Recurrence After First–time Ablation for Persistent Atrial Fibrillation a Trial–level Network Evidence Synthesis of Contemporary Strategies

Background Pulmonary vein isolation (PVI) remains the cornerstone of catheter ablation in persistent atrial fibrillation (PersAF), yet recurrence is frequent. Multiple adjunctive strategies have been tested with heterogeneous results. Methods We performed a focused synthesis of major randomized controlled trials (RCTs) in PersAF comparing PVI–based catheter ablation with adjunctive or alternative strategies. The primary endpoint was atrial tachyarrhythmia recurrence/failure at ∼12 months after a 90–day blanking period. Effects are presented as risk ratios (RR) for recurrence/failure (RR‹1 favours intervention). A sensitivity analysis included STAR AF II (18–month follow–up). Results Nine randomized comparisons were included (CAPLA, VENUS, DECAAF II, ERASE–AF, SUPPRESS–AF, CONVERGE, CRRF–PeAF, and two STAR AF II arms), encompassing ›3,000 patients overall (Figure 1). Routine posterior wall isolation did not reduce recurrence vs PVI (52.4% vs 53.6% free; HR≈0.99). MRI–guided fibrosis ablation also showed no benefit and increased safety events (43.0% vs 46.1% recurrence; HR≈0.95). In contrast, strategies targeting non–PV substrate showed favourable signals: vein of Marshall ethanol improved freedom from arrhythmia (49% vs 38%). Low–voltage substrate modification reduced recurrence (35% vs 50%). LVA–guided ablation improved 1–year arrhythmia–free survival (61% vs 50%; HR≈0.78). Hybrid Convergent outperformed endocardial catheter ablation (67.7% vs 50.0% effectiveness). Cryoballoon was non–inferior to radiofrequency. CFAE/linear lesions did not improve outcomes (Figure 2). Conclusions In PersAF, empiric anatomic lesion sets (posterior wall, CFAE/lines) and MRI–guided fibrosis ablation do not meaningfully reduce recurrence, whereas mechanistic substrate approaches (VOM ethanol, low–voltage targeting) and hybrid epicardial–endocardial ablation show the most consistent signals toward lower recurrence, warranting further head–to–head trials.