Genetic Variants Linked to Decreased Response to Clopidogrel, Increased Cardiovascular Risk

Polymorphisms in the gene encoding the cytochrome P-450 2C19 enzyme (CYP2C19) not only confer reduced response to clopidogrel, but also are associated with increased risk for cardiovascular events, according to three studies published online by the New England Journal of Medicine and Lancet.

In the first NEJM study, healthy adults exposed to clopidogrel who carried at least one CYP2C19 reduced-function allele had lower plasma concentrations of the drug's active metabolite and decreased platelet aggregation, relative to noncarriers. In addition, among nearly 1500 patients with acute coronary syndromes who received clopidogrel, carriers of CYP2C19 alleles — primarily CYP2C19*2 — faced greater risk for major cardiovascular events than did noncarriers.

Similarly, the second NEJM study, conducted among some 2200 patients given clopidogrel after MI, found that CYP2C19 reduced-function polymorphisms were associated with higher risk for cardiovascular outcomes.

And in Lancet, researchers again found that CYP2C19*2 was associated with a greater incidence of cardiovascular events among MI patients on clopidogrel. The author of an accompanying commentary calls this observation "fascinating," but concludes that genotyping cardiac patients "is not necessarily the appropriate solution without further work to validate such an approach."