CYP2C19 Polymorphisms and Clinical Outcomes Following Percutaneous Coronary Intervention in the Million Veteran Program.

CYP2C19 loss-of-function (LOF) alleles decrease the antiplatelet effect of clopidogrel following percutaneous coronary intervention (PCI) in patients presenting with acute coronary syndrome (ACS). The impact of genotype in patients undergoing PCI for stable ischemic heart disease (SIHD) in real-world populations is less clear. We determined time to major adverse cardiac event (MACE), defined as the composite of cardiovascular death, stroke, or myocardial infarction, within 12 months following PCI in the VA Million Veteran Program (MVP) participants treated with clopidogrel from 1/1/2009 to 9/30/2017. Among 9061 Veterans (mean age 66.4 ± 8.7 years, 98% male, 13% Black); 43% had ACS, 57% had SIHD, and 28% carried a CYP2C19 LOF allele. In total, 619 patients (6.8%) experienced MACE, 317 (8.2%) in the ACS group and 302 (5.8%) in the SIHD group. Overall, a trend toward increased MACE risk was seen in the LOF carriers vs. non-carriers (adjusted hazard ratio [aHR] 1.13, confidence interval [95% CI] 0.98-1.31, P = 0.097), with a stronger risk among those presenting with ACS (aHR 1.20, 95% CI 0.98-1.47; P = 0.083). In post hoc analyses, LOF was associated with a significantly increased risk of MACE among younger (< 66 years) patients with ACS (aHR 1.41 [1.04-1.91], P = 0.028); however, no difference in risk was observed among older patients (aHR 1.07, 95% CI 0.80-1.40, P = 0.676). There was no impact of genotype in patients with SIHD (aHR 1.09, 95% CI 0.82-1.44, P = 0.565). Clinical factors may be more important than CYP2C19 genotype in determining the risk of MACE in older Veterans treated with clopidogrel undergoing PCI for ACS.