Comparison of the Effect of Proton Pump Inhibitors Versus Histamine-2 Receptor Antagonists on Cardiovascular Outcomes on Clopidogrel-Based Dual Antiplatelet Therapy: A Nationwide Cohort Study

Background: Dual antiplatelet therapy (DAPT) is essential after percutaneous coronary intervention (PCI) but increases gastrointestinal (GI) bleeding risk, necessitating acid suppressants. The cardiovascular safety of concomitant proton pump inhibitor (PPI) use with clopidogrel has been debated due to potential drug-drug interactions, although recent evidence suggests that these concerns may be less clinically significant. Objective: This study aimed to compare the risk of cardiovascular events and the prevention of GI bleeding associated with the use of PPIs with histamine type 2 receptor antagonists (H2RAs) in patients receiving clopidogrel after PCI, and to investigate potential differences among PPIs. Methods: In this retrospective cohort study conducted in Korea, 75 600 patients who had been discharged after PCI between September 2017 and August 2020 and maintaining DAPT of aspirin-clopidogrel for at least 90 days were divided into 2 groups: 20 843 patients received PPIs and 4239 patients received H2RAs. Propensity score matching resulted in 4238 patients in each group. The major outcome was a composite of acute myocardial infarction, acute ischemic stroke, revascularization, and in-hospital death up to 2 years of discharge. The secondary outcomes included major GI bleeding. Results: For the composite outcome, the incidence was not significantly higher in the PPIs group than in the H2RAs group (PPIs vs H2RAs after matching: 260 6.13% vs 197 4.65%; hazard ratio = 1.13; 95% confidence interval = 0.94, 1.36). No significant differences were observed in each outcome comprising the composite and bleeding outcome. Subgroup analysis stratified by CYP2C19 inhibition potential also showed no significant differences. Conclusion and Relevance: Concomitant use of PPIs was not significantly associated with increased cardiovascular outcomes compared with concomitant use of H2RAs, and no significant differences in the potential interaction with CYP2C19 were observed in real-world data. These findings suggest that potential pharmacokinetic interactions may have limited clinical impact.