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Aliment Pharmacol Ther 2012; 35: 165–174Cytochrome P450 inhibition by proton pump inhibitors (PPIs) may attenuate the effectiveness of clopidogrel.To examine whether PPI use modifies the association between clopidogrel use and major adverse cardiovascular events (MACE) after percutaneous coronary intervention (PCI) with stent implantation, using time-varying drug exposure ascertainment.We conducted this population-based cohort study in Western Denmark (population 3 million) using medical databases. We identified all 13 001 patients with coronary stent implantation between 2002 and 2005 and ascertained their reported comorbidities. During the recommended 12-month postintervention treatment period, we tracked use of clopidogrel and PPI and the rate of MACE. We used Cox regression to compute hazard ratios (HRs), controlling for potential confounders.During follow-up, one or more prescriptions were redeemed by 91% of patients for clopidogrel and by 21% of patients for PPIs. Of the patients, 15% experienced a MACE. The adjusted HR for MACE comparing clopidogrel use with non-use was 0.57 [95% confidence interval (CI): 0.44–0.74] among PPI users and 0.47 (95% CI: 0.42–0.53) among PPI non-users, yielding an interaction effect (i.e. relative rate increase) of 1.20 (95% CI: 0.91–1.58). PPI users treated from before PCI had a 25% increased rate of MACE compared to PPI non-users, independent of clopidogrel use [adjusted HR = 1.24 (95% CI: 0.97–1.58) for clopidogrel users and 1.26 (95% CI: 0.97–1.63) for clopidogrel non-users].The use of PPIs as a class did not modify the protective effect of clopidogrel, but its use was associated with major adverse cardiovascular events itself, particularly among patients having used PPIs before percutaneous coronary intervention.