Effects of CYP2C19 Genotype on Outcomes of Clopidogrel Treatment

Among 5059 genotyped patients with acute coronary syndromes, clopidogrel as compared with placebo significantly reduced the rate of the primary efficacy outcome, irrespective of the genetically determined metabolizer phenotype (P = 0.12 for heterogeneity). The effect of clopidogrel in reducing the rate of the primary efficacy outcome was similar in patients who were heterozygous or homozygous for loss-offunction alleles and in those who were not carriers of the alleles (rate among carriers, 8.0% with clopidogrel vs. 11.6% with placebo; hazard ratio with clopidogrel, 0.69; 95% confidence interval [CI], 0.49 to 0.98; rate among noncarriers, 9.5% vs. 13.0%; hazard ratio, 0.72; 95% CI, 0.59 to 0.87). In contrast, gain-of-function carriers derived more benefit from clopidogrel treatment as compared with placebo than did noncarriers (rate of primary outcome among carriers, 7.7% vs. 13.0%; hazard ratio, 0.55; 95% CI, 0.42 to 0.73; rate among noncarriers, 10.0% vs. 12.2%; hazard ratio, 0.85; 95% CI, 0.68 to 1.05; P = 0.02 for interaction). The effect of clopidogrel on bleeding did not vary according to genotypic subgroups. Among 1156 genotyped patients with atrial fibrillation, there was no evidence of an interaction with respect to either efficacy or bleeding between the study treatment and the metabolizer phenotype, loss-of-function carrier status, or gain-of-function carrier status. Conclusions Among patients with acute coronary syndromes or atrial fibrillation, the effect of clopidogrel as compared with placebo is consistent, irrespective of CYP2C19 lossof-function carrier status. (Funded by Sanofi-Aventis and Bristol-Myers Squibb; ClinicalTrials.gov number, NCT00249873.)