Abstract 3997: Impact of Cytochrome P450 2C19*17 Polymorphism on Post-Treatment Platelet Reactivity after a 600-mg Loading Dose of Clopidogrel in a Large Cohort of Patients Undergoing PCI
The antiplatelet effect of clopidogrel requires formation of an active metabolite by two metabolic reactions with distinct contribution of various isoenzymes of the cytochrome P450 (CYP) system involved. The extent of bioactivation determines the antiplatelet effect of clopidogrel. Patients carrying at least one CYP2C19*2 loss-of-function allele are prone to an increased residual platelet activity after clopidogrel which constituted a three-fold increased risk for death and myocardial infarction within 12 months after percutaneous coronary intervention (PCI) in the EXCELSIOR study. A recently described novel CYP2C19*17 allele was associated with increased activity of this isoenzyme due to the recruitment of transcription factor(s) to the mutated −806C>T site. In a secondary analysis of the EXCELSIOR study, we, therefore, investigated the impact of the CYP2C19*17 polymorphism on the antiplatelet effect of clopidogrel. The antiplatelet effect of a 600-mg loading dose of clopidogrel was determined by light transmission aggregometry (ADP 5 μM) in 802 patients with elective PCI and stent implantation before loading, at the time of PCI and pre-discharge at day 1 after PCI. Genotyping for CYP2C19*2 and *17 could be performed by real-time PCR in 788 patients. Out of this cohort, 272 (34.5%) were heterozygous and 41 (5.2%) were homozygous for the CYP2C19*17 allele, corresponding to an allele frequency of 22.5%. Residual platelet aggregation (RPA) at baseline (i.e. before clopidogrel) was not affected by the presence of the *17 allele (p=0.333). The increased RPA after clopidogrel in patients carrying the CYP2C19*2 loss of function variant was partially reversed by the presence of the CYP2C19*17 allele. In patients with at least one CYP2C19*2 allele, RPA before PCI was at median 25.0% (interquartile range: 9.0 –38.0%) in non-carriers of the *17 allele vs. 17.5% (4.0 –38.0%) in patients with the *17 allele (p=0.147) and at day 1 after PCI 12.0% (5.0 –25.0%) vs. 8.0% (2.0 –18.0%; p=0.012). In conclusion, patients carrying a CYP2C19*2 allele encoding for a non-functional form of this isoenzyme and no *17 allele represent a subgroup of patients with a genetic background prone for a high likelihood of increased platelet reactivity during treatment with clopidogrel.