The Impact of Cytochrome P450 2C19 Polymorphism on Cardiovascular Events in Indonesian Patients with Coronary Artery Disease

Abstract

Background: The polymorphism of cytochrome P450 2C19 (CYP2C19) has been documented as the determinant variability in the antiplatelet effect of clopidogrel. The relation between CYP2C19 polymorphism and the antiplatelet efficacy of clopidogrel in Indonesian patients with coronary artery disease (CAD) is unknown. To address this issue, we examined the distribution of CYP2C19 genotypes and platelet aggregation, and assessed the impact of CYP2C19 polymorphism on response to clopidogrel and cardiovascular events. Methods: This observational analytic study with prospective cohort approach was conducted in Wahidin Sudirohusodo and Hasanuddin University Hospital, Makassar. We measured the CYP2C19 genotype by polymerase chain reaction-restriction fragment linked polymorphism (PCR-RFLP) method and platelet aggregation by optical platelet aggregometry with 10 μmol of adenosine diphosphate (ADP) in 69 patients with stable CAD who were treated with clopidogrel. Platelet hyperaggregation was defined as maximal platelet aggregation > 94.3%. The patients were followed up every month at the outpatient department for 6 months or at end point. The end point was acute myocardial infarction, ischemic stroke, or cardiovascular death. Results: Distribution of CYP2C19 alleles were 89.8%, 40.6%, and 11.6%, in CYP2C19*1, CYP2C19*2, and CYP2C19*3, respectively. Distribution of CYP2C19 genotype were 50.7%, 29.0%, 8.7%, 8.7%, and 2.9% in CYP2C19*1/*1, *1/*2, *1/*3, *2/*2, and *2/*3, respectively. Platelet hyper aggregation was more in patients with polymorphism than wild type (p 0.034; OR 3.707) and was associated with cardiovascular events (p 0.030; OR 13.250). There was acute myocardial infarction in 2 patients, ischemic stroke in 1 patient, and cardiovascular death in 1 patient. All of these patients were carrying at least one variant allele of CYP2C19; details of genotype were in two patients with CYP2C19*1/*2, one patient with *2/*2, and one with *2/*3 alleles. Conclusion: CYP2C19*2 and *3 were associated with cardiovascular events due to platelet hyper aggregation.