EAST-AFNET 4: Early Rhythm Control for Atrial Fibrillation

Trial Investigators. Early Rhythm-Control Therapy in Patients with Atrial Fibrillation.

Kirchhof P, Camm AJ, Goette A, et al.; EAST-AFNET 4

N Engl J Med. 2020 Oct 1;383(14):1305-1316. [Full text]

NEJM Video summary

Summary by Rameel Ahmad

Atrial Fibrillation is the most common encountered arrhythmia in clinical practice and there are currently over 33.5 million patients diagnosed with atrial fibrillation in the world. In America, 70% of cases of atrial fibrillation are in patients over the age of 65. There are currently several treatments for atrial fibrillation that generally involve either a rate control or rhythm control strategy, with anticoagulation (AC) possibly indicated was well pased on a patient’s CHADsVASC score. Despite these evidenced based treatments, patients with atrial fibrillation remain at risk for stroke, acute coronary syndrome (ACS), heart failure (HF) and cardiovascular (CV) death at a rate of approximately 5% each year. The risk of these adverse CV outcomes is increased during the first year after atrial fibrillation is diagnosed.

Given the mortality and morbidity associated with atrial fibrillation, there has been interest in determining if rate vs rhythm improves CV outcomes; however neither has been definitively shown to be superior. Since some of those early landmark rate versus rhythm control studies, (i.e. AFFIRM), there have been advances in rhythm control options (see CABANA or CASTLE-AF) that may lead to improved CV outcomes. The Early Rhythm-Control Therapy in Patients with Atrial Fibrillation, or EAST-AFNET 4 trial, looked at cardiovascular mortality and stroke with the intervention of early rhythm control as compared to the “usual” care of rate control therapy. 

Patient population and Design

This study was an international (11 countries), multi-center (135 sites) prospective, parallel group, randomized, open, blinded-outcome trial that looked at early atrial fibrillation (diagnosed <12 mo prior to enrollment). It included adults who were ≥75, had had a previous TIA/stroke, or met two of the following criteria: age >65, female sex, heart failure, hypertension, diabetes mellitus, severe CAD, CKD 3 or 4, and left ventricular hypertrophy. The exclusion criteria were if patients had less than 1 year of life expectancy, severe mitral stenosis, prosthetic mitral valve, hepatic dysfunction requiring therapy, or thyroid dysfunction requiring therapy.


This study looked at several outcomes. One co-primary outcome was a composite of CV mortality, stroke (either ischemic or hemorrhagic), or hospitalization with worsening of heart failure or acute coronary syndrome, analyzed in a time to event analysis. The co-primary outcome was the number of nights spent in the hospital per year. 

Secondary outcomes included the individual components of the composite co-primary outcome, rhythm, left ventricular function, quality of life (assessed with the European Quality of Life Dimensions [EQ-5D] and 12 item Short Form General Health Survey [SF-12]), atrial fibrillation symptoms (assessed as the European Heart Rhythm Association [EHRA] score), and cognitive function (MoCA score) at 2 years out.  The primary safety outcome was a composite of death from any cause, stroke, or pre-specified serious adverse events of special interest capturing complications of rhythm control therapy.


The trial was stopped early for efficacy at the 5 year mark. The composite co-primary outcome occurred less frequently in the early rhythm control arm as compared to the usual care (rate control) group ;249 of 6399 (3.9%) vs. 316 of 6332 (5.0%), HR 0.79 (95% CI 0.66 to 0.94). This represent an absolute difference in risk of 1.1 events per 100 person years. There was no significant difference in the mean number of nights spent in the hospital between the treatment groups (5.8 vs 5.1% HR 1.08; 95% CI 0.92 to 1.28).  

In regards to secondary outcomes, there was also a lower risk of the individual components of death from cardiovascular causes (HR 0.72; 95% CI 0.52 to 0.98) and stroke (HR 0.65; 95% CI 0.44 to 0.97). Hospitalization for worsening heart failure or for acute coronary syndrome did not differ between the groups (2.1 vs 2.6 HR 0.81; 95% CI 0.65 to 1.02 and 0.8 vs 1.0 HR 1.08; 95% CI 0.92 to 1.28, respectively). The effect was consistent across subgroups.  

In terms of secondary outcomes, there was no significant difference in left ventricular ejection fraction +1.5% vs. +0.8% (mean difference 0.23; 95% CI -0.46 to 0.91). There was no statistical difference in EQ-5D score  -1.0 vs. -2.7 (mean difference 1.07; 95% CI -0.68 to 2.82). There was not a statistical significant difference in change from baseline atrial fibrillation related symptoms (EHRA score) or in cognitive condition as defined by the MoCA score with 74% vs. 73% (OR 1.14; 95% CI 0.93 to 1.40) and +0.1 vs. +0.1 (mean difference -0.14; 95% CI -0.39 to 0.12) respectively. Notably, more patients in the rhythm control arm were in sinus rhythm 82% vs 60% (OR 3.13; 95% CI 2.55 to 3.84) at the 2 year follow up mark. 

The overall number of patients with a primary safety outcome did not differ significantly between the two groups with (231 vs. 223 events). There was no difference in mortality among the two treatment groups. Stroke occurred less frequently among patients assigned to early rhythm control than rate control (2.9 vs. 4.4%) but with more serious adverse events related to rhythm control (4.9% vs 1.4% in a 5 year follow up period) though each was relatively infrequent. These serious adverse effects include things such as nonfatal cardiac arrest, toxic effects of the anti-arrhythmic drugs, torsades, tamponade (from ablation procedures), and syncope to name a few. 


EAST-AFNET 4 suggests that in early atrial fibrillation, defined as a first episode occurring within 12 mo, rhythm control may improve outcomes with similar adverse effects as the usual care of rate control. The morbidity and mortality associated with atrial fibrillation has long been attributed to episodes of rapid ventricular response as well as increased stroke risk. Thus, attempts at rate control have been employed to reduce those episodes of rapid rates and thus reduce associated adverse cardiovascular outcomes. The AFFIRM trial is now nearly 20 years old and was a landmark trial that randomized patients to rate vs. rhythm control strategies. It found that there was no statistical difference between the groups at 5 years with respect to mortality (23.8% and 21.3%, respectively; P=0.08) or percentage of patients with ischemic stroke (7.1% and 5.5%, P=0.79). A 2005 meta-analysis of five randomized trials showed no significant difference with respect to all cause mortality and stroke, though results appeared to favor rate control [4]. Thus, rate control strategies became the most frequent strategy employed, with rhythm control often reserved for those that fail rate control or who had persistent symptoms. 

That the results of EAST-AFNET 4 are contrary to these earlier findings may be explained by the advances in rhythm control made subsequent. For example, dronedarone was not then available but is associated with lower risk of adverse cardiovascular outcomes and stroke [5]. Additionally, catheter ablation therapy for atrial fibrillation has become more common and there have been significant advancements in treatment efficacy in recent years (see CABANA or CASTLE-AF). Catheter ablation was used in 8% of the rhythm control arm at randomization and 20% by trial end as compared to the AFFIRM trial which only used catheter ablation if patient’s failed therapy. 

Timing of treatment and relation to the patient’s course of atrial fibrillation is an important distinction that may affect outcomes. Atrial fibrillation itself has been associated with atrial cardiomyopathies and this remodeling overtime makes treatment and conversion to sinus rhythm difficult. Early treatment for atrial fibrillation with rhythm control may limit these maladaptive changes. Ultimately, mortality and morbidity seems proportional to time spent in atrial fibrillation and efforts to reduce that duration seem to improve outcomes. 

Another key difference from earlier work was the duration of AC. In the AFFIRM trial, if patients were found to be in normal sinus rhythm for a period of 4 weeks, their AC could be discontinued. The majority of ischemic strokes occurred in patients with AC held which were patients largely in the rhythm control group. In EAST-AFNET 4, AC was continued over the entire course of the study. 

A limitation of this study was it was not blinded. An additional limitation related to real world implementation was that the patients in the rhythm arm had ECGs transmitted to providers every two weeks for medication titration. It may be difficult to sustain that degree of follow up in clinical practice, though home monitors are becoming more readily available.

Overall, this study gives us an updated practice consideration when faced with the challenge of treating patients who were recently diagnosed with atrial fibrillation. It demonstrates significant overall risk reduction in cardiovascular mortality and stroke with rhythm control with agents that include newer anti-arrhythmic medication and catheter ablation. Though it is currently the practice to escalate to rhythm control after rate control may fail, early treatment with an attempt to maintain sinus rhythm may become the new standard. 

F: Follow up5 years
R: RandomizationYes
I: Intention to treatYes
S: Similar at baselineDigoxin and beta-blockers was slightly more common and statin less common in the usual care group
B: BlindingNO, Open label, blinded outcome
E: Equal treatmentExcept by design
S: Source (funding)German Ministry of Education and Research and others

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