BackgroundCatheter ablation (CA) is a highly effective therapy for the treatment of paroxysmal atrial fibrillation (AF) when compared with antiarrhythmic drug therapy (ADT). No randomized studies have compared the two strategies in persistent AF. The present randomized trial aimed to compare the effectiveness of CA vs. ADT in treating persistent AF.Methods and resultsPatients with persistent AF were randomly assigned to CA or ADT (excluding patients with long-standing persistent AF). Primary endpoint at 12-month follow-up was defined as any episode of AF or atrial flutter lasting >24 h that occurred after a 3-month blanking period. Secondary endpoints were any atrial tachyarrhythmia lasting >30 s, hospitalization, and electrical cardioversion. In total, 146 patients were included (aged 55 ± 9 years, 77% male). The ADT group received class Ic (43.8%) or class III drugs (56.3%). In an intention-to-treat analysis, 69 of 98 patients (70.4%) in the CA group and 21 of 48 patients (43.7%) in the ADT group were free of the primary endpoint (P = 0.002), implying an absolute risk difference of 26.6% (95% CI 10.0–43.3) in favour of CA. The proportion of patients free of any recurrence (>30 s) was higher in the CA group than in the ADT group (60.2 vs. 29.2%; P < 0.001) and cardioversion was less frequent (34.7 vs. 50%, respectively; P = 0.018).ConclusionCatheter ablation is superior to medical therapy for the maintenance of sinus rhythm in patients with persistent AF at 12-month follow-up.Clinical Trial Registration InformationNCT00863213 ().