Objective: To analyze association of CYP2C19 genotype and platelet function phenotype and their impact on clinical outcomes including bleeding events of coronary artery disease(CAD) patients received clopidogrel post percutaneous coronary intervention(PCI). Methods: Coronary atherosclerotic heart diseases patients underwent elective PCI and coronary stent implantation in Fuwai hospital were prospectively enrolled during May 2012 to April 2013. Patients were assigned into groups by genotype of CYP2C19 (extensive metabolizers, intermediate metabolizers, and poor metabolizers) and phenotype of platelet function (clopidogrel responders, semi-responders, and non-responders). The rates of major adverse cardiovascular events, combined cardiovascular events, and bleeding events were recorded during a at least 12 months follow-up period and compared among above defined groups. The association between genotype or phenotype and clinical outcome was assessed using multivariable Cox regression hazards model. Results: Three hundred and eighty patients received coronary stent implantation and met the inclusion criteria of the study, including 157(41.3%) clopidogrel extensive metabolizers, 176(46.3%) intermediate metabolizers, and 47(12.4%) poor metabolizers according to the genotype grouping; 98(25.8%) were responders to clopidogrel, 149(39.2%) were semi-responders, and 133 (35.0%) were non-responders according to the phenotype grouping. Three hundred and seventy-six patients accomplished follow-up. The highest combined cardiovascular events rate was observed in the poor metabolizers (34.0%(16/47)) as compared to the intermediate metabolizers (19.0%(33/174), P=0.026) and the extensive metabolizers (15.5%(24/155), P=0.005). The highest bleeding events rate was observed in the clopidogrel responders (33.7%(33/98)) as compared to the semi-responders (18.9%(28/149), P=0.008) and non-responders (17.7%(23/130), P=0.008). In multivariable Cox regression analysis, the adjusted risk of cardiovascular death, acute myocardial infarction, stent embolism, target lesion revascularization and angina onset was 2.305 times higher in clopidogrel poor metabolizers than in extensive and semi-metabolizers (95%CI=1.208-4.399, P=0.011). The adjusted HR for bleeding events was 0.540 (95%CI=0.321-0.909, P=0.021) among semi-responders vs. responders, was 0.52 (95%CI=0.301-0.905, P=0.021) among non-responders vs. responders during the 12 months follow-up period. Conclusions: Among CAD patients underwent stenting and clopidogrel treatment, poor CYP2C19 metabolizers group carries a significantly higher risk for combined cardiovascular events than in extensive metabolizers group, while clopidogrel responders patients are at significantly higher risk for bleeding as compared to the semi-responders and non-responders.
目的： 评价冠心病患者经皮冠状动脉介入治疗后服用氯吡格雷治疗期间CYP2C19基因型、血小板聚集率变化与临床预后的相关性。 方法： 入选2012年5月至2013年4月于阜外医院冠状动脉造影并置入支架的冠心病患者共380例，检测CYP2C19*2、*3、*17位点基因型，分为超快或快代谢、中间代谢和慢代谢型。以ADP光学比浊法测定血小板聚集率，将患者分为氯吡格雷良好反应、中度反应和无反应型。随访严重心脏事件(心血管死亡、急性心肌梗死、支架内血栓、靶病变再次血运重建)、联合心脏事件(上述事件及心绞痛)、出血共12个月，比较不同分组方法患者组间事件的发生率是否存在差异，并分析事件的发生风险及与基因型、表现型的相关性。 结果： 根据基因型检测结果，超快或快代谢、中间代谢和慢代谢型患者分别为157例(41.3%)、176例(46.3%)及47例(12.4%)；根据表现型检测结果，氯吡格雷良好反应、中度反应和无反应型患者分别为98例(25.8%)、149例(39.2%)及133例(35.0%)。完成随访376例。慢代谢型发生联合心脏事件高于中间代谢型[34.0%(16/47)比19.0%(33/174)，P＝0.026]及超快或快代谢型的[15.5%(24/155)，P＝0.005]。在校正了性别、年龄、体重指数、吸烟史、高脂血症、高血压病、糖尿病、血红蛋白浓度及血小板计数后，慢代谢型患者联合事件的发生风险高于超快或快代谢型患者(HR＝2.305, 95%CI＝1.208～4.399，P＝0.011)。共84例发生出血事件，良好反应型患者出血发生率为33.7%(33/98)，明显高于中度反应型的18.9%(28/149，P＝0.008)及无反应型的17.7%(23/130，P＝0.008)。在校正了性别、年龄、体重指数、吸烟史、高脂血症、高血压病、糖尿病后，中度反应型患者出血事件的发生风险低于良好反应型(HR＝0.54，95%CI＝0.321～0.909，P＝0.021)，无反应型发生出血事件风险低于良好反应型(HR＝0.52，95%CI＝0.301～0.905，P＝0.021)。 结论： 服用氯吡格雷的冠心病患者，支架置入术后1年的心脏缺血性事件与CYP2C19基因型相关，而出血事件与用药后血小板聚集率的变化相关。.
Keywords: Angioplasty; Coronary artery disease; Platelet aggregation inhibitors.