抗血小板药物基因检测技术在冠状动脉旁路移植术后个体化用药中的临床应用
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(阜外华中心血管病医院 河南省人民医院心脏中心心血管外科,河南省郑州市 451464)

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轩继中,硕士,住院医师,研究方向为冠心病的外科治疗及微创心脏外科,E-mail为xuanjizhong2009@163.com。通信作者程兆云,博士,主任医师,研究方向为冠状动脉外科及终末期心脏病的外科综合治疗,E-mail为13903712068@163.com。

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河南省医学科技攻关计划省部共建项目(201601011)


Clinical application of antiplatelet drug gene detection technology in individualized medication after coronary artery bypass grafting
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Department of Cardiovascular Surgery, Fuwai Central China Cardiovascular Hospital & Heart Center of Henan Provincial People's Hospital, Zhengzhou, Henan 451464, China)

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    摘要:

    目的 研究国人阿司匹林、氯吡格雷药物基因检测结果特点及该技术在指导冠状动脉旁路移植术后个体化用药中的临床应用价值。方法 选取行单纯冠状动脉旁路移植术患者846例,术前均行阿司匹林、氯吡格雷药物基因检测,分别统计两种药物基因检测结果的特点,术后依据基因检测结果及循证医学证据的建议进行个体化抗血小板治疗,分析术后在院期间新发动脉血栓形成事件及抗血小板药物应用相关出血的发生率,并随机抽取部分患者应用血栓弹力图来验证抗血小板疗效。结果 阿司匹林检测血小板内皮聚集受体1(PEAR1)基因野生型(GG)321例(37.9%),突变杂合型(GA)407例(48.1%),突变纯合型(AA)118例(14.0%),其中基因型为野生型的患者如合并高龄(≥70岁)、消化道溃疡病史或胃大部切除术后,则使用铝镁匹林片(Ⅱ)(阿斯德)(114 mg/d)进行抗血小板治疗,其余患者使用阿司匹林肠溶片(拜阿司匹灵)常规剂量(100 mg/d)。氯吡格雷检测的基因为细胞色素P450 2C19(CYP2C19)和对氧磷酶1(PON1),其中,基因型组合为GG+GG、GG+GA、GA+GG即表明患者对氯吡格雷应答良好或仅有较低的抵抗风险,此类患者给予氯吡格雷常规剂量(75 mg/d)应用,共429例(50.7%);相反,基因型组合为AA+AA、AA+GA、AA+GG、GA+AA、GA+GA及GG+AA的患者均存在较高的氯吡格雷抵抗风险,共417例(49.3%),使用氯吡格雷抗血小板治疗需至少增加50%~70%的剂量或已不适合应用该药进行抗血小板治疗,研究采用直接替换为替格瑞洛180 mg/d(分两次服用)的方法进行双联抗血小板治疗。术后在院期间新发心肌梗死4例、脑梗死3例、抗血小板药物应用相关出血3例(鼻出血2例,牙龈出血1例)。术后口服抗血小板药物治疗3~5天随机选择完成血栓弹力图血小板功能检查的患者共109例,结果显示AA抑制率(63.48±8.85)%,ADP抑制率(53.43±14.10)%,MAADP值36.67±6.25 mm。结论 对于冠状动脉旁路移植术后的双联抗血小板治疗,单中心结果显示国人具有较高的氯吡格雷基因抵抗概率,基因检测技术在氯吡格雷和替格瑞洛的药物选择上具有重要的参考价值。而有消化道出血高危因素的患者,阿司匹林基因检测结果可以作为药物减量的重要依据。

    Abstract:

    Aim To study the characteristics of aspirin and clopidogrel pharmacogenomic testing results in Chinese patients, and to evaluate the clinical application using this technology as an individualized medication guidance after coronary artery bypass grafting. Methods Eight hundred fourty six patients who underwent coronary artery bypass grafting were included. All patients underwent preoperative aspirin and clopidogrel gene detection. The characteristics of the two drugs' testing results were counted respectively. Postoperative individualized antiplatelet therapy was implemented according to the genetic testing results and the evidence-based suggestions. The postoperative inpatients' arterial thrombosis events and the hemorrhage rate associated with antiplatelet drugs application were analyzed. The thrombelastogram (TEG) was used to verify the antiplatelet efficacy randomly. Results The platelet endothelial aggregation receptor 1 (PEAR1) gene was detected for patients with aspirin medication, including 321 cases of wild type (GG) (37.9%), 407 cases of heterozygous mutation (GA) (48.1%), and 118 cases of homozygous mutation (AA) (14%). The aluminium,magnesium and aspinin tablets (Ⅱ) (114 mg/ day) for antiplatelet therapy was applied for the wild type patients over 70 years old, or with a history of peptic ulcer or subtotal gastrectomy. For the remaining patients, aspirin enteric-coated tablets with routine dose (100 mg/ day) was used. Clopidogrel's detected genes were CYP2C19 and PON1. The genotype combination of GG+GG, GG+GA and GA+GG indicates a good response to clopidogrel or a low risk of resistance. Such patients, a total of 429 cases (50.7%), were given a conventional dose of clopidogrel (75 mg/day). On the contrary, genotype combination of AA+AA, AA+GA, AA+GG, GA+AA, GA+GA and GG+AA indicates a high risk of clopidogrel genetic resistance. For these patients, a total of 417 cases (49.3%), the dose of clopidogrel for antiplatelet therapy should increase at least by 50%~70%. Ticagrelor 180 mg/day (two doses) was used for those that were not suitable. In the postoperative hospital-stay period, there were 4 cases of myocardial infarction, 3 cases of cerebral infarction, and 3 cases of bleeding associated with antiplatelet drugs (2 cases of epistaxis and 1 case of gingival bleeding). There were 109 cases received the platelet function test of TEG on 3~5 days after oral antiplatelet therapy randomly. The inhibition rate of AA was (63.48±8.85)%; the inhibition rate of ADP was (53.43±14.10)%; and the MAADP value was 36.67±6.25 mm.Conclusions For the dual antiplatelet therapy after coronary artery bypass grafting, single center results showed that Chinese people had high probability of clopidogrel gene resistance. Gene detection technology has important reference value in the selection of clopidogrel and ticagrelor. For patients with high risk factors for gastrointestinal bleeding, the results of aspirin gene detection can be used as an important basis for drug reduction.

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轩继中,程兆云,赵子牛,王圣,夏东升,胡俊龙.抗血小板药物基因检测技术在冠状动脉旁路移植术后个体化用药中的临床应用[J].中国动脉硬化杂志,2018,26(9):920~924.

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  • 收稿日期:2017-12-20
  • 最后修改日期:2018-03-11
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  • 在线发布日期: 2018-10-16