Left Atrial Appendage Closure in Atrial Fibrillation Patients With High Risk of Stroke and Bleeding

Background Percutaneous left atrial appendage closure (LAAC) is increasingly used as an alternative to oral anticoagulation for stroke prevention in atrial fibrillation. Its comparative effectiveness and safety in patients at a high risk of both stroke and bleeding remain uncertain. Objectives We evaluated the efficacy and safety of LAAC vs contemporary medical therapy in a high-risk population using individual participant data from randomized trials. Methods Bibliographic databases and trial registries through August 5, 2026, were searched for randomized trials comparing percutaneous LAAC with contemporary medical therapy in populations with a trial-level mean CHA2DS2-VASc score ≥4. A 1-stage common-effect analysis used Cox models stratified by trial and adjusted for age, sex, CHA2DS2-VASc score, and HAS-BLED score. Both primary outcomes were time to first stroke, systemic embolism, or cardiovascular/unknown death (efficacy) and time to first major bleeding (safety). A flexible time-varying Cox model was used for major bleeding. The protocol was submitted to PROSPERO (CRD420261335972). Results CLOSURE-AF (Left Atrial Appendage CLOSURE in Patients With Atrial Fibrillation Compared to Medical Therapy) and PRAGUE-17 (Left Atrial Appendage Closure vs. Novel Anticoagulation Agents in Atrial Fibrillation) contributed 1,290 participants (647 assigned to LAAC and 643 to control). Median age was 77.3 years (Q1-Q3: 71.4-81.9 years), and 809 participants (62.7%) were men. The primary efficacy outcome occurred in 142 LAAC participants (21.9%) and 133 control subjects (20.7%) (adjusted HR: 0.98; 95% CI: 0.77-1.24; P = 0.842). Major bleeding occurred in 86 LAAC participants (13.3%) and 80 control subjects (12.4%) (adjusted HR: 1.03; 95% CI: 0.75-1.39; P = 0.874). The treatment effect on major bleeding varied over time (P for treatment-by-time interaction < 0.001), with a cumulative major bleeding incidence of 9.4% with LAAC vs 6.0% with control (absolute risk difference, 3.4 percentage points; 95% CI: 0.4-6.3 percentage points) at 1 year and 13.2% vs 12.1% (absolute risk difference, 1.1 percentage points; 95% CI: -2.8 to 5.0 percentage points) at 3 years. Conclusions In high-risk patients with atrial fibrillation, no statistically significant difference was detected between LAAC and contemporary medical therapy for the primary efficacy outcome or major bleeding. The major bleeding hazard varied over time, with higher early and lower later conditional hazard estimates; however, a cumulative bleeding benefit was not demonstrated by 3 years. Long-term randomized data are needed to improve the precision of later treatment-effect estimates.