EAST-AFNET 4 Favors Rhythm Control, but It's Complicated

John Mandrola, MD


September 01, 2020

The EAST-AFNET 4 trial asked whether an early rhythm-control strategy vs usual care would lead to better outcomes in patients with atrial fibrillation (AF).

The AFFIRM trial addressed this question 18 years ago and found that rhythm control compared to rate control did not reduce outcomes. Much has changed since then. We have learned the importance of continuing anticoagulation, become more skillful in our use of antiarrhythmic drugs and risk factor modification, and, of course, we now have AF ablation.

The multicenter EAST-AFNET 4 trial, which was presented at the European Society of Cardiology (ESC) Congress 2020  and published in the New England Journal of Medicine, randomized patients with AF to early rhythm control (ERC) or usual care. The trial was open-label but had blinded outcome assessment.

The authors chose co-primary efficacy endpoints: the first was a composite of cardiovascular (CV) death, stroke, hospital admission for heart failure or acute coronary syndrome, and the second was days spent in the hospital. The primary safety outcome was a composite of death, stroke, or serious adverse events related to rhythm control.

The mean age of enrolled patients was 70 years, nearly half were women, and the median CHA₂DS₂VASc score was 3. The patients enrolled were typical of a cardiology practice: for 38% this was their first episode of AF; 36% had paroxysmal AF, 26% had persistent AF, and 31% had AF without symptoms.

About 90% of both groups continued to receive oral anticoagulant therapy throughout the trial. Patients in the ERC arm received an antiarrhythmic drug or ablation. Adherence was a challenge: nearly 35% of these patients were no longer receiving any rhythm-control therapy at 2 years. The usual care group was mostly treated with rate control.


EAST-AFNET 4 was stopped for efficacy after a median of 5 years. A primary outcome event occurred in 249 patients in the ERC arm vs 316 patients in the usual care arm.  The hazard ratio was 0.79, with a confidence interval of 0.66 to 0.94 (P=.005). The absolute risk reduction was 1.1% per 100 person-years and 3% over 5 years.

Each component of the primary outcome was numerically lower in the ERC arm. In a trial of almost 2800 patients, there were 27 fewer CV deaths in the ERC group (1.0% vs 1.3% per 100 patient-years). The average days spent in hospital were similar in both groups.

The overall primary safety outcome did not differ significantly between the two treatment arms; however, serious adverse events related to rhythm-control therapy occurred in 4.9% of the patients assigned to early rhythm control and 1.4% of the patients assigned to usual care.

At 2 years, sinus rhythm was observed in 82% of the ERC group and 60% of the usual care group (assessed with electrocardiography only). Notably, by 2 years, 72% of all patients were asymptomatic. There were no significant differences in any quality-of-life scores or changes in left ventricular ejection fraction.

EAST-AFNET was a clearly positive trial that had a small effect size and important caveats.

Internal Validity Concerns

Missing data: This was a 5-year pragmatic trial of two different strategies. Some dropout is expected. This totaled 9% in the ERC arm vs 6.6% in the usual care arm.

By email, Sanjay Kaul, MD, from Cedars-Sinai in Los Angeles, who is an expert on clinical trial design, wrote that missing data approaching 10% can potentially invalidate an intention-to-treat analysis. He, like the EAST-AFNET 4 editorialists, noted that dropout was not uniform.

The authors did multiple statistical maneuvers to accommodate for the dropout, and these upheld the main findings. But we don't know the characteristics of the patients who withdrew, which is a reason for caution.

Bias-sensitive endpoints: Another internal validity concern is that two components of the primary endpoint (hospitalization for heart failure or acute coronary syndrome) hinge on a clinician's decision. EAST-AFNET 4 was open label.

Consider that participating centers were chosen because they had expert clinicians. Said experts are likely to be proponents of rhythm control, especially when it involves AF ablation. Unconscious bias may have led to fewer patients in the rhythm-control arm being hospitalized.

This too is another reason to be cautious.

External Validity or Generalizability

Plausibility:  Why did the results of EAST-AFNET 4 differ from those of AFFIRM?

The authors highlight the importance of background therapy. I agree. Years ago, we falsely believed maintenance of sinus rhythm allowed patients to stop taking anticoagulation drugs. In this trial, unlike AFFIRM, more than 90% of patients continued taking oral anticoagulants.

Trial discussant Tatjana Potpara, MD, from Belgrade University, Serbia, pointed to the very low event rates in EAST-AFNET compared with other contemporary clinical trials (novel oral anticoagulant vs warfarin trials, for example). This was likely due to strict adherence to oral anticoagulation and other background therapy.

A take-home message would be that no matter the strategy chosen, if you pay attention to basic preventive measures, patients will experience very low rates of adverse outcomes.

Effect size: While the 20% relative risk reduction of events with ERC was statistically robust, the absolute risk reduction was modest. A yearly risk reduction of 1.1% means that about 99% of people—similar to those enrolled in this trial—get the same result with either strategy.

And remember, this modest absolute risk reduction was mostly driven by nonfatal outcomes.

Net clinical benefit: Although the topline safety results show no difference between treatment strategies (16.6% vs 16.0%), I urge you to look deeper. The safety endpoint was a three-part composite of stroke, death, and specific adverse effects from rhythm control.

The components diverged. Stroke and death favored ERC, but serious adverse events due to rhythm control strongly favored usual care—4.9% of patients in the ERC arm had an adverse event vs 1.4% of those receiving usual care.

The problem comes in using stroke and death in both the efficacy and the safety results. As Kaul explained, when you leverage an advantage in efficacy outcome (eg, stroke reduction) for an advantage in safety, the benefit-risk ratio is skewed in favor of the test intervention. The reduction in stroke was a driver of benefit in the ERC arm. Including stroke in the safety composite dilutes the effect of serious adverse events due to rhythm control.

Without the overlap of efficacy and safety endpoints, the conversation over EAST-AFNET 4 might be that the 3% absolute risk reduction with ERC over 5 years was balanced by a 3.5% higher risk for serious adverse events.

Low ablation rates: The most surprising finding from this trial was the infrequent use of ablation for rhythm control. Only 8% of the nearly 1400 patients had early ablation, and just 20% had undergone the procedure by 2 years.

I highlight this because I worry that the positive results from EAST-AFNET will be used to further promote AF ablation. Resist that urge. We already know from CABANA that AF ablation did not significantly reduce outcomes compared with antiarrhythmic drugs.

Conclusion and Final Take-Home

Pragmatic trials of strategies will never be as clear-cut as a placebo-controlled trial of a single drug.

EAST-AFNET 4 shows that an early rhythm-control strategy, used in the setting of a clinical trial, in selected expert centers, with good adherence to background therapy may improve outcomes compared with a strategy of rate control.

These potential gains come with a risk for serious adverse events. Thus, the trial should not be oversimplified to mean "use more antiarrhythmic drugs" or "do more ablation." Instead, the nuance and tradeoffs in these findings strongly support a shared understanding between clinician and patient.

John Mandrola practices cardiac electrophysiology in Louisville, Kentucky, and is a writer and podcaster for Medscape. He espouses a conservative approach to medical practice. He participates in clinical research and writes often about the state of medical evidence. 

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