Polymorphisms and Clinical Outcomes Following Percutaneous Coronary Intervention (PCI) in the Million Veterans Program (MVP)
CYP2C19 reduced function (RF) alleles (*2, *3) have been shown to impair clopidogrel effectiveness following percutaneous coronary intervention (PCI) in the setting of acute coronary syndromes (ACS); however, this association has not been explored in the Veterans Health Administration.
CYP2C19 RF alleles are associated with major adverse cardiac events (MACE) in patients treated with clopidogrel
MACE and CYP2C19 genotype were determined in MVP participants who underwent PCI between 2009-2017 with 1 year follow-up. Age was restricted to <65 years of age to exclude Veterans likely receiving care outside VHA. DNA extracted from whole blood was genotyped using a customized array and imputed to the 1000 Genomes reference panel. MACE, encompassing all-cause mortality, myocardial infarction and ischemic stroke, was ascertained in VA electronic health records using ICD 9/10 codes. Time to first MACE was determined in the whole cohort and in the subgroup with ACS and stable coronary disease using Kaplan-Meier estimators and Cox proportional hazard models adjusted for clinical covariates and clopidogrel exposure modeled as a time-varying covariate.
Among 4,490 Veterans (age 59.1 ± 5 years, 18% African American, 6% Hispanic, 44% ACS) who were prescribed clopidogrel following PCI, 1,261 (28%) had RF CYP2C19 alleles. The overall MACE rate was 7.0%. MACE was associated with ACS as initial presentation, diagnosis of diabetes, chronic kidney disease, peripheral vascular disease, congestive heart failure, history of stroke, prior MI. Among the subgroup presenting with ACS, the adjusted risk of MACE was greater in participants with RF alleles compared to those with wildtype alleles (HR 1.38, 95% CI 1.002-1.916). There was no impact of RF alleles on MACE risk in those in the non-ACS group (HR 1.00, 95% CI 0.702-1.429).
These data from the largest integrated health system in the US demonstrate that in Veterans presenting with ACS undergoing PCI, there was a higher risk of MACE in CYP2C19 RF carriers prescribed clopidogrel vs. wildtype carriers. The impact of the CYP2C19-clopidogrel interaction was not observed in the non-ACS patients. Further studies should explore the role of pharmacogenetic testing in Veterans.
Chanfreau-Coffinier, C; Anglin-Foote, T; Lee, KM; Lu, Z; lynch, J; Plomondon, ME; DuVall, SL; Friede, KA; Voora, D; Vassy, JL; Waldo, SW; Cleator, JH; Maddox, TM; Damrauer, SM; Rader, DJ; Assimes, TL; O'Donnell, C; Giri, J; Tsao, PS; Chang, K-M; Tuteja, S
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