CYP2C9 Polymorphisms and the Risk of Cardiovascular Events in Patients Treated with Clopidogrel: Combined Data from the POPular Genetics and POPular AGE Trials.

Abstract

The cytochrome P450 (CYP)2C9 enzyme plays a role in the metabolization of clopidogrel. Carriage of a CYP2C9 loss-of-function (LoF) allele has been associated with attenuated pharmacokinetics, leading to a diminished pharmacodynamic response and increased risk for developing stent thrombosis in patients treated with clopidogrel. In this study, we aimed to determine the effect of the CYP2C9*2 and *3 LoF alleles on thrombotic events. Therefore, a post hoc analysis was performed in 878 patients with available CYP2C9 genotype status included in the POPular Genetics and POPular Age trials, which enrolled patients with ST-elevation myocardial infarction and non-ST-elevation myocardial infarction, respectively. The primary thrombotic outcome was a composite of cardiovascular death, myocardial infarction or stroke. A total of 526 (60%) patients were CYP2C9 LoF allele noncarriers and 352 (40%) were CYP2C9 LoF allele (*2 or *3) carriers. After correction for differences in baseline characteristics, there were no significant differences between CYP2C9 LoF allele carriers and noncarriers for the combined thrombotic outcome (6.3% vs. 5.9%, hazard ratio 1.16 [0.67-2.0], p=0.60), or the individual thrombotic outcomes. Moreover, no differences were seen in the event rates for clinically relevant bleeding (Bleeding Academic Research Consortium [BARC] 2-5 bleeding) as well as major bleeding (BARC 3 or 5 bleeding). Carriers of a CYP2C9 *2 or *3 LoF allele presenting with acute coronary syndrome and treated with clopidogrel did not have an increased risk for thrombotic events compared with noncarriers. Given the limited number of poor metabolizers, no firm conclusions could be drawn with regard to the thrombotic risk for patients carrying two CYP2C9 LoF alleles.