Clopidogrel: To Test or Not to Test? That Is the Question—Still

Abstract

“Personalized medicine” holds great promise to help target therapies to achieve the best clinical benefit for patients. One area where cardiovascular disease and personalized medicine intersect is in the use of genetic and platelet-function testing for evaluating the antiplatelet effects of the antiplatelet agent clopidogrel. While some have begun early adoption of this approach and the US Food and Drug Administration (FDA)2 has recently called attention to this issue via a “black box” warning (1), caution has recently been raised with a study by Pare et al. (2), who found the value of platelet genetic testing to be less clear. An emerging consensus is that additional larger clinical-outcome studies are needed to specifically evaluate any potential strategy of genetic and platelet testing with antiplatelet therapy adjustment before this approach can be recommended for clinical use. The focus on clopidogrel began with a series of studies that showed marked variation in the level of platelet inhibition achieved with the standard fixed dose of this drug. Because clopidogrel is a prodrug, its metabolism in the liver to the active metabolite became a focus of research to explain this variation in platelet response. In particular, several studies showed that clopidogrel-treated patients who had a reduced-function allele of CYP2C19 (cytochrome P450, family 2, subfamily C, polypeptide 19) (most commonly the *2 or *3 allele, roughly 30% of patients) had a significantly higher risk of cardiovascular events than those who had a normally functioning CYP2C19 enzyme (3). Patients with reduced-function alleles were also documented to have lower concentrations of the active clopidogrel metabolite and lower levels of platelet inhibition (3). Thus, data appeared to support the full chain of events: A genetic polymorphism of the reduced-function enzyme can lead to reduced active metabolite, less platelet inhibition, and an increased risk of cardiovascular events. Several …