Abstract
<title>Abstract</title> <p>Background Left atrial appendage occlusion (LAAO) has emerged as a non-pharmacologic alternative to oral anticoagulation (OAC) for stroke prevention in patients with non-valvular atrial fibrillation (AF). Despite accumulating evidence, comparative effectiveness across hard clinical endpoints remains incompletely synthesized. Methods We conducted a PRISMA 2020 compliant systematic review and meta-analysis of randomized controlled trials (RCTs) and propensity-matched observational studies comparing LAAO versus OAC in adult non-valvular AF patients. Electronic databases (MEDLINE, EMBASE, CENTRAL, ClinicalTrials.gov) were searched from inception through March 2025. Binary outcomes were pooled using the DerSimonian-Laird random-effects model and expressed as odds ratios (ORs) with 95% confidence intervals (CIs). Results Twelve studies (5 RCTs, 7 observational) were included. LAAO was associated with a significant reduction in major bleeding (OR 0.71; 95% CI 0.51–0.97; p = 0.033; I²=86.0%) and cardiac mortality (OR 0.72; 95% CI 0.52–0.99; p = 0.046; I²=73.2%). All-cause mortality showed a directional non-significant benefit overall (OR 0.73; 95% CI 0.52–1.03; p = 0.072; I²=83.1%), driven by observational studies (OR 0.55; 95% CI 0.32–0.94) and null in RCTs (OR 1.00; 95% CI 0.77–1.31). Ischemic stroke (OR 0.89; 95% CI 0.70–1.14) and systemic thromboembolism (OR 0.92; 95% CI 0.53–1.60) did not significantly differ between arms. Substantial heterogeneity was driven principally by study design. Conclusions LAAO is associated with significant reductions in major bleeding and cardiac mortality compared to OAC in AF patients. The divergent all-cause mortality findings between study designs reflect channeling of higher bleeding-risk patients toward LAAO in real-world practice. These findings support the current Class IIa guideline indication for LAAO in anticoagulant-intolerant patients.</p>