NDLI: Effects of CYP2C19 genotype on outcomes of clopidogrel treatment.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Anand, Sonia S. Paré, Guillaume Fox, Keith A. A. Yusuf, Salim Mehta, Shamir R. Simonsen, Katy Hirsh, Jack Connolly, Stuart J. Eikelboom, John W. Bhatt, Deepak L.
Description	Author Affiliation: Paré G ( Population Health Research Institute, Hamilton Health Sciences, Hamilton, ON, Canada. pareg@mcmaster.ca)
Abstract	BACKGROUND: It has been suggested that clopidogrel may be less effective in reducing the rate of cardiovascular events among persons who are carriers of loss-of-function CYP2C19 alleles that are associated with reduced conversion of clopidogrel to its active metabolite. METHODS: We genotyped patients from two large, randomized trials that showed that clopidogrel, as compared with placebo, reduced the rate of cardiovascular events (the primary efficacy outcome) among patients with acute coronary syndromes and among patients with atrial fibrillation. Patients were genotyped for three single-nucleotide polymorphisms (2, 3, *17) that define the major CYP2C19 alleles. RESULTS: 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-of-function 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 loss-of-function carrier status. (Funded by Sanofi-Aventis and Bristol-Myers Squibb; ClinicalTrials.gov number, NCT00249873.).
ISSN	00284793
Issue Number	18
Volume Number	363
e-ISSN	15334406
Journal	New England Journal of Medicine
Language	English
Publisher	Massachusetts Medical Society (United States)
Publisher Date	2010-10-28
Publisher Place	United States
Access Restriction	Subscribed
Subject Keyword	Acute Coronary Syndrome Drug Therapy Aryl Hydrocarbon Hydroxylases Genetics Atrial Fibrillation Platelet Aggregation Inhibitors Therapeutic Use Ticlopidine Analogs & Derivatives Aged Cytochrome P-450 CYP2C19 Female Genotype Hemorrhage Chemically Induced Humans Male Middle Aged Mutation Adverse Effects Treatment Outcome Comparative Study Journal Article Randomized Controlled Trial Research Support, Non-U.S. Gov't Medicine
Content Type	Text
Resource Type	Article
Subject	Medicine

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