Abstract
Purpose: To investigate the prognostic impacts of a combined clopidogrel-metabolizing genotypes CYP 2C19 (+ or －)*2/(+ or －)*17 on patients with acute coronary syndrome (ACS). Population and methods: Prospective, longitudinal study of 95 patients admitted for ACS to a single coronary care unit. Patients less than 75 years of age, who survived hospitalization and to whom clopidogrel was prescribed, were included. CYP2C19 genotyping was performed at dis- charge. For analysis, the patients were grouped as follows: Group A ([+]*2/[+]*17) n = 8; Group B ([+]*2/[－]*17) n = 18; Group C ([－]*2/[+]*17) n = 27; and Group D ([－]*2/[－]*17) n = 42. Platelet function was assessed by an ADP platelet aggregation test using a commercially available kit. The primary end-point was a composite of mortality or readmission for ACS. The median time of follow-up was 136.0 (79.0 － 188.0) days. Results: The mean age of the study patients was 59.9 ± 10.7 years, and 83.2% were male. The allele frequencies of CYP2C19*2 and CYP2C19 *17 were 14.2% and 20%, respectively. Both allele frequencies were in Hardy Weinberg equilibrium. The patient groups were homogenous for demographic data, cardiovascular risk factors, GRACE and CRUSADE bleeding scores, left ventricular ejection fraction, and coronary anatomy. ADP platelet aggre-gation was similar for all groups (respective rates for groups A, B, C, D were 17.5 U (10.3 – 18.7) vs 20.0 U (17.3 – 26.8) vs 16 U (12 – 19) vs 12 U (8 – 22), p = 0.4). Event-free survival was significantly lower for group B (respective rates for Groups A, B, C, D were 87.5% vs 68.8% vs 96.3% vs 92.5%; p = 0.02). By multivariate Cox regression analysis, the CYP2C19 (+)*2/(－)*17 diplotype was an independent predictor of outcome, conferring a 5.2-fold higher adjusted risk for the composite endpoint than the others diplotypes. Conclusion: In our study, patients with the intermediate plus non-ultrarapid clopidogrel-metabolizing genotype ([+]*2/[－]*17) had a significantly poor medium-term prognosis for ischemic events, compared with the other diplotypes.
Highlights
Clopidogrel, a second-generation thienopyridine, is a prodrug that requires enzymatic biotransformation into its active thiol metabolite before interacting with the P2Y12 receptor on platelets
A common genetic variant within the CYP2C19 gene, the CYP2C19*2 loss-of-function polymorphism, was found to be associated with an attenuated response to clopidogrel [2,3,4,5], which resulted in worse clinical outcomes for patients undergoing coronary stenting [6,7] or with acute myocardial infarction (AMI) [8]
Patients were excluded if they were immediately referred to surgery, or if they were enrolled in 2 other clinical trials investigating antiplatelet therapy: The TRACER (Trial to Assess the Effects of SCH 530348 in Preventing Heart Attack and Stroke in Patients With Acute Coronary Syndrome—ClinicalTrials.gov identifier: NCT00527943) [16] and the TRILOGY acute coronary syndrome (ACS) (A Comparison of Prasugrel and Clopidogrel in Acute Coronary Syndrome Subjects—ClinicalTrials.gov identifier: NCT00699998) [17]
Summary
Clopidogrel, a second-generation thienopyridine, is a prodrug that requires enzymatic biotransformation into its active thiol metabolite before interacting with the P2Y12 receptor on platelets. A common genetic variant within the CYP2C19 gene, the CYP2C19*2 loss-of-function polymorphism, was found to be associated with an attenuated response to clopidogrel [2,3,4,5], which resulted in worse clinical outcomes for patients undergoing coronary stenting [6,7] or with acute myocardial infarction (AMI) [8]. Carriage of CYP2C19*17 was significantly associated with enhanced response to clopidogrel and an increased risk of bleeding in the context of percutaneous coronary intervention [14], but was found to confer protection against ischemic events in patients after AMIs [15]. It has been reported that combinations of the alleles CYP2C19*2 and CYP2C19*17 have significant effects on platelet aggregation [3], there have been no reports on prognosis regarding ischemic events after an AMI. We undertook a study of patients carrying combinationsof CYP2C19 *2 and CYP2C19*17 variant alleles, to determine mediumterm outcomes after an acute coronary syndrome (ACS)
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