氯吡格雷抵抗及CYP2C19基因型对ACS患者PCI术后临床预后的影响

Effects of clopidogrel resistence and CYP2C19 genotype on the clinical prognosis of patients with acute coronary syndrome undergoing percutaneous coronary intervention

目的探讨急性冠状动脉综合征(ACS)患者氯吡格雷抵抗及细胞色素P4502C19(CYP2C19)基因型对经皮冠状动脉介入治疗(PCI)术后临床预后的影响。方法本研究为回顾性队列研究,选取2015年10月至2017年1月在北京安贞医院接受PCI治疗的ACS患者。采用血栓弹力图监测二磷酸腺苷(ADP)抑制率,根据监测结果将纳入患者分为氯吡格雷抵抗组和氯吡格雷非抵抗组。采用TaqMan探针实时荧光PCR检测CYP2C19基因型,根据检测结果将患者分为3组(快代谢型组、中代谢型组和慢代谢型组)。术后随访12个月,观察终点包括全因死亡、心原性死亡、心绞痛、心肌梗死、支架内血栓形成、缺血性卒中和出血等。将心绞痛、心肌梗死、支架内血栓和缺血性卒中组成的复合事件定义为联合血栓事件。比较不同分组患者的终点事件的发生率,采用Cox回归分析氯吡格雷抵抗和CYP2C19基因型对联合血栓事件、心原性死亡和出血的影响。结果共入选1696例患者,年龄(59.4±9.6)岁,男性1280例(75.5%)。氯吡格雷抵抗组471例(27.8%),氯吡格雷非抵抗组1225例(72.2%);慢代谢型组218例(12.9%),中代谢型组668例(39.4%),快代谢型组810例(47.8%)。中位随访时间13.3个月,失访率为7.7%(131/1696)。与氯吡格雷非抵抗组比较,氯吡格雷抵抗组的心肌梗死发生率较高[7.6%(36/471)比5.1%(62/1225),P=0.041],而出血[13.2%(62/471)比17.9%(219/1225),P=0.020]、小出血[11.5%(54/471)比15.8%(194/1225),P=0.022]的发生率较低。在全因死亡、心原性死亡、心绞痛、支架内血栓、缺血性卒中及大出血发生率方面,两组比较差异无统计学意义(P均>0.05)。不同CYP2C19基因型组的终点事件发生率差异均无统计学意义(P均>0.05)。Cox回归分析结果显示,氯吡格雷抵抗是联合血栓事件(OR=2.334,95%CI 1.215~4.443,P=0.016)及出血事件(OR=0.481,95%CI 0.174~0.901,P=0.023)的独立影响因素。CYP2C19基因型不是联合血栓事件、心原性死亡和出血的影响因素(P均>0.05)。结论对于PCI术后的ACS患者,氯吡格雷抵抗可增加联合血栓事件的发生风险,但出血风险也相应降低;CYP2C19基因型不是临床预后的独立影响因素。

Objective To investigate the effects of clopidogrel resistence and CYP2C19 genotype on the clinical prognosis of acute coronary syndrome(ACS)patients undergoing percutaneous coronary intervention(PCI).Methods This study was a retrospective cohort study.ACS patients who underwent PCI in Beijing Anzhen Hospital from October 2015 to January 2017 were recruited.The inhibition rate of adenosine diphosphate(ADP)was monitored by thromboelastography.All of these patients were divided into clopidogrel resistance and non-resistance group according to the monitoring results.CYP2C19 genotype was detected by TaqMan probe-based real-time quantitative PCR.Patients were divided into slow,medium and fast metabolic group,according to the CYP2C19 genotype.After 12 months of follow-up,the end points included all-cause death,cardiac death,angina,myocardial infarction,stent thrombosis,ischemic stroke and hemorrhage were collected.Combined thrombotic events were defined as a composite of angina,myocardial infarction,stent thrombosis and ischemic stroke.The differences of the incidence of clinical events between groups were compared.Cox regression was used to analyze the effects of clopidogrel resistance and CYP2C19 genotype on the combined thrombotic events,cardiac death and hemorrhage.Results A total of 1696 patients were included,and the age was(59.4+9.6)years,with 1280(75.5%)males.There were 471 cases(27.8%)in clopidogrel resistance group,and 1225 cases(72.2%)in clopidogrel non-resistance group.There were 218 patients(12.9%)were in slow metabolic group,668(39.4%)in medium metabolic group,and 810(47.89%)in fast metabolic group.The median follow-up time was 13.3 months,and 131 cases were lost to follow-up,with a loss follow-up rate of 7.7%.Compared with the clopidogrel non-resistance group,the clopidogrel resistance group had a higher incidence of myocardial infarction(7.6%(36/471)vs.5.1%(62/1225),P=0.041),a lower incidence of hemorrhage(13.2%(62/471)vs.17.9%(219/1225),P=0.020)and minor hemorrhage(11.5%(54/471)vs.15.8%(194/1225),P=0.022).There were no statistically significant difference in all-cause death,cardiac death,angina,stent thrombosis,ischemic stroke and severe bleeding between clopidogrel resistance and non resistance group(all P>0.05).There was no statistically significant difference in the incidence of endpoint events among different CYP2C19 genotypes(all P>0.05).Cox regression analysis showed that clopidogrel resistance was an independent factor of combined thrombotic events(OR=2.334,95%Cl 1.215-4.443,P=0.016)and bleeding events(OR=0.481,95%CI 0.174-0.901,P=0.023).While CYP2C19 genotype was not independent factor for combined thrombotic events,cardiac death and hemorrhage(all P>0.05).Conclusion For ACS patients after PCI,clopidogrel resistance can increase the risk of combined thrombotic events,but also reduce the risk of bleeding;while CYP2C19 genotype is not an independent factor for clinical prognosis.