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Study Summary

The EAST-AFNET4 trial was designed to test whether or not early rhythm control, either through anti-arrhythmic drug therapy or atrial fibrillation (AF) ablation, would be associated with better outcomes in patients. A total of 2789 patients underwent randomization (at a mean time period of 36 days from the time of diagnosis): 1395 assigned to early rhythm control, and 1394 assigned to usual care. At 2 years, 82.1% of patients in the rhythm-control group and 60.5% of patients in the usual-care group were in sinus rhythm. The trial was stopped for efficacy after a median follow-up of 5.1 years. The primary outcome (death from cardiovascular causes, stroke [ischemic or hemorrhagic], or hospitalization with worsening of heart failure or acute coronary syndrome) occurred in 249 patients in the rhythm-control group whereas it occurred in 316 patients in the usual-care group (HR 0.79, 96% CI: 0.66-0.94), with significant reductions in both death (HR 0.72, CI 0.52-0.98) and stroke (HR 0.65, CI: 0.44-0.97) with early rhythm control (see accompanying Hurst's Central Illustration). Interestingly, the absolute risk reduction with rhythm control was 1.1%. More serious adverse events occurred in the rhythm-control group than in the usual-care group (4.9% versus 1.4%), mostly due to effects of antiarrhythmic drug therapy and procedural complications.


Study Strengths: EAST-AFNET4 is the first trial to demonstrate significant benefit of early rhythm control in patients with a new diagnosis of AF, with respect to both mortality and stroke reduction. Importantly, both groups in this trial had 90% of patients on anticoagulation at 2 years, indicating the importance of anticoagulation to reduced ischemic stroke rates. AF is a progressive disease that leads to adverse remodeling of the left atrium causing atrial cardiomyopathy and atrial functional mitral regurgitation. Therefore, EAST-AFNET4 suggests that early initiation of rhythm control may prevent atrial cardiomyopathy and improve outcomes.

Study Limitations: Significant limitations of the EAST-AFNET4 include its low event rates and attrition of follow-up, with 9.0% of patients lost to follow-up in the early-rhythm-control group and 6.6% in the usual-care group. Additionally, AF burden was not tracked, so the extent to which outcomes can be attributed to maintenance of sinus rhythm is unclear.

Next Steps/Clinical Perspective: In the AFFIRM Trial, there was no significant difference between rate and rhythm control with respect to mortality or stroke, but patients in the rate-control arm had fewer adverse events attributed to toxicities of antiarrhythmic therapy. However, in a post hoc analysis, the presence of sinus rhythm was significantly associated with a lower risk of death. Since then, there have been significant advancements in both AF ablation techniques and pharmacology to achieve rhythm control. The CABANA Trial showed lower risk of recurrence of AF with catheter ablation as well as a reduction in the composite end point of mortality or hospitalization for cardiovascular causes (HR 0.83, 95% CI 0.74-0.93) than antiarrhythmic drugs. Interestingly, in EAST-AFNET4, only 19% of patients underwent ablation for rhythm control. Further research is required to define optimal rhythm control strategies in patients with new onset AF.

Trial Reference

Kirchof  P, Camm  AJ, Goette  A,  et al. Early rhythm-control therapy in patients with atrial fibrillation. N Engl J Med. doi:10.1056/NEJMoa2019422.

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