Introduction
AF is the most prevalent cardiac arrhythmia worldwide and is associated with increased morbidity and mortality.¹ Although anticoagulation can reduce the risk of stroke and death remarkably well and rate control renders many patients asymptomatic, approximately 5% of patients with AF experience severe complications (cardiovascular death, stroke, worsening of heart failure (HF), or acute coronary syndrome) per year. Based on several trials comparing rhythm-control therapy using technology and knowledge available at the time in patients with established AF,^2,3 rhythm-control therapy is currently indicated only to improve AF-related symptoms. Sub-analyses of cohorts enrolled in anticoagulation trials suggest that mortality and ischemic strokes may be lower in patients with intermittent forms of AF compared with those with permanent AF.^4-6 In addition, early initiation of rhythm-control therapy, before AF-induced atrial damage (atrial cardiopathy or atrial structural remodelling) has irreversibly damaged the atria, could be more effective and safer than the current symptom-based—and therefore delayed—approach to rhythm-control therapy.

Design of EAST-AFNET 4
EAST-AFNET 4 (Early Treatment of Atrial Fibrillation for Stroke Prevention Trial), an international, randomized, open, blinded outcome assessment trial, was planned by the German Atrial Fibrillation Competence Network and the European Heart Rhythm Association. EAST-AFNET 4 randomized patients with recently diagnosed AF (diagnosed not more than 12 months prior to randomization) and cardiovascular conditions approximating a CHA₂DS₂VASc score of 2 or more to either systematic early rhythm control on top of initiation of oral anticoagulation and embedded in a comprehensive treatment strategy or to usual care with rate control. Usual care limited rhythm control to symptomatic patients.⁷ Early rhythm-control therapy comprised antiarrhythmic drugs, cardioversion, or catheter ablation, used immediately after randomization, and was guided by telemetric electrocardiographic monitoring. The choice of rhythm-control modality was left to the study teams at each site. Follow-up was carried out in the form of questionnaires in 6-month intervals and outpatient examinations including electrocardiography and echocardiography after 12 and 24 months.

The first primary outcome was a composite of death from cardiovascular causes, stroke, or hospitalization with worsening HF or acute coronary syndrome; the second primary outcome was the number of nights spent in the hospital per year. The primary safety outcome measure was a composite of stroke, all-cause death, and serious adverse events caused by rhythm-control therapy.

Main Results of EAST-AFNET 4
From 2011 to 2016, a total of 2,789 patients with recently diagnosed AF and with at least 2 cardiovascular comorbidities was enrolled at 135 sites in 11 countries and underwent randomization: 1,395 were assigned to early rhythm control and 1,394 to usual care. Mean age was 70 years, and mean CHA₂DS₂VASc score was 3.3. Almost 40% of patients were randomized with their first episode of AF, and the median time from AF diagnosis to randomization was 36 days. At randomization, 30% of patients were asymptomatic (European Heart Rhythm Association score = 1). There was no relevant difference regarding patients' baseline characteristics between both groups with the exception of a slightly (5-10%) higher use of rate-controlling agents (digoxin/digitoxin and beta-blockers) in patients randomized to usual care (6% vs. 3% and 86% vs. 76%, respectively). Use of anticoagulation (>90%), antihypertensive and HF therapy (>70%), and rate control was excellent.

After randomization, 95% of patients randomized to early rhythm control received rhythm-control therapy, including therapy with flecainide or propafenone (43%), amiodarone (20%), dronedarone (17%), or catheter ablation (8%). At 2 years, 82% of patients were in sinus rhythm and 65% were still on active rhythm control, including 19.4% who underwent AF ablation. Of patients randomized to usual care, 96% were initially managed without rhythm-control therapy. At 2 years, 60% were in sinus rhythm and 15% were on rhythm-control therapy.

The primary comparison was in the intention-to-treat population, and all patients were included in the analysis as randomized. The trial was stopped at the third planned interim analysis after accrual of 75% of the planned first primary outcome parameters. During a median follow-up of 5.1 years, the first primary outcome occurred in 249 (3.9%) patients randomized to early rhythm-control therapy and in 316 (5.0%) patients in the usual care arm. Adjusting for the group-sequential trial design, the endpoint occurred statistically significantly less often in patients randomized to early rhythm-control strategy (hazard ratio 0.79; confidence interval 0.67-0.94; p = 0.005). The clinical benefit of an early rhythm-control strategy was consistent across subgroups, including asymptomatic patients and those without HF.

Regarding the second primary outcome analysis, no significant difference was observed for nights spent in hospital between both groups (5.8 ± 21.9 days/year for early rhythm control; 5.1 ± 15.5 days/year usual care; p = 0.226).

Primary composite safety outcome, a composite of stroke, death, and serious adverse events related to rhythm-control therapy, was neutral. Over the 5-year observation time, there were 231 (17%) events for the early rhythm control patients and 223 (16%) events for the usual care patients. Patients randomized to early rhythm control experienced numerically fewer deaths from cardiovascular causes (67 vs. 94; hazard ratio 0.72; 95% confidence interval, 0.52-0.98), statistically significant fewer strokes (40 vs. 62; p = 0.03) ,and more complications of rhythm-control therapy (68 vs. 19; p < 0.0001). Both early rhythm control and usual care controlled symptoms very well, with almost 3/4 of patients being asymptomatic at 2 years.

In conclusion, the results of the EAST-AFNET 4 trial demonstrate that a rhythm-control strategy, initiated early after AF diagnosis, is superior to usual care in improving cardiovascular outcomes among patients with recent diagnosis of AF and concomitant cardiovascular conditions.⁷

Discussion
Results of the EAST-AFNET 4 trial are different from results of other similar, previously published trials such as AFFIRM (Atrial Fibrillation Follow-up Investigation of Rhythm Management), AF-CHF (Atrial Fibrillation and Congestive Heart Failure), RACE (Rate Control Versus Electrical Cardioversion), PIAF (Rhythm or Rate Control in Atrial Fibrillation-Pharmacological Intervention in Atrial Fibrillation), and STAF (Strategies of Treatment of Atrial Fibrillation).^2,8-11 One of the most important differences is between the populations: recent onset (diagnosed ≤1 year before, median AF duration 36 days between first diagnosis and randomization) in EAST-AFNET 4 versus longer established, persistent AF in earlier trials,^2,8-10 with potentially more advanced atrial fibrosis and known to have poorer outcomes.

Furthermore, early rhythm control in EAST-AFNET 4 used antiarrhythmic drugs with guideline-based safety precautions and included dronedarone, an agent that was not available at the time of the earlier trials. Importantly, a substantial proportion of patients underwent catheter ablation of AF as first-line rhythm-control strategy (8% at enrollment) and/or to improve sinus rhythm maintenance (almost 20% by 2 years) compared with previous studies on this topic. The safety of early rhythm-control therapy was very good, comparable to the safety of antiarrhythmic drugs and AF ablation reported in MANTRA-PAF (Medical Antiarrhythmic Treatment or Radiofrequency Ablation in Paroxysmal Atrial Fibrillation) and CABANA (Catheter Ablation vs Antiarrhythmic Drug Therapy in Atrial Fibrillation),^12,13 leading to a neutral overall safety (with fewer strokes and numerically fewer deaths in patients randomized to early therapy) and associated with satisfying long-term clinical outcome rates, especially in patients suffering from paroxysmal AF.^12,13

We can speculate that the proportion of catheter ablation therapy in the rhythm-control arm would be even higher nowadays, which, taking into account the aforementioned aspects, might further influence results of future trials comparing early rhythm-control therapy versus usual care only. EAST-AFNET 4 confirmed that a strategy of initiating rhythm-control therapy in patients with early AF and concomitant cardiovascular conditions was associated with a lower risk of death from cardiovascular causes, stroke, or hospitalization for HF or acute coronary syndrome than usual care over a follow-up time of more than 5 years.⁷ Based on these results, rhythm-control therapy should be offered to all patients with recently diagnosed AF and cardiovascular risk factors, including those who present without AF-related symptoms, in addition to anticoagulation, rate control, and therapy of concomitant conditions. Early initiation of rhythm-control therapy conveys a clear clinical benefit in patients with recently diagnosed AF.

Future Perspectives
The results emphasize the importance of early AF detection by means of screening in order to ensure that therapy can be initiated early after diagnosis. Whether early initiation of rhythm-control therapy is also warranted in patients with screening-detected atrial arrhythmias warrants further testing. Further studies are desirable to investigate whether early ablation therapy in addition to usual care or as an alternative treatment strategy improves the prognosis even for patients with asymptomatic AF.

References

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2. Wyse DG, Waldo AL, DiMarco JP, et al. A comparison of rate control and rhythm control in patients with atrial fibrillation. N Engl J Med 2002;347:1825-33.
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4. Bansilal S, Bloomgarden Z, Halperin JL, et al. Efficacy and safety of rivaroxaban in patients with diabetes and nonvalvular atrial fibrillation: the Rivaroxaban Once-daily, Oral, Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF Trial). Am Heart J 2015;170:675-682.e8.
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7. 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.
8. Van Gelder IC, Hagens VE, Bosker HA, et al. A comparison of rate control and rhythm control in patients with recurrent persistent atrial fibrillation. N Engl J Med 2002;347:1834-40.
9. Hohnloser SH, Kuck KH. Randomized trial of rhythm or rate control in atrial fibrillation: the Pharmacological Intervention in Atrial Fibrillation Trial (PIAF). Eur Heart J 2001;22:801-2.
10. Carlsson J, Miketic S, Windeler J, et al. Randomized trial of rate-control versus rhythm-control in persistent atrial fibrillation: the Strategies of Treatment of Atrial Fibrillation (STAF) study. J Am Coll Cardiol 2003;41:1690-6.
11. Pluymaekers NA, Dudink EA, Luermans JG, et al. Early or Delayed Cardioversion in Recent-Onset Atrial Fibrillation. N Engl J Med 2019;380:1499-508.
12. Cosedis Nielsen J, Johannessen A, Raatikainen P, et al. Radiofrequency ablation as initial therapy in paroxysmal atrial fibrillation. N Engl J Med 2012;367:1587-95.
13. Packer DL, Mark DB, Robb RA, et al. 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;321:1261-74.

Clinical Topics: Acute Coronary Syndromes, Arrhythmias and Clinical EP, Implantable Devices, EP Basic Science, SCD/Ventricular Arrhythmias, Atrial Fibrillation/Supraventricular Arrhythmias

Keywords: Anti-Arrhythmia Agents, Atrial Fibrillation, Amiodarone, Flecainide, Propafenone, Electric Countershock, Antihypertensive Agents, Digoxin, Furylfuramide, Digitoxin, Acute Coronary Syndrome, Outpatients, Follow-Up Studies, Arrhythmias, Cardiac

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