Pharmacogenetics in clopidogrel

Abstract

The cytochrome P450 (CYP) 2C19 loss-of-function *2 allele is associated with reduced clopidogrel bioactivation, increasing the risk of atherothrombotic complications after percutaneous coronary intervention (PCI). In-stent restenosis (ISR) is a complication that limits the long-term prognosis of PCI. The aim of the research was to investigate the association between CYP2C19*2 and the incidence of ISR within one year after PCI in patients prescribed dual antiplatelet therapy (DAPT) with aspirin and clopidogrel. A retrospective matched case-control study design with prospective follow-up was adopted. All (N=2,908) patients who underwent PCI with stent implantation between January 2014 and December 2018 were screened using the Cardiovascular Information Management System at the Department of Cardiology at Mater Dei Hospital. Patients with angiographically-confirmed drug eluting stent (DES)-ISR within 1 year when on DAPT with aspirin and clopidogrel were identified (Cases), and patients with no documented ISR post-PCI in the study period (Controls) were case-matched for age, gender, diabetes mellitus and estimated glomerular filtration rate (eGFR). Cases and controls were invited by the cardiologist for CYP2C19*2 genotyping. After obtaining informed written patient consent, a data collection form was completed, an EDTA-blood sample was collected, and genomic DNA extraction was performed. CYP2C19*2 genotyping of cases and controls was undertaken with the Autoimmun Diagnostika GmbH kits using gradient polymerase chain reaction and reverse hybridisation. The association between CYP2C19*2 and incidence of coronary ISR was analysed using the Fisher’s Exact test (univariate analysis) and binary logistic regression (multivariate analysis); p<0.05 considered statistically significant. Eighty-one patients with angiographically-confirmed DES-ISR within one-year post-PCI while on clopidogrel were identified, of whom 13 patients passed away, 7 refused enrolment into the study, and 1 was on haemodialysis, and these were excluded. Sixty cases (mean age 65±9.86 years, 51 male, 30 diabetics, mean eGFR 77±20.29 mL/min/1.73m2) and 60 matched controls were enrolled. Twenty-six (43.3%) cases and 5 (8.3%) controls were carriers of CYP2C19*2. The association between CYP2C19*2 carrier status and ISR within one-year post-PCI was statistically significant (p<0.001) in both the univariate and multivariate analysis. Univariate analysis showed an odds ratio of ISR occurrence in CYP2C19*2 carriers of 8.4, which increased to 22.6 in the multivariate analysis. The proportion of CYP2C19*2 carriers who presented with ISR within one-year post-PCI while on clopidogrel was significantly higher compared to patients with no documented ISR. Previous revascularisation, heart failure and active smoking were other variables observed to be significantly associated with the incidence of ISR. The study indicates that CYP2C19*2 genotyping may be used as a tool together with consideration of nongenetic factors for precision antiplatelet therapy to decrease the risk of ISR.