Pharmacodynamic Effects of Concomitant Versus Staggered Clopidogrel and Omeprazole Intake

Abstract

Background— A drug interaction between clopidogrel and omeprazole resulting in impaired platelet inhibition has been reported. It has been suggested that staggering administration of clopidogrel and omeprazole may overcome this pharmacodynamic (PD) interaction. Methods and Results— This prospective, open-label, 3-period, randomized crossover study was performed in 20 healthy volunteers. Subjects were randomly selected to receive omeprazole (40 mg daily) concomitantly (CONC) or staggered by 8 to 12 hours (STAG) for 1 week on a background of clopidogrel therapy in a crossover fashion, with a 2- to 4-week washout period between treatments. After another 2- to 4-week washout period, all subjects were treated for 1 week with clopidogrel alone. Clopidogrel was administered as a 600-mg loading dose followed by a 75-mg maintenance dose during all phases. PD effects were assessed by vasodilator-stimulated phosphoprotein phosphorylation assay, VerifyNow P2Y 12 system, and light transmittance aggregometry at baseline, 24 hours, and 1 week. The primary end point was the comparison of P2Y 12 reactivity index assessed by vasodilator-stimulated phosphoprotein phosphorylation assay at 1 week between CONC and STAG regimens. No significant difference in the primary end point was observed (least squares mean±SEM, 56.1±3.5% for CONC versus 61.6±3.4% for STAG; P =0.08). P2Y 12 reactivity index values were significantly lower in the clopidogrel regimen (48.8±3.4%) than in the CONC ( P =0.02) and STAG ( P =0.001) regimens. No PD differences were observed between regimens at baseline and 24 hours. Concordant results were obtained by P2Y 12 -specific assessments using VerifyNow but not with light transmittance aggregometry. Conclusions— Omeprazole impairs clopidogrel-induced antiplatelet effects in the maintenance phase of treatment irrespective of timing of their administration.