Increased Risk of Ischemic Events in Patients With Stroke Treated With Clopidogrel and a P-CAB or PPI

BACKGROUND: Potassium-competitive acid blockers (P-CABs) are newly introduced gastrointestinal protectants, but their interaction with clopidogrel remains uncharacterized. Proton pump inhibitors (PPIs) are often coprescribed with clopidogrel, despite potential pharmacodynamic interactions. This study evaluated the effectiveness and safety of P-CAB and PPI coadministered with clopidogrel in patients with ischemic stroke. METHODS: This population-based, longitudinal, retrospective cohort study used the Korean National Health Insurance Service database, covering 51.4 million individuals (≈97% of the Korean population) from 2016 to 2022. Patients with incident ischemic stroke were identified using predefined criteria. Propensity score matching compared the 6-month incidence of major adverse cardiovascular events (including myocardial infarction, stroke recurrence, and all-cause mortality) and gastrointestinal bleeding among 3 cohorts: clopidogrel alone, clopidogrel+P-CAB, and clopidogrel+PPI. RESULTS: Between 2017 and 2021, 40 752 of 65 180 patients with incident stroke (62.5%) received clopidogrel. A total of 6680 patients (16.4%) formed the clopidogrel-alone cohort, 578 (1.4%) the clopidogrel+P-CAB cohort, and 8806 (21.6%) the clopidogrel+PPI cohort. During the follow-up period, stroke recurred in 268 patients (4.0%) receiving clopidogrel alone, 26 patients (4.5%) receiving clopidogrel+P-CAB, and 431 patients (4.9%) receiving clopidogrel+PPI. After propensity score matching, the clopidogrel+P-CAB cohort showed a higher risk of major adverse cardiovascular events (hazard ratio [HR], 2.40 [95% CI, 1.18-4.85]) and stroke recurrence (HR, 2.64 [95% CI, 1.27-5.47]) than the clopidogrel-alone cohort. The clopidogrel+PPI cohort also had an increased risk of major adverse cardiovascular events (HR, 1.38 [95% CI, 1.17-1.63]) and stroke recurrence (HR, 1.41 [95% CI, 1.20-1.67]) relative to clopidogrel alone. Among PPIs, esomeprazole was associated with a higher risk of major adverse cardiovascular events (HR, 1.46 [95% CI, 1.10-1.92]) and stroke recurrence (HR, 1.50 [95% CI, 1.13-2.00]). Gastrointestinal bleeding did not differ significantly among the clopidogrel-alone, clopidogrel+P-CAB, and clopidogrel+PPI cohorts. CONCLUSIONS: Concomitant use of P-CABs or PPIs with clopidogrel was associated with an increased risk of ischemic events in patients with stroke. P-CABs or PPIs should, therefore, be prescribed cautiously for patients with stroke treated with clopidogrel.