Clopidogrel and CYP2C19 Testing: Ready for Clinical Prime Time?

Abstract

Effective platelet inhibition has become a cornerstone in the management of patients with acute coronary syndromes (ACSs).4 The addition of clopidogrel, a blocker of the ADP platelet receptor, to aspirin therapy significantly reduces major cardiovascular events in ACS patients and reduces the frequency of percutaneous coronary intervention (PCI) with stent implantation. As PCI became the dominant approach for myocardial revascularization, clopidogrel use grew steadily, and clopidogrel is now the second most highly prescribed medicine in the US. Even though clopidogrel was approved for use in 1997, its mechanism of action continues to be progressively understood. The response to clopidogrel is highly variable among patients. Patients with low or incomplete platelet inhibition (so-called high residual on-clopidogrel platelet reactivity) are at a greater risk of cardiovascular events (1). Multiple mechanisms have been proposed for the variable response to clopidogrel. Pharmacokinetic and pharmacodynamic analyses have established that a substantial portion of the variation in platelet response is explained by the variability in plasma concentrations of the active metabolite of clopidogrel (2–4). Clopidogrel is a prodrug that requires bioactivation to achieve its antiplatelet efficacy. Only 15% of the prodrug is available for transformation to the active agent; the remaining 85% is hydrolyzed by esterases into inactive forms. The cytochrome P450 enzyme CYP2C19 contributes an estimated 21% to the generation of the active metabolite (5). Like many other members of the cytochrome P450 gene superfamily, the CYP2C19 (cytochrome P450, family 2, subfamily C, polypeptide 19) gene is highly polymorphic, with >25 variant alleles known. The most common CYP2C19 loss-of-function allele is * 2 (c.681G>A; rs4244285), with allele frequencies of approximately 15% in Caucasians and Africans, and 29%–35% in Asians. Carriers of two * 2 alleles are defined as poor metabolizers, whereas carriers of only one * 2 allele are defined as intermediate …