Proton Pump Inhibitor Use and Clinical Outcomes in Atrial Fibrillation During Anticoagulation

Purpose: Proton pump inhibitors are commonly used during oral anticoagulant therapy in patients with atrial fibrillation, but evidence regarding outcomes beyond upper gastrointestinal bleeding remains limited. We evaluated whether concomitant proton pump inhibitor use during oral anticoagulant therapy was associated with thromboembolic events, bleeding outcomes, and all-cause mortality. Methods: This retrospective multicenter cohort study included patients with atrial fibrillation who initiated oral anticoagulant therapy. Concomitant proton pump inhibitor use was modeled as a time-varying exposure with a prespecified 7-day lag. The primary outcome was a composite of thromboembolic events, major bleeding, and all-cause mortality. Secondary outcomes included each component outcome and gastrointestinal bleeding. Associations were estimated using time-dependent Cox proportional hazard models after multiple imputation of missing baseline variables. Results: Among 11,203 patients (median age 71 years [interquartile range 62–78]; 4743 women [42.3%]), 7-day lagged time-varying proton pump inhibitor exposure was associated with a higher risk of the composite outcome (hazard ratio 1.29, 95% confidence interval 1.08–1.55), major bleeding (1.80, 1.36–2.37), gastrointestinal bleeding (1.77, 1.18–2.66), and all-cause mortality (1.58, 1.00–2.48). No statistically significant association was observed for thromboembolic events. Across robustness analyses, the overall pattern was broadly maintained, although estimates varied according to exposure timing. Conclusions: In this observational cohort of patients with atrial fibrillation receiving oral anticoagulant therapy, concomitant proton pump inhibitor use modeled with a 7-day lagged time-varying framework was associated with higher risks of several bleeding-related outcomes and all-cause mortality, but not thromboembolism. These findings should be interpreted as associations rather than causal effects.