Abstract Body (Do not enter title and authors here): Background
Oral anticoagulation (OAC) is the standard for stroke prevention in atrial fibrillation (AF), but high bleeding risk or intolerance limits its use in some patients. Left atrial appendage occlusion (LAAO) has emerged as an alternative, showing similar outcomes to OAC in recent trials for stroke, bleeding, and mortality. However, sex-based differences in outcomes remain underexplored. Women, who face higher AF-related stroke risks, are underrepresented in key LAAO randomized controlled trials (RCTs).

Objective
This study evaluates sex-based differences in the effectiveness and safety of LAAO versus OAC in non-valvular AF.

Methods
We searched PubMed, Embase, Scopus, and Web of Science through November 2024 for RCTs, secondary analyses, and observational studies comparing LAAO and OAC, including sex-stratified outcomes. Data were pooled using a random-effects model, as risk ratios (RR) with 95% confidence intervals (CI). Review Manager 5.4 was used for statistical analysis.

Results
4 RCTs and 4 observational studies comprising 296,135 males and 289,772 females, were included in the final analysis. Overall, LAAO was associated with a statistically significant reduction in the composite outcome of stroke, embolism, death, and bleeding compared to OAC. In sex-specific subgroup analyses, for the composite outcome, LAAO showed a trend towards a reduction in males, though not statistically significant (RR 0.79[0.59-1.05], P=0.10), while no significant difference was observed in females (RR 0.88[0.70-1.12], P=0.30). LAAO was associated with a statistically significant reduction in bleeding in males (RR 0.61[0.38-0.98], P=0.04), but not females (RR 0.89[0.59-1.36], P=0.60). LAAO also led to a statistically significant reduction in mortality in both males (RR 0.69[0.52-0.92], P=0.01) and females (RR 0.61[0.46-0.81], P=0.0007). No statistically significant difference was found in stroke risk between LAAO and OAC in males (RR 0.80[0.50-1.29], P=0.37) or females (RR 0.82[0.50-1.34], P=0.42).

Conclusion
LAAO was associated with significant reductions in stroke, embolism, death, and bleeding compared to OAC. These benefits were consistent across sexes, with no significant differences in treatment effect between males and females. However, further large-scale RCTs are needed to confirm these results. Future studies should prioritize the inclusion of female participants.