Proton Pump Inhibitors, Platelet Reactivity, and Cardiovascular Outcomes After Drug-Eluting Stents in Clopidogrel-Treated Patients

Background— Certain proton pump inhibitors (PPIs) interfere with clopidogrel metabolism, potentially attenuating P2Y12 receptor inhibition. Previous observational and randomized trials report conflicting results regarding the clinical significance of this pharmacological interaction. We examined the interaction between concomitant administration of PPI and clopidogrel on platelet reactivity and clinical outcomes in the large-scale, prospective Assessment of Dual AntiPlatelet Therapy With Drug-Eluting Stents study. Methods and Results— On-treatment P2Y12 platelet reactivity testing was performed using the VerifyNow assay after clopidogrel loading and successful drug-eluting stent implantation at 11 sites in the United States and Germany. PPIs were prescribed at the discretion of treating physicians; patients were followed for 2 years. High platelet reactivity was defined as P2Y12 reactivity units >208. Of 8582 enrolled patients, 2697 (31.4%) were taking a PPI at the time of coronary intervention. After adjustment for differences in baseline characteristics, PPI use was independently associated with high platelet reactivity (odds ratio, 1.38: 95% confidence interval, 1.25–1.52, P =0.0001). A total of 2162 (25.2%) patients were prescribed a PPI at hospital discharge. In a propensity-adjusted multivariable analysis, discharge PPI use was independently associated with increased risk for postdischarge major adverse cardiac events (cardiac death, myocardial infarction, or ischemia-driven target lesion revascularization) at 2-year follow-up (hazard ratio, 1.21; 95% confidence interval, 1.04–1.42, P =0.02). Conclusions— In patients treated with clopidogrel after successful drug-eluting stents implantation, the concomitant administration of PPI was associated with high platelet reactivity and a greater rate of adverse outcomes during long-term follow-up. Additional studies are warranted to determine the risk–benefit ratio of PPIs in patients with drug-eluting stents treated with clopidogrel. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00433966.