Abstract Body (Do not enter title and authors here): Background: Left atrial appendage closure (LAAC) is increasingly used as an alternative to long-term anticoagulation in patients with atrial fibrillation (AF) who are at high thromboembolic risk. While LAAC aims to reduce the risk of stroke, real-world data on the long-term incidence of ischemic stroke and its predictors remain limited. We sought to assess the risk and predictors of ischemic stroke during the 3-year follow up period in a large dataset.

Methods: We analyzed 3-year follow-up data from the TriNetX research network on ischemic stroke in the patients who had undergone LAAC between 01/2015 and 12/2021. The primary outcome of our study was ischemic stroke, Cox proportional hazards modeling was used to identify independent predictors of stroke, adjusting for baseline demographics, comorbidities, and medication use.

Results: Among the 9,227 patients who underwent LAAC during the study period, 1,253 (13.6%) experienced an ischemic stroke. In the multivariable Cox model, diabetes mellitus (HR: 1.09; 95% CI: 1.01–1.18; p = 0.024), chronic kidney disease (HR: 1.11; 95% CI: 1.02–1.20; p = 0.011), left ventricular ejection fraction ≤55% (HR: 1.12; 95% CI: 1.00–1.26; p = 0.043), and chronic ischemic heart disease (HR: 1.10; 95% CI: 1.02–1.19; p = 0.0148) were independently associated with increased stroke risk. Age was modestly associated with lower stroke risk (HR: 0.99 per year; p = 0.0006), and male sex showed a borderline protective trend (HR: 0.93; 95% CI: 0.87–1.00; p = 0.059). Anticoagulant use was not significantly associated with stroke risk.

Conclusions: In this large real-world cohort of patients undergoing LAAC, we found a 13.6% incidence of ischemic stroke over 3 years, with diabetes, CKD, reduced LVEF, and chronic ischemic heart disease emerging as independent predictors. Anticoagulant use was not significantly associated with stroke risk, likely because nearly all patients were uniformly treated with anticoagulation post-procedure. Age showed a modest inverse association with stroke risk, and male sex showed a borderline protective effect. These findings emphasize that even after LAAC, patients with significant cardiovascular comorbidities remain at elevated stroke risk. Continued risk stratification and individualized follow-up remain essential in this high-risk population.