Abstract 455: Peri-interventional Antiplatelet Effect of Clopidogrel in Patients Undergoing Percutaneous Coronary Intervention is Attenuated by Cytochrome P450 2C19*2 Polymorphism

The thienopyridine derivative clopidogrel is an inactive pro-drug requiring biotransformation by cytochrome P450 isoenzymes (CYP) in order to generate an active metabolite. This metabolite inhibits irreversibly the platelet P2Y12 receptor, thereby exerting the antiplatelet effect of the drug. The EXCELSIOR study showed a 7-fold 30-day risk of major adverse cardiac events in patients with inadequate peri-interventional platelet response to loading with clopidogrel 600 mg. Studies in healthy volunteers on the impact of the CYP2C19 genotype to the interindividual variability in antiplatelet effect of clopidogrel showed conflicting results. The EXCELSIOR study enrolled 802 patients undergoing elective percutaneous coronary intervention (PCI) with stent implantation. The antiplatelet effect of a loading dose of clopidogrel 600 mg was determined by optical aggregometry (5μM ADP) before administration of clopidogrel, at the time of PCI and pre-discharge at day 1after PCI. CYP2C19 genotype (681G>A) was analyzed in 697 patients by real-time PCR. Antiplatelet efficacy of clopidogrel was determined for the different genotypes. Within the subset of the EXCELSIOR cohort, 485 patients (69.6%) were CYP2C19 wild-type homozygous (*1/*1), 199 (28.6%) were CYP2C19*1/*2 and 13 (1.9%) were CYP2C19*2/*2 carrying two allelic variants encoding a deficient CYP2C19 enzyme. Residual platelet aggregation (median; interquartile ranges) determined 5 minutes after addition of ADP 5μM is summarized in relation to the CYP2C19 genotypes in the Table below. These results indicate that the antiplatelet response to a loading dose of clopidogrel 600 mg is substantially attenuated in patients carrying at least one CYP2C19*2 allele. It seems that the CYP2C19 genotype is a major factor contributing to the observed variability in the antiplatelet effect of clopidogrel and might therefore affect clinical outcome of patients undergoing PCI. Relationship Between Genotype and ADP-induced Platelet Aggregation (%)