【作者】 李毅；

【导师】 韩雅玲； 王守力； 康建； 闫承慧；

【作者基本信息】 第四军医大学 ， 内科学， 2009， 博士

【摘要】 研究背景和目的抗血小板治疗可显著降低冠状动脉支架术后血栓事件的发生率,但约5%~35%的病人由于存在抗血小板药物抵抗而导致血栓事件风险明显增高。目前对抗血小板药物抵抗的诊断方法尚不普及、诊断标准不统一,且缺乏理想的干预手段。本研究旨在筛选简便、可靠的抗血小板药物抵抗诊断方法,分析抗血小板药物抵抗与临床高危因素的相关性并初步探索对抗血小板药物抵抗进行临床干预的有效性和安全性。方法2006年6月至2007年2月,前瞻性入选行冠状动脉支架术病人305例,分别于抗血小板药物治疗前及治疗后24h测定血小板功能,主要指标包括CD62P、血小板活化复合物(PAC)-1的表达及20μmol/L ADP诱导的血小板聚集率(IPA),以治疗前后20μmol/L ADP诱导的IPA变化值小于10%作为诊断氯吡格雷抵抗(CR)金标准。病人入选后随机分入优化抗血小板治疗组(n=154)及标准治疗组(n=151)。标准治疗组所有病例均采用标准阿司匹林、氯吡格雷两联抗血小板治疗;优化治疗组病人根据血小板功能检查结果分为CR和非CR,非CR病人抗血小板治疗方案与标准治疗组相同,CR病人在常规两联治疗基础上加用西洛他唑6个月。研究主要终点为随访1年时的死亡、心肌梗死(MI)和缺血性卒中复合终点。次要终点包括(1)随访1年时的死亡、MI、症状驱动的血运重建、缺血性卒中及外周动脉闭塞的复合终点。(2)TIMI出血事件发生率。(3)亚急性支架内血栓(SAT)及迟发性支架内血栓发生率。结果(1)入选病人CR发生率为23.8%。受试者操作特征曲线(ROC)分析表明,CD62P及PAC-1诊断CR的价值不大,而用药后测定的20μmol/L ADP诱导的IPA与金标准相比,曲线下面积(AUC)为0.878,临界值为>71.8%,诊断CR的敏感性和特异性分别为77.8%和85.2%。(2)多因素分析结果显示,年龄≥65岁[比值比(OR)=10.31, 95%可信区间(CI)= 4.265- 24.926, P<0.001]、糖尿病(OR=9.3, 95%CI= 3.413-25.344, P<0.001)、既往缺血病史(OR=7.139, 95%CI=2.658-19.180, P<0.001)、肌钙蛋白T(TnT)阳性(OR=7.6, 95%CI=1.505-38.391, P=0.014)、多支病变(OR=2.355, 95%CI=1.054- 5.261, P=0.037)是CR的临床预测因素。以临床预测因素个数≥2作为CR判别标准,与金标准相比AUC为0.899,敏感性和特异性分别达86.5%和79.7%。(3)优化治疗组主要终点事件风险较标准治疗组下降37%(5.8%比9.3%),但差异无统计学显著意义(P=0.257)。优化治疗组与标准治疗组的死亡(1.9%比2.6%, P=0.489)、MI(2.6%比4.6%,P=0.340)及缺血性卒中(1.3%比2.0,P=0.491)发生率均无显著差别。两组心性死亡、MI、缺血性卒中、缺血驱动的血运重建及下肢动脉闭塞的复合终点事件发生率无显著差异[9.7%(15/154)比14.6(22/151),P=0.197],但在优化治疗组中有降低趋势。两组支架血栓及出血事件均无差异。优化治疗组和对照组CR病例数分别为41例(26.6%)和33例(21.9%),在两联抗血小板治疗基础上加用西洛他唑可显著降低CR病人的IPA[(77.5±12.1)%比(64.5±12.1)%,P<0.001]。优化治疗组CR病人的主要终点事件与对照组CR病人相比无统计学显著意义[19.5%(8/41)比36.4%(12/33), P=0.105],但有降低趋势[相对风险(RR)= 54%,95%CI:0.25-1.16]。结论用药后单次测定20μmol/L ADP诱导的IPA可作为CR的诊断标准。年龄≥65岁、糖尿病、既往缺血病史、TnT阳性、多支病变是CR的临床预测因素,存在危险因素越多,临床存在CR的风险越高。根据IPA测定值调整抗血小板治疗方案(对CR病人进行强化的三联抗血小板治疗)可能有利于改善长期预后,但其有效性和安全性还需大样本临床研究证实。更多还原

【Abstract】 Background and Objectives Antiplatelet therapy significantly decreases the incidence of thrombotic events after coronary stenting. However, about 5%~35% of patients were associated with an increased risk of thrombotic events because of antiplatelet resistance. At present, there was no uniform diagnosis standard of antiplatelet resistance, as well as effective therapeutic methods. The present study was aimed to screen effective and convenient diagnosis measures of aniplatelet resistance, to analyze the relationship between antiplatelet resistance and clinical risk factors, and to explore the efficacy and safety of optimal anitplatelet therapy in managing antiplatelet resistance.Methods Between June 2006 and February 2007, a total of 305 patients who underwent coronary stenting were prospectively enrolled. Expression of platelet CD62P, platelet activated complex -1(PAC-1) and 20μmol/L ADP induced platelet aggregation (IPA) were assayed before and 24 h after administration of antiplatelet agents. An absolute reduction of IPA <10% compared with baseline was served as the golden standard of the diagnosis of clopidogrel resistance (CR). Enrolled patients were randomly assigned to receive optimal (optimal group, n=154) or standard antiplatelet therapy (standard group, n=151). The antiplatelet regimen of standard group was dual antiplatelet therapy with aspirin and clopidogrel. Antiplatelet therapy for the patients in optimal group depended on the results of IPA assay: patients with CR were received cilostazol for 6 months in addition to dual anitplatelet therapy, whereas non-CR patients received standard dual antiplatelet therapy. The primary endpoint was the composite of death, myocardial infarction (MI) and stroke at 1 year. The secondary end points was the composite of death, MI, ischemic driven revascularization, stroke and peripheral artery occlusions, TIMI hemorrhagic events, subacute and late stent thrombosis.Results (1) The incidence of CR was 23.8%. Recipient operation characteristic curve showed that CD62P and PAC-1 were not valuable in diagnosis of CR. However, post therapy IPA induced by 20μmol/L ADP was valuable for the diagnosis of CR with an area under curve of 0.878 and cutoff value of 71.8%. The sensitivity and specificity were 77.8% and 85.2%, respectively. (2) Multivariate analysis demonstrated that≥65 years old (OR=10.31, 95%CI= 4.265- 24.926, P<0.001), diabetes (OR=9.3, 95%CI= 3.413-25.344, P<0.001), history of ischemic events (OR=7.139, 95%CI= 2.658-19.180, P<0.001), positive TnT (OR=7.6, 95%CI=1.505-38.39, P=0.014) and multivessel disease (OR=2.355, 95%CI=1.054- 5.261, P=0.037) were predictors of CR. Two or more risk above mentioned risk factors strongly predicted CR (AUC 0.899, sensitivity of 86.5% and specificity of 79.7%). (3) Patients in optimal group were associated with a 37% reduction in the risk of primary events compared with their counterparts in standaardl group (5.8% vs. 9.3%, P=0.257). The rates of death (1.9% vs. 2.6%, P=0.489), M(I2.6% vs. 6%, P=0.340)and ischemic stroke(1.3% vs. 2.0,P=0.491)were not significantly different between the two groups. Optimal group was also associated with a tendency of decreased incidence of secondary end points [9.7%(15/154) vs. 14.6(22/151),P=0.197]. There was no difference in the rates of stent thrombosis and hemorrhagic events between the two groups. 41(26.6%)patients in the optimal group and 33(21.9%) in the standardl group were diagnosed as CR according to IPA assay. In CR patients, IPA were significantly reduced after cilostazol treatment [(77.5±12.1)% vs. (64.5±12.1)%,P<0.001]. CR patients in optimal group had a lower but not statistically significant incidence of primary events [19.5%(8/41)比36.4%(12/33), RR= 54%,95%CI:0.25-1.16, P=0.105].Conclusions IPA induced by 20μmol/L ADP after antiplatelet treatment is reasonable to be served as the diagnosis standard of CR. Clinical risk factors such as≥65 years old, diabetes, history of ischemic events, TnT positive and multivessel coronary artery disease are predictors of CR and the number of the risk factors are associated with the risk of CR. Adjusting antiplatelet regimen according to IPA assay results might be effective in improving long-term outcomes for patients undergoing coronary stenting, especially for those diagnosed as CR. However, the effectiveness and safety need further confirmation by clinical trials with large sample size.更多还原