Abstract 1439: Cytochrome P450 Genetic Variants Predict Cardiovascular Outcomes following Treatment with Clopidogrel but not with Prasugrel

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Background : Prasugrel and clopidogrel require transformation into active metabolites by cytochrome P450 (CYP) enzymes. Variants in CYP genes, particularly CYP2C19 , are associated w/ reduced levels of metabolite and platelet inhibition w/ clopidogrel but not prasugrel. We investigated the impact of variants in CYP genes on clinical outcomes. Methods : TRITON-TIMI 38 randomized ACS patients w/ planned PCI to prasugrel (60 mg load, 10 mg qd) or clopidogrel (300 mg, 75 mg qd) for 6–15 mos. DNA was available in 2943 subjects who were genotyped for functional polymorphisms in CYP2C19 , 2C9 , 3A4/5 , 2B6 , and 1A2 and classified for each gene as carriers or non-carriers of ≥1 reduced function allele. Results : Among subjects treated with clopidogrel, CYP2C19 reduced function allele carriers (27% of population) had a 53% increased risk of the primary efficacy endpoint of CV death, MI, or stroke (HR 1.53, P=0.007, Fig ) and a 3-fold increased risk of ARC-defined definite or probable stent thrombosis (HR 3.09, P=0.038) compared w/ non-carriers. In contrast, with prasugrel CYP2C19 reduced function allele carriers were not at increased risk of CV death, MI, or stroke (HR 0.89, P=0.86) or stent thrombosis (HR 0.60, P=0.57). No association between genotype and bleeding was observed w/ either treatment. There were no statistically significant associations between any other tested CYP genotypes and outcomes. Conclusions : CYP2C19 genetic variants identify patients at significantly higher risk for CV death, MI, or stroke and for stent thrombosis among those treated with clopidogrel but not among those treated with prasugrel. CYP2C19 genotyping offers the potential to help tailor antiplatelet therapy.