Impact of proton pump inhibitor use on clinical outcomes in East Asian patients receiving clopidogrel following drug-eluting stent implantation

Abstract

Background: Concomitant use of clopidogrel and proton pump inhibitor (PPI) is common, but PPI may reduce the antiplatelet effects of clopidogrel in patients undergoing percutaneous coronary intervention (PCI). We evaluated the impact of PPI use on clinical outcomes in post-PCI patients, by incorporating P2Y12 reaction unit (PRU) and CYP2C19 genotyping results.

Methods: From a multicenter registry of patients who underwent PCI with drug-eluting stent implantation and received clopidogrel-based dual antiplatelet therapy (DAPT), patients who were prescribed a PPI at the time of PCI (PPI users) were compared to those who were not (non-users). The primary outcome included all-cause death, myocardial infarction, stent thrombosis, or cerebrovascular accident at 12 months. Major bleeding (Bleeding Academic Research Consortium [BARC] types 3-5) and gastrointestinal (GI) bleeding (BARC types 3-5) were important secondary outcomes. The adjusted outcomes were compared using a 1:1 propensity-score (PS) matching and competing risk analysis.

Results: Of 13,160 patients, 2,235 (17.0%) were prescribed PPI, with an average age of 65.4 years. PPI users had higher on-treatment PRU levels than non-users. After PS matching, the primary outcome occurred in 51 patients who were PPI users (cumulative incidence, 4.7%) and 41 patients who were non-users (cumulative incidence, 3.7%; log-rank p = 0.27). In carriers of both CYP2C19 loss-of-function alleles, PPI use was linked to an increased risk of the primary outcome (hazard ratio, 3.22; 95% confidence interval, 1.18-8.78). The incidence of major bleeding and GI bleeding (BARC types 3-5) was comparable between PPI users and non-users in the PS-matched cohort.

Conclusions: In post-PCI patients receiving clopidogrel-based DAPT, PPI use was not linked to an increased risk of adverse cardiac and cerebrovascular events, but there was a small but significant increase in on-treatment PRU. Future research using a more individualized approach would further elucidate these interactions and guide evidence-based clinical practices.

Keywords: Bleeding; Clopidogrel; Myocardial infarction; Platelet reactivity; Poor metabolizer; Proton pump inhibitor.

Fig. 1

Distribution of the PRU before and after clopidogrel loading in the PS-matched cohort. The VerifyNow PRU results showed that baseline PRU values were similar between PPI users and non-users, with average values of 307.3 ± 63.9 and 309.1 ± 60.6, respectively (p = 0.48). However, after clopidogrel loading, on-treatment PRU values were significantly higher in PPI users (232.0 ± 82.9) than in non-users (224.4 ± 81.7). PPI, proton pump inhibitor; PRU, P2Y12 reaction unit; PS, propensity-score

Fig. 2

Cumulative incidence of major adverse cardiac and cerebrovascular events before and after PS matching. Before matching, the 12-month cumulative incidence of the primary outcome was higher in PPI users than in non-users (A). After 1:1 matching, the incidence rate was similar between PPI users and non-users (B). CI, confidence interval; HR, hazard ratio; PPI, proton pump inhibitor; PS, propensity-score

Fig. 3

Cumulative incidence of secondary outcomes in the PS-matched cohort. Key secondary outcomes included all-cause death, with PPI users experiencing a 2.6% incidence rate versus 1.8% in non-users (A). PPI users showed a numerically higher incidence of spontaneous myocardial infarction than non-users (B). Major bleeding events were similar between groups, 3.5% for PPI users and 3.8% for non-users (C). Major GI bleeding also showed no significant differences between the two groups (D). BARC, Bleeding Academic Research Consortium; CI, confidence interval; HR, hazard ratio; GI, gastrointestinal; PPI, proton pump inhibitor; PS, propensity-score