Comparative Safety of Potassium-Competitive Acid Blockers on the Risk of Clostridioides difficile Infection: A Multicenter Cohort Study

INTRODUCTION: Proton pump inhibitors (PPIs) have been associated with an increased risk of Clostridioides difficile infection (CDI) in previous observational studies. However, real-world evidence on the CDI risk of potassium-competitive acid blockers (P-CABs), a newer class of acid suppressive agents, remains limited. METHODS: We conducted a retrospective cohort study using electronic health record data from 15 hospitals standardized to the Observational Medical Outcomes Partnership Common Data Model and integrated through Federated E-Health Big Data for Evidence Renovation Network. Patients newly prescribed P-CABs, proton pump inhibitors (PPIs), or histamine 2 receptor antagonists (H2RAs) were included and the primary outcome was the occurrence of CDI. After 1:4 propensity score matching, pairwise comparisons were conducted using Cox proportional hazards models. Hazard ratios (HRs) and 95% confidence intervals (CIs) were then pooled across databases by meta-analysis. RESULTS: In the 1:4 matched cohorts, we identified 61,596 P-CAB users (mean follow-up, 72.6 ± 29.9 days) and 132,683 PPI users (74.9 ± 28.6 days), 42,794 P-CAB users (69.5 ± 32.4 days) and 89,415 H2RA users (69.9 ± 33.1 days), and 85,686 PPI users (71.1 ± 31.2 days) and 159,178 H2RA users (68.0 ± 33.8 days) across the 3 pairwise comparisons. The pooled HRs were 0.87 (95% CI, 0.69-1.10) for P-CABs vs PPIs, 0.85 (0.64-1.12) for P-CABs vs H2RAs, and 1.13 (0.98-1.29) for PPIs vs H2RAs. Results were generally consistent across subgroup and sensitivity analyses. DISCUSSION: In this cohort study, P-CAB use was not associated with a higher risk of CDI compared with PPIs or H2RAs.