P‐ CAB vs. PPI for Upper Gastrointestinal Bleeding Prevention in Patients With Atherothrombotic Disease on Antithrombotic Therapy: A CDM Cohort Study

BACKGROUND: Randomised trials have suggested the benefit of potassium-competitive acid blockers (P-CABs) is superior to proton pump inhibitors (PPIs) for ulcer recurrence in high-risk aspirin users. However, real-world comparative effectiveness across diverse antithrombotic regimens remains poorly defined. OBJECTIVE: We evaluated P-CABs versus PPIs for preventing upper gastrointestinal (GI) bleeding in patients with acute atherothrombotic disease and using antithrombotic therapy. DESIGN: This retrospective cohort study utilised hospital-based Common Data Model data (2018-2024). Patients with acute cardiovascular or cerebrovascular disease receiving antithrombotic therapy who initiated a PPI or P-CAB were included. Drug exposure was modelled as a time-varying variable to mitigate immortal-time bias. The primary outcome was upper GI bleeding, analysed via time-dependent Cox regression adjusted for age, sex, comorbidities, and concomitant medications. RESULTS: Among 2255 patients (PPI: 1726; P-CAB: 529) in which 53 upper GI bleeding events occurred during a median follow-up of 637 days. P-CAB use was associated with a significantly lower risk of upper GI bleeding than PPIs (incidence rate 5.7 vs. 25.8 per 1000 person-year; adjusted hazard ratio HR 0.22, 95% CI 0.06-0.75, p = 0.016). P-CABs showed a profound reduction in moderate-to-severe upper GI bleeding (HR 0.11, 95% CI 0.02-0.60; p = 0.011). Notably, no bleeding events occurred in P-CAB users with high antithrombotic burden (≥ 2 agents). CONCLUSIONS: In patients receiving antithrombotic therapy, P-CABs are associated with a significantly lower risk of clinically significant GI bleeding compared to PPIs. These findings support P-CABs as a potent acid-suppressive strategy for gastroprotection in high-risk populations.