| Objective:Ischemic stroke is a common cause of death and a leading cause of disability, and also has a high recurrent rate. As an antiplatelet drug, the efficacy and safety of clopidogrel in preventing subsequent thrombotic events in patients with coronary heart disease or ischemic stroke have been confirmed. However, clinical practice observed that a considerable proportion of patients continue to experience vascular events disregarding clopidogrel treatment. Recently, polymorphisms of genes encoding CYP450 enzymes, which are responsible for converting clopidogrel into the pharmacodynamically active metabolite, have been associated with the variant individual response to clopidogrel. Most studies on genotype-clopidogrel response were carried out in Caucasian patients with coronary heart disease to date. The results, therefore, were insufficient to weight the overall impact of genotypes on clopidogrel response, especially in Asian who has a higher frequency of loss-of-function alleles. Due to their evident discrepancies in etiology and pathogenesis, findings derived from coronary heart disease may be inapplicable to ischemic stroke, which was recommended in current guidelines as indication for clopidogrel. This study aimed to evaluate whether CYP450 genetic variants associated with subsequent vascular events in a cohort of Chinese patients with ischemic stroke and receiving clopidogrel.Methods:Consecutive patients with ischemic stroke registered in Nanjing Stroke Registry Program (NSRP) between May 2008 and April 2010 were enrolled in this study. Single-nucleotide polymorphisms (SNPS) genotyped included CYP2C19*2, CYP2C19*3, CYP2C19*17, CYP3A4*1G, CYP3A5*3, PON1 Q192R, PON1 L55M. Genotypes were determined by Improved Multiple Ligase Detection Reaction (iMLDR). All patients were genotyped and clinical outcomes were determined with three monthly follow-up. The primary endpoint was a composite of vascular death, and nonfatal ischemic stroke and MI and secondary endpoint was bleeding events. Possible deviation of genotype distribution was tested from Hardy-Weinberg equilibrium proportions using Pearson’s goodness-of-fit test. Cumulative risk of primary endpoint according to genotypes was presented with Kaplan-Meier survival curve. Differences between genotypes in respect to clinical events were assessed by univariate and multivariable Cox proportional-hazards model, which allowed the calculation of hazard ratios (HRs) and the corresponding 95% confidence intervals (CIs).Results:Of the enrolled 625 patients, the mean age was 61.6±12.2 years; Prevalence of hypertension, diabetic mellitus (DM), dyslipidemia, and coronary heart disease (CHD) were 70.6%,28.0%,46.7%, and 10.6% respectively. The median duration of clopidogrel exposure was 13.2 months. During the mean follow-up of 12.7 months (SD=5.1), vascular death was observed in 13 (2.1%), non-fatal ischemic stroke in 65 (10.4%), and non-fatal MI in 7 (1.1%) patients. The overall primary endpoint was observed in 85 (13.6%) patients. Bleeding events happened in 13 (1.2%) patients. Frequencies of CYP2C19*1,*2,*3 and *17 alleles were 61.2%,34.0%,3.8%,1.0% respectively, Frequencies of CYP3A4*1G and CYP3A5*3 alleles were 23.7% and 25.5%, Frequencies of PON1 Q192 and PON155M alleles were 38.1% and 2.8%. For genotypes of CYP2C19*2, primary endpoint was observed in 25 (8.9%) of 280 patients with wild-type homozygote patients, in 43 (16.0%) of 264 patients with heterozygote patients, and in 17 (21.0%) of 81 homozygous patients with during follow-up. Carriers of CYP2C19 LOF alleles were associated with increased risk of adverse clinical events (HR=2.16,95%CI 1.31-3.56, P=0.003). After adjusted for age, sex, and major cardiovascular risk factors, CYP2C19 LOF alleles were independently associated with primary endpoint (HR=2.31,95% CI:1.39-3.84, P=0.001).For genotypes of PON1 Q192R, primary endpoint was observed in 62 (15.7%) of 394 patients with QQ/QR, in 23 (10.0%) of 231 patients with RR during follow-up. PON1 Q192 alleles were associated with increased risk of adverse clinical events (HR=1.68, 95%CI 1.04-2.71, P=0.03). After adjusted for age, sex, and major cardiovascular risk factors, PON1 Q192 alleles carriage were independently associated with primary endpoint(HR=1.88,95% CI 1.56-3.05, P=0.01). No relationship between CYP2C19*17, CYP3A4*1B, CYP3A5*3 and PON1 L55M genetic polymorphisms and clinical outcomes were detected.Conclusions:Our results suggested that both CYP2C19 LOF and PON1Q192R polymorphisms may be determinants of clinical efficacy of clopidogrel in ischemic stroke patients in China. A worse clinical outcome occurred in patients carrying CYP2C19 LOF or PON1Q192 who were treated with clopidogrel after ischemic stroke. Our studies could have important implications for optimizing antiplantelet therapy in patients with ischemic stroke. |
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