Comparison of Cardiovascular Events in Patients Receiving Concomitant Clopidogrel and Proton Pump Inhibitors Classified by CYP2C19 Inhibitory Potency

BACKGROUND: Proton pump inhibitors (PPIs) may potentially reduce clopidogrel's antiplatelet effect and increase cardiovascular risk. The degree of CYP (cytochrome P450) 2C19 inhibition varies among PPIs. Few studies have evaluated individual PPIs by CYP2C19 inhibition strength across countries. This study aimed to compare the incidence of cardiovascular events between strong CYP2C19-inhibiting potency and weak CYP2C19-inhibiting potency (weak or non-CYP2C19-inhibiting PPIs) in patients receiving clopidogrel. METHODS: We conducted an international observational cohort study using 14 databases from the United States, South Korea, and Taiwan. We included patients aged ≥18 years who received clopidogrel with PPIs from 1985 to 2023. PPIs were classified into strong CYP2C19-inhibiting PPIs and weak or non-CYP2C19-inhibiting PPIs based on CYP2C19 inhibition. We compared the hazard ratios and 95% CIs for major adverse cardiovascular events, including myocardial infarction, stroke, and cardiovascular mortality, using the Cox proportional hazards model after 1:1 propensity score matching. Secondary outcomes included cardiovascular mortality, myocardial infarction, stroke, and all-cause mortality. A random-effects model calculated pooled hazard ratios and 95% CIs. Only databases meeting all diagnostic criteria were included in the meta-analysis. RESULTS: Large-scale propensity score matching identified 166 005 patient pairs. During the 365-day follow-up, the risk of major adverse cardiovascular events did not differ significantly between patients receiving clopidogrel plus strong CYP2C19-inhibiting PPIs and those receiving clopidogrel plus weak or non-CYP2C19-inhibiting PPIs (17.63 per 1000 person-years versus 16.82 per 1000 person-years; calibrated hazard ratio, 1.00 [95% CI, 0.79-1.26]). No significant difference was observed in the risk of secondary outcomes (calibrated hazard ratio, cardiovascular mortality 1.10 [95% CI, 0.87-1.39], myocardial infarction 0.98 [95% CI, 0.81-1.19], stroke 1.05 [95% CI, 0.87-1.27], and all-cause mortality 1.18 [95% CI, 0.93-1.50]). CONCLUSIONS: Concomitant use of clopidogrel and strong CYP2C19-inhibiting PPIs was not associated with a higher cardiovascular risk compared with concomitant use of clopidogrel and weak or non-CYP2C19-inhibiting PPIs. This large-scale study does not support the clinical significance of potential interactions between PPIs and clopidogrel.