CYP2C19 loss‐of‐function alleles and use of omeprazole or esomeprazole increase the risk of cardiovascular outcomes in patients using clopidogrel

Our aim was to investigate in a real‐life prospective patient cohort how CYP2C19 loss‐of‐function (LOF) variants and CYP2C19 inhibitor omeprazole or esomeprazole influence the incidence of cardiovascular events in patients using clopidogrel. Data based simultaneously on these factors are conflicting and sparse. A cohort of prospective patients (n = 1972) with acute coronary syndrome (n = 1302) or symptomatic chronic coronary disease (n = 656) was followed for 365 days after hospitalization with information on purchased prescription drugs, hospital discharge, death, and genotype for CYP2C19*2, CYP2C19*3, and CYP2C19*8 LOF variants. The primary study outcome measurement was cardiovascular death or recurring myocardial infarction or stroke. Altogether, 608 patients (30.8%) carried CYP2C19 LOF alleles. During the 365‐day follow‐up 252 patients (12.8%) had an ischemic vascular event. Cardiovascular events were significantly more frequent in carriers of CYP2C19 LOF alleles (14.8%, 95% confidence interval [CI], 11.7–17.8) than in non‐carriers (10.8%, 95% CI, 9.0–12.6, p = 0.0159). Omeprazole or esomeprazole use was similar among LOF allele carriers (n = 131, 21.5%) and non‐carriers (n = 250, 18.3%, p = 0.185). Cardiovascular events were significantly more common in a composite group consisting of all CYP2C19 LOF carriers regardless of proton pump inhibitor use status and non‐carriers using omeprazole or esomeprazole than in non‐carriers not using omeprazole or esomeprazole (14.8%, 95% CI, 12.2–17.3 vs. 9.9%, 95% CI, 8.0–11.9, p = 0.00173). We observed significantly more cardiovascular events in carriers of CYP2C19 LOF variants and in non‐carriers using omeprazole or esomeprazole. For optimal patient care, both genetics and concomitant medication should be considered.