Cytochrome P-450 Polymorphisms and Response to Clopidogrel

Abstract

Conclusion: Persons with a reduced function of the CYP2C19 allele have significantly lower levels of active metabolite of clopidogrel, with diminished platelet inhibition and higher rates of major cardiovascular events than noncarriers of the CYP2C19 allele. Summary: Clopidogrel is a thienopyridine inhibitor of the platelet P2Y12 adenosine diphosphate (ADP) receptor. It is a “prodrug” that requires biotransformation to an active metabolite by a cytochrome P-450 enzyme. Esterases shunt most of clopidogrel to an inactive pathway, with the remaining prodrug requiring two separate CYP-dependent oxidative steps. Genes encoding CYP enzymes are polymorphic, with some alleles conferring reduced enzymatic function. Therefore, it is possible CYP polymorphisms can effect conversion of clopidogrel to active metabolite and hence affect the degree of clopidogrel induced platelet inhibition. In this study the authors tested the association between functional variance in CYP genes, plasma concentration of active clopidogrel drug metabolite, and platelet inhibition in response to clopidogrel. There were 162 healthy subjects analyzed as well as 1477 individuals with acute coronary syndromes treated with clopidogrel in a trial to assess improvement in therapeutic outcomes by optimizing platelet inhibition in patients with myocardial infarction (TRITON-TIMI 38). Approximately 30% of the healthy participants were carriers of at least one CYP2C19 reduced-function allele. These individuals had a reduction of 32.4% in plasma exposure to the active metabolite of clopidogrel compared with noncarriers (P < .001). Carriers also had reduced reduction in maximal platelet aggregation compared with noncarriers (P < .001). Among clopidogrel-treated patients in TRITON-TIMI 38, carriers of reduced-function alleles had a relative increase of 53% in the composite primary end point of death due to cardiovascular causes, myocardial infarction, or stroke compared with noncarriers (12.1% vs 8%; hazard ratio [HR] for carriers, 1.53; 95% confidence interval [CI] 1.07-2.19; P = .01). Carriers had an increase by a factor of three in the risk of stent thrombosis (2.6% vs 0.8%; HR, 3.09; 95% CI, 1.19-8.00; P = .02). Comment: This study, along with the similar study also appearing in the same issue of the New England Journal of Medicine (2009;360:363-75), provides strong evidence linking genetic variations in CYP genes to reduced exposure to active drug metabolite in patients treated with clopidogrel. These polymorphisms are seen in approximately 30% of white patients, 40% of African Americans, and >55% of people of East Asian origin. Of course multiple other genetic and environmental factors can also contribute to platelet aggregation. Nevertheless, the data are quite convincing that genetic variation in the genes encoding CYP enzymes can result in meaningful and profound clinical effects.