【作者】 杨玉恒；

【导师】 齐向前；

【作者基本信息】 天津医科大学 ， 内科学， 2011， 博士

【摘要】 背景：心血管疾病,尤其是冠状动脉粥样硬化性心脏病(coronary atherosclerotic heart disease, CAD)是严重威胁人类健康的主要疾病。冠心病的发病率和死亡率逐年上升,我国冠心病的负担越来越大。冠状动脉介入治疗(percutaneous coronary interventions, PCI)已经成为治疗冠心病的重要有效方法,我国PCI的患者数量越来越多。但是,伴随的相关血栓并发症也是越来越多。双联抗血小板(阿司匹林+氯吡格雷)已经成为PCI术后的标准方案。然而,进口氯吡格雷价格昂贵,国产非专利氯吡格雷价格便宜,其对血小板聚集的抑制和对PCI术后的疗效及安全性尚无大样本资料证实。目的：1、探讨等剂量国产和进口氯吡格雷对血小板聚集率影响效果是否相同；2、等剂量国产和进口氯吡格雷对凝血系统影响效果是否相同；3、等剂量国产和进口氯吡格雷对血细胞计数代表的血液系统的影响效果是否相同；4、等剂量国产和进口氯吡格雷对PCI术后疗效及安全性是否相同5、等剂量国产和进口氯吡格雷对急诊PCI术后疗效及安全性是否相同。方法：1、连续入选199例不稳定性心绞痛患者,随机分为国产氯吡格雷(泰嘉组,89例)和进口氯吡格雷(波立维组,110例),按照相同的应用剂量及应用方法,并应用电阻法在用药前、用药后8-12小时、24～36小时、48～60小时测定二磷酸腺苷(ADP)诱导的血小板聚集率,在用药前和用药后48-60小时测定白细胞计数、红细胞计数、血小板计数、D—二聚体(D-dimer)、凝血系统[包括凝血酶原时间(PT)、凝血酶原时间国际标准化比值(INR)、活化部分凝血活酶时间(APTT)、凝血酶时间(TT)、纤维蛋白原(FIB)]等指标。2、入选1798例接受PCI治疗的冠心病患者,随机分为泰嘉组(1104例)及波立维组(694例),在PCI术前给予300mg负荷剂量,序贯75mg/d,随访3-28个月,观察急性、亚急性、晚期、极晚期支架内血栓和心肌梗死、心源性死亡、脑卒中的联合终点MACE事件的影响以及出血等相关副作用的影响。3、入选204例接受急诊PCI治疗的急性心肌梗死患者,随机分为泰嘉组(123例)及波立维组(81例),在急诊室给予300mg负荷剂量,序贯75mg/d,随访3-28个月,观察急性、亚急性、晚期、极晚期支架内血栓和心肌梗死、心源性死亡、脑卒中的联合终点MACE事件的影响以及出血等相关副作用的影响。结果：1、泰嘉组及波立维组血小板聚集率均随用药时间延长而降低,在负荷量后降低最明显,泰嘉组与波立维组用药前、用药后8～12小时、24～36小时、48～60小时的血小板聚集率电阻值分别为7.67±3.48欧姆(ohm),4.67±3.84ohm,3.46±3.93 ohm,3.36±3.86 ohm和6.84±3.25ohm,4.25±3.94ohm,2.63±3.27ohm,2.59±3.50ohm,经单个重复测量因素的方差分析,两组间差异无统计学意义(F=3.092,P=0.080),4次重复测量的血小板聚集率之间差异具有统计学意义(F=117.101,P=0.000);而凝血系统PT、INR、APTT、TT、FIB、D-dimer治疗前无显著差异(t值分别为0.825、1.260、1.448、0.299、1.112、0.388,P值分别为0.411、0.209、0.149、0.765、0.267、0.699)；治疗后PT、INR、APTT、TT、FIB、D-dimer治疗前无显著差异(t值分别为1.350、1.159、1.406、0.915、1.810、0.372,P值分别为0.179、0.248、0.161、0.361、0.072、0.710)；血常规的各项血细胞计数WBC、RBC、HGB、PLT治疗前比较无差异(t值分别为1.840、0.101、0.664、2.027,P值分别为0.067、0.920、0.507、0.054)；治疗后WBC、RBC、HGB、PLT比较无差异(t值分别为1.404、0.083、0.565、1.581,P值分别为0.162、0.934、0.574、0.116)。泰嘉组和波立维组治疗前后PT、INR、APTT、TT、D-dimer经自身配对t检验无显著差异(t值分别为1.198和1.016、0.989和0.697、0.872和0.981、0.368和1.225、0.051和0.032,P值分别为0.234和0.311、0.325和0.487、0.385和0.328、0.714和0.223、0.959和0.975)；而泰嘉组和波立维组FIB均较前升高(t值分别为3.389和2.074,P值分别为0.001和0.040)；泰嘉组和波立维组治疗前后WBC及PLT计数经自身配对t检验无明显变化(t值分别为0.248和0.808、1.654和1.618,P值分别为0.804和0.421、0.102和0.109)；而泰嘉组和波立维组治疗后RBC计数及HGB定量均较治疗前明显下降,经自身配对t检验,有显著性差异(t值分别为7.539和9.562、9.224和10.856,P值分别为0.000和0.000、0.000和0.000)。2、泰嘉组和波立维组靶血管重建、联合终点事件发生率,经统计学检验,差异无显著性意义(X2值分别为2.176、3.287,P值分别为0.140、0.070)；支架内血栓及心源性死亡经Fisher’s精确概率计算,无显著性差异(P值分别为0.440、0.149)；出血和大出血事件发生率,经统计学检验,差异无显著性意义(P值分别为0.072和0.380)；两组之间无事件生存情况经Kaplan-Meier生存分析,Log Rank (Mantel-Cox)比较,无显著差异(X2值=3.438,P值=0.064)；累积MACE事件经Kaplan-Meier生存分析,Log Rank (Mantel-Cox)比较,无显著差异(X2值=1.076,P值=0.300)。3、泰嘉组和波立维组均无支架内血栓和出血事件；波立维组有2例心源性死亡,分别为心源性休克及心脏破裂；两组靶血管重建及联合终点事件发生率,经统计学检验,差异无显著性意义(X2分别为0.000和0.921,P值分别为0.989和0.337)；两组之间累积MACE事件经Kaplan-Meier生存分析计算,绘制K-M曲线见图3.1,经Log Rank (Mantel-Cox)比较,无显著差异(X2值=0.679,P值=0.410)。结论：1、大样本、随机、阳性对照比较同剂量、同方案国产氯吡格雷和进口氯吡格雷对电阻法测定的血小板聚集率的影响,进行了“头对头”的疗效比较,以及对凝血系统、血液系统的影响,发现二者具有等同影响,疗效及安全性类似。2、国内最大样本量(应用国产氯吡格雷超过1000例)、随机、阳性对照比较同剂量、同方案国产氯吡格雷和进口氯吡格雷对PCI术后疗效及安全性的比较,发现二者对PCI术后的疗效及安全性相似,发现在白细胞下降副作用方面,国产氯吡格雷(泰嘉)优于进口氯吡格雷(波立维)。3、大样本、随机、阳性对照比较同剂量、同方案国产氯吡格雷和进口氯吡格雷对AMI患者急诊PCI术后疗效及安全性的比较,发现二者对急诊PCI术后的疗效及安全性相似。更多还原

【Abstract】 Background:Over the past two centuries, the Industrial and Technological Revolutions and their associated economic and social transformations have resulted in dramatic shifts in the diseases responsible for illness and death. Cardiovascular disease (CVD) has emerged as the dominant chronic disease in many parts of the world, and early in the 21st century it is predicted to become the main cause of disability and death worldwide. CVD is a major disease threaten human health, especially coronary atherosclerotic heart disease (CAD). Morbidity and mortality of CAD rises year by year and the burden of CAD is more and more accelerating in China. Percutaneous coronary interventions has been the major and effect therapy and there were more and more CAD patients to underwent CAG and PCI, however, there were more and more stent thrombus complication correlation PCI. Dual antiplatelet therapy (aspirin and clopidogrel) has been the standard proposal after PCI, however, the cost of imported clopidogrel (PlavixTM) is expensive and the domestic generic clopidogrel (TalcomTM) is cheap relative PlavixTM. There are not large sample data to confirm the effect to inhibit platelet aggregation and the effect and safety after PCI of TalcomTM.Objective:1.To explore whether the effects of isodose domestic clopidogrel (TalcomTM) and imported clopidogrel (PlavixTM) on platelet function in patients with unstable angina (UAP).2. To explore whether the effects of isodose TalcomTM and PlavixTM on parameters of blood clot system in patients with unstable angina (UAP). 3. To explore whether the safety of isodose TalcomTM and PlavixTM on parameters of blood routin test in patients with unstable angina (UAP).4. To compare the efficacy and safety of TalcomTM and PlavixTM on PCI.5. To compare the efficacy and safety of TalcomTM and PlavixTM on directed PCI in AMI patients.Methods:1.199 patients with UAP were randomized to two groups, including TalcomTM group (n=89), PlavixTM group (n=110). Venous blood samples were obtained before taking orally clopidogrel,8-12 hours after taking loading dose clopidogrel 300 mg, and after 75 mg/day for 24 hours,48 hours in two clopidogrel groups in order to test platelet aggregation rate induced by adenosine diphosphate (ADP) detected by electric resistance method and before taking orally clopidogrel and after 75 mg/day for 48 hours in two clopidogrel groups in order to test lencocyte count, red blood cell count, blood platelets count, D-dimer, prothrombin time (PT), international normalized ratio of prothrombin time (INR), activated partial thromboplastin time (APTT), thrombin time (TT), fibrinogen.2.1798 patients with CAD to undergo CAG+PCI were randomized to two groups, including TalcomTM group (n=1104), PlavixTM group (n=694).300mg loading dose clopidogrel was oral before PCI and 75mg/d foreword one year. There were follow-up 3-28 month to survey the incidence rate of MACE of combination end point of acute, subacute, late stage, very late stage stent thrombus and AMI, cardiac death, stroke and correlated adverse reaction of bleed, major bleed, gastrointestinal complaint, and etc. 3.204 patients with AMI to undergo directed CAG+PCI were randomized to two groups, including TalcomTM group (n=123), PlavixTM group (n=81).300mg loading dose clopidogrel was oral before PCI in emergency room and 75mg/d foreword one year. There were follow-up 3-28 month to survey the incidence rate of MACE of combination end point of acute, subacute, late stage, very late stage stent thrombus and AMI, cardiac death, stroke and correlated adverse reaction of bleed, major bleed, gastrointestinal complaint, and etc.Results:There were no significant differences in the platelet aggregation rate and blood cell count and the item of blood clot system between Talcom group and Plavix group before treatment. There were no significant differences in the aforementioned markers between TalcomTM group and PlavixTM group after treatment. With the time, platelet aggregation rate of TalcomTM group and PlavixTM group was degrading, and there was the most obviously after orally loading dose, and resistance value of TalcomTM group and PlavixTM group in before taking orally, after orally 8～12 hour, 24～36 hour,48～60 hour was 7.67±3.48ohm,4.67±3.84 ohm,3.46±3.93 ohm, 3.36±3.86 ohm and 6.84±3.25ohm,4.25±3.94ohm,2.63±3.27ohm,2.59±3.50ohm, respectively. There were significant differences in 4 repeated detected platelet aggretion rate by one way repeated measure factor ANOVA, (F=117.101, P=0.000). There were no significant differences in the parameters (PT, INR, APTT, TT, FIB, D-dimer) of blood clot system between TalcomTM group and PlavixTM group before treatment (t value 0.825,1.260,1.448,0.299,1.112,0.388, P value 0.411, 0.209,0.149,0.765,0.267,0.699, respectively); There were no significant differences in the parameters (PT, INR, APTT, TT, FIB, D-dimer) of blood clot system between TalcomTM group and PlavixTM group after treatment (t value 1.350、1.159、1.406、0.915、1.810、0.372, P value 0.179、0.248、0.161、0.361、0.072、 0.710, respectively); There were no significant differences in the parameters (WBC, RBC, HGB, PLT) of blood routin test between TalcomTM group and PlavixTM group before treatment (t value 1.840,0.101,0.664,2.027, P value 0.067,0.920,0.507, 0.054, respectively); There were no significant differences in the parameters (WBC, RBC, HGB, PLT) of blood routin test between TalcomTM group and PlavixTM group after treatment (t value 1.404,0.083,0.565,1.581, P value 0.162,0.934,0.574,0.116, respectively). There were no significant differences in the parameters (PT, INR, APTT, TT, FIB, D-dimer) of blood clot system between before and after treatment both TalcomTM group and PlavixTM group by paired sample t test (t value 1.198 and 1.016,0.989 and 0.697,0.872 and 0.981,0.368 and 1.225,0.051 and 0.032, P value 0.234 and 0.311,0.325 and 0.487,0.385 and 0.328,0.714 and 0.223,0.959 and 0.975, respectively); but the level of FIB of after treatment is increase to compare to before treatment both TalcomTM group and PlavixTM group by paired sample t test (t value 3.389 and 2.074, P value 0.001 and 0.040, respectively); There were no significant differences in the parameters (WBC and PLT) of blood routin test to compare to before treatment both TalcomTM group and PlavixTM group by paired sample t test (t value 0.248 and 0.808,1.654 and 1.618, P value 0.804 and 0.421,0.102 and 0.109, respectively); but the level of the count of RBC and the quantitation of HGB of after treatment is decrease to compare to before treatment both TalcomTM group and PlavixTM group by paired sample t test (t value 7.539 and 9.562,9.224 and 10.856, P value 0.000 and 0.000,0.000 and 0.000, respectively).2. There were no significant differences in the incidence of target vessel revascularization and combination end point between TalcomTM group and PlavixTM group (X2 value 2.176,3.287, P value 0.140,0.070). There were no significant differences in the incidence of stent thrombus and cardiac death between TalcomTM group and PlavixTM group by Fisher’s exact probability (P value 0.440,0.149). There were no significant differences in the incidence of bleed and major bleed between TalcomTM group and PlavixTM group (P value 0.072 and 0.380). There were no significant differences in survival without event and accumulation MACE hazard analysised by Kaplan-Meier survival analysis (X2 3.438 and 1.076, P=0.064 and 0.300).3. There were not stent thrombus and bleed event both TalcomTM group and PlavixTM group. There are two patients death of cardiac shock and heart rupture in PlavixTM group. There were no significant differences in the incidence of target vessel revascularization and combination end point between TalcomTM group and PlavixTM group (X2 value 0.000 and 0.921, P value 0.989 and 0.337). There were no significant differences in accumulation MACE hazard analysised by Kaplan-Meier survival analysis(X20.679, P=0.410).Conclusions:1.The anti-platelet aggregation and antiplatelet activation effects of isodose TalcomTM are similar to those of PlavixTM. The two drugs have good anti-platelet effects. Furthermore, the two drugs have no significant adverse drug reaction.2. Effects and safety of isodose TalcomTM used in underwent PCI patients are similar to those of PlavixTM.3. Effects and safety of isodose TalcomTM used in AMI patients that underwent directed PCI are similar to those of PlavixTM.更多还原