Assessing Impact of Concomitant Use of Proton Pump Inhibitors and Clopidogrel on Incidence of Major Adverse Cardiovascular Events: A Retrospective Cohort Study

PURPOSE: Clopidogrel, an antiplatelet agent used to prevent ischemic events, may interact with proton pump inhibitors (PPIs), especially omeprazole and esomeprazole, and reduce its effectiveness. The evidence surrounding this interaction remains controversial. This study investigates whether co-prescribing clopidogrel with PPIs is associated with a higher incidence of major adverse cardiovascular events (MACEs) compared to clopidogrel monotherapy. METHODS: We conducted a retrospective cohort study analyzing data from the Real-world Evidence Research Network in Saudi Arabia from 2016 to 2023. Patients were followed from their initial clopidogrel prescription until the occurrence of MACEs or the end of follow-up. We employed stabilized inverse probability of treatment weighting (SIPTW) to adjust for potential confounders and the Cox proportional hazards model to assess risks. RESULTS: A total of 29 572 patients were included, with 21 480 in the clopidogrel + PPI group and 8092 in the clopidogrel-only group. Baseline characteristics were balanced post SIPTW, with similar mean ages (clopidogrel + PPI: 65.9 years; clopidogrel only: 66.1 years) and 64% male representation. The incidence rate of MACE was 3.22 versus 2.92 per 10 000 person-days in the clopidogrel + PPI and clopidogrel-only groups, respectively. The weighted hazard ratio for MACE was 1.20 (95% CI, 1.01-1.43). CONCLUSIONS: In this large real-world cohort study, we observed a modest but statistically significant increase in the risk of MACEs among patients who received concomitant clopidogrel and proton pump inhibitor therapy. Given the widespread use of these medications, these findings emphasize the need for individualized risk assessments when co-prescribing PPIs and clopidogrel.