Influence of proton pump inhibitors on the antiplatelet properties of two clopidogrel dosing regimens and the role of CYP2C19 genotype

Background: Clopidogrel is a prodrug that requires a cytochrome P450-dependent conversion to become active. Besides genetic variations in CYP2C19, concomitant use of CYP2C19-metabolized proton pump inhibitors (PPIs) might attenuate clopidogrel's platelet inhibitory effect. Objectives: To evaluate the impact of the clopidogrel and PPI interaction in patients scheduled for elective PCI and to assess the effect of CYP2C19 polymorphisms on this interaction. Methods: Adenosine-induced platelet aggregation (PA) was assessed in 428 patients on clopidogrel and aspirin. Of these, 131 patients received a 300 mg clopidogrel loading dose 1-5 days prior to PCI, followed by 75 mg/day. The remaining 297 patients were on clopidogrel maintenance therapy of 75 mg/day for > 5 days before PCI. Of all patients CYP2C19 genotypes were determined. Results: A total of 98 patients (22.9%) used PPIs. In the loading dose group, PPIs increased on-clopidogrel platelet reactivity (?PA 12.4% for 10 μM ADP, p = 0.011). The use of PPIs was stronger associated with clopidogrel poor-response (defined as PA > 70% with 20 μM ADP) in CYP2C19∗1/∗1 wild-types than in carriers of the ∗2 variant allele (OR: 4.6, 95% CI: 1.1 - 20.0 and OR: 2.0, 95% CI: 0.5 - 6.0, respectively). In the maintenance therapy group, PPIs had no effect on on-clopidogrel platelet reactivity. Conclusions: The effect of a clopidogrel loading dose on platelet function was attenuated by PPI use. In this treatment group, CYP2C19∗2 tended to reduce the impact of the interaction between PPIs and clopidogrel. Clopidogrel maintenance therapy, however, was not affected by concomitant PPI use.