2013
;
2
:
e004549
.

611

Di Biase
L
,
Mohanty
P
,
Mohanty
S
,
Santangeli
P
,
Trivedi
C
,
Lakkireddy
D
,
Reddy
M
,
Jais
P
,
Themistoclakis
S
,
Dello Russo
A
,
Casella
M
,
Pelargonio
G
,
Narducci
ML
,
Schweikert
R
,
Neuzil
P
,
Sanchez
J
,
Horton
R
,
Beheiry
S
,
Hongo
R
,
Hao
S
,
Rossillo
A
,
Forleo
G
,
Tondo
C
,
Burkhardt
JD
,
Haissaguerre
M
,
Natale
A.
Ablation versus amiodarone for treatment of persistent atrial fibrillation in patients with congestive heart failure and an implanted device: results from the AATAC multicenter randomized trial
.
Circulation
2016
;
133
:
1637
1644
.

612

Kuck
KH
,
Brugada
J
,
Furnkranz
A
,
Metzner
A
,
Ouyang
F
,
Chun
KR
,
Elvan
A
,
Arentz
T
,
Bestehorn
K
,
Pocock
SJ
,
Albenque
JP
,
Tondo
C
; FIRE AND ICE Investigators.
Cryoballoon or radiofrequency ablation for paroxysmal atrial fibrillation
.
N Engl J Med
2016
;
374
:
2235
2245
.

613

Sohara
H
,
Ohe
T
,
Okumura
K
,
Naito
S
,
Hirao
K
,
Shoda
M
,
Kobayashi
Y
,
Yamauchi
Y
,
Yamaguchi
Y
,
Kuwahara
T
,
Hirayama
H
,
YeongHwa
C
,
Kusano
K
,
Kaitani
K
,
Banba
K
,
Fujii
S
,
Kumagai
K
,
Yoshida
H
,
Matsushita
M
,
Satake
S
,
Aonuma
K.
HotBalloon ablation of the pulmonary veins for paroxysmal AF: a multicenter randomized trial in Japan
.
J Am Coll Cardiol
2016
;
68
:
2747
2757
.

614

Hakalahti
A
,
Biancari
F
,
Nielsen
JC
,
Raatikainen
MJ.
Radiofrequency ablation vs. antiarrhythmic drug therapy as first line treatment of symptomatic atrial fibrillation: systematic review and meta-analysis
.
Europace
2015
;
17
:
370
378
.

615

Nielsen
JC
,
Johannessen
A
,
Raatikainen
P
,
Hindricks
G
,
Walfridsson
H
,
Pehrson
SM
,
Englund
A
,
Hartikainen
J
,
Mortensen
LS
,
Hansen
PS
; MANTRA-PAF Investigators.
Long-term efficacy of catheter ablation as first-line therapy for paroxysmal atrial fibrillation: 5-year outcome in a randomised clinical trial
.
Heart
2017
;
103
:
368
376
.

616

Chen
C
,
Zhou
X
,
Zhu
M
,
Chen
S
,
Chen
J
,
Cai
H
,
Dai
J
,
Xu
X
,
Mao
W.
Catheter ablation versus medical therapy for patients with persistent atrial fibrillation: a systematic review and meta-analysis of evidence from randomized controlled trials
.
J Interv Card Electrophysiol
2018
;
52
:
9
18
.

617

Packer
DL
,
Mark
DB
,
Robb
RA
,
Monahan
KH
,
Bahnson
TD
,
Poole
JE
,
Noseworthy
PA
,
Rosenberg
YD
,
Jeffries
N
,
Mitchell
LB
,
Flaker
GC
,
Pokushalov
E
,
Romanov
A
,
Bunch
TJ
,
Noelker
G
,
Ardashev
A
,
Revishvili
A
,
Wilber
DJ
,
Cappato
R
,
Kuck
KH
,
Hindricks
G
,
Davies
DW
,
Kowey
PR
,
Naccarelli
GV
,
Reiffel
JA
,
Piccini
JP
,
Silverstein
AP
,
Al-Khalidi
HR
,
Lee
KL
; CABANA Investigators.
Effect of catheter ablation vs antiarrhythmic drug therapy on mortality, stroke, bleeding, and cardiac arrest among patients with atrial fibrillation: the CABANA randomized clinical trial
.
JAMA
2019
;
321
:
1261
1274
.

618

Noseworthy
PA
,
Gersh
BJ
,
Kent
DM
,
Piccini
JP
,
Packer
DL
,
Shah
ND
,
Yao
X.
Atrial fibrillation ablation in practice: assessing CABANA generalizability
.
Eur Heart J
2019
;
40
:
1257
1264
.

619

Teh
AW
,
Kistler
PM
,
Lee
G
,
Medi
C
,
Heck
PM
,
Spence
SJ
,
Sparks
PB
,
Morton
JB
,
Kalman
JM.
Electroanatomic remodeling of the left atrium in paroxysmal and persistent atrial fibrillation patients without structural heart disease
.
J Cardiovasc Electrophysiol
2012
;
23
:
232
238
.

620

D'Ascenzo
F
,
Corleto
A
,
Biondi-Zoccai
G
,
Anselmino
M
,
Ferraris
F
,
di Biase
L
,
Natale
A
,
Hunter
RJ
,
Schilling
RJ
,
Miyazaki
S
,
Tada
H
,
Aonuma
K
,
Yenn-Jiang
L
,
Tao
H
,
Ma
C
,
Packer
D
,
Hammill
S
,
Gaita
F.
Which are the most reliable predictors of recurrence of atrial fibrillation after transcatheter ablation?: a meta-analysis
.
Int J Cardiol
2013
;
167
:
1984
1989
.

621

Berruezo
A
,
Tamborero
D
,
Mont
L
,
Benito
B
,
Tolosana
JM
,
Sitges
M
,
Vidal
B
,
Arriagada
G
,
Mendez
F
,
Matiello
M
,
Molina
I
,
Brugada
J.
Pre-procedural predictors of atrial fibrillation recurrence after circumferential pulmonary vein ablation
.
Eur Heart J
2007
;
28
:
836
841
.

622

Nedios
S
,
Kosiuk
J
,
Koutalas
E
,
Kornej
J
,
Sommer
P
,
Arya
A
,
Richter
S
,
Rolf
S
,
Husser
D
,
Hindricks
G
,
Bollmann
A.
Comparison of left atrial dimensions in CT and echocardiography as predictors of long-term success after catheter ablation of atrial fibrillation
.
J Interv Card Electrophysiol
2015
;
43
:
237
244
.

623

Njoku
A
,
Kannabhiran
M
,
Arora
R
,
Reddy
P
,
Gopinathannair
R
,
Lakkireddy
D
,
Dominic
P.
Left atrial volume predicts atrial fibrillation recurrence after radiofrequency ablation: a meta-analysis
.
Europace
2018
;
20
:
33
42
.

624

Costa
FM
,
Ferreira
AM
,
Oliveira
S
,
Santos
PG
,
Durazzo
A
,
Carmo
P
,
Santos
KR
,
Cavaco
D
,
Parreira
L
,
Morgado
F
,
Adragao
P.
Left atrial volume is more important than the type of atrial fibrillation in predicting the long-term success of catheter ablation
.
Int J Cardiol
2015
;
184
:
56
61
.

625

Marrouche
NF
,
Wilber
D
,
Hindricks
G
,
Jais
P
,
Akoum
N
,
Marchlinski
F
,
Kholmovski
E
,
Burgon
N
,
Hu
N
,
Mont
L
,
Deneke
T
,
Duytschaever
M
,
Neumann
T
,
Mansour
M
,
Mahnkopf
C
,
Herweg
B
,
Daoud
E
,
Wissner
E
,
Bansmann
P
,
Brachmann
J.
Association of atrial tissue fibrosis identified by delayed enhancement MRI and atrial fibrillation catheter ablation: the DECAAF study
.
JAMA
2014
;
311
:
498
506
.

626

Kosich
F
,
Schumacher
K
,
Potpara
T
,
Lip
GY
,
Hindricks
G
,
Kornej
J.
Clinical scores used for the prediction of negative events in patients undergoing catheter ablation for atrial fibrillation
.
Clin Cardiol
2019
;
42
:
320
329
.

627

Kornej
J
,
Hindricks
G
,
Shoemaker
MB
,
Husser
D
,
Arya
A
,
Sommer
P
,
Rolf
S
,
Saavedra
P
,
Kanagasundram
A
,
Patrick Whalen
S
,
Montgomery
J
,
Ellis
CR
,
Darbar
D
,
Bollmann
A.
The APPLE score: a novel and simple score for the prediction of rhythm outcomes after catheter ablation of atrial fibrillation
.
Clin Res Cardiol
2015
;
104
:
871
876
.

628

Kornej
J
,
Hindricks
G
,
Arya
A
,
Sommer
P
,
Husser
D
,
Bollmann
A.
The APPLE score – a novel score for the prediction of rhythm outcomes after repeat catheter ablation of atrial fibrillation
.
PLoS One
2017
;
12
:
e0169933
.

629

Kornej
J
,
Schumacher
K
,
Dinov
B
,
Kosich
F
,
Sommer
P
,
Arya
A
,
Husser
D
,
Bollmann
A
,
Lip
GYH
,
Hindricks
G.
Prediction of electro-anatomical substrate and arrhythmia recurrences using APPLE, DR-FLASH and MB-LATER scores in patients with atrial fibrillation undergoing catheter ablation
.
Sci Rep
2018
;
8
:
12686
.

630

Kosiuk
J
,
Dinov
B
,
Kornej
J
,
Acou
WJ
,
Schonbauer
R
,
Fiedler
L
,
Buchta
P
,
Myrda
K
,
Gasior
M
,
Polonski
L
,
Kircher
S
,
Arya
A
,
Sommer
P
,
Bollmann
A
,
Hindricks
G
,
Rolf
S.
Prospective, multicenter validation of a clinical risk score for left atrial arrhythmogenic substrate based on voltage analysis: DR-FLASH score
.
Heart Rhythm
2015
;
12
:
2207
2212
.

631

Mujovic
N
,
Marinkovic
M
,
Markovic
N
,
Shantsila
A
,
Lip
GY
,
Potpara
TS.
Prediction of very late arrhythmia recurrence after radiofrequency catheter ablation of atrial fibrillation: the MB-LATER clinical score
.
Sci Rep
2017
;
7
:
40828
.

632

Mesquita
J
,
Ferreira
AM
,
Cavaco
D
,
Moscoso Costa
F
,
Carmo
P
,
Marques
H
,
Morgado
F
,
Mendes
M
,
Adragao
P.
Development and validation of a risk score for predicting atrial fibrillation recurrence after a first catheter ablation procedure – ATLAS score
.
Europace
2018
;
20
:
f428
f435
.

633

Winkle
RA
,
Jarman
JW
,
Mead
RH
,
Engel
G
,
Kong
MH
,
Fleming
W
,
Patrawala
RA.
Predicting atrial fibrillation ablation outcome: the CAAP-AF score
.
Heart Rhythm
2016
;
13
:
2119
2125
.

634

Canpolat
U
,
Aytemir
K
,
Yorgun
H
,
Sahiner
L
,
Kaya
EB
,
Oto
A.
A proposal for a new scoring system in the prediction of catheter ablation outcomes: promising results from the Turkish Cryoablation Registry
.
Int J Cardiol
2013
;
169
:
201
206
.

635

Wojcik
M
,
Berkowitsch
A
,
Greiss
H
,
Zaltsberg
S
,
Pajitnev
D
,
Deubner
N
,
Hamm
CW
,
Pitschner
HF
,
Kuniss
M
,
Neumann
T.
Repeated catheter ablation of atrial fibrillation: how to predict outcome?
Circ J
2013
;
77
:
2271
2279
.

636

Pathak
RK
,
Middeldorp
ME
,
Lau
DH
,
Mehta
AB
,
Mahajan
R
,
Twomey
D
,
Alasady
M
,
Hanley
L
,
Antic
NA
,
McEvoy
RD
,
Kalman
JM
,
Abhayaratna
WP
,
Sanders
P.
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
.

637

Trines
SA
,
Stabile
G
,
Arbelo
E
,
Dagres
N
,
Brugada
J
,
Kautzner
J
,
Pokushalov
E
,
Maggioni
AP
,
Laroche
C
,
Anselmino
M
,
Beinart
R
,
Traykov
V
,
Blomstrom-Lundqvist
C.
Influence of risk factors in the ESC-EHRA EORP atrial fibrillation ablation long-term registry
.
Pacing Clin Electrophysiol
2019
;
42
:
1365
1373
.

638

Wong
CX
,
Sullivan
T
,
Sun
MT
,
Mahajan
R
,
Pathak
RK
,
Middeldorp
M,
,
Twomey
D
,
Ganesan
AN
,
Rangnekar
G
,
Roberts-Thomson
KC
,
Lau
DH
,
Sanders
P.
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
.

639

Wokhlu
A
,
Hodge
DO
,
Monahan
KH
,
Asirvatham
SJ
,
Friedman
PA
,
Munger
TM
,
Cha
YM
,
Shen
WK
,
Brady
PA
,
Bluhm
CM
,
Haroldson
JM
,
Hammill
SC
,
Packer
DL.
Long-term outcome of atrial fibrillation ablation: impact and predictors of very late recurrence
.
J Cardiovasc Electrophysiol
2010
;
21
:
1071
1078
.

640

Arya
A
,
Hindricks
G
,
Sommer
P
,
Huo
Y
,
Bollmann
A
,
Gaspar
T
,
Bode
K
,
Husser
D
,
Kottkamp
H
,
Piorkowski
C.
Long-term results and the predictors of outcome of catheter ablation of atrial fibrillation using steerable sheath catheter navigation after single procedure in 674 patients
.
Europace
2010
;
12
:
173
180
.

641

Santoro
F
,
Di Biase
L
,
Trivedi
C
,
Burkhardt
JD
,
Paoletti Perini
A
,
Sanchez
J
,
Horton
R
,
Mohanty
P
,
Mohanty
S
,
Bai
R
,
Santangeli
P
,
Lakkireddy
D
,
Reddy
M
,
Elayi
CS
,
Hongo
R
,
Beheiry
S
,
Hao
S
,
Schweikert
RA
,
Viles-Gonzalez
J
,
Fassini
G
,
Casella
M
,
Dello Russo
A
,
Tondo
C
,
Natale
A.
Impact of uncontrolled hypertension on atrial fibrillation ablation outcome
.
JACC Clin Electrophysiol
2015
;
1
:
164
173
.

642

Letsas
KP
,
Weber
R
,
Burkle
G
,
Mihas
CC
,
Minners
J
,
Kalusche
D
,
Arentz
T.
Pre-ablative predictors of atrial fibrillation recurrence following pulmonary vein isolation: the potential role of inflammation
.
Europace
2009
;
11
:
158
163
.

643

Jongnarangsin
K
,
Chugh
A
,
Good
E
,
Mukerji
S
,
Dey
S
,
Crawford
T
,
Sarrazin
JF
,
Kuhne
M
,
Chalfoun
N
,
Wells
D
,
Boonyapisit
W
,
Pelosi
F
Jr.
,
Bogun
F
,
Morady
F
,
Oral
H.
Body mass index, obstructive sleep apnea, and outcomes of catheter ablation of atrial fibrillation
.
J Cardiovasc Electrophysiol
2008
;
19
:
668
672
.

644

Patel
D
,
Mohanty
P
,
Di Biase
L
,
Shaheen
M
,
Lewis
WR
,
Quan
K
,
Cummings
JE
,
Wang
P
,
Al-Ahmad
A
,
Venkatraman
P
,
Nashawati
E
,
Lakkireddy
D
,
Schweikert
R
,
Horton
R
,
Sanchez
J
,
Gallinghouse
J
,
Hao
S
,
Beheiry
S
,
Cardinal
DS
,
Zagrodzky
J
,
Canby
R
,
Bailey
S
,
Burkhardt
JD
,
Natale
A.
Safety and efficacy of pulmonary vein antral isolation in patients with obstructive sleep apnea: the impact of continuous positive airway pressure
.
Circ Arrhythm Electrophysiol
2010
;
3
:
445
451
.

645

Matiello
M
,
Nadal
M
,
Tamborero
D
,
Berruezo
A
,
Montserrat
J
,
Embid
C
,
Rios
J
,
Villacastin
J
,
Brugada
J
,
Mont
L.
Low efficacy of atrial fibrillation ablation in severe obstructive sleep apnoea patients
.
Europace
2010
;
12
:
1084
1089
.

646

Chilukuri
K
,
Dalal
D
,
Gadrey
S
,
Marine
JE
,
Macpherson
E
,
Henrikson
CA
,
Cheng
A
,
Nazarian
S
,
Sinha
S
,
Spragg
D
,
Berger
R
,
Calkins
H.
A prospective study evaluating the role of obesity and obstructive sleep apnea for outcomes after catheter ablation of atrial fibrillation
.
J Cardiovasc Electrophysiol
2010
;
21
:
521
525
.

647

Ng
CY
,
Liu
T
,
Shehata
M
,
Stevens
S
,
Chugh
SS
,
Wang
X.
Meta-analysis of obstructive sleep apnea as predictor of atrial fibrillation recurrence after catheter ablation
.
Am J Cardiol
2011
;
108
:
47
51
.

648

Naruse
Y
,
Tada
H
,
Satoh
M
,
Yanagihara
M
,
Tsuneoka
H
,
Hirata
Y
,
Ito
Y
,
Kuroki
K
,
Machino
T
,
Yamasaki
H
,
Igarashi
M
,
Sekiguchi
Y
,
Sato
A
,
Aonuma
K.
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
.
Heart Rhythm
2013
;
10
:
331
337
.

649

Li
L
,
Wang
ZW
,
Li
J
,
Ge
X
,
Guo
LZ,
,
Wang
Y
,
Guo
WH
,
Jiang
CX
,
Ma
CS.
Efficacy of catheter ablation of atrial fibrillation in patients with obstructive sleep apnoea with and without continuous positive airway pressure treatment: a meta-analysis of observational studies
.
Europace
2014
;
16
:
1309
1314
.

650

Kawakami
H
,
Nagai
T
,
Fujii
A
,
Uetani
T
,
Nishimura
K
,
Inoue
K
,
Suzuki
J
,
Oka
Y
,
Okura
T
,
Higaki
J
,
Ogimoto
A
,
Ikeda
S.
Apnea-hypopnea index as a predictor of atrial fibrillation recurrence following initial pulmonary vein isolation: usefulness of type-3 portable monitor for sleep-disordered breathing
.
J Interv Card Electrophysiol
2016
;
47
:
237
244
.

651

Congrete
S
,
Bintvihok
M
,
Thongprayoon
C
,
Bathini
T
,
Boonpheng
B
,
Sharma
K
,
Chokesuwattanaskul
R
,
Srivali
N
,
Tanawuttiwat
T
,
Cheungpasitporn
W.
Effect of obstructive sleep apnea and its treatment of atrial fibrillation recurrence after radiofrequency catheter ablation: a meta-analysis
.
J Evid Based Med
2018
;
11
:
145
151
.

652

Deng
F
,
Raza
A
,
Guo
J.
Treating obstructive sleep apnea with continuous positive airway pressure reduces risk of recurrent atrial fibrillation after catheter ablation: a meta-analysis
.
Sleep Med
2018
;
46
:
5
11
.

653

Wokhlu
A
,
Monahan
KH
,
Hodge
DO
,
Asirvatham
SJ
,
Friedman
PA
,
Munger
TM
,
Bradley
DJ
,
Bluhm
CM
,
Haroldson
JM
,
Packer
DL.
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
.

654

Reddy
VY
,
Dukkipati
SR
,
Neuzil
P
,
Natale
A
,
Albenque
JP
,
Kautzner
J
,
Shah
D
,
Michaud
G
,
Wharton
M
,
Harari
D
,
Mahapatra
S
,
Lambert
H
,
Mansour
M.
Randomized, controlled trial of the safety and effectiveness of a contact force-sensing irrigated catheter for ablation of paroxysmal atrial fibrillation: results of the TactiCath Contact Force Ablation Catheter Study for Atrial Fibrillation (TOCCASTAR) Study
.
Circulation
2015
;
132
:
907
915
.

655

Mark
DB
,
Anstrom
KJ
,
Sheng
S
,
Piccini
JP
,
Baloch
KN
,
Monahan
KH
,
Daniels
MR
,
Bahnson
TD
,
Poole
JE
,
Rosenberg
Y
,
Lee
KL
,
Packer
DL.
Effect of catheter ablation vs medical therapy on quality of life among patients with atrial fibrillation: the CABANA randomized clinical trial
.
JAMA
2019
;
321
:
1275
1285
.

656

Kirchhof
P
,
Breithardt
G
,
Camm
AJ
,
Crijns
HJ
,
Kuck
KH
,
Vardas
P
,
Wegscheider
K.
Improving outcomes in patients with atrial fibrillation: rationale and design of the Early treatment of Atrial fibrillation for Stroke prevention Trial
.
Am Heart J
2013
;
166
:
442
448
.

657

Marrouche
NF
,
Brachmann
J
,
Andresen
D
,
Siebels
J
,
Boersma
L
,
Jordaens
L
,
Merkely
B
,
Pokushalov
E
,
Sanders
P
,
Proff
J
,
Schunkert
H
,
Christ
H
,
Vogt
J
,
Bansch
D
; CASTLE-AF Investigators.
Catheter ablation for atrial fibrillation with heart failure
.
N Engl J Med
2018
;
378
:
417
427
.

658

Noseworthy
PA
,
Van Houten
HK
,
Gersh
BJ,
,
Packer
DL
,
Friedman
PA
,
Shah
ND
,
Dunlay
SM
,
Siontis
KC
,
Piccini
JP
,
Yao
X.
Generalizability of the CASTLE-AF trial: catheter ablation for patients with atrial fibrillation and heart failure in routine practice
.
Heart Rhythm
2020
;17:1057–1065.

659

Kuck
KH
,
Merkely
B
,
Zahn
R
,
Arentz
T
,
Seidl
K
,
Schluter
M
,
Tilz
RR
,
Piorkowski
C
,
Geller
L
,
Kleemann
T
,
Hindricks
G.
Catheter ablation versus best medical therapy in patients with persistent atrial fibrillation and congestive heart failure: the randomized AMICA trial
.
Circ Arrhythm Electrophysiol
2019
;
12
:
e007731
.

660

Packer DL, Monahan KH, Al-KhalidiHR, Silverstein AP, Poole JP, Bahnson TD, Mark DB, Lee KL. Ablation of Atrial Fibrillation in Heart Failure Patients: Additional outcomes of the CABANATrial. Heart Rhythm 2019;16(suppl):S35.

661

Khan
MN
,
Jais
P
,
Cummings
J
,
Di Biase
L
,
Sanders
P
,
Martin
DO
,
Kautzner
J
,
Hao
S
,
Themistoclakis
S
,
Fanelli
R
,
Potenza
D
,
Massaro
R
,
Wazni
O
,
Schweikert
R
,
Saliba
W
,
Wang
P
,
Al-Ahmad
A
,
Beheiry
S
,
Santarelli
P
,
Starling
RC
,
Dello Russo
A
,
Pelargonio
G
,
Brachmann
J
,
Schibgilla
V
,
Bonso
A
,
Casella
M
,
Raviele
A
,
Haissaguerre
M
,
Natale
A
; PABA-CHF Investigators.
Pulmonary-vein isolation for atrial fibrillation in patients with heart failure
.
N Engl J Med
2008
;
359
:
1778
1785
.

662

MacDonald
MR
,
Connelly
DT
,
Hawkins
NM
,
Steedman
T
,
Payne
J
,
Shaw
M
,
Denvir
M
,
Bhagra
S
,
Small
S
,
Martin
W
,
McMurray
JJ
,
Petrie
MC.
Radiofrequency ablation for persistent atrial fibrillation in patients with advanced heart failure and severe left ventricular systolic dysfunction: a randomised controlled trial
.
Heart
2011
;
97
:
740
747
.

663

Jones
DG
,
Haldar
SK
,
Hussain
W
,
Sharma
R
,
Francis
DP
,
Rahman-Haley
SL
,
McDonagh
TA
,
Underwood
SR
,
Markides
V
,
Wong
T. A
randomized trial to assess catheter ablation versus rate control in the management of persistent atrial fibrillation in heart failure
.
J Am Coll Cardiol
2013
;
61
:
1894
1903
.

664

Hunter
RJ
,
Berriman
TJ
,
Diab
I
,
Kamdar
R
,
Richmond
L
,
Baker
V
,
Goromonzi
F
,
Sawhney
V
,
Duncan
E
,
Page
SP
,
Ullah
W
,
Unsworth
B
,
Mayet
J
,
Dhinoja
M
,
Earley
MJ
,
Sporton
S
,
Schilling
RJ.
A randomized controlled trial of catheter ablation versus medical treatment of atrial fibrillation in heart failure (the CAMTAF trial)
.
Circ Arrhythm Electrophysiol
2014
;
7
:
31
38
.

665

Al Halabi
S
,
Qintar
M
,
Hussein
A
,
Alraies
MC
,
Jones
DG
,
Wong
T
,
MacDonald
MR
,
Petrie
MC
,
Cantillon
D
,
Tarakji
KG
,
Kanj
M
,
Bhargava
M
,
Varma
N
,
Baranowski
B
,
Wilkoff
BL
,
Wazni
O
,
Callahan
T
,
Saliba
W
,
Chung
MK.
Catheter ablation for atrial fibrillation in heart failure patients: a meta-analysis of randomized controlled trials
.
JACC Clin Electrophysiol
2015
;
1
:
200
209
.

666

Prabhu
S
,
Taylor
AJ
,
Costello
BT
,
Kaye
DM
,
McLellan
AJA
,
Voskoboinik
A
,
Sugumar
H
,
Lockwood
SM
,
Stokes
MB
,
Pathik
B
,
Nalliah
CJ
,
Wong
GR
,
Azzopardi
SM
,
Gutman
SJ
,
Lee
G
,
Layland
J,
,
Mariani
JA
,
Ling
LH
,
Kalman
JM
,
Kistler
PM.
Catheter ablation versus medical rate control in atrial fibrillation and systolic dysfunction: the CAMERA-MRI study
.
J Am Coll Cardiol
2017
;
70
:
1949
1961
.

667

Elgendy
AY
,
Mahmoud
AN
,
Khan
MS
,
Sheikh
MR
,
Mojadidi
MK
,
Omer
M
,
Elgendy
IY
,
Bavry
AA
,
Ellenbogen
KA
,
Miles
WM
,
McKillop
M.
Meta-analysis comparing catheter-guided ablation versus conventional medical therapy for patients with atrial fibrillation and heart failure with reduced ejection fraction
.
Am J Cardiol
2018
;
122
:
806
813
.

668

Briceno
DF
,
Markman
TM
,
Lupercio
F
,
Romero
J
,
Liang
JJ
,
Villablanca
PA
,
Birati
EY
,
Garcia
FC
,
Di Biase
L
,
Natale
A
,
Marchlinski
FE
,
Santangeli
P.
Catheter ablation versus conventional treatment of atrial fibrillation in patients with heart failure with reduced ejection fraction: a systematic review and meta-analysis of randomized controlled trials
.
J Interv Card Electrophysiol
2018
;
53
:
19
29
.

669

Ma
Y
,
Bai
F
,
Qin
F
,
Li
Y
,
Tu
T
,
Sun
C
,
Zhou
S
,
Liu
Q.
Catheter ablation for treatment of patients with atrial fibrillation and heart failure: a meta-analysis of randomized controlled trials
.
BMC Cardiovasc Disord
2018
;
18
:
165
.

670

Kheiri
B
,
Osman
M
,
Abdalla
A
,
Haykal
T
,
Ahmed
S
,
Bachuwa
G
,
Hassan
M
,
Bhatt
DL.
Catheter ablation of atrial fibrillation with heart failure: an updated meta-analysis of randomized trials
.
Int J Cardiol
2018
;
269
:
170
173
.

671

Khan
SU
,
Rahman
H
,
Talluri
S
,
Kaluski
E.
The clinical benefits and mortality reduction associated with catheter ablation in subjects with atrial fibrillation: a systematic review and meta-analysis
.
JACC Clin Electrophysiol
2018
;
4
:
626
635
.

672

Martin
CA
,
Lambiase
PD.
Pathophysiology, diagnosis and treatment of tachycardiomyopathy
.
Heart
2017
;
103
:
1543
1552
.

673

Raymond-Paquin
A
,
Nattel
S
,
Wakili
R
,
Tadros
R.
Mechanisms and clinical significance of arrhythmia-induced cardiomyopathy
.
Can J Cardiol
2018
;
34
:
1449
1460
.

674

Brembilla-Perrot
B
,
Ferreira
JP
,
Manenti
V
,
Sellal
JM
,
Olivier
A
,
Villemin
T
,
Beurrier
D
,
De Chillou
C
,
Louis
P
,
Brembilla
A
,
Juilliere
Y
,
Girerd
N.
Predictors and prognostic significance of tachycardiomyopathy: insights from a cohort of 1269 patients undergoing atrial flutter ablation
.
Eur J Heart Fail
2016
;
18
:
394
401
.

675

Dagres
N
,
Varounis
C
,
Gaspar
T
,
Piorkowski
C
,
Eitel
C
,
Iliodromitis
EK
,
Lekakis
JP
,
Flevari
P
,
Simeonidou
E
,
Rallidis
LS
,
Tsougos
E
,
Hindricks
G
,
Sommer
P
,
Anastasiou-Nana
M.
Catheter ablation for atrial fibrillation in patients with left ventricular systolic dysfunction. A systematic review and meta-analysis
.
J Card Fail
2011
;
17
:
964
970
.

676

Prabhu
S
,
Costello
BT
,
Taylor
AJ
,
Gutman
SJ
,
Voskoboinik
A
,
McLellan
AJA
,
Peck
KY
,
Sugumar
H
,
Iles
L
,
Pathik
B
,
Nalliah
CJ
,
Wong
GR
,
Azzopardi
SM
,
Lee
G
,
Mariani
J
,
Kaye
DM
,
Ling
LH
,
Kalman
JM
,
Kistler
PM.
Regression of diffuse ventricular fibrosis following restoration of sinus rhythm with catheter ablation in patients with atrial fibrillation and systolic dysfunction: a substudy of the CAMERA MRI trial
.
JACC Clin Electrophysiol
2018
;
4
:
999
1007
.

677

Tamborero
D
,
Mont
L
,
Berruezo
A
,
Matiello
M
,
Benito
B
,
Sitges
M
,
Vidal
B
,
de Caralt
TM
,
Perea
RJ
,
Vatasescu
R
,
Brugada
J.
Left atrial posterior wall isolation does not improve the outcome of circumferential pulmonary vein ablation for atrial fibrillation: a prospective randomized study
.
Circ Arrhythm Electrophysiol
2009
;
2
:
35
40
.

678

Natale
A
,
Reddy
VY
,
Monir
G
,
Wilber
DJ
,
Lindsay
BD
,
McElderry
HT
,
Kantipudi
C
,
Mansour
MC
,
Melby
DP
,
Packer
DL
,
Nakagawa
H
,
Zhang
B
,
Stagg
RB
,
Boo
LM
,
Marchlinski
FE.
Paroxysmal AF catheter ablation with a contact force sensing catheter: results of the prospective, multicenter SMART-AF trial
.
J Am Coll Cardiol
2014
;
64
:
647
656
.

679

McLellan
AJ
,
Ling
LH
,
Azzopardi
S
,
Lee
GA
,
Lee
G
,
Kumar
S
,
Wong
MC
,
Walters
TE
,
Lee
JM
,
Looi
KL,
,
Halloran
K
,
Stiles
MK,
,
Lever
NA
,
Fynn
SP
,
Heck
PM
,
Sanders
P,
,
Morton
JB
,
Kalman
JM
,
Kistler
PM
.
A minimal or maximal ablation strategy to achieve pulmonary vein isolation for paroxysmal atrial fibrillation: a prospective multi-centre randomized controlled trial (the Minimax study)
.
Eur Heart J
2015
;
36
:
1812
1821
.

680

Verma
A
,
Jiang
CY
,
Betts
TR
,
Chen
J
,
Deisenhofer
I
,
Mantovan
R
,
Macle
L
,
Morillo
CA
,
Haverkamp
W
,
Weerasooriya
R
,
Albenque
JP
,
Nardi
S
,
Menardi
E
,
Novak
P
,
Sanders
P
; STAR AF II Investigators.
Approaches to catheter ablation for persistent atrial fibrillation
.
N Engl J Med
2015
;
372
:
1812
1822
.

681

Luik
A
,
Radzewitz
A
,
Kieser
M
,
Walter
M
,
Bramlage
P
,
Hormann
P
,
Schmidt
K
,
Horn
N
,
Brinkmeier-Theofanopoulou
M
,
Kunzmann
K
,
Riexinger
T
,
Schymik
G
,
Merkel
M
,
Schmitt
C.
Cryoballoon versus open irrigated radiofrequency ablation in patients with paroxysmal atrial fibrillation: the prospective, randomized, controlled, noninferiority FreezeAF study
.
Circulation
2015
;
132
:
1311
1319
.

682

Dukkipati
SR
,
Cuoco
F
,
Kutinsky
I
,
Aryana
A
,
Bahnson
TD
,
Lakkireddy
D
,
Woollett
I
,
Issa
ZF
,
Natale
A
,
Reddy
VY
; HeartLight Study Investigators.
Pulmonary vein isolation using the visually guided laser balloon: a prospective, multicenter, and randomized comparison to standard radiofrequency ablation
.
J Am Coll Cardiol
2015
;
66
:
1350
1360
.

683

Kuck
KH
,
Hoffmann
BA
,
Ernst
S
,
Wegscheider
K
,
Treszl
A
,
Metzner
A
,
Eckardt
L
,
Lewalter
T
,
Breithardt
G
,
Willems
S
; Gap-AF–AFNET 1 Investigators.
Impact of complete versus incomplete circumferential lines around the pulmonary veins during catheter ablation of paroxysmal atrial fibrillation: results from the Gap-Atrial Fibrillation-German Atrial Fibrillation Competence Network 1 trial
.
Circ Arrhythm Electrophysiol
2016
;
9
:
e003337
.

684

Nery
PB
,
Belliveau
D
,
Nair
GM
,
Bernick
J
,
Redpath
CJ
,
Szczotka
A
,
Sadek
MM
,
Green
MS
,
Wells
G
,
Birnie
DH.
Relationship between pulmonary vein reconnection and atrial fibrillation recurrence: a systematic review and meta-analysis
.
JACC Clin Electrophysiol
2016
;
2
:
474
483
.

685

Bassiouny
M
,
Saliba
W
,
Hussein
A
,
Rickard
J
,
Diab
M
,
Aman
W
,
Dresing
T
,
Tt
Callahan
,
Bhargava
M
,
Martin
DO
,
Shao
M
,
Baranowski
B
,
Tarakji
K
,
Tchou
PJ
,
Hakim
A
,
Kanj
M
,
Lindsay
B
,
Wazni
O.
Randomized study of persistent atrial fibrillation ablation: ablate in sinus rhythm versus ablate complex-fractionated atrial electrograms in atrial fibrillation
.
Circ Arrhythm Electrophysiol
2016
;
9
:
e003596
.

686

Hindricks
G
,
Sepehri Shamloo
A
,
Lenarczyk
R
,
Kalarus
Z
,
Arya
A
,
Kircher
S
,
Darma
A
,
Dagres
N.
Catheter ablation of atrial fibrillation: current status, techniques, outcomes and challenges
.
Kardiol Pol
2018
;
76
:
1680
1686
.

687

Nanthakumar
K
,
Plumb
VJ
,
Epstein
AE
,
Veenhuyzen
GD
,
Link
D
,
Kay
GN.
Resumption of electrical conduction in previously isolated pulmonary veins: rationale for a different strategy?
Circulation
2004
;
109
:
1226
1229
.

688

Verma
A
,
Kilicaslan
F
,
Pisano
E
,
Marrouche
NF
,
Fanelli
R
,
Brachmann
J
,
Geunther
J
,
Potenza
D
,
Martin
DO
,
Cummings
J
,
Burkhardt
JD
,
Saliba
W
,
Schweikert
RA
,
Natale
A.
Response of atrial fibrillation to pulmonary vein antrum isolation is directly related to resumption and delay of pulmonary vein conduction
.
Circulation
2005
;
112
:
627
635
.

689

Ouyang
F
,
Antz
M
,
Ernst
S
,
Hachiya
H
,
Mavrakis
H
,
Deger
FT
,
Schaumann
A
,
Chun
J
,
Falk
P
,
Hennig
D
,
Liu
X
,
Bansch
D
,
Kuck
KH.
Recovered pulmonary vein conduction as a dominant factor for recurrent atrial tachyarrhythmias after complete circular isolation of the pulmonary veins: lessons from double Lasso technique
.
Circulation
2005
;
111
:
127
135
.

690

Cheema
A
,
Dong
J
,
Dalal
D
,
Marine
JE
,
Henrikson
CA
,
Spragg
D
,
Cheng
A
,
Nazarian
S
,
Bilchick
K
,
Sinha
S
,
Scherr
D
,
Almasry
I
,
Halperin
H
,
Berger
R
,
Calkins
H.
Incidence and time course of early recovery of pulmonary vein conduction after catheter ablation of atrial fibrillation
.
J Cardiovasc Electrophysiol
2007
;
18
:
387
391
.

691

Pratola
C
,
Baldo
E
,
Notarstefano
P
,
Toselli
T
,
Ferrari
R.
Radiofrequency ablation of atrial fibrillation: is the persistence of all intraprocedural targets necessary for long-term maintenance of sinus rhythm?
Circulation
2008
;
117
:
136
143
.

692

Rajappan
K
,
Kistler
PM
,
Earley
MJ
,
Thomas
G
,
Izquierdo
M
,
Sporton
SC
,
Schilling
RJ.
Acute and chronic pulmonary vein reconnection after atrial fibrillation ablation: a prospective characterization of anatomical sites
.
Pacing Clin Electrophysiol
2008
;
31
:
1598
1605
.

693

Bansch
D
,
Bittkau
J
,
Schneider
R
,
Schneider
C
,
Wendig
I
,
Akin
I
,
Nienaber
CA.
Circumferential pulmonary vein isolation: wait or stop early after initial successful pulmonary vein isolation?
Europace
2013
;
15
:
183
188
.

694

Nakamura
K
,
Naito
S
,
Kaseno
K
,
Tsukada
N
,
Sasaki
T
,
Hayano
M
,
Nishiuchi
S
,
Fuke
E
,
Miki
Y
,
Sakamoto
T
,
Nakamura
K
,
Kumagai
K
,
Kataoka
A
,
Takaoka
H
,
Kobayashi
Y
,
Funabashi
N
,
Oshima
S.
Optimal observation time after completion of circumferential pulmonary vein isolation for atrial fibrillation to prevent chronic pulmonary vein reconnections
.
Int J Cardiol
2013
;
168
:
5300
5310
.

695

Neuzil
P
,
Reddy
VY
,
Kautzner
J
,
Petru
J
,
Wichterle
D
,
Shah
D
,
Lambert
H
,
Yulzari
A
,
Wissner
E
,
Kuck
KH.
Electrical reconnection after pulmonary vein isolation is contingent on contact force during initial treatment: results from the EFFICAS I study
.
Circ Arrhythm Electrophysiol
2013
;
6
:
327
333
.

696

Jiang
RH
,
Po
SS
,
Tung
R
,
Liu
Q
,
Sheng
X
,
Zhang
ZW
,
Sun
YX
,
Yu
L
,
Zhang
P
,
Fu
GS
,
Jiang
CY.
Incidence of pulmonary vein conduction recovery in patients without clinical recurrence after ablation of paroxysmal atrial fibrillation: mechanistic implications
.
Heart Rhythm
2014
;
11
:
969
976
.

697

Kim
TH
,
Park
J
,
Uhm
JS
,
Joung
B
,
Lee
MH
,
Pak
HN.
Pulmonary vein reconnection predicts good clinical outcome after second catheter ablation for atrial fibrillation
.
Europace
2017
;
19
:
961
967
.

698

Bordignon
S
,
Furnkranz
A
,
Perrotta
L
,
Dugo
D
,
Konstantinou
A
,
Nowak
B
,
Schulte-Hahn
B
,
Schmidt
B
,
Chun
KR.
High rate of durable pulmonary vein isolation after second-generation cryoballoon ablation: analysis of repeat procedures
.
Europace
2015
;
17
:
725
731
.

699

Ullah
W
,
McLean
A
,
Tayebjee
MH
,
Gupta
D
,
Ginks
MR
,
Haywood
GA
,
O’Neill
M
,
Lambiase
PD
,
Earley
MJ
,
Schilling
RJ
, Group UKMT.
Randomized trial comparing pulmonary vein isolation using the SmartTouch catheter with or without real-time contact force data
.
Heart Rhythm
2016
;
13
:
1761
1767
.

700

Phlips
T
,
Taghji
P
,
El Haddad
M
,
Wolf
M
,
Knecht
S
,
Vandekerckhove
Y
,
Tavernier
R
,
Duytschaever
M.
Improving procedural and one-year outcome after contact force-guided pulmonary vein isolation: the role of interlesion distance, ablation index, and contact force variability in the ‘CLOSE’-protocol
.
Europace
2018
;
20
:
f419
f427
.

701

Shah
D
,
Haissaguerre
M
,
Jais
P
,
Hocini
M.
Nonpulmonary vein foci: do they exist?
Pacing Clin Electrophysiol
2003
;
26
:
1631
1635
.

702

Nademanee
K
,
McKenzie
J
,
Kosar
E
,
Schwab
M
,
Sunsaneewitayakul
B
,
Vasavakul
T
,
Khunnawat
C
,
Ngarmukos
T.
A new approach for catheter ablation of atrial fibrillation: mapping of the electrophysiologic substrate
.
J Am Coll Cardiol
2004
;
43
:
2044
2053
.

703

Haissaguerre
M
,
Sanders
P
,
Hocini
M
,
Takahashi
Y
,
Rotter
M
,
Sacher
F
,
Rostock
T
,
Hsu
LF
,
Bordachar
P
,
Reuter
S
,
Roudaut
R
,
Clementy
J
,
Jais
P.
Catheter ablation of long-lasting persistent atrial fibrillation: critical structures for termination
.
J Cardiovasc Electrophysiol
2005
;
16
:
1125
1137
.

704

Haissaguerre
M
,
Hocini
M
,
Sanders
P
,
Sacher
F
,
Rotter
M
,
Takahashi
Y
,
Rostock
T
,
Hsu
LF
,
Bordachar
P
,
Reuter
S
,
Roudaut
R
,
Clementy
J
,
Jais
P.
Catheter ablation of long-lasting persistent atrial fibrillation: clinical outcome and mechanisms of subsequent arrhythmias
.
J Cardiovasc Electrophysiol
2005
;
16
:
1138
1147
.

705

Jaïs
P
,
O’Neill
MD
,
Takahashi
Y
,
Jönsson
A
,
Hocini
M
,
Sacher
F
,
Sanders
P
,
Kodali
S
,
Rostock
T
,
Rotter
M
,
Clémenty
J
,
Haïssaguerre
M.
Stepwise catheter ablation of chronic atrial fibrillation:importance of discrete anatomic sites for termination
.
J Cardiovasc Electrophysiol
2006
;
17
:
S28
S36
.

706

Atienza
F
,
Almendral
J
,
Jalife
J
,
Zlochiver
S
,
Ploutz-Snyder
R
,
Torrecilla
EG
,
Arenal
A
,
Kalifa
J
,
Fernandez-Aviles
F
,
Berenfeld
O.
Real-time dominant frequency mapping and ablation of dominant frequency sites in atrial fibrillation with left-to-right frequency gradients predicts long-term maintenance of sinus rhythm
.
Heart Rhythm
2009
;
6
:
33
40
.

707

Stavrakis
S
,
Nakagawa
H
,
Po
SS,
,
Scherlag
BJ
,
Lazzara
R
,
Jackman
WM.
The role of the autonomic ganglia in atrial fibrillation
.
JACC Clin Electrophysiol
2015
;
1
:
1
13
.

708

Di Biase
L
,
Burkhardt
JD
,
Mohanty
P
,
Mohanty
S
,
Sanchez
JE
,
Trivedi
C
,
Gunes
M
,
Gokoglan
Y
,
Gianni
C
,
Horton
RP
,
Themistoclakis
S
,
Gallinghouse
GJ
,
Bailey
S
,
Zagrodzky
JD
,
Hongo
RH
,
Beheiry
S
,
Santangeli
P
,
Casella
M
,
Dello Russo
A
,
Al-Ahmad
A
,
Hranitzky
P
,
Lakkireddy
D
,
Tondo
C
,
Natale
A.
Left atrial appendage isolation in patients with longstanding persistent af undergoing catheter ablation: BELIEF trial
.
J Am Coll Cardiol
2016
;
68
:
1929
1940
.

709

Gianni
C
,
Mohanty
S
,
Di Biase
L
,
Metz
T
,
Trivedi
C
,
Gokoglan
Y
,
Gunes
MF
,
Bai
R
,
Al-Ahmad
A
,
Burkhardt
JD
,
Gallinghouse
GJ
,
Horton
RP
,
Hranitzky
PM
,
Sanchez
JE
,
Halbfass
P
,
Muller
P
,
Schade
A
,
Deneke
T
,
Tomassoni
GF
,
Natale
A.
Acute and early outcomes of focal impulse and rotor modulation (FIRM)-guided rotors-only ablation in patients with nonparoxysmal atrial fibrillation
.
Heart Rhythm
2016
;
13
:
830
835
.

710

Santangeli
P
,
Zado
ES
,
Hutchinson
MD
,
Riley
MP
,
Lin
D
,
Frankel
DS
,
Supple
GE
,
Garcia
FC
,
Dixit
S
,
Callans
DJ
,
Marchlinski
FE.
Prevalence and distribution of focal triggers in persistent and long-standing persistent atrial fibrillation
.
Heart Rhythm
2016
;
13
:
374
382
.

711

Katritsis
DG
,
Pokushalov
E
,
Romanov
A
,
Giazitzoglou
E
,
Siontis
GC
,
Po
SS
,
Camm
AJ
,
Ioannidis
JP.
Autonomic denervation added to pulmonary vein isolation for paroxysmal atrial fibrillation: a randomized clinical trial
.
J Am Coll Cardiol
2013
;
62
:
2318
2325
.

712

Arbelo
E
,
Guiu
E
,
Ramos
P
,
Bisbal
F
,
Borras
R
,
Andreu
D
,
Tolosana
JM
,
Berruezo
A
,
Brugada
J,
,
Mont
L.
Benefit of left atrial roof linear ablation in paroxysmal atrial fibrillation: a prospective, randomized study
.
J Am Heart Assoc
2014
;
3
:
e000877
.

713

Da Costa
A
,
Levallois
M
,
Romeyer-Bouchard
C
,
Bisch
L
,
Gate-Martinet
A
,
Isaaz
K.
Remote-controlled magnetic pulmonary vein isolation combined with superior vena cava isolation for paroxysmal atrial fibrillation: a prospective randomized study
.
Arch Cardiovasc Dis
2015
;
108
:
163
171
.

714

Wong
KC
,
Paisey
JR
,
Sopher
M
,
Balasubramaniam
R
,
Jones
M
,
Qureshi
N
,
Hayes
CR
,
Ginks
MR
,
Rajappan
K
,
Bashir
Y
,
Betts
TR.
No benefit of complex fractionated atrial electrogram ablation in addition to circumferential pulmonary vein ablation and linear ablation: Benefit of Complex Ablation Study
.
Circ Arrhythm Electrophysiol
2015
;
8
:
1316
1324
.

715

Vogler
J
,
Willems
S
,
Sultan
A
,
Schreiber
D
,
Luker
J
,
Servatius
H
,
Schaffer
B
,
Moser
J
,
Hoffmann
BA
,
Steven
D.
Pulmonary vein isolation versus defragmentation: the CHASE-AF clinical trial
.
J Am Coll Cardiol
2015
;
66
:
2743
2752
.

716

Faustino
M
,
Pizzi
C
,
Agricola
T
,
Xhyheri
B
,
Costa
GM
,
Flacco
ME
,
Capasso
L
,
Cicolini
G
,
Di Girolamo
E
,
Leonzio
L
,
Manzoli
L.
Stepwise ablation approach versus pulmonary vein isolation in patients with paroxysmal atrial fibrillation: randomized controlled trial
.
Heart Rhythm
2015
;
12
:
1907
1915
.

717

Scott
PA
,
Silberbauer
J
,
Murgatroyd
FD.
The impact of adjunctive complex fractionated atrial electrogram ablation and linear lesions on outcomes in persistent atrial fibrillation: a meta-analysis
.
Europace
2016
;
18
:
359
367
.

718

Driessen
AHG
,
Berger
WR
,
Krul
SPJ
,
van den Berg
NWE
,
Neefs
J
,
Piersma
FR
,
Chan Pin Yin
D
,
de Jong
J
,
van Boven
WP
,
de Groot
JR.
Ganglion plexus ablation in advanced atrial fibrillation: the AFACT study
.
J Am Coll Cardiol
2016
;
68
:
1155
1165
.

719

Qin
M
,
Liu
X
,
Wu
SH
,
Zhang
XD.
Atrial substrate modification in atrial fibrillation: targeting GP or CFAE? Evidence from meta-analysis of clinical trials
.
PLoS One
2016
;
11
:
e0164989
.

720

Hu
X
,
Jiang
J
,
Ma
Y
,
Tang
A.
Is there still a role for additional linear ablation in addition to pulmonary vein isolation in patients with paroxysmal atrial fibrillation? An updated meta-analysis of randomized controlled trials
.
Int J Cardiol
2016
;
209
:
266
274
.

721

Wynn
GJ
,
Panikker
S
,
Morgan
M
,
Hall
M
,
Waktare
J
,
Markides
V
,
Hussain
W
,
Salukhe
T
,
Modi
S
,
Jarman
J
,
Jones
DG
,
Snowdon
R
,
Todd
D
,
Wong
T
,
Gupta
D.
Biatrial linear ablation in sustained nonpermanent AF: results of the substrate modification with ablation and antiarrhythmic drugs in nonpermanent atrial fibrillation (SMAN-PAF) trial
.
Heart Rhythm
2016
;
13
:
399
406
.

722

Zhang
Z
,
Letsas
KP
,
Zhang
N
,
Efremidis
M
,
Xu
G
,
Li
G
,
Liu
T.
Linear ablation following pulmonary vein isolation in patients with atrial fibrillation: a meta-analysis
.
Pacing Clin Electrophysiol
2016
;
39
:
623
630
.

723

Fink
T
,
Schluter
M
,
Heeger
CH
,
Lemes
C
,
Maurer
T
,
Reissmann
B
,
Riedl
J
,
Rottner
L
,
Santoro
F
,
Schmidt
B
,
Wohlmuth
P
,
Mathew
S
,
Sohns
C
,
Ouyang
F
,
Metzner
A
,
Kuck
KH.
Stand-alone pulmonary vein isolation versus pulmonary vein isolation with additional substrate modification as index ablation procedures in patients with persistent and long-standing persistent atrial fibrillation: the randomized Alster-Lost-AF trial (Ablation at St. Georg Hospital for long-standing persistent atrial fibrillation
).
Circ Arrhythm Electrophysiol
2017
;
10
.

724

Kim
TH
,
Uhm
JS
,
Kim
JY
,
Joung
B
,
Lee
MH
,
Pak
HN.
Does additional electrogram-guided ablation after linear ablation reduce recurrence after catheter ablation for longstanding persistent atrial fibrillation? A prospective randomized study
.
J Am Heart Assoc
2017
;
6
:
e004811
.

725

Kircher
S
,
Arya
A
,
Altmann
D
,
Rolf
S
,
Bollmann
A
,
Sommer
P
,
Dagres
N
,
Richter
S
,
Breithardt
OA
,
Dinov
B
,
Husser
D
,
Eitel
C
,
Gaspar
T
,
Piorkowski
C
,
Hindricks
G.
Individually tailored vs. standardized substrate modification during radiofrequency catheter ablation for atrial fibrillation: a randomized study
.
Europace
2018
;
20
:
1766
1775
.

726

Ammar-Busch
S
,
Bourier
F
,
Reents
T
,
Semmler
V
,
Telishevska
M
,
Kathan
S
,
Hofmann
M
,
Hessling
G
,
Deisenhofer
I.
Ablation of complex fractionated electrograms with or without ADditional LINEar Lesions for Persistent Atrial Fibrillation (the ADLINE trial)
.
J Cardiovasc Electrophysiol
2017
;
28
:
636
641
.

727

Blandino
A
,
Bianchi
F
,
Grossi
S
,
Biondi-Zoccai
G
,
Conte
MR
,
Gaido
L
,
Gaita
F
,
Scaglione
M
,
Rametta
F
.
Left atrial substrate modification targeting low-voltage areas for catheter ablation of atrial fibrillation: a systematic review and meta-analysis
.
Pacing Clin Electrophysiol
2017
;
40
:
199
212
.

728

Yang
B
,
Jiang
C
,
Lin
Y
,
Yang
G
,
Chu
H
,
Cai
H
,
Lu
F
,
Zhan
X
,
Xu
J
,
Wang
X
,
Ching
CK
,
Singh
B
,
Kim
YH
,
Chen
M
; STABLE-SR Investigators.
STABLE-SR (Electrophysiological Substrate Ablation in the Left Atrium During Sinus Rhythm) for the treatment of nonparoxysmal atrial fibrillation: a prospective, multicenter randomized clinical trial
.
Circ Arrhythm Electrophysiol
2017
;
10
:pii: e005405.

729

Yu
HT
,
Shim
J
,
Park
J
,
Kim
IS
,
Kim
TH
,
Uhm
JS
,
Joung
B
,
Lee
MH
,
Kim
YH
,
Pak
HN.
Pulmonary vein isolation alone versus additional linear ablation in patients with persistent atrial fibrillation converted to paroxysmal type with antiarrhythmic drug therapy: a multicenter, prospective, randomized study
.
Circ Arrhythm Electrophysiol
2017
;
10
:pii: e004915.

730

Wang
YL
,
Liu
X
,
Zhang
Y
,
Jiang
WF
,
Zhou
L
,
Qin
M
,
Zhang
DL
,
Zhang
XD
,
Wu
SH
,
Xu
K.
Optimal endpoint for catheter ablation of longstanding persistent atrial fibrillation: a randomized clinical trial
.
Pacing Clin Electrophysiol
2018
;
41
:
172
178
.

731

Perez
FJ
,
Schubert
CM
,
Parvez
B
,
Pathak
V
,
Ellenbogen
KA
,
Wood
MA.
Long-term outcomes after catheter ablation of cavo-tricuspid isthmus dependent atrial flutter: a meta-analysis
.
Circ Arrhythm Electrophysiol
2009
;
2
:
393
401
.

732

Natale
A
,
Newby
KH
,
Pisano
E
,
Leonelli
F
,
Fanelli
R
,
Potenza
D
,
Beheiry
S
,
Tomassoni
G.
Prospective randomized comparison of antiarrhythmic therapy versus first-line radiofrequency ablation in patients with atrial flutter
.
J Am Coll Cardiol
2000
;
35
:
1898
1904
.

733

Wazni
O
,
Marrouche
NF
,
Martin
DO
,
Gillinov
AM
,
Saliba
W
,
Saad
E
,
Klein
A
,
Bhargava
M
,
Bash
D
,
Schweikert
R
,
Erciyes
D
,
Abdul-Karim
A
,
Brachman
J
,
Gunther
J
,
Pisano
E
,
Potenza
D
,
Fanelli
R
,
Natale
A.
Randomized study comparing combined pulmonary vein-left atrial junction disconnection and cavotricuspid isthmus ablation versus pulmonary vein-left atrial junction disconnection alone in patients presenting with typical atrial flutter and atrial fibrillation
.
Circulation
2003
;
108
:
2479
2483
.

734

Shah
DC
,
Sunthorn
H
,
Burri
H
,
Gentil-Baron
P.
Evaluation of an individualized strategy of cavotricuspid isthmus ablation as an adjunct to atrial fibrillation ablation
.
J Cardiovasc Electrophysiol
2007
;
18
:
926
930
.

735

Neumann
T
,
Kuniss
M
,
Conradi
G
,
Janin
S
,
Berkowitsch
A
,
Wojcik
M
,
Rixe
J
,
Erkapic
D
,
Zaltsberg
S
,
Rolf
A
,
Bachmann
G
,
Dill
T
,
Hamm
CW
,
Pitschner
HF.
MEDAFI-Trial (Micro-embolization during ablation of atrial fibrillation): comparison of pulmonary vein isolation using cryoballoon technique vs. radiofrequency energy
.
Europace
2011
;
13
:
37
44
.

736

Herrera Siklody
C
,
Deneke
T
,
Hocini
M
,
Lehrmann
H
,
Shin
DI
,
Miyazaki
S
,
Henschke
S
,
Fluegel
P
,
Schiebeling-Romer
J
,
Bansmann
PM
,
Bourdias
T
,
Dousset
V
,
Haissaguerre
M
,
Arentz
T.
Incidence of asymptomatic intracranial embolic events after pulmonary vein isolation: comparison of different atrial fibrillation ablation technologies in a multicenter study
.
J Am Coll Cardiol
2011
;
58
:
681
688
.

737

Herrera Siklody
C
,
Arentz
T
,
Minners
J
,
Jesel
L
,
Stratz
C
,
Valina
CM
,
Weber
R
,
Kalusche
D
,
Toti
F
,
Morel
O
,
Trenk
D.
Cellular damage, platelet activation, and inflammatory response after pulmonary vein isolation: a randomized study comparing radiofrequency ablation with cryoablation
.
Heart Rhythm
2012
;
9
:
189
196
.

738

Pokushalov
E
,
Romanov
A
,
Artyomenko
S
,
Baranova
V
,
Losik
D
,
Bairamova
S
,
Karaskov
A
,
Mittal
S
,
Steinberg
JS.
Cryoballoon versus radiofrequency for pulmonary vein re-isolation after a failed initial ablation procedure in patients with paroxysmal atrial fibrillation
.
J Cardiovasc Electrophysiol
2013
;
24
:
274
279
.

739

Schmidt
M
,
Dorwarth
U
,
Andresen
D
,
Brachmann
J
,
Kuck
KH
,
Kuniss
M
,
Lewalter
T
,
Spitzer
S
,
Willems
S
,
Senges
J
,
Junger
C
,
Hoffmann
E.
Cryoballoon versus RF ablation in paroxysmal atrial fibrillation: results from the German Ablation Registry
.
J Cardiovasc Electrophysiol
2014
;
25
:
1
7
.

740

Perez-Castellano
N
,
Fernandez-Cavazos
R
,
Moreno
J
,
Canadas
V
,
Conde
A
,
Gonzalez-Ferrer
JJ
,
Macaya
C
,
Perez-Villacastin
J.
The COR trial: a randomized study with continuous rhythm monitoring to compare the efficacy of cryoenergy and radiofrequency for pulmonary vein isolation
.
Heart Rhythm
2014
;
11
:
8
14
.

741

Hunter
RJ
,
Baker
V
,
Finlay
MC
,
Duncan
ER
,
Lovell
MJ
,
Tayebjee
MH
,
Ullah
W
,
Siddiqui
MS
,
Mc
LA
,
Richmond
L
,
Kirkby
C
,
Ginks
MR
,
Dhinoja
M,
,
Sporton
S
,
Earley
MJ
,
Schilling
RJ.
Point-by-point radiofrequency ablation versus the cryoballoon or a novel combined approach: a randomized trial comparing 3 methods of pulmonary vein isolation for paroxysmal atrial fibrillation (the Cryo Versus RF trial)
.
J Cardiovasc Electrophysiol
2015
;
26
:
1307
1314
.

742

Squara
F
,
Zhao
A
,
Marijon
E
,
Latcu
DG
,
Providencia
R
,
Di Giovanni
G
,
Jauvert
G
,
Jourda
F
,
Chierchia
GB
,
De Asmundis
C
,
Ciconte
G
,
Alonso
C
,
Grimard
C
,
Boveda
S
,
Cauchemez
B
,
Saoudi
N
,
Brugada
P
,
Albenque
JP
,
Thomas
O.
Comparison between radiofrequency with contact force-sensing and second-generation cryoballoon for paroxysmal atrial fibrillation catheter ablation: a multicentre European evaluation
.
Europace
2015
;
17
:
718
724
.

743

Straube
F
,
Dorwarth
U
,
Ammar-Busch
S
,
Peter
T
,
Noelker
G
,
Massa
T
,
Kuniss
M
,
Ewertsen
NC
,
Chun
KR
,
Tebbenjohanns
J
,
Tilz
R
,
Kuck
KH
,
Ouarrak
T
,
Senges
J
,
Hoffmann
E
; Freeze Cohort Investigators.
First-line catheter ablation of paroxysmal atrial fibrillation: outcome of radiofrequency vs. cryoballoon pulmonary vein isolation
.
Europace
2016
;
18
:
368
375
.

744

Schmidt
M
,
Dorwarth
U
,
Andresen
D
,
Brachmann
J
,
Kuck
K
,
Kuniss
M
,
Willems
S
,
Deneke
T
,
Tebbenjohanns
J
,
Gerds-Li
JH
,
Spitzer
S
,
Senges
J,
,
Hochadel
M
,
Hoffmann
E.
German ablation registry: cryoballoon vs. radiofrequency ablation in paroxysmal atrial fibrillation – one-year outcome data
.
Heart Rhythm
2016
;
13
:
836
844
.

745

Boveda
S
,
Providencia
R
,
Defaye
P
,
Pavin
D
,
Cebron
JP
,
Anselme
F
,
Halimi
F
,
Khoueiry
Z
,
Combes
N
,
Combes
S
,
Jacob
S
,
Albenque
JP
,
Sousa
P.
Outcomes after cryoballoon or radiofrequency ablation for persistent atrial fibrillation: a multicentric propensity-score matched study
.
J Interv Card Electrophysiol
2016
;
47
:
133
142
.

746

Kuck
KH
,
Furnkranz
A
,
Chun
KR
,
Metzner
A
,
Ouyang
F
,
Schluter
M
,
Elvan
A
,
Lim
HW
,
Kueffer
FJ
,
Arentz
T
,
Albenque
JP
,
Tondo
C
,
Kuhne
M
,
Sticherling
C
,
Brugada
J
; FIRE AND ICE Investigators.
Cryoballoon or radiofrequency ablation for symptomatic paroxysmal atrial fibrillation: reintervention, rehospitalization, and quality-of-life outcomes in the FIRE AND ICE trial
.
Eur Heart J
2016
;
37
:
2858
2865
.

747

Buist
TJ
,
Adiyaman
A
,
Smit
JJJ
,
Ramdat Misier
AR
,
Elvan
A.
Arrhythmia-free survival and pulmonary vein reconnection patterns after second-generation cryoballoon and contact-force radiofrequency pulmonary vein isolation
.
Clin Res Cardiol
2018
;
107
:
498
506
.

748

Gunawardene
MA
,
Hoffmann
BA
,
Schaeffer
B
,
Chung
DU
,
Moser
J
,
Akbulak
RO
,
Jularic
M
,
Eickholt
C
,
Nuehrich
J
,
Meyer
C
,
Willems
S.
Influence of energy source on early atrial fibrillation recurrences: a comparison of cryoballoon vs. radiofrequency current energy ablation with the endpoint of unexcitability in pulmonary vein isolation
.
Europace
2018
;
20
:
43
49
.

749

Mortsell
D
,
Arbelo
E
,
Dagres
N
,
Brugada
J
,
Laroche
C
,
Trines
SA
,
Malmborg
H
,
Hoglund
N
,
Tavazzi
L
,
Pokushalov
E
,
Stabile
G
,
Blomstrom-Lundqvist
C
; ESC-EHRA Atrial Fibrillation Ablation Long-Term Registry Investigators.
Cryoballoon vs. radiofrequency ablation for atrial fibrillation: a study of outcome and safety based on the ESC-EHRA atrial fibrillation ablation long-term registry and the Swedish catheter ablation registry
.
Europace
2019
;
21
:
581
589
.

750

Akkaya
E
,
Berkowitsch
A
,
Zaltsberg
S
,
Greiss
H
,
Hamm
CW
,
Sperzel
J
,
Neumann
T
,
Kuniss
M.
Ice or fire? Comparison of second-generation cryoballoon ablation and radiofrequency ablation in patients with symptomatic persistent atrial fibrillation and an enlarged left atrium
.
J Cardiovasc Electrophysiol
2018
;
29
:
375
384
.

751

Murray
MI
,
Arnold
A
,
Younis
M
,
Varghese
S
,
Zeiher
AM.
Cryoballoon versus radiofrequency ablation for paroxysmal atrial fibrillation: a meta-analysis of randomized controlled trials
.
Clin Res Cardiol
2018
;
107
:
658
669
.

752

Chen
CF
,
Gao
XF
,
Duan
X
,
Chen
B
,
Liu
XH
,
Xu
YZ.
Comparison of catheter ablation for paroxysmal atrial fibrillation between cryoballoon and radiofrequency: a meta-analysis
.
J Interv Card Electrophysiol
2017
;
48
:
351
366
.

753

Buiatti
A
,
von Olshausen
G
,
Barthel
P
,
Schneider
S
,
Luik
A
,
Kaess
B
,
Laugwitz
KL
,
Hoppmann
P.
Cryoballoon vs. radiofrequency ablation for paroxysmal atrial fibrillation: an updated meta-analysis of randomized and observational studies
.
Europace
2017
;
19
:
378
384
.

754

Cardoso
R
,
Mendirichaga
R
,
Fernandes
G
,
Healy
C
,
Lambrakos
LK
,
Viles-Gonzalez
JF
,
Goldberger
JJ
,
Mitrani
RD
.
Cryoballoon versus radiofrequency catheter ablation in atrial fibrillation: a meta-analysis
.
J Cardiovasc Electrophysiol
2016
;
27
:
1151
1159
.

755

Kabunga
P
,
Phan
K
,
Ha
H
,
Sy
RW.
Meta-analysis of contemporary atrial fibrillation ablation strategies: irrigated radiofrequency versus duty-cycled phased radiofrequency versus cryoballoon ablation
.
JACC Clin Electrophysiol
2016
;
2
:
377
390
.

756

Bollmann
A
,
Ueberham
L
,
Schuler
E
,
Wiedemann
M
,
Reithmann
C
,
Sause
A
,
Tebbenjohanns
J
,
Schade
A
,
Shin
DI
,
Staudt
A
,
Zacharzowsky
U
,
Ulbrich
M
,
Wetzel
U
,
Neuser
H
,
Bode
K
,
Kuhlen
R
,
Hindricks
G.
Cardiac tamponade in catheter ablation of atrial fibrillation: German-wide analysis of 21 141 procedures in the Helios atrial fibrillation ablation registry (SAFER)
.
Europace
2018
;
20
:
1944
1951
.

757

Ueberham
L
,
Schuler
E
,
Hindricks
G
,
Kuhlen
R
,
Bollmann
A.
SAFER
.
Eur Heart J
2018
;
39
:
2023
2024
.

758

Hummel
J
,
Michaud
G
,
Hoyt
R
,
DeLurgio
D
,
Rasekh
A
,
Kusumoto
F
,
Giudici
M
,
Dan
D
,
Tschopp
D
,
Calkins
H
,
Boersma
L
; TTOP-AF Investigators.
Phased RF ablation in persistent atrial fibrillation
.
Heart Rhythm
2014
;
11
:
202
209
.

759

Boersma
LV
,
van der Voort
P
,
Debruyne
P
,
Dekker
L
,
Simmers
T
,
Rossenbacker
T
,
Balt
J
,
Wijffels
M
,
Degreef
Y.
Multielectrode pulmonary vein isolation versus single tip wide area catheter ablation for paroxysmal atrial fibrillation: a multinational multicenter randomized clinical trial
.
Circ Arrhythm Electrophysiol
2016
;
9
:
e003151
.

760

Nagashima
K
,
Okumura
Y
,
Watanabe
I
,
Nakahara
S
,
Hori
Y
,
Iso
K
,
Watanabe
R
,
Arai
M
,
Wakamatsu
Y
,
Kurokawa
S
,
Mano
H
,
Nakai
T
,
Ohkubo
K
,
Hirayama
A.
Hot balloon versus cryoballoon ablation for atrial fibrillation: lesion characteristics and middle-term outcomes
.
Circ Arrhythm Electrophysiol
2018
;
11
:
e005861
.

761

Ucer
E
,
Janeczko
Y
,
Seegers
J
,
Fredersdorf
S
,
Friemel
S
,
Poschenrieder
F
,
Maier
LS
,
Jungbauer
CG.
A RAndomized Trial to compare the acute reconnection after pulmonary vein ISolation with Laser-BalloON versus radiofrequency Ablation: RATISBONA trial
.
J Cardiovasc Electrophysiol
2018
;
29
:
733
739
.

762

De Greef
Y
,
Stroker
E
,
Schwagten
B
,
Kupics
K
,
De Cocker
J
,
Chierchia
GB
,
de Asmundis
C
,
Stockman
D
,
Buysschaert
I.
Complications of pulmonary vein isolation in atrial fibrillation: predictors and comparison between four different ablation techniques: results from the Middelheim PVI-registry
.
Europace
2018
;
20
:
1279
1286
.

763

Steinbeck
G
,
Sinner
MF
,
Lutz
M
,
Muller-Nurasyid
M
,
Kaab
S
,
Reinecke
H.
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
.

764

Fink
T
,
Metzner
A
,
Willems
S
,
Eckardt
L
,
Ince
H
,
Brachmann
J
,
Spitzer
SG
,
Deneke
T
,
Schmitt
C
,
Hochadel
M
,
Senges
J
,
Rillig
A.
Procedural success, safety and patients satisfaction after second ablation of atrial fibrillation in the elderly: results from the German ablation registry
.
Clin Res Cardiol
2019
;108:1354–1363.

765

Szegedi
N
,
Szeplaki
G
,
Herczeg
S
,
Tahin
T
,
Sallo
Z
,
Nagy
VK
,
Osztheimer
I
,
Ozcan
EE
,
Merkely
B
,
Geller
L.
Repeat procedure is a new independent predictor of complications of atrial fibrillation ablation
.
Europace
2019
;
21
:
732
737
.

766

Cappato
R
,
Calkins
H
,
Chen
SA
,
Davies
W
,
Iesaka
Y
,
Kalman
J
,
Kim
YH
,
Klein
G
,
Natale
A
,
Packer
D
,
Skanes
A
,
Ambrogi
F
,
Biganzoli
E.
Updated worldwide survey on the methods, efficacy, and safety of catheter ablation for human atrial fibrillation
.
Circ Arrhythm Electrophysiol
2010
;
3
:
32
38
.

767

Lee
G
,
Sparks
PB
,
Morton
JB
,
Kistler
PM
,
Vohra
JK
,
Medi
C
,
Rosso
R
,
Teh
A
,
Halloran
K
,
Kalman
JM.
Low risk of major complications associated with pulmonary vein antral isolation for atrial fibrillation: results of 500 consecutive ablation procedures in patients with low prevalence of structural heart disease from a single center
.
J Cardiovasc Electrophysiol
2011
;
22
:
163
168
.

768

Deshmukh
A
,
Patel
NJ
,
Pant
S
,
Shah
N
,
Chothani
A
,
Mehta
K
,
Grover
P
,
Singh
V
,
Vallurupalli
S
,
Savani
GT
,
Badheka
A
,
Tuliani
T
,
Dabhadkar
K
,
Dibu
G
,
Reddy
YM
,
Sewani
A
,
Kowalski
M
,
Mitrani
R
,
Paydak
H
,
Viles-Gonzalez
JF.
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
.

769

Tripathi
B
,
Arora
S
,
Kumar
V
,
Abdelrahman
M
,
Lahewala
S
,
Dave
M
,
Shah
M
,
Tan
B
,
Savani
S
,
Badheka
A
,
Gopalan
R
,
Shantha
GPS
,
Viles-Gonzalez
J
,
Deshmukh
A.
Temporal trends of in-hospital complications associated with catheter ablation of atrial fibrillation in the United States: an update from Nationwide Inpatient Sample database (2011–2014
).
J Cardiovasc Electrophysiol
2018
;
29
:
715
724
.

770

Voskoboinik
A
,
Sparks
PB
,
Morton
JB
,
Lee
G
,
Joseph
SA
,
Hawson
JJ
,
Kistler
PM
,
Kalman
JM.
Low rates of major complications for radiofrequency ablation of atrial fibrillation maintained over 14 years: a single centre experience of 2750 consecutive cases
.
Heart Lung Circ
2018
;
27
:
976
983
.

771

Berger
WR
,
Meulendijks
ER
,
Limpens
J
,
van den Berg
NWE
,
Neefs
J
,
Driessen
AHG
,
Krul
SPJ
,
van Boven
WJP
,
de Groot
JR.
Persistent atrial fibrillation: a systematic review and meta-analysis of invasive strategies
.
Int J Cardiol
2019
;
278
:
137
143
.

772

Shah
AN
,
Mittal
S
,
Sichrovsky
TC
,
Cotiga
D
,
Arshad
A
,
Maleki
K
,
Pierce
WJ
,
Steinberg
JS
.
Long-term outcome following successful pulmonary vein isolation: pattern and prediction of very late recurrence
.
J Cardiovasc Electrophysiol
2008
;
19
:
661
667
.

773

Sawhney
N
,
Anousheh
R
,
Chen
WC
,
Narayan
S
,
Feld
GK.
Five-year outcomes after segmental pulmonary vein isolation for paroxysmal atrial fibrillation
.
Am J Cardiol
2009
;
104
:
366
372
.

774

Ouyang
F
,
Tilz
R
,
Chun
J
,
Schmidt
B
,
Wissner
E
,
Zerm
T
,
Neven
K
,
Kokturk
B
,
Konstantinidou
M
,
Metzner
A
,
Fuernkranz
A
,
Kuck
KH.
Long-term results of catheter ablation in paroxysmal atrial fibrillation: lessons from a 5-year follow-up
.
Circulation
2010
;
122
:
2368
2377
.

775

Bertaglia
E
,
Tondo
C
,
De Simone
A
,
Zoppo
F
,
Mantica
M
,
Turco
P
,
Iuliano
A
,
Forleo
G
,
La Rocca
V
,
Stabile
G.
Does catheter ablation cure atrial fibrillation? Single-procedure outcome of drug-refractory atrial fibrillation ablation: a 6-year multicentre experience
.
Europace
2010
;
12
:
181
187
.

776

Weerasooriya
R
,
Khairy
P
,
Litalien
J
,
Macle
L
,
Hocini
M
,
Sacher
F
,
Lellouche
N
,
Knecht
S
,
Wright
M
,
Nault
I
,
Miyazaki
S
,
Scavee
C
,
Clementy
J
,
Haissaguerre
M
,
Jais
P.
Catheter ablation for atrial fibrillation: are results maintained at 5 years of follow-up?
J Am Coll Cardiol
2011
;
57
:
160
166
.

777

Medi
C
,
Sparks
PB
,
Morton
JB
,
Kistler
PM
,
Halloran
K
,
Rosso
R
,
Vohra
JK
,
Kumar
S
,
Kalman
JM.
Pulmonary vein antral isolation for paroxysmal atrial fibrillation: results from long-term follow-up
.
J Cardiovasc Electrophysiol
2011
;
22
:
137
141
.

778

Schreiber
D
,
Rostock
T
,
Frohlich
M
,
Sultan
A
,
Servatius
H
,
Hoffmann
BA
,
Luker
J
,
Berner
I
,
Schaffer
B
,
Wegscheider
K
,
Lezius
S
,
Willems
S
,
Steven
D.
Five-year follow-up after catheter ablation of persistent atrial fibrillation using the stepwise approach and prognostic factors for success
.
Circ Arrhythm Electrophysiol
2015
;
8
:
308
317
.