Abstract 19096: Cytochrome P450 Single-Nucleotide Polymorphisms and Cardiovascular Events in Patients Treated With Drug-Eluting Stent
Background: Pharmacogenetic determinants of the response of patients to clopidogrel contribute to variability in the biologic antiplatelet activity of the drug. Several studies have demonstrated that the allelic variants of genes modulating clopidogrel metabolic activation is associated with reduced clopidogrel responsiveness in patients with coronary artery disease. It is not known whether the loss-of-function polymorphism of cytochrome P450 is related with cardiac events in patients treated with drug-eluting stents (DES), for whom long-term use of clopidogrel is essential for protection against stent thrombosis.
Methods: We enrolled 2128 patients treated with DES and dual antiplatelet therapy in three center registry. We then assessed the relation of two allelic variants of genes modulating clopidogrel metabolic activation (CYP2C19*2, CYP3A5*3) to the risk of cardiac death, nonfatal myocardial infarction, stent thrombosis, and coronary revascularization during 2 year of follow-up. Platelet function was measured with the VerifyNow P2Y12 assay in 1404 patients.
Results: Of the patients studied, 1131 (53.1 %) were CYP2C19*2 wild-type homozygotes (GG), 829 (39.0 %) were heterozygotes (GA), and 168 (7.9 %) were mutant homozygotes (AA) and 1261 (59.3 %) were CYP3A5*3 wild-type homozygotes (GG), 752 (35.3 %) were heterozygotes (GA), and 115 (5.4 %) were mutant homozygotes (AA). The mean PRU was significantly higher in CYP2C19*2 non-GG (GA/AA) than in GG (non-GG vs. GG = 251±76 vs. 231±82, p<0.001). During six month follow-up, the hard cardiac events including cardiac death, non-fatal MI, and stent thrombosis occurred more frequently in CYP2C19*2 non-GG than in GG (15 vs. 5 events; hazard ratio [HR] 3.4 [95% CI 1.2-9.5], P=0.0113). The effect of CYP2C19*2 persisted also throughout the two-year follow-up period (24 vs. 11 events; HR 2.5114 [95% CI 1.2-5.2], P=0.0094). The single-nucleotide polymorphisms in CYP3A5*3 was not associated with a risk of an adverse cardiac events.
Conclusion: CYP2C19*2 genetic variant is significantly associated with an increased incidence of cardiac events in patients treated with drug-eluting stent and dual-antiplatelet therapy and this is mostly due to the increased rate of hard cardiac events.
- © 2010 by American Heart Association, Inc.