Early Rhythm Control Therapy for Atrial Fibrillation Unchanged by Diabetes, Obesity

A secondary analysis of the EAST-AFNET 4 trial has indicated the lasting effectiveness of early rhythm control (ERC) therapy for patients with early atrial fibrillation (AF) and cardiovascular conditions is not impacted by the presence of obesity or diabetes.

AF is the most frequent form of arrhythmia and has been associated with significant increases in morbidity and mortality. Obesity is one of the leading factors in AF recurrences, due in part to the direct and indirect effects of epicardial fat on atrial function. However, despite obesity having a significant influence on AF recurrence, little literature exists determining the efficacy of ERC therapy in patients with obesity or diabetes.1

“The effect of ERC therapy is independent of AF-related symptoms and mediated by sinus rhythm,” wrote Andreas Metzner, MD, department of cardiology, University Heart and Vascular Center, University Medical Center Hamburg-Eppendorf, and colleagues. “Whether this effectiveness is retained in patients with obesity and in those with diabetes is not known. The current subanalysis of the EAST-AFNET 4 study therefore assesses the effects of body mass index and of diabetes on outcomes in EAST-AFNET 4.”1

EAST-AFNET 4 was an international randomized, parallel-assignment, open-label trial examining the efficacy of structured rhythm control therapy based on antiarrhythmic drugs and catheter ablation could prevent AF-related complications compared to usual care. Patients were randomized to either early therapy or usual care; the early therapy patients received either catheter ablation – typically via pulmonary vein isolation – or antiarrhythmic drug therapy at an early point.2

Patients selected for EAST-AFNET 4 had to have AF onset within 1 year before enrollment, ≥1 ECG within the last 12 months documenting an AF episode longer than 30 seconds, and prior cardiovascular events. Patients were excluded if life expectancy was limited to <1 year, if patients had previously participated in the EAST trial, or had prior AF ablation or surgical therapy of AF, among others.2

Investigators in EAST-AFNET 4 included a collective 2789 patients with AF were randomized to ERC therapy (n = 1395) or usual care (n = 1394). The team primarily targeted rate control in patients receiving usual care, with rhythm control being used in patients remaining symptomatic on optimal rate control therapy. Both EAST-AFNET 4 and the secondary analysis noted a composite of cardiovascular death, stroke, hospitalization due to heart failure, and acute coronary syndrome as the primary endpoint.1

This secondary analysis categorized patients into binary groups by BMI (<30 versus ≥30) and the presence of diabetes. Efficacy and safety outcomes were analyzed for interactions between treatment groups and BMI/diabetes groups. A Cox proportional hazards model was implemented to calculate time-to-event outcomes, such as cardiovascular death, first stroke, first hospitalization for worsening heart failure or acute coronary syndrome.1

The analysis included 1086 patients with obesity, with a mean (standard deviation [SD]) BMI of 34.5 (4.2), and 1690 patients without obesity with a mean BMI of 25.9 (2.6). Investigators noted more outcomes in patients with obesity than those without; however, it did not change the effect of ERC on the first primary outcome. There were no significant differences observed for cardiovascular death (.76 versus .62; P = .58), stroke (.78 versus .34; P = .1), and hospitalization with acute coronary syndrome (.71 versus 1.05; P - .12).1

A total of 694 patients with diabetes were included in the trial, with no difference between randomized groups. Diabetes also exhibited no interaction with the treatment effect of ERC (HR .77 with diabetes versus HR .78 without; P for interaction = .93). There was also no influence on hospitalization or death from cardiovascular causes.1

Investigators also noted no difference in safety outcomes between patients with and without diabetes or obesity. No adverse events related to anti-arrhythmic drug therapy and AF ablation were significantly different between any group.1

“This analysis showed that ERC is similarly effective and safe in patients with diabetes and in patients with obesity compared to patients without diabetes and without obesity with AF,” Metzner and colleagues wrote. “Put simply, neither obesity nor diabetes should be a reason to withhold ERC therapy in patients with AF.”1

References

1. Metzner A, Willems S, Borof K, et al. Diabetes and obesity and treatment effect of early rhythm control vs usual care in patients with atrial fibrillation. JAMA Cardiology. Published online July 30, 2025. doi:10.1001/jamacardio.2025.2374

2. Atrial Fibrillation Network. Early Treatment of Atrial Fibrillation for Stroke Prevention Trial (EAST). ClinicalTrials.gov identifier: NCT01288352. Updated July 23, 2020. Accessed August 11, 2025. https://www.clinicaltrials.gov/study/NCT01288352