Background: In the Early Treatment of Atrial Fibrillation for Stroke Prevention Trial (EAST-AFNET 4), early rhythm-control therapy (ERC) was associated with a clinical benefit in patients with recently diagnosed atrial fibrillation (AF) and concomitant cardiovascular conditions compared to the current practice of limited rhythm-control therapy to improve AF-related symptoms. Recent subgroup analyses suggest a more pronounced effectiveness of ERC in patients with a high comorbidity burden (CHA₂DS₂-VASc score ≥4). The aim of this study was to evaluate the generalizability of these findings in routine practice by interrogating a health records data set and a population-based registry.

Methods: Using a large US administrative database, we identified 109,739 patients with newly diagnosed AF during the enrollment period of the EAST-AFNET 4 trial from July 2011 to December 2016. Patients without an elevated comorbidity burden (CHA₂DS₂-VASc score 0-1) were excluded from the analysis. ERC was defined as AF ablation and/or any antiarrhythmic drug therapy within the first year after AF diagnosis. Patients were classified as 1) ERC & high comorbidity burden (CHA₂DS₂-VASc score ≥4); 2) ERC & lower comorbidity burden (CHA₂DS₂-VASc score 2-3); 3) no ERC & high comorbidity burden; and 4) no ERC & lower comorbidity burden. The follow up started 12 months after the first AF diagnosis. Propensity score overlap weighting was used to balance patients. Cox proportional hazards regression was used to compare the primary composite outcome of all-cause mortality, stroke, or hospitalization with the diagnoses heart failure or myocardial infarction between groups. A primary composite safety outcome containing death, stroke, intracranial hemorrhage, major bleeding, and prespecified serious adverse events (SAE) of special interest capturing complications of ERC was compared between groups. Furthermore, participants in the prospective and population-based UK Biobank were analyzed in the same manner.

Results: In 101,842 patients, 76,921 had a high comorbidity burden (CHA₂DS₂-VASc score ≥4). During a mean follow-up time of 2.6 ± 1.8 years, ERC was associated with fewer composite outcomes (ERC: n=17,229 vs. no ERC: n=59,692; hazard ratio [HR] 0.84; 95% confidence interval [CI] 0.74–0.97; P=0.015) and a reduction of stroke risk (HR 0.65; 95% CI 0.45–0.93; P=0.019) in patients with a high comorbidity burden. In patients with a lower comorbidity burden (CHA₂DS₂-VASc score 2-3; n=24,921), ERC did not affect the primary composite outcome (ERC: n=7,153 vs. no ERC: n=17,768; HR 0.92; 95% CI 0.54–1.56; P=0.757) or any of the secondary outcomes. No increased risk for the primary composite safety outcome with ERC was observed in patients with a high comorbidity burden (HR 0.90; 95% CI 0.80–1.01; P=0.087) or in patients with a lower comorbidity burden (HR 1.00; 95% CI 0.69–1.46; P=0.997). We will report our analyses in the UKB.

Conclusion: Early rhythm-control therapy is mainly associated with reduced cardiovascular outcomes (death, stroke, or hospitalization for heart failure or myocardial infarction) in patients with recently diagnosed AF and a high comorbidity burden. These results encourage the preferential use of ERC in patients with multiple cardiovascular comorbidities.