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Does Genotype Affect a Patient’s Response to Clopidogrel?

Evidence that it does is mounting.

Dual antiplatelet therapy with aspirin and clopidogrel is an important secondary preventive measure after treatment of MI or coronary ischemia. Clopidogrel is converted to an effective metabolite by cytochrome P-450 (CYP) enzymes. In two new studies, investigators assessed how patients’ genetic profiles affect platelet inhibition by clopidogrel and plasma concentrations of the active drug metabolite.

In a study sponsored by the manufacturer of a competitor to clopidogrel, investigators examined reduced-function alleles of CYP2C19 (which are present in 30% of whites, 40% of blacks, and 55% of East Asians). After clopidogrel administration, the level of the active metabolite was 32% lower in healthy carriers of at least one reduced-function allele than in healthy noncarriers. The reduction in platelet aggregation was also smaller in carriers, by 25%. In an analysis of data from TIMI-38, a randomized trial with a clopidogrel arm, the rate of cardiovascular death, MI, or stroke was 12.1% in carriers of at least one reduced-function allele, compared with 8.0% in noncarriers: a 53% increase in relative risk. Stent thrombosis also occurred in a higher proportion of carriers than noncarriers (2.6% vs. 0.8%).

In a study from a nationwide registry in France, investigators assessed polymorphisms modulating clopidogrel absorption, metabolic activation, and biological activity in 2208 patients with acute MI who received clopidogrel. The rate of adverse events was higher in patients with any two CYP2C19 reduced-function alleles than in those with the wild-type genotype (21.5% vs 13.3%; hazard ratio, 1.98; 95% confidence interval, 1.10–3.58). An increase in event rate was also seen in carriers of two variant alleles of ABCB1, which modulates clopidogrel absorption (15.5% vs. 10.7%; HR, 1.72; 95% CI, 1.20–2.47). In patients who underwent percutaneous coronary intervention, the risk for death, MI, or stroke was higher in those with two CYP2C19 variants than in those with the wild-type genotype (HR, 3.58; 95% CI, 1.71–7.51), but no significant increase was seen in those with the ABCB1 variants.

Comment: These findings suggest that a person’s genotype affects his or her response to clopidogrel and risk for adverse outcomes. Such studies as these are providing evidence that may rapidly lead us to an era of personalized medicine, in which a person’s genetic profile is a consideration in the choice of treatment strategy.

— Harlan M. Krumholz, MD, SM

Published in Journal Watch Cardiology January 21, 2009

Citation(s):

Mega JL et al. Cytochrome P-450 polymorphisms and response to clopidogrel. N Engl J Med 2009 Jan 22; 360:354.

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• Medline abstract (Free)

Simon T et al. for the French Registry of Acute ST-Elevation and Non–ST-Elevation Myocardial Infarction (FAST-MI) investigators. Genetic determinants of response to clopidogrel and cardiovascular events. N Engl J Med 2009 Jan 22; 360:363.

• Original article (Subscription may be required)
• Medline abstract (Free)