Abstract 5493: Genetic or Acquired CYP2C19 Enzyme Deficit is Associated With an Excess of Cardiovascular Risk in Clopidogrel-treated Patients

Abstract

Introduction: Metabolic activation by CYP2C19 has emerged as a crucial determinant of clopidogrel responsiveness and efficacy. An increased risk of cardio-vascular events has been associated with the CYP2C19*2 allele, which causes loss-of-function, and with the use of proton pump inhibitors (PPI), which may also inhibit the CYP2C19, in clopidogrel-treated patients. We performed a meta-analysis to further estimate the relative effect in both sub-groups. Methods: Sixteen published or presented studies evaluating the association between the loss-of-function CYP2C19*2 genetic variant (8 studies, 9427 patients) or the use of PPI (8 studies, 35108 patients) and outcomes in patients treated with clopidogrel were included. Data on the occurrence of ischemic events (death, recurrent myocardial infarction, urgent revascularization) were extracted and combined using a fixed-effect model. Results: Of the 9427 patients, carriers of the loss-of-function CYP2C19*2 allele (28%, n=2674) displayed a 30% increase in the risk in any ischemic events compared to non carriers (10.4% vs 8.3%) (OR, 1.31; 95% CI, 1.12–1.53; p<0.001). This single gene variant (CYP2C19*2) was also associated with an excess of cardiovascular mortality (1.8% vs 1.0%)(OR 1.79; 95% CI: 1.10–2.91, p<0.019)(n=6225). PPI users (43%, n=15197) displayed an increased risk of ischemic events compared to non users (25.5% vs 19.4%) (OR, 1.48; 95% CI, 1.40–1.57; p<0.001)(n=34496). This metanalysis also showed an excess of mortality (16.9% vs 11.5%)(OR 1.20; 95% CI: 1.08–1.33, p<0.001)(n=15157) in PPI users compared to non users. When combining all data, CYP2C19 alteration due to the deficient allele or drug interaction has a 50% increased risk of ischemic events occurrence in clopidogrel treated patients (OR 1.49; 95% CI: 1.42–1.57, p<0.001). Conclusions: CYP2C19*2 carriers and/or PPI users are patients exposed to a significantly increased risk of cardiovascular events when they are treated with clopidogrel.