Efficacy, safety, and strategy-modifying factors of pulsed field ablation for persistent and long-standing persistent atrial fibrillation: a systematic review and meta-analysis

Background Pulsed field ablation (PFA) is increasingly applied in persistent atrial fibrillation (PerAF) and long-standing persistent atrial fibrillation (LSPAF). Previous reviews of mixed AF populations suggested potential advantages in procedural efficiency and esophageal safety, but PerAF/LSPAF-specific evidence on long-term rhythm outcomes and on the value of posterior wall or extended substrate strategies remains limited, with substantial heterogeneity in lesion sets, endpoint definitions, and comparator types. Methods We searched PubMed, Web of Science, Embase, Cochrane Library, and Scopus through April 18, 2026, with an updated verification search performed in August 2026. Because of clinical and methodological heterogeneity, formal pairwise pooling was restricted to comparisons supported by at least two clinically homogeneous head-to-head studies; single-study comparisons were synthesized narratively, and strategy-level outcomes were explored with single-arm proportion meta-analysis of exact-count cohorts. Off-antiarrhythmic drug (off-AAD) outcomes were prioritized when available. Certainty of evidence was rated using the GRADE approach. Results Twenty-two studies (approximately 3,100 patients) were included. In an exploratory pooled analysis of the only two available head-to-head comparisons (380 patients, with imbalanced study weights and different lesion sets: PVI-only vs. PVI plus posterior wall isolation), PFA was associated with lower 12-month atrial arrhythmia recurrence than cryoballoon ablation [risk ratio [RR] 0.71, 95% confidence interval [CI] 0.51–0.98; GRADE certainty: very low]; this is best regarded as a preliminary signal. No statistically detectable difference in major complications was observed between PFA and cryoballoon [risk difference (RD) 0.00, 95% CI −0.02 to 0.02], reflecting absence of a demonstrable difference rather than proven equivalence. Single-study comparisons against radiofrequency ablation (RR 0.65, 95% CI 0.45–0.94) and hybrid-convergent ablation (RR 1.11, 95% CI 0.67–1.86) yielded directionally discordant results and are presented narratively. Exploratory, non-comparative single-arm analyses yielded pooled 12-month freedom from atrial arrhythmia of 66.0% (95% CI 55.5%–75.2%; I²=79.0%) for PVI plus posterior wall cohorts and 82.6% (95% CI 76.3%–87.5%; I 2 = 0%) for beyond-PV/extended substrate cohorts; these estimates derive from different, non-randomized cohorts and are hypothesis-generating only. Conclusions Current evidence suggests favorable efficacy and safety of PFA in PerAF/LSPAF, but certainty is low to very low for all key outcomes. The lower recurrence vs. cryoballoon ablation is an encouraging but preliminary signal requiring confirmation in adequately powered randomized trials with uniform lesion sets. Whether extended substrate strategies improve outcomes cannot be determined from current non-comparative data. Future studies should apply standardized off-AAD endpoints, uniform rhythm monitoring, and stratification by atrial myopathy burden and PFA platform. Systematic Review Registration identifier INPLASY202640082; doi: 10.37766/inplasy2026.4.0082