Early Treatment of Atrial Fibrillation for Stroke Prevention Trial - EAST-AFNET 4

Contribution To Literature:

Highlighted text has been updated as of September 12, 2022.

The EAST-AFNET 4 trial showed that a rhythm-control strategy is superior to usual care in improving cardiovascular (CV) outcomes at 5 years among patients with recent diagnosis of AF and concomitant CV conditions.


The goal of the trial was to compare a rhythm-control strategy vs. usual care (rate control in the majority of cases) among patients with a recent diagnosis of atrial fibrillation (AF).

Study Design

Patients with AF diagnosis within 1 year were randomized in a 1:1 fashion to either rhythm control (n = 1,395) or usual care (n = 1,394). Early rhythm control required antiarrhythmic drugs or AF ablation, as well as cardioversion of persistent AF, to be initiated early after randomization. Usual care was initially treated with rate-control therapy without rhythm control.

  • Total screened: 2,810
  • Total number of enrollees: 2,789
  • Duration of follow-up: 5.1 years
  • Mean patient age: 70.3 years
  • Percentage female: 46%

Inclusion criteria:

  • Early AF (AF diagnosed within 1 year) and >75 years of age and had a previous transient ischemic attack (TIA) or stroke, OR
  • Met two of the following criteria: age >65 years, female sex, heart failure (HF), hypertension, diabetes mellitus, severe coronary artery disease, chronic kidney disease, left ventricular hypertrophy (diastolic septal wall width >15 mm)

Other salient features/characteristics:

  • First AF: 38%, paroxysmal: 36%
  • Median days since AF diagnosis: 36
  • HF: 29%
  • Prior CVA/TIA: 11%
  • Oral anticoagulant: 90%
  • Beta-blocker: 80%

In the rhythm-control arm, initial choice of strategy was flecainide 36%, amiodarone 20%, AF ablation 8%.

Principal Findings:

The trial was stopped early due to efficacy. The primary outcome, CV death, stroke, hospitalization for HF, or acute coronary syndrome (ACS), for rhythm control vs. usual care, was 3.9 vs. 5.0/100 person-years (P-Y) (hazard ratio [HR] 0.79, 95% confidence interval [CI] 0.66-0.94, p = 0.005)

  • CV death: 1 vs. 1.3/100 P-Y (HR 0.72, 95% CI 0.52-0.98)
  • Stroke: 0.6 vs. 0.9/100 P-Y (HR 0.65, 95% CI 0.44-0.98)
  • HF hospitalization: 2.1 vs. 2.6/100 P-Y
  • ACS hospitalization: 0.8 vs. 1.0/100 P-Y

Secondary outcomes for rhythm control vs. usual care:

  • Nights spent in the hospital: 5.8 vs. 5.1 days
  • Change in left ventricular ejection fraction (LVEF) at 2 years: 1.5 vs. 0.8%
  • Sinus rhythm: 82.1% vs. 60.5% (p < 0.05)
  • All-cause mortality: 9.9% vs. 11.8%
  • Adverse event related to rhythm-control therapy: 4.9% vs. 1.4%

Patients with HF (NYHA class II/III symptoms or EF <50%) (n = 798): The majority had HF with preserved EF (HFpEF; EF ≥50%, mean LVEF 61%). Composite outcome for rhythm control vs. usual care was 5.7 vs. 7.9/100 P-Y (HR 0.74, 95% CI 0.56-0.97, p = 0.03) (p for interaction = 0.63). EF improved in both arms (5.3% vs. 4.9%, p = 0.43). Hospitalization for worsening of HF was 3.9% vs. 4.7% (p = 0.91).

Symptomatic vs. asymptomatic patients: 30.4% were asymptomatic. Use of anticoagulation and rhythm-control strategies were similar between asymptomatic and symptomatic patients. Primary efficacy endpoint for rhythm control vs. usual care for asymptomatic patients was 4.2% vs. 5.5% (HR 0.77, 95% CI 0.57-1.03). For mild to moderate symptomatic patients: 3.6% vs. 5.5% (HR 0.84, 95% CI 0.66-1.09); for severely symptomatic patients: 4.5% vs. 6.6% (HR 0.68, 95% CI 0.47-0.99; p for interaction = 0.74). Other endpoints were similar.

Causal mediation analysis: Sinus rhythm at 12 months explained 81% of the treatment effect of early rhythm control therapy compared to usual care during the remainder of follow-up.


The results of this important trial indicate that a rhythm-control strategy is superior to usual care (rate control in the majority of cases) in improving CV outcomes at 5 years among patients with recent diagnosis of AF and concomitant CV conditions. Results were similar in the subgroup of patients with HF and irrespective of symptom status. Significant reductions were noted for the primary composite endpoint, as well as for CV death and stroke. The effectiveness of early rhythm control therapy is mediated by the presence of sinus rhythm at 12 months.

Results of this trial are different from other similar trials such as CABANA-AF, AFFIRM, and RACE. One difference is the population enrolled – recent onset (within 12 months) in EAST-AFNET 4 vs. more sustained AF in the other trials. There was also a reasonably high rate of AF ablation (8% at enrollment, 20% by 5 years) in the current trial.

Of note, this trial is only single-blinded (not to intervention received). That could confound assessment of the various endpoints. Based on recent experiences from important sham-controlled trials (SYMPLICITY, ORBITA), these findings should prompt consideration for a sham-controlled trial to assess the true efficacy of catheter ablation in modulating CV outcomes among patients with AF.


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.

Editorial Comment: Linz D, McIntyre WF. Sinus rhythm: the sine qua non for rhythm control? Eur Heart J 2022;43:4145-7.

Presented by Dr. Lars Eckardt at the European Society of Cardiology Congress (ESC 2022), Barcelona, Spain, August 29, 2022.

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.

Presented by Dr. Stephan Willems at the European Society of Cardiology Virtual Congress, August 27, 2021.

Rillig A, Magnussen C, Ozga AK, et al. Early Rhythm Control Therapy in Patients With Atrial Fibrillation and Heart Failure. Circulation 2021;144:845-58.

Kirchhof P, Camm AJ, Goette A, et al., on behalf of the EAST-AFNET 4 Trial Investigators. Early Rhythm-Control Therapy in Patients With Atrial Fibrillation. N Engl J Med 2020;383:1305-16.

Editorial: Bunch TJ, Steinberg BA. Revisiting Rate versus Rhythm Control in Atrial Fibrillation — Timing Matters. N Engl J Med 2020;383:1383-4.

Presented by Dr. Paulus Kirchhof at the European Society of Cardiology Virtual Congress, August 29, 2020.

Clinical Topics: Acute Coronary Syndromes, Anticoagulation Management, Arrhythmias and Clinical EP, Geriatric Cardiology, Heart Failure and Cardiomyopathies, Prevention, Atherosclerotic Disease (CAD/PAD), Anticoagulation Management and ACS, Anticoagulation Management and Atrial Fibrillation, Implantable Devices, EP Basic Science, SCD/Ventricular Arrhythmias, Atrial Fibrillation/Supraventricular Arrhythmias, Acute Heart Failure, Hypertension

Keywords: ESC Congress, ESC22, ESC21, ESC20, Acute Coronary Syndrome, Anti-Arrhythmia Agents, Arrhythmias, Cardiac, Anticoagulants, Atrial Fibrillation, Catheter Ablation, Coronary Artery Disease, Diabetes Mellitus, Electric Countershock, Geriatrics, Heart Failure, Hypertension, Hypertrophy, Left Ventricular, Ischemic Attack, Transient, Renal Insufficiency, Stroke, Stroke Volume, Secondary Prevention, Ventricular Function, Left

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