氯吡格雷药物基因在缺血性卒中和急性冠脉综合征病人中的观察性研究

发布时间：2018-07-20 19:21

【摘要】：[背景]心脑血管疾病是世界范围内人口死亡的主要原因。氯吡格雷(波利维)因其有效的降低心脑血管疾病的发病风险和死亡率及更好的安全性,成为目前世界范围内最常使用的抗血小板药物,但氯吡格雷的疗效具有个体差异性,有相当一部分的患者会对氯吡格雷产生低应答。越来越多的研究结果证明氯吡格雷应答的差异是由于不同人群中的基因多态性引起的。为探究这一问题,本研究以中国人群中缺血性卒中和急性冠脉综合征患者为样本,进行多中心前瞻性观察研究,拟通过药物基因组学和血小板功能检测开展对临床事件的预测研究。 [方法]本研究针对中国人群中缺血性卒中和急性冠脉综合征患者,首先对其进行10个氯吡格雷药物相关候选SNP的基因分型；对于缺血性卒中患者在初次顿服300mg氯吡格雷后6±1d进行VerifyNow检测血小板活性,对急性冠脉综合征患者在其顿服氯毗格雷30±7d时通过VerifyNow检测血小板活性；并且对于缺血性卒中患者在初次服药后1个月、3个月和12个月时进行随访,观察临床终点事件(心源性死亡、非致死性心梗和新发缺血性脑卒中)的发生以及安全性。 [结果]本研究首次在中国缺血性卒中人群中揭示了CYP2C19功能缺失基因CYP2C19*2与服用氯毗格雷进行抗血小板治疗后的高血小板活性和临床缺血性事件的发生具有显著关联,并且在中国进行支架手术后的急性冠脉综合征病人中验证了CYP2C19*2是发生氯吡格雷抵抗的独立危险因素。在我们的前期研究中发现至少携带有一个CYP2C19*2或CYP2C19*3基因的病人占总样本量的60.1%，在本研究中也通过VerifyNow测定发现存在氯吡格雷抵抗(PRU≥230)的病人占25.9%,也就是说中国人群中有大量病人在接受氯吡格雷抗血小板治疗中血小板活性并没有得到良好的抑制,仍处于再发缺血性事件的高风险状态。 [结论]在中国缺血性卒中和急性冠脉综合征患者开展的药物基因组学研究证实了CYP2C19*2与氯毗格雷抵抗和临床缺血性事件显著相关,可作为临床抗血小板个体化治疗的理论依据。
[Abstract]:Background: cardiovascular and cerebrovascular diseases are the main causes of death in the world. Clopidogrel (Polyvir) has become the most commonly used antiplatelet drug in the world because it can effectively reduce the risk and mortality of cardiovascular and cerebrovascular diseases, but the efficacy of clopidogrel has individual differences. A significant number of patients have a low response to clopidogrel. A growing number of studies have shown that differences in clopidogrel responses are due to genetic polymorphisms in different populations. To explore this problem, a multicenter prospective study was conducted in Chinese patients with ischemic stroke and acute coronary syndrome (ACS). To study the prediction of clinical events by pharmacogenomics and platelet function test. [methods] in this study, 10 clopidogrel drug related candidate SNPs were genotyped for ischemic stroke and acute coronary syndrome (ACS) in Chinese population. The platelet activity was measured by VerifyNow on 6 卤1 day after 300mg clopidogrel, and 30 卤7 days by VerifyNow in patients with acute coronary syndrome. Patients with ischemic stroke were followed up for 1 month, 3 months and 12 months after the first medication to observe the occurrence and safety of clinical endpoint events (cardiac death, nonfatal myocardial infarction and new ischemic stroke). [results] this study for the first time revealed a significant association between CYP2C19 deletion gene CYP2C19m2 and high platelet activity and clinical ischemic events after antiplatelet therapy with clopidogrel in Chinese patients with ischemic stroke. In Chinese patients with acute coronary syndrome after stenting, CYP2C19 / 2 was confirmed as an independent risk factor for clopidogrel resistance. In our previous study, we found that patients with at least one CYP2C19k2 or CYP2C19O3 gene accounted for 60.1% of the total sample. In this study, 25.9% of patients with clopidogrel resistance (PRU 鈮，

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