Repeat Ablation for Persistent Atrial Fibrillation: CFA/DOA-Guided Substrate Ablation Versus Re-PVI Alone in the Prematurely Terminated Randomized AF-CAM Trial

Background and Aims: Currently, no standard approach exists for substrate ablation in persistent atrial fibrillation (AF). This study aimed to assess whether repeat pulmonary vein isolation (Re-PVI) plus targeted substrate ablation improves long-term outcomes compared with Re-PVI alone in patients with persistent AF undergoing a second ablation. Methods: The AF-CAM study is an investigator-initiated, prospective, randomized, open-label, blinded-endpoint, multi-center clinical trial. Patients with persistent AF undergoing a second ablation for arrhythmia recurrence were randomized 1:1 to either Group A (Re-PVI alone) or Group B (Re-PVI plus targeted ablation). The primary endpoint was freedom from any atrial arrhythmia (>30 s) between 3 and 12 months of follow-up. Results: Between August 2021 and November 2023, 56 patients (mean age 68 ± 10 years, 32% women) were randomized before the trial was terminated prematurely. There was no evidence of a difference in arrhythmia recurrence between the treatment groups (hazard ratio [HR] for recurrence, Group B vs. Group A: 1.07; 95% confidence interval [CI] 0.50 to 2.33; p = 0.85). Pulmonary vein reconnection was present in 86% of patients and was not associated with the risk of atrial arrhythmia recurrence (HR 0.927, 95% CI [0.275, 3.120]). Across both groups, catheter ablation was associated with improvements in quality of life (AFEQT score) and reductions in BNP levels during follow-up. Conclusions: In this prematurely terminated randomized trial, adding CFA- and DOA-guided substrate ablation to Re-PVI did not demonstrate an improvement in freedom from atrial arrhythmia compared with Re-PVI alone. The small sample size and imprecise treatment estimate preclude a definitive conclusion about the efficacy of the adjunctive strategy. AFEQT scores increased and BNP levels decreased over follow-up in the studied patients. Larger studies are needed to further evaluate the complex atrial substrate in persistent AF.