Preventive Measures and Treatment Options for Atrial Fibrillation

Background: With approximately 1.6 million people affected in Germany, atrial fibrillation (AF) is the most common arrhythmia. The management of AF, from prevention to treatment, including anticoagulation, is therefore of major clinical importance in terms of these patients’ quality of life and their mortality.

Methods: This first German clinical practice guideline on AF was developed in accordance with the Regelwerk Leitlinien (rules for guidelines) of the Association of the Scientific Medical Societies in Germany (Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften e. V., AWMF). The available evidence on all relevant issues was retrieved by a systematic literature search and evaluated with the participation of many medical specialty societies.

Results: AF is classified on clinical grounds as paroxysmal, persistent, longstanding persistent, or permanent. It is associated with a 1.5– to 2-fold increase in mortality and a 4– to 5-fold increase in the risk of stroke. Nonetheless, general screening for AF is not currently recommended, as the data on this question are conflicting. Lifestyle interventions and the reduction of risk factors lessen the frequency of AF. Female sex is only a minor risk factor; the CHA₂DS₂-VA-Score is recommended to assess the risk of thromboembolic events. If it is 2 or higher, oral anticoagulation (OAC) is indicated, of a type that should be decided on an individual basis. In patients with cardiovascular risk factors, early rhythm control has been shown to reduce prognostically relevant cardiovascular endpoints (3.9 versus 5.0 per 100 patient-years). Multiple studies have shown that catheter ablation is superior to drug-based antiarrhythmic therapy in patients with paroxysmal symptomatic AF as well as in those with heart failure and AF.

Conclusion: It is hoped that the recommendations contained in this guideline will lead to intensified measures for the prevention of AF, resulting in a lower prevalence of AF and its adverse sequelae. The available evidence supports the evaluation of the indications for OAC, early rhythm control, and the use of catheter ablation, especially in patients with paroxysmal AF or heart failure.

Cite this as: Willems S, Wegner F, Eckardt L: Clinical practice guideline: Preventive measures and treatment options for atrial fibrillation. Dtsch Arztebl Int 2025; 122: 439–44. DOI: 10.3238/arztebl.m2025.0082

Atrial fibrillation (AF) affects approximately 1.6 million people in Germany. It is the most common persistent cardiac arrhythmia and is associated with high morbidity (1) and, often, an impaired quality of life. AF is expected to become much more common because of the aging of the population and the rise in comorbidities (2, 3). Individualized treatment is needed, not just to treat the symptoms of AF, but also to prevent thromboembolism and heart failure, along with treatment of comorbid conditions (4, 5, 6). Thus, in recent years, a holistic approach to the treatment of AF has been widely adopted (Box). Moreover, the methods of managing AF have been expanded, across the spectrum from prevention and anticoagulation to rhythm control with an early intervention (Figure 1). This first-ever AF guideline of the Association of Scientific Medical Societies in Germany (Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften e. V., AWMF) is intended to improve patient care on the basis of the current scientific evidence. For specific questions and scenarios, the reader is referred to the text of the guideline itself (7).

Box

What is new?

Figure 1

Overview of the main recommendations

Methods

The German clinical practice guideline on atrial fibrillation meets the requirements stated in the guideline regulations of the AWMF (8): it was issued by multidisciplinary panel comprising 15 medical-scientific societies and institutions and two patient organizations, conflicts of interest were dealt with transparently, evidence retrieved by a systematic search was evaluated according to the GRADE criteria (“Grading of Recommendations Assessment, Development and Evaluation”), and there was a structured, formal consensus process. 19 systematic searches on specific interventions and cross-topic systematic reviews were conducted from April 2022 to December 2023. The searches were conducted in the following databases, depending on the topic: MedLine, Cochrane clinical trials (primary studies), Cochrane database of systematic reviews, Epistemonikos, as well as in the websites of the Institute for Quality and Efficiency in Health Care (IQWiG), the European Medicines Agency (EMA), the National Institute for Health and Care Excellence (NICE), and the Agency for Healthcare Research and Quality (AHRQ) for systematic reviews and regulatory documents. In the formulation of the recommendations, consideration was taken not only of the evidence retrieved by systematic search and its evaluation, but also of clinical expertise, aspects of care, and the perspective of patient representatives.

Definition, classification, and diagnosis

Atrial fibrillation is characterized by rapid and uncoordinated electrical activation of the atrial myocardium, resulting in limited or absent atrial contraction and thereby creating a risk of thrombus formation. In addition, the physiological coordination between the atria and the ventricles is disrupted. This typically leads to an irregular, often accelerated heartbeat, which has adverse hemodynamic effects and increases the risk of stroke (9, 10, 11, 12). The diagnosis of AF is made by electrocardiography (EKG) (13, 14).

AF is called “subclinical” when it is detected in asymptomatic patients in whom AF has not previously been diagnosed by EKG. Subclinical AF can be detected by cardiac implantable electronic devices (CIEDs, such as pacemakers, defibrillators, and implantable event recorders) or wearable monitors (such as smartwatches), which is why the term “device-detected” AF (DDAF) has recently come into use.

The current classification mainly considers the phenotype of clinical AF in terms of the distribution pattern or duration of AF episodes. However, many patients with persistent AF do not differ from those with paroxysmal AF (PAF) with respect to the success of antiarrhythmic therapy (9, 15). Epidemiological studies have shown that an estimated 15–30% of patients with PAF develop persistent AF within 1–3 years (16, 17, 18). Most patients with AF have symptoms such as palpitations, dyspnea, or reduced performance. The modified EHRA (European Heart Rhythm Association) score has been established as a measure of the limitation of everyday activities, the impairment of the quality of life, and the success of treat (eTable 1). In patients with AF, it is recommended that risk factors should be identified (e.g., arterial hypertension, diabetes mellitus, sleep apnea syndrome, alcohol consumption) and that concomitant illnesses (such as heart failure) and psychosocial factors should be documented.

eTable 1

Modified European Heart Rhythm Association (EHRA) scoring system, adapted from Van Gelder, et al., European Heart Journal 2024

Screening

The systematic, population-wide AF screening programs that have tested to date prevent stroke less than previously expected (19, 20, 21, 22), for multiple reasons. On the one hand, half of the people contacted in the population-based programs declined the invitation to be screened (20, 23). On the other hand, patients whose AF is detected by screening have a lower risk of stroke than those whose AP is detected by EKG in routine everyday clinical practice (21, 22). Systematic, population-based screening is therefore not recommended.

Prevention and lifestyle measures

AF is clearly associated with obesity, hypertension, diabetes mellitus, sleep apnea, and physical inactivity (24), as well as with mental illnesses such as depression, anxiety disorders, and post-traumatic stress disorder and with lower socioeconomic status. Evidence from randomized, controlled trials suggests that lifestyle interventions reduce various risk factors for AF and lower its frequency.

There seems to be a dose-dependent association between alcohol consumption and AF. A meta-analysis from 2022 showed a 6% increase in the incidence of AF in persons who drank one alcoholic drink per day (relative risk [RR] 1.06; 95% confidence interval [CI] [1.03; 1.08]). There are sex-specific differences; in men, the relationship between alcohol consumption and AF is linear (25). Prognostic studies (e.g., the Rotterdam study [26]) have also linked smoking to a higher risk of AF.

Stroke prevention

The risk of thromboembolic events, particularly strokes, is approximately four to five times higher in patients with AF, depending on their age and other risk factors. Stroke in AF patients also carries higher morbidity and mortality than stroke of other causes (27, 28, 29, 30). The prevention of ischemic stroke and other thromboembolic events in AT patients is, therefore, very important. Sex affects the risk only weakly (31); the CHA₂DS₂-VA score is recommendd as a risk estimator (eTable 2). ). The treating physician and the patient decide together whether, and how, to treat with oral anticoagulation, according to the principle of shared decision-making. If the CHA₂DS₂-VA score is 2 or higher, the benefits of oral anticoagulation outweigh the risk of bleeding, and anticoagulation is generally indicated (eTable 3). With a CHA₂DS₂-VA score of 1, the benefits and risks of oral anticoagulation are closely balanced, and decisions whether to anticoagulate should be made on an individual basis (32).

eTable 2

CHA₂DS₂-VA score for estimating the risk of thromboembolic events in patients with atrial fibrillation

eTable 3

The effect of anticoagulation in one year, depending on the prior stratification of stroke risk (modified from NICE 2021)

The direct oral anticoagulants (DOACs) investigated in approval studies (33, 34, 35, 36) were found to cause fewer hemorrhagic complications than warfarin, and, in particular, only half as many intracranial hemorrhages (37, 38). German healthcare data (e1, e2, e3, e4, e5, e6, e7) indicate that the advantages demonstrated in randomized studies of DOAC compared to warfarin may be of lesser size when DOAC are compared to phenprocoumon. For example, the TTR (“time in therapeutic range,” INR 2–3) values were higher in both the intervention and the control groups (74% and 75%, respectively) than in the warfarin comparison group (TTR 55–65%) in the DOAC approval studies. Therefore, in contrast to other international guidelines (e8, e9), the German guideline group has decided not to recommend DOACs as first-line therapy for oral anticoagulation in AF. Instead, the decision on whether to use a DOAC or phenprocoumon should be left to the treating physician and the patient.

Interventional or surgical closure of the left atrial appendage can lower the risk of thrombus formation in the left atrial appendage and the risk of thromboembolism. Occlusion of the left atrial appendage performed during cardiac surgery can lower the rate of thromboembolism (attributable risk [AR] 4.8% vs. 7.0%; hazard ratio [HR] 0.67 (95% CI: [0.53–0.85]), provided that oral anticoagulation is given after the intervention (e10, e11, e12).

Rhythm control

An overview of the recommendations for rhythm control is provided in Figure 2. In patients with unclear symptoms, cardioversion may be considered so the situation and any changes in left ventricular pump function can be evaluated again afterward in sinus rhythm (symptom-rhythm correlation). In patients who present as an emergency with acute symptoms, electrical cardioversion can also be used to terminate the current AF episode and alleviate symptoms (e13, e14). In hemodynamically stable patients with acute, symptomatic AF, one can wait 48 hours at first to see whether sinus rhythm returns without cardioversion (e15). When cardioversion is planned, a long-term treatment plan should be established as well, as the recurrence rate without concomitant antiarrhythmic therapy is 30% at 3 months 50–70% at one year (e16, e17).

Figure 2

Overview of recommendations in the guideline concerning the indications for rhythm control

After cardioversion of AF lasting longer than 24 hours, there is a higher risk of a thromboembolic event. All such patients, therefore, whatever their estimated annual risk of such an event, should be orally anticoagulated for three weeks, or else an intracardiac thrombus should be ruled out before cardioversion, generally by echocardiography (e18, e19, e20). Whatever the risk profile, oral anticoagulation is always recommended for at least 4 weeks after electrical cardioversion. The individual stroke risk (CHA₂DS₂-VA score) determines whether it should be continued thereafter (e18).

Assessing the indication for rhythm control

Progression of AF is known to be associated with the development of an arrhythmogenic substrate in the left atrium (e.g., through progressive atrial fibrosis) (e21, e22). Early (first-line) catheter ablation of PAF can prevent progression from paroxysmal to persistent AF (e23, e24). In the EAST-AFNET-4 trial (EAST, “early treatment of atrial fibrillation for stroke prevention”), the presence of sinus rhythm after one year was the most important predictor of reduction in the primary endpoint (stroke, death from cardiovascular disease, hospitalization due to heart failure or acute coronary syndrome) (e25, e26). In the group with early rhythm control, 86% of participants had sinus rhythm on EKG at one year (p < 0.001), compared with 66% in the control group. Thus, early and effective rhythm control should be considered in all patients with newly diagnosed AF (Figure 2).

To date, rhythm control treatment for AF has been reserved primarily for symptomatic patients. However, with growing evidence that rhythm control also lessens hospitalization and mortality (e25), it is now recommended for asymptomatic persons as well. In a subgroup analysis of the EAST-AFNET-4 trial, early rhythm control therapy was shown to have a benefit on cardiovascular endpoints in patients aged 70 and above with relevant cardiovascular risk factors, whether or not they had symptoms (e27).

Tachycardia- or arrhythmia-induced cardiomyopathy (AiCM) (e28, e29) lessens the left ventricular ejection fraction, but this can be reversed by the restoration of a stable sinus rhythm. In cases of newly diagnosed, primarily tachycardic AF with impaired left ventricular pump function, arrhythmia-induced cardiomyopathy (AiCM) should be considered as a possible diagnosis (e28).

Rhythm control in AF and heart failure

AF and heart failure due to structural heart disease are known to reinforce each other (e30, e31, e32, e33, e34, e35, e36, e37). For the diagnosis of AF-related cardiomyopathy, rhythm control can be attempted first, followed by re-evaluation of left ventricular function in sinus rhythm with echocardiography in 3–6 months. If the suspicion is confirmed by an improvement of the ejection fraction, permanent rhythm control is recommended (e38, e39, e40). Current evidence suggests that rhythm control therapy improves on left ventricular function, with reverse remodeling (e41). Catheter ablation is recommended for long-term rhythm control (Figures 2 and 3) (e18, e42). The findings of recent randomized trials suggest that patients suffering from these two conditions benefit from rhythm control by catheter ablation (e43, e44).(e43, e44).

Catheter ablation for rhythm control

Randomized trials (e45, e46) have shown that catheter ablation, compared to pharmacotherapy, yields more frequent freedom from arrhythmia (53% vs. 32.2%), fewer hospitalizations, and improved quality of life in patients with symptomatic, paroxysmal AF who have not previously been treated with antiarrhythmic drugs (number needed to treat [NNT], 5). Catheter ablation is therefore recommended as first-line therapy for symptomatic, paroxysmal atrial fibrillation (PAF) (Figures 2 and 3). Studies have also shown that catheter ablation of PAF can prevent progression to persistent AF (e23, e24). Catheter ablation is, moreover, associated with a reduction in recurrence rates, hospital stays, and the need for cardioversion in patients persistent AF (e47). The available evidence on how persistent AF should be treated with interventions beyond pulmonary vein isolation is not determinative (e48, e49, e50). There is evidence suggesting that some patients with persistent AF may benefit from substrate ablation in the left atrium (e51).

Although rhythm control and the presence of sinus rhythm are important in the treatment of AF, there are patient groups in whom rhythm control is not expected to succeed over the long term because of disease progression and can therefore be dispensed with. For example, left atrial dilatation is associated with less successful rhythm control and a higher AF recurrence rate (e52, e53, e54). The LA volume should be used as a measure of left atrial dilatation (e55, e56). The upper bound of normal LA volume is 34 ml/m2 for both sexes; this should be used as the cut-off value for a dilated left atrium, according to the EHRA recommendation (e57).

Rhythm control with drugs

Class IC antiarrhythmic drugs (flecainide and propafenone) are an important pharmacotherapeutic option for rhythm control (Figure 4). They are effective in early rhythm control and have a low risk profile (e58). Unlike amiodarone, they should only be used in patients with a structurally healthy heart; where indicated, they can be used only as needed and, if necessary, as medication on demand (e59, e60) (Figure 3). Of all the available antiarrhythmic drugs, amiodarone is the most effective, but also the most prone to side effects (e61, e62). Its wide-ranging side effects can affect, e.g., the thyroid, lungs, and liver; as it can also have proarrhythmic effects, safety considerations and close therapeutic monitoring are needed (e63, e64, e65, e66, e67, e68). Since alternative therapies such as catheter ablation are available, the guideline group, after weighing the risks and benefits, recommends against long-term amiodarone treatment for most patients.

Figure 3

Overview of the options for antiarrhythmic treatment

Figure 4

Simplified flowchart

Longstanding atrial fibrillation

The success rates of catheter ablation as a sole treatment are much lower in longstanding AF (≥ 12 months) than in paroxysmal or persistent AF. Hybrid procedures with catheter ablation followed by surgical ablation were found, in a meta-analysis, to lower the AF recurrence rate (e69, e70). When rhythm control is indicated in a symptomatic patient in the context of cardiac surgery, simultaneous intraoperative AF ablation is recommended, as it has been found to lower the rate of atrial tachyarrhythmias from 51.0 to 24.1% (e71).

Rate control

If rhythm control therapy is not used, adequate rate control can reduce the exacerbation of heart failure and the occurrence of tachycardia-induced cardiomyopathy and, above all, ameliorate symptoms and improve in exercise capacity and quality of life (e72, e73, e74, e75, e76, e77) (Figure 4).

If rhythm control therapy is not used, adequate rate control can minimize the likelihood of exacerbation of heart failure and tachycardia-induced cardiomyopathy. Above all, it can lead to a reduction in symptoms and an improvement in exercise capacity and the quality of life (e72, e73, e74, e75, e76, e77) (Figure 4).

In general, a three-step treatment algorithm is recommended for rate control (Figure 4). IIn the first step, moderate rate control is used. If AF-related symptoms persist, stricter rate control is implemented. A third option is pacemaker therapy with AV node ablation (e72, e73, e74, e75, e76, e77).

Summary

The high prevalence and incidence of AF and the highly variable quality of treatment at present call for stepped-up efforts to improve the care of patients with this condition. The authors of the German clinical practice guideline on atrial fibrillation hope to bring about improvement in the following ways:

• by supporting participatory decision-making and strengthening the role of patients
• by improving treatment adherence by fostering the communication and adoption of shared treatment goals
• by lowering the incidence of AF with evidence-based primary prevention measures
• by promoting beneficial lifestyle changes
• by improving management, including thromboembolism prevention
• by promoting a paradigm shift from rate control to early rhythm control.

Acknowledgments

These guidelines could not have been produced without the continuous collaboration of the entire team (see eBox 2). Special thanks are due to the staff of the ÄZQ, Corinna Schaefer, Katrin Pieper, and Peggy Prien. In particular, we would like to thank Ms. Schaefer for her tireless commitment, even after the ÄZQ was dissolved.

eBox 1

Participating specialty societies

eBox 2

Contributors to the guideline (collaborators)

Conflict of interest statement

SW refers to the declaration of his conflicts of interest to the AWMF. He also states that the German Society of Cardiology reimbursed his travel expenses.

FW states that he has received lecture honoraria from Abbott and reimbursement of travel expenses from Boston Scientific and Bayer. He is a member of the DGK, ESC, and EHRA and reports that he is engaged in clinical scientific activities on supraventricular arrhythmias, thromboembolism in atrial fibrillation, and cardiac implantable devices.

LE refers to the declaration of his conflicts of interest to the AWMF. He reports that he has given lectures for various companies in the pharmaceutical and medical technology industries. He also states that he has received reimbursement of travel expenses and meeting participation fees in connection with his participation in numerous national and international studies in various capacities. He is a member of the DGK, ESC, and EHRA, and reports in this context: committee work in the umbrella organizations; research on rhythmology, pathophysiology of rhythm disorders, atrial fibrillation, and ventricular tachycardia; clinical work in cardiology/rhythmology, electrical device therapy, catheter ablation, atrial fibrillation, and ventricular tachycardia; and participation in continuing education/training: member of the planning group of the DGK “Academy.”

Manuscript received on 20 March 2025 and accepted after revision on 5 May 2025.

Clinical practice guidelines in the Deutsches Ärzteblatt, as in many other journals, are not subject to a peer review process, since clinical practice (S3 level) guidelines are texts which have already been evaluated, discussed, and broadly agreed upon multiple times by experts (peers).

Translated from the original German by Ethan Taub, M.D.

Corresponding author
Prof. Dr. med. Stephan Willems

References

1. Dai H, Zhang Q, Much AA, et al.: Global, regional, and national prevalence, incidence, mortality, and risk factors for atrial fibrillation, 1990–2017: results from the Global Burden of Disease Study 2017. Eur Heart J Qual Care Clin Outcomes 2021; 7: 574–82

2. Benjamin EJ, Muntner P, Alonso A, et al.: Heart disease and stroke statistics—2019 update: A report from the American Heart Association. Circulation 2019; 139: e56–e528

3. Staerk L, Sherer JA, Ko D, Benjamin EJ, Helm RH: Atrial fibrillation: Epidemiology, pathophysiology, and clinical outcomes. Circ Res 2017; 120: 1501–17

4. Ding M, Ebeling M, Ziegler L, Wennberg A, Modig K: Time trends in atrial fibrillation-related stroke during 2001–2020 in Sweden: A nationwide, observational study. Lancet Reg Health Eur 2023; 28: 100596

5. Joglar JA, Chung MK, Armbruster AL, et al.: 2023 ACC/AHA/ACCP/HRS Guideline for the diagnosis and management of atrial fibrillation: A report of the ACC/AHA joint committee on clinical practice guidelines. Circulation 2024; 149: e1–e156

6. Odutayo A, Wong CX, Hsiao AJ, Hopewell S, Altman DG, Emdin CA: Atrial fibrillation and risks of cardiovascular disease, renal disease, and death: Systematic review and meta-analysis. BMJ 2016; 354: i4482

7. Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften (AWMF): S3-Leitlinie Vorhofflimmern (cited: 2025–04–30). www.register.awmf.org/de/leitlinien/detail/019-014 .

8. Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften (AWMF): Ständige Kommission Leitlinien. AWMF-Regelwerk Leitlinien: Version 2.0. 2020 (cited: 2021–03–22). www.awmf.org/leitlinien/awmf-regelwerk.html .

9. Boriani G, Pettorelli D: Atrial fibrillation burden and atrial fibrillation type: Clinical significance and impact on the risk of stroke and decision making for longterm anticoagulation. Vascul Pharmacol 2016; 83: 26–35

10. Staerk L, Sherer JA, Ko D, Benjamin EJ, Helm RH: Atrial fibrillation: epidemiology, pathophysiology, and clinical outcomes. Circ Res 2017; 120: 1501–17

11. Tsao CW, Aday AW, Almarzooq ZI, et al.: Heart disease and stroke statistics—2023 update: A report from the American Heart Association. Circulation 2023; 147: e93–e621

12. Ding M, Ebeling M, Ziegler L, Wennberg A, Modig K: Time trends in atrial fibrillation-related stroke during 2001–2020 in Sweden: A nationwide, observational study. Lancet Reg Health Eur 2023; 28: 100596

13. Joglar JA, Chung MK, Armbruster AL, et al.: 2023 ACC/AHA/ACCP/HRS guideline for the diagnosis and management of atrial fibrillation: A report of the ACC/AHA Joint committee on clinical practice guidelines. Circulation 2024; 149: e1–e156

14. Van Gelder IC, Rienstra M, Bunting KV, et al.: 2024 ESC guidelines for the management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J 2024; 45: 3314–414

15. 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: 2840–8

16. De Vos CB, Breithardt G, Camm AJ, et al.: Progression of atrial fibrillation in the registry on cardiac rhythm disorders assessing the control of atrial fibrillation cohort: clinical correlates and the effect of rhythm control therapy. Am Heart J 2012; 163: 887–93

17. Sakamoto H, Kurabayashi M, Nagai R, Fujii J: Prediction of transition to chronic atrial fibrillation in patients with paroxysmal atrial fibrillation. Circulation 1998; 98: 1045–6

18. Abe Y, Fukunami M, Yamada T, et al.: Prediction of transition to chronic atrial fibrillation in patients with paroxysmal atrial fibrillation by signal-averaged electrocardiography: a prospective study. Circulation 1997; 96: 2612–6

19. Tsivgoulis G, Palaiodimou L, Triantafyllou S, et al.: Prolonged cardiac monitoring for stroke prevention: A systematic review and meta-analysis of randomized-controlled clinical trials. Eur Stroke J 2023; 8: 106–16

20. Force USPST, Davidson KW, Barry MJ, et al.: Screening for atrial fibrillation: US preventive services task force recommendation statement. JAMA 2022; 327: 360–7

21. Svendsen JH, Diederichsen SZ, Hojberg S, et al.: Implantable loop recorder detection of atrial fibrillation to prevent stroke (The LOOP Study): A randomised controlled trial. Lancet 2021; 398: 1507–16

22. Wong ZY, Yuen LZ, Tan YK, et al.: Detection of atrial fibrillation after ischemic stroke with an insertable cardiac monitor: A systematic review and individual patient data meta-analysis of randomised clinical trials. Cerebrovasc Dis 2024; 53: 316–26

23. Svennberg E, Friberg L, Frykman V, Al-Khalili F, Engdahl J, Rosenqvist M: Clinical outcomes in systematic screening for atrial fibrillation (STROKESTOP): A multicentre, parallel group, unmasked, randomised controlled trial. Lancet 2021; 398: 1498–506

24. Boursiquot BC, Bellettiere J, LaMonte MJ, LaCroix AZ, Perez MV: Sedentary behavior and atrial fibrillation in older women: The OPACH study. J Am Heart Assoc 2022; 11: e023833

25. Jiang H, Mei X, Jiang Y, et al.: Alcohol consumption and atrial fibrillation risk: An updated dose-response meta-analysis of over 10 million participants. Front Cardiovasc Med 2022; 9: 979982

26. Heeringa J, Kors JA, Hofmann A, van Rooij FJA, Wittemann JCM: Cigarette smoking and risk of atrial fibrillation: The Rotterdam study. Am Heart J 2008; 156: 1163–9

27. Banerjee A, Taillandier S, Olesen JB, et al.: Pattern of atrial fibrillation and risk of outcomes: the Loire Valley Atrial Fibrillation Project. Int J Cardiol 2013; 167: 2682–7

28. Wolf PA, Abbott RD, Kannel WB: Atrial fibrillation as an independent risk factor for stroke: The Framingham Study. Stroke 1991; 22: 983–8

29. Wolf PA, Abbott RD, Kannel WB: Atrial fibrillation: A major contributor to stroke in the elderly. The Framingham study. Arch Intern Med 1987; 147: 1561–4

30. Friberg L, Hammar N, Rosenqvist M: Stroke in paroxysmal atrial fibrillation: Report from the Stockholm cohort of atrial fibrillation. Eur Heart J 2010; 31: 967–75

31. Champsi A, Mobley AR, Subramanian A, et al.: Gender and contemporary risk of adverse events in atrial fibrillation. Eur Heart J 2024; 45: 3707–17

32. Anjum M, Ariansen I, Hjellvik V, et al.: Stroke and bleeding risk in atrial fibrillation with CHA 2 DS 2 -VASC risk score of one: the Norwegian AFNOR study. Eur Heart J 2024; 45: 57–66

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

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

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

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

37. Bruins Slot KM, Berge E: Factor Xa inhibitors versus vitamin K antagonists for preventing cerebral or systemic embolism in patients with atrial fibrillation. Cochrane Database Syst Rev 2018; 3: CD008980

38. Salazar CA, del Aguila D, Cordova EG: Direct thrombin inhibitors versus vitamin K antagonists for preventing cerebral or systemic embolism in people with non-valvular atrial fibrillation. Cochrane Database Syst Rev 2014; 2014: CD009893

e1. Hohnloser SH, Basic E, Hohmann C, Nabauer M: Effectiveness and safety of non-vitamin K oral anticoagulants in comparison to phenprocoumon: Data from 61,000 patients with atrial fibrillation. Thromb Haemost 2018; 118: 526–38

e2. Paschke LM, Klimke K, Altiner A, von Stillfried D, Schulz M: Comparing stroke prevention therapy of direct oral anticoagulants and vitamin K antagonists in patients with atrial fibrillation: A nationwide retrospective observational study. BMC Med 2020; 18: 254

e3. Ujeyl M, Köster I, Wille H, et al.: Comparative risks of bleeding, ischemic stroke and mortality with direct oral anticoagulants versus phenprocoumon in patients with atrial fibrillation. Eur J Clin Pharmacol 2018; 74: 1317–25

e4. Warkentin L, Hueber S, Deiters B, Klohn F, Kühlein T: Vitamin-K-antagonist phenprocoumon versus low-dose direct oral anticoagulants (DOACs) in patients with atrial fibrillation: a real-world analysis of German claims data. Thromb J 2022; 20: 31

e5. Warkentin L, Klohn F, Deiters B, Kühlein T, Hueber S: Vitamin-K-antagonist phenprocoumon versus direct oral anticoagulants in patients with atrial fibrillation: A real-world analysis of German claims data. BMJ Open 2023; 13: e063490

e6. Voss A, Kollhorst B, Platzbecker K, Amann U, Haug U: Risk profiles of new users of oral anticoagulants between 2011 and 2019 in Germany. Clin Epidemiol 2023; 15: 827–37

e7. Engelbertz C, Marschall U, Feld J, et al.: Apixaban, edoxaban and rivaroxaban but not dabigatran are associated with higher mortality compared to vitamin-K antagonists: A retrospective German claims data analysis. J Intern Med 2024; 296: 362–76

e8. Van Gelder IC, Rienstra M, Bunting KV, et al.: 2024 ESC Guidelines for the management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J 2024; 45: 3314–414

e9. Joglar JA, Chung MK, Armbruster AL, et al.: 2023 ACC/AHA/ACCP/HRS Guideline for the diagnosis and management of atrial fibrillation: a report of the American College of Cardiology/American Heart Association Joint Committee on clinical practice guidelines. J Am Coll Cardiol 2024; 83: 109–279

e10. Whitlock RP, Belley-Cote EP, Paparella D, et al.: Left atrial appendage occlusion during cardiac surgery to prevent stroke. N Engl J Med 2021; 384: 2081–91

e11. Boersma LV, Ince H, Kische S, et al.: Evaluating real-world clinical outcomes in atrial fibrillation patients receiving the WATCHMAN left atrial appendage closure technology: Final 2-Year outcome data of the EWOLUTION trial focusing on history of stroke and hemorrhage. Circ Arrhythm Electrophysiol 2019; 12: e006841

e12. Landmesser U, Tondo C, Camm J, et al.: Left atrial appendage occlusion with the AMPLATZER Amulet device: One-year follow-up from the prospective global Amulet observational registry. EuroIntervention 2018; 14: e590–e7

e13. Vinter N, Holst-Hansen MZB, Johnsen SP, Lip GYH, Frost L, Trinquart L: Electrical energy by electrode placement for cardioversion of atrial fibrillation: A systematic review and meta-analysis. Open Hear 2023; 10: e002456

e14. Nguyen ST, Belley-Côté EP, Ibrahim O, et al.: Techniques improving electrical cardioversion success for patients with atrial fibrillation: A systematic review and meta-analysis. Europace 2023; 25: 318–30

e15. Pluymaekers NAHA, Dudink EAMP, Luermans JGLM, et al.: Early or delayed cardioversion in recent-onset atrial fibrillation. N Engl J Med 2019; 380: 1499–1508

e16. Fornengo C, Antolini M, Frea S, et al.: Prediction of atrial fibrillation recurrence after cardioversion in patients with left-atrial dilation. Eur Heart J Cardiovasc Imaging 2015; 16: 335–41

e17. Van Gelder IC, Crijns HJ: Cardioversion of atrial fibrillation and subsequent maintenance of sinus rhythm. Pacing Clin Electrophysiol 1997; 20: 2675–83

e18. Van Gelder IC, Rienstra M, Bunting KV, et al.: 2024 ESC Guidelines for the management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J 2024; 45: 3314–414

e19. Klein AL, Grimm RA, Murray RD, et al.: Use of transesophageal echocardiography to guide cardioversion in patients with atrial fibrillation. N Engl J Med 2001; 344: 1411–20

e20. Telles-Garcia N, Dahal K, Kocherla C, Lip GYH, Reddy P, Dominic P: Non-vitamin K antagonists oral anticoagulants are as safe and effective as warfarin for cardioversion of atrial fibrillation: A systematic review and meta-analysis. Int J Cardiol 2018; 268:143–8

e21. Gunawardene MA, Willems S: Atrial fibrillation progression and the importance of early treatment for improving clinical outcomes. Europace 2022; 24 (Suppl 2): ii22–ii28

e22. De With RR, Marcos EG, Dudink EAMP, et al.: Atrial fibrillation progression risk factors and associated cardiovascular outcome in well-phenotyped patients: data from the AF-RISK study. Europace 2020; 22: 352–60

e23. Kuck K, Lebedev DS, Mikhaylov EN, et al.: Catheter ablation or medical therapy to delay progression of atrial fibrillation: The randomized controlled atrial fibrillation progression trial (ATTEST). Europace 2021; 23: 362–9

e24. Andrade JG, Deyell MW, Macle L, et al.: Progression of atrial fibrillation after cryoablation or drug therapy. N Engl J Med 2023; 388: 105–16

e25. Kirchhof P, Camm AJ, Goette A, et al.: Early rhythm-control therapy in patients with atrial fibrillation. N Engl J Med 2020; 383: 1305–16

e26. Eckardt L, Sehner S, Suling A, et al.: Attaining sinus rhythm mediates improved outcome with early rhythm control therapy of atrial fibrillation: The EAST-AFNET 4 trial. Eur Heart J 2022; 43: 4127–44

e27. Willems S, Borof K, Brandes A, et al.: Systematic, early rhythm control strategy for atrial fibrillation in patients with or without symptoms: The EAST-AFNET 4 trial. Eur Heart J 2022; 43: 1219–30

e28. Huizar JF, Ellenbogen KA, Tan AY, Kaszala K: Arrhythmia-induced cardiomyopathy: JACC state-of-the-art review. J Am Coll Cardiol 2019; 73: 2328–44

e29. Raymond-Paquin A, Nattel S, Wakili R, Tadros R: Mechanisms and clinical significance of arrhythmia-induced cardiomyopathy. Can J Cardiol 2018; 34: 1449–60

e30. Verhaert DVM, Brunner-La Rocca HP, van Veldhuisen DJ, Vernooy K: The bidirectional interaction between atrial fibrillation and heart failure: consequences for the management of both diseases. Europace 2021; 23 (23 Suppl 2): ii40–ii5

e31. Verma A, Kalman JM, Callans DJ: Treatment of patients with atrial fibrillation and heart failure with reduced ejection fraction. Circulation 2017; 135: 1547–63

e32. 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: 840–4

e33. Zuin M, Bertini M, Vitali F, Turakhia M, Boriani G: Heart failure-related death in subjects with atrial fibrillation in the United States, 1999 to 2020. J Am Heart Assoc 2024; 13: e033897

e34. Chamberlain AM, Redfield MM, Alonso A, Weston SA, Roger VL: Atrial fibrillation and mortality in heart failure: A community study. Circ Heart Fail 2011; 4: 740–6

e35. Hartupee J, Mann DL: Neurohormonal activation in heart failure with reduced ejection fraction. Nat Rev Cardiol 2017; 14: 30–8

e36. Wasmund SL, Li JM, Page RL, et al.: Effect of atrial fibrillation and an irregular ventricular response on sympathetic nerve activity in human subjects. Circulation 2003; 107: 2011–5

e37. Tuinenburg AE, Van Veldhuisen DJ, Boomsma F, Van Den Berg MP, De Kam PJ, Crijns HJ: Comparison of plasma neurohormones in congestive heart failure patients with atrial fibrillation versus patients with sinus rhythm. Am J Cardiol 1998; 81: 1207–10

e38. Gentlesk PJ, Sauer WH, Gerstenfeld EP, et al.: Reversal of left ventricular dysfunction following ablation of atrial fibrillation. J Cardiovasc Electrophysiol 2007; 18: 9–14

e39. Brembilla-Perrot B, Ferreira JP, Manenti V, et al.: 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

e40. Dagres N, Varounis C, Gaspar T, et al.: Catheter ablation for atrial fibrillation in patients with left ventricular systolic dysfunction. A systematic review and meta-analysis. J Card Fail 2011; 17: 964–70

e41. Prabhu S, Costello BT, Taylor AJ, et al.: 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.

e42. Joglar JA, Chung MK, Armbruster AL, et al.: 2023 ACC/AHA/ACCP/HRS Guideline for the diagnosis and management of atrial fibrillation: a report of the American College of Cardiology/American Heart Association joint committee on clinical practice guidelines. Circulation 2024; 149: e1–e156.

e43. Sohns C, Fox H, Marrouche NF, et al.: Catheter ablation in end-stage heart failure with atrial fibrillation. N Engl J Med 2023; 389: 1380–9.

e44. Marrouche NF, Brachmann J, Andresen D, et al.: Catheter ablation for atrial fibrillation with heart failure. N Engl J Med 2018; 378: 417–27.

e45. Turagam MK, Musikantow D, Whang W, et al.: Assessment of catheter ablation or antiarrhythmic drugs for first-line therapy of atrial fibrillation: A meta-analysis of randomized clinical trials. JAMA Cardiol 2021; 6: 697–705.

e46. Chen S, Pürerfellner H, Ouyang F, et al.: Catheter ablation vs. antiarrhythmic drugs as “first-line” initial therapy for atrial fibrillation: A pooled analysis of randomized data. Europace 2021; 23: 1950–60.

e47. Chen C, Zhou X, Zhu M, et al.: 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.

e48. Verma A, Jiang CY, Betts TR, et al.: Approaches to catheter ablation for persistent atrial fibrillation. N Engl J Med 2015; 372: 1812–22.

e49. Vogler J, Willems S, Sultan A, et al.: Pulmonary vein isolation versus defragmentation. J Am Coll Cardiol 2015; 66: 2743–52.

e50. Marrouche NF, Wazni O, McGann C, et al.: Effect of MRI-guided fibrosis ablation vs conventional catheter ablation on atrial arrhythmia recurrence in patients with persistent atrial fibrillation: the DECAAF II randomized clinical trial. JAMA 2022; 327: 2296–305.

e51. Huo Y, Gaspar T, Schönbauer R, et al.: Low-voltage myocardium-guided ablation trial of persistent atrial fibrillation. NEJM Evid 2022; 1: EVIDoa2200141.

e52. Njoku A, Kannabhiran M, Arora R, et al.: Left atrial volume predicts atrial fibrillation recurrence after radiofrequency ablation: A meta-analysis. Europace 2018; 20: 33–42.

e53. D’Ascenzo F, Corleto A, Biondi-Zoccai G, et al.: Which are the most reliable predictors of recurrence of atrial fibrillation after transcatheter ablation?: A meta-analysis. Int J Cardiol 2013; 167: 1984–9.

e54. Costa FM, Ferreira AM, Oliveira S, et al.: Left atrial volume is more important than the type of atrial fibrillation in predicting the long-term success of catheter ablation. Int J Cardiol 2015; 184: 56–61.

e55. Pritchett AM, Jacobsen SJ, Mahoney DW, et al.: Left atrial volume as an index of left atrial size: A population-based study. J Am Coll Cardiol 2003; 41: 1036–43.

e56. Tsang TSM, Abhayaratna WP, Barnes ME, et al.: Prediction of cardiovascular outcomes with left atrial size: Is volume superior to area or diameter? J Am Coll Cardiol 2006; 47: 1018–23.

e57. Goette A, Kalman JM, Aguinaga L, et al.: EHRA/HRS/APHRS/SOLAECE expert consensus on atrial cardiomyopathies: Definition, characterization, and clinical implication. Europace 2016; 18: 1455–90.

e58. Rillig A, Eckardt L, Borof K, et al.: Safety and efficacy of long-term sodium channel blocker therapy for early rhythm control: The EAST-AFNET 4 trial. Europace 2024; 26: euae121.

e59. Echt DS, Liebson PR, Mitchell LB, et al.: Mortality and morbidity in patients receiving encainide, flecainide, or placebo. The cardiac arrhythmia suppression trial. N Engl J Med 1991; 324: 781–8.

e60. Echt DS, Ruskin JN: Use of flecainide for the treatment of atrial fibrillation. Am J Cardiol 2020; 125: 1123–33.

e61. Valembois L, Audureau E, Takeda A, Jarzebowski W, Belmin J, Lafuente-Lafuente C: Antiarrhythmics for maintaining sinus rhythm after cardioversion of atrial fibrillation. Cochrane Database Syst Rev 2019; 9: CD005049.

e62. Freemantle N, Lafuente-Lafuente C, Mitchell S, Eckert L, Reynolds M: Mixed treatment comparison of dronedarone, amiodarone, sotalol, flecainide, and propafenone, for the management of atrial fibrillation. Europace 2011; 13: 329–45.

e63. Freemantle N, Lafuente-Lafuente C, Mitchell S, Eckert L, Reynolds M: Mixed treatment comparison of dronedarone, amiodarone, sotalol, flecainide, and propafenone, for the management of atrial fibrillation. Europace 2011; 13: 329–45.

e64. Colby R, Geyer H: Amiodarone-induced pulmonary toxicity. JAAPA 2017; 30: 23–6.

e65. Papiris SA, Triantafillidou C, Kolilekas L, Markoulaki D, Manali ED: Amiodarone: Review of pulmonary effects and toxicity. Drug Saf 2010; 33: 539–58.

e66. Kirchhof P, Franz MR, Bardai A, Wilde AM: Giant T-U waves precede torsades de pointes in long QT syndrome: A systematic electrocardiographic analysis in patients with acquired and congenital QT prolongation. J Am Coll Cardiol 2009; 54: 143–9.

e67. Basaria S, Cooper DS: Amiodarone and the thyroid. Am J Med 2005; 118: 706–14.

e68. Pollak PT: Clinical organ toxicity of antiarrhythmic compounds: Ocular and pulmonary manifestations. Am J Cardiol 1999; 84 (9A): 37R–45R.

e69. Shrestha S, Plasseraud KM, Makati K, et al.: Hybrid convergent ablation for atrial fibrillation: A systematic review and meta-analysis. Heart Rhythm O2 2022; 3: 396–404.

e70. Osmancik P, Budera P, Talavera D, et al.: Five-year outcomes in cardiac surgery patients with atrial fibrillation undergoing concomitant surgical ablation versus no ablation. The long-term follow-up of the PRAGUE-12 Study. Heart Rhythm 2019; 16: 1334–40.

e71. Huffman MD, Karmali KN, Berendsen MA, et al.: Concomitant atrial fibrillation surgery for people undergoing cardiac surgery. Cochrane database Syst Rev 2016; 2016: CD011814.

e72. Van Gelder IC, Groenveld HF, Crijns HJ, et al.: Lenient versus strict rate control in patients with atrial fibrillation. N Engl J Med 2010; 362: 1363–73.

e73. Mulder BA, Van Veldhuisen DJ, Crijns HJ, et al.: Lenient vs. strict rate control in patients with atrial fibrillation and heart failure: A post-hoc analysis of the RACE II study. Eur J Heart Fail 2013; 15: 1311–8.

e74. Groenveld HF, Crijns HJ, Van den Berg MP, et al.: 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: 1795–803.

e75. Chatterjee S, Sardar P, Lichstein E, Mukherjee D, Aikat S: Pharmacologic rate versus rhythm-control strategies in atrial fibrillation: An updated comprehensive review and meta-analysis. Pacing Clin Electrophysiol 2013; 36: 122–33.

e76. Rienstra M, Van Gelder IC, Van den Berg MP, Boomsma F, Hillege HL, Van Veldhuisen DJ: A comparison of low versus high heart rate in patients with atrial fibrillation and advanced chronic heart failure: Effects on clinical profile, neurohormones and survival. Int J Cardiol 2006; 109: 95–100.

e77. Olsson LG, Swedberg K, Ducharme A, et al.: Atrial fibrillation and risk of clinical events in chronic heart failure with and without left ventricular systolic dysfunction: Results from the candesartan in heart failure-assessment of reduction in mortality and morbidity (CHARM) program. J Am Coll Cardiol 2006; 47: 1997–2004.