【摘要】：[背景]心腦血管疾病是世界范圍內(nèi)人口死亡的主要原因。氯吡格雷(波利維)因其有效的降低心腦血管疾病的發(fā)病風(fēng)險和死亡率及更好的安全性,成為目前世界范圍內(nèi)最常使用的抗血小板藥物,但氯吡格雷的療效具有個體差異性,有相當(dāng)一部分的患者會對氯吡格雷產(chǎn)生低應(yīng)答。越來越多的研究結(jié)果證明氯吡格雷應(yīng)答的差異是由于不同人群中的基因多態(tài)性引起的。為探究這一問題,本研究以中國人群中缺血性卒中和急性冠脈綜合征患者為樣本,進(jìn)行多中心前瞻性觀察研究,擬通過藥物基因組學(xué)和血小板功能檢測開展對臨床事件的預(yù)測研究。 [方法]本研究針對中國人群中缺血性卒中和急性冠脈綜合征患者,首先對其進(jìn)行10個氯吡格雷藥物相關(guān)候選SNP的基因分型；對于缺血性卒中患者在初次頓服300mg氯吡格雷后6±1d進(jìn)行VerifyNow檢測血小板活性,對急性冠脈綜合征患者在其頓服氯毗格雷30±7d時通過VerifyNow檢測血小板活性；并且對于缺血性卒中患者在初次服藥后1個月、3個月和12個月時進(jìn)行隨訪,觀察臨床終點(diǎn)事件(心源性死亡、非致死性心梗和新發(fā)缺血性腦卒中)的發(fā)生以及安全性。 [結(jié)果]本研究首次在中國缺血性卒中人群中揭示了CYP2C19功能缺失基因CYP2C19*2與服用氯毗格雷進(jìn)行抗血小板治療后的高血小板活性和臨床缺血性事件的發(fā)生具有顯著關(guān)聯(lián),并且在中國進(jìn)行支架手術(shù)后的急性冠脈綜合征病人中驗證了CYP2C19*2是發(fā)生氯吡格雷抵抗的獨(dú)立危險因素。在我們的前期研究中發(fā)現(xiàn)至少攜帶有一個CYP2C19*2或CYP2C19*3基因的病人占總樣本量的60.1%，在本研究中也通過VerifyNow測定發(fā)現(xiàn)存在氯吡格雷抵抗(PRU≥230)的病人占25.9%,也就是說中國人群中有大量病人在接受氯吡格雷抗血小板治療中血小板活性并沒有得到良好的抑制,仍處于再發(fā)缺血性事件的高風(fēng)險狀態(tài)。 [結(jié)論]在中國缺血性卒中和急性冠脈綜合征患者開展的藥物基因組學(xué)研究證實了CYP2C19*2與氯毗格雷抵抗和臨床缺血性事件顯著相關(guān),可作為臨床抗血小板個體化治療的理論依據(jù)。
[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 鹵1 day after 300mg clopidogrel, and 30 鹵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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