急性冠状动脉综合征患者金属裸支架、药物洗脱支架的有效性与安全性比较研究

发布时间：2018-09-13 09:21

【摘要】：第一部分金属裸支架、第一代和第二代药物洗脱支架用于急性心肌梗死患者的有效性与安全性比较研究研究背景冠状动脉粥样硬化性心脏病(简称冠心病)是常见的心血管疾病,严重危害人类的健康。与单纯药物治疗相比,经皮冠状动脉介入术(PCI)显著改善了冠心病患者的治疗效果及预后。经过多年的技术开发与临床应用,冠状动脉支架先后经历了不同的发展阶段。与最初的金属裸支架(BMS)相比,近年来开发的药物洗脱支架(DES)进一步提高了经皮冠状动脉介入术(PCI)的有效性与安全性。急性心肌梗死(AMI)是冠心病发展过程中的严重事件,其病理学基础通常为不稳定粥样硬化斑块发生破裂,导致激活的血小板聚集于病变部位形成急性血栓、并阻塞冠状动脉内血流,导致心脏组织因缺血缺氧而发生急性坏死,AMI严重影响患者的预后,需要积极防治。冠状动脉内置入BMS和DES是治疗AMI的重要手段,但是对于我国患有急性ST段抬高型心肌梗死(STEMI)、并接受PCI术的患者而言,BMS与第一代和第二代药物洗脱支架(G1-DES和G2-DES)的有效性和安全性尚缺乏较大规模的研究报告。研究目的本研究目的：在明确诊断为STEMI、并接受急诊PCI术的患者当中,比较BMS、 G1-DES和G2-DES的有效性与安全性差异,为冠状动脉支架的优化临床应用提供真实世界的证据。研究方法本研究回顾性纳入了2004年4月至2014年5月之间于中国医学科学院阜外医院明确诊断为STEMI,并接受急诊PCI术的1,623例连续患者。排除标准包括：(1)因支架内再狭窄、或支架内血栓形成而导致的STEMI,共排除95例患者,(2)置入除BMS、G1-DES或G2-DES以外类型的支架、或同时置入不同种类型支架的患者,共排除305例患者。最终纳入1,223例患者数据。根据患者置入支架类型将其分为3组,分别为BMS组、G1-DES组和G2-DES组。随访时间为1年,随访调查的终点包括有效性终点和安全性终点。有效性终点为主要不良心血管事件(MACE),包括由靶血管相关心肌梗死(TV-MI)、靶血管重建(TVR)、靶病变重建(TLR)和心源性死亡组成的联合终点,以及上述独立终点事件；安全性终点为支架内血栓,本研究所报告的支架内血栓根据ARC定义为确定的(definite)和可能性大的(probable)支架内血栓。经过1年随访后,应用卡方检验、Kaplan-Meier法比较了靶血管相关心肌梗死(TV-MI)、靶血管重建(TVR)、靶病变重建(TLR)、心源性死亡和支架内血栓的发生率,并应用多因素Cox比例风险回归模型、以及Logistic回归模型比较了上述不良事件在不同支架类型之间的发生风险。研究结果在确诊为STEMI并接受急诊PCI术的1,223名连续患者当中,1年随访结果表明与BMS组相比,G1-DES和G2-DES组的MACE事件发生率显著降低(分别为20.4%、4.2%和4.1%,P 0.001; BMS与G1-DES相比,P 0.001; BMS与G2-DES相比,P0.001),而在G1-DES和G2-DES组之间,MACE事件发生率无显著差异(P=0.969)。在MACE事件当中,TV-MI发生率在分别为2.6%(BMS)、 0.3%(G1-DES)和1.0%(G2-DES),三组间比较结果具有显著性差异(P=0.017),而事后分析表明G1-DES组的TV-MI事件低于BMS组(P=0.009),在BMS组和G2-DES组之间(P=0.070)、以及在G1-DES组和G2-DES组之间(P=0.216)均无显著差异。此外与BMS组相比,G1-DES和G2-DES组的TVR、TLR和心源性死亡率显著降低(TVR分别为10.4%、2.5%和1.8%；TLR分别为7.8%、1.1%和1.2%；心源性死亡率分别为9.2%、1.7%和1.8%；P值均为0.001),而上述事件发生率在G1-DES和G2-DES组之间无显著差异(P值分别为0.458、0.999和0.908)。1年内血栓支架发生率在三组间未见差别(P=0.354)。Kaplan-Meier曲线显示在G1-DES组和G2-DES组当中,1年内无TLR生存率和无心源性死亡生存率明显高于BMS组(P值均为0.001),而G1-DES组和G2-DES组之间则无此差异(P值分别为0.927和0.700)。多因素Cox比例风险回归分析显示与BMS相比,G1-DES和G2-DES是降低TVR (G1-DES, HR 0.24,95%CI[0.11-0.50], P0.001; G2-DES, HR= 0.40,95%CI [0.27-0.58], P 0.001)和TLR (G1-DES, HR= 0.15,95%CI [0.05-0.43], P 0.001; G2-DES, HR= 0.39,95% CI [0.25-0.61], P 0.001)的保护性因素,而TVR和TLR的发生风险在上述两组之间无显著差异。Logistic回归分析显示,支架类型不是导致支架内血栓的危险因素。研究结论(1)在确诊为急性ST段抬高型心肌梗死、并接受急诊PCI治疗的患者当中,BMS组MACE事件发生率明显高于G1-DES和G2-DES组,而在G1-DES和G2-DES组之间MACE事件发生率无显著差异；(2)与金属裸支架相比,置入G1-DES或G2-DES能够在1年之内降低TVR和TLR的发生率和发生风险,而在G1-DES和G2-DES之间尚无明显差别；(3)在置入上述三种类型支架后1年内,支架内血栓的发生率和发生风险无明显差异；此外,TV-MI和心源性死亡风险在三组间无显著差异。第二部分急性冠状动脉综合征患者置入第一代和第二代药物洗脱支架的有效性与安性比较研究研究背景急性冠状动脉综合征(ACS)包括急性ST段抬高型心肌梗死(STEMI)、非ST段抬高型心肌梗死(NSTEMI)和不稳定型心绞痛,其共同的病理学机制为不稳定斑块破裂或侵蚀引起不同程度的血栓形成,从而导致冠状动脉内血流急性减少。ACS通常表现为突发性,且具有潜在致命性,故应受到重视并积极防治。既往研究报道与稳定型冠心病相比,ACS是增加支架内血栓的独立危险因素,因此在针对ACS介入治疗过程中需要谨慎选择冠状动脉支架类型。针对G1-DES和G2-DES用于ACS患者介入治疗的有效性和安全性比较结果尚有争议,而目前尚未见文献报道G1-DES和G2-DES用于中国ACS患者的作用比较研究。研究目的本研究拟在确诊为ACS并接受冠状动脉支架置入术的患者中,明确G1-DES和G2-DES的有效性和安全性差异,从而为我国ACS患者介入治疗支架类型选择提供一定理论依据。研究方法本研究前瞻性筛选纳入2013年1月至2013年12月中国医学科学院阜外医院确诊为急性冠状动脉综合征,并接受PCI治疗的连续患者。患者排除标准包括(1)仅接受经皮冠状动脉腔内成形术(PTCA)治疗,而未接受支架置入的患者；(2)G1-DES或G2-DES以外类型的支架、或同时置入不同种类型支架的患者；(3)诊断为急性心肌梗死或不稳定型心绞痛以外的非ACS患者。最终纳入3,929例患者数据,包括急性ST段抬高型心肌梗死心肌梗死862例,非ST段抬高型心肌梗死284例和不稳定型心绞痛2,783例。根据患者置入支架的类型,将其分为G1-DES组和G2-DES组。随访时间为2年,随访终点事件同上文所述,本研究所报告的支架内血栓包括确定的(definite)、可能性大的(probable)和可能的(possible)支架内血栓。采用倾向性评分匹配法,以1：1比例匹配了两组患者,匹配后患者数目为2,284例,随后应用卡方检验、Kaplan-Meier法和多因素Cox比例风险回归模型在两组间分析并比较了终点事件的发生率和危险因素。研究结果在接受PCI治疗的ACS患者当中,由倾向性评分匹配法筛选了2,248例患者,G1-DES组和G2-DES组各包含1,124例患者。2年随访结果显示,两组间MACE事件发生率无显著差异(分别为4.8%和3.9%,P=0.302)。在G1-DES和G2-DES两组之间TV-MI发生率无显著差异(分别为0.7%和0.7%,P0.999),而TVR(分别为5.5%和3.5%,P=0.019)/TLR(分别为4.1%和2.5%,P=0.033)和心源性死亡率(分别为0.5%和1.40%,P=0.032)则明显不同。在G1-DES和G2-DES之间,急性、亚急性、晚期、极晚期和2年累计支架内血栓发生率均无显著差异(急性支架内血栓：0.0%和0.2%,P=0.500；亚急性支架内血栓：0.0%和0.1%,P0.999;晚期支架内血栓：0.2%和0.2%,P=0.790;2年累计支架内血栓：0.7%和0.5%,P=0.826)。经Kaplan-Meier分析发现,在G2-DES组TLR生存率显著增高(P=0.038),而无心源性死亡生存率显著降低(P=0.039)。多因素Cox比例风险回归分析结果显示,与G1-DES相比,(G2-DES是能够降低TLR的保护性因素(HR=0.592,95% CI[0.370-0.947],P=0.029),而TV-MI、心源性死亡和累计支架内血栓的发生风险在两组间无明显差异(TV-MI:HR=1.121,95%CI[0.380-3.303],P=0.836；心源性死亡：ⅠIR=2.469,95%CI[0.883-7.057],P=0.084；累计支架血栓：HR=1.197, 95%CI[0.471-3.041],P=0.706)。研究结论(1)在确诊为急性冠状动脉综合征并接受PCI治疗的患者当中,G1-DES和G2-DES之间MACE事件发生无无显著性差异；(2)与G1-DES相比,G2-DES是能够降低靶病变重建的保护性因素；(3)在G1-DES和G2-DES之间,靶病变相关心肌梗死、心源性死亡和累计支架内血栓的发生风险无显著差异。
[Abstract]:Background Coronary atherosclerotic heart disease (CHD) is a common cardiovascular disease that seriously endangers human health. Compared with drug therapy alone, percutaneous coronary intervention (PTCA) Coronary stents have undergone different stages of development after years of technical development and clinical application. Drug-eluting stents (DES) have been developed in recent years to further improve percutaneous coronary intervention (PCI) compared with bare metal stents (BMS). Acute myocardial infarction (AMI) is a serious event in the development of coronary heart disease. Its pathological basis is usually the rupture of unstable atherosclerotic plaques, resulting in the aggregation of activated platelets in the lesion site to form acute thrombosis, and obstruction of coronary artery blood flow, resulting in acute ischemia and hypoxia of heart tissue. Coronary artery implantation of BMS and DES is an important method for the treatment of AMI, but for patients with acute ST-segment elevation myocardial infarction (STEMI) and undergoing PCI in China, BMS is effective and safe with the first and second generation drug-eluting stents (G1-DES and G2-DES). Objective: To compare the efficacy and safety of BMS, G1-DES and G2-DES in patients with STEMI who underwent emergency PCI and to provide real-world evidence for optimal clinical application of coronary stents. 1,623 consecutive patients were diagnosed as STEMI in Fuwai Hospital of Chinese Academy of Medical Sciences from April to May 2014 and underwent emergency PCI. The exclusion criteria included: (1) STEMI due to in-stent restenosis or stent thrombosis, excluding 95 patients; (2) stent placement other than BMS, G1-DES or G2-DES, or the same. 305 patients were excluded when different types of stents were placed. The final data of 1,223 patients were included. The patients were divided into three groups according to the type of stents, namely BMS group, G1-DES group and G2-DES group. Catheter events (MACE) included a combined endpoint consisting of target vessel-related myocardial infarction (TV-MI), target vessel reconstruction (TVR), target lesion reconstruction (TLR) and cardiac death, as well as the above independent endpoint events; the safety endpoint was in-stent thrombosis, which was defined as definite and highly probable by ARC in this study. After a year of follow-up, Kaplan-Meier method was used to compare the incidence of target vessel-related myocardial infarction (TV-MI), target vessel reconstruction (TVR), target lesion reconstruction (TLR), cardiac death and stent thrombosis. Multivariate Cox proportional hazard regression model and Logistic regression model were used to compare the above results. Out of 1,223 consecutive patients diagnosed with STEMI and undergoing emergency PCI, 1-year follow-up showed a significantly lower incidence of MACE events in G1-DES and G2-DES groups (20.4%, 4.2% and 4.1%, respectively, P 0.001; BMS and G1-DES, P 0.001; BMS and G2-DES, P There was no significant difference in the incidence of MACE events between G1-DES and G2-DES groups (P = 0.969). Among MACE events, the incidence of TV-MI was 2.6% (BMS), 0.3% (G1-DES) and 1.0% (G2-DES), respectively. There was a significant difference among the three groups (P = 0.017), and the post-event analysis showed that the incidence of TV-MI events in G1-DES group was lower than that in BMS group (P = 0.009). There was no significant difference between BMS group and G2-DES group (P = 0.070), and between G1-DES group and G2-DES group (P = 0.216). In addition, compared with BMS group, TVR, TLR and cardiac mortality in G1-DES and G2-DES groups were significantly reduced (TVR were 10.4%, 2.5% and 1.8%, TLR was 7.8%, 1.1% and 1.2%, cardiac mortality was 9.2%, 1.7% and 1.8%, respectively. There was no significant difference in the incidence of these events between G1-DES and G2-DES groups (P 0.458, 0.999 and 0.908, respectively). There was no difference in the incidence of stent thrombosis between the three groups within one year (P = 0.354). Kaplan-Meier curves showed that TLR-free survival and cardiac death-free survival rates were significantly higher in G1-DES and G2-DES groups within one year (P = 0.354). MultivariatCox proportional hazard regressianalysis showed that G1-DES and G2-DES decreased TVR (G1-DES, HR 0.24, 95% CI [0.11-0.50], P 0.001; G2-DES, HR = 0.40, 95% CI [0.40, 95% CI [0.27-0.58], P 0.57-0.58], P 0.001) and TLR (G1-DES, G1-DES, HR 0.24, 95% CI [0.11-0.50], P 0.001; G2-DES, HR = 0.40, HR = 0.40, 95% CI [0.27-0.58], P 0.58], P.001) and TLR (G1-DES, G1-DES, HR 0.15, 95% 0.05-0 There was no significant difference in the risk of TVR and TLR between the two groups. Logistic regression analysis showed that stent type was not a risk factor for stent thrombosis. The incidence of MACE events in BMS group was significantly higher than that in G1-DES and G2-DES groups, but there was no significant difference between G1-DES and G2-DES groups; (2) G1-DES or G2-DES could reduce the incidence and risk of TVR and TLR within one year compared with bare metal stents, but there was no clear difference between G1-DES and G2-DES. (3) There was no significant difference in the incidence and risk of in-stent thrombosis between the three groups within one year after stent placement. In addition, there was no significant difference between the three groups in the risk of cardiac death and the incidence of in-stent thrombosis. Background Acute coronary syndromes (ACS) include acute ST-segment elevation myocardial infarction (STEMI), non-ST-segment elevation myocardial infarction (NSTEMI) and unstable angina pectoris. The common pathological mechanism of ACS is that unstable plaque rupture or erosion causes thrombosis in varying degrees, which leads to acute decrease of coronary blood flow. Previous studies have reported that ACS is an independent risk factor for increased stent thrombosis compared with stable coronary artery disease. Therefore, careful selection of stent types should be made during interventional therapy for ACS. G1-DES and G2-DES should be used for ACS. The efficacy and safety of G1-DES and G2-DES in patients with ACS in China are still controversial, but there is no comparative study on the efficacy and safety of G1-DES and G2-DES in patients with ACS in China. Methods A prospective study was conducted to select consecutive patients with ACS who were admitted to Fuwai Hospital of Chinese Academy of Medical Sciences from January 2013 to December 2013 and received PCI treatment. Endovascular percutaneous transluminal angioplasty (PTCA) was performed in patients without stenting; (2) patients with stenting other than G1-DES or G2-DES, or with different types of stenting at the same time; (3) patients with non-ACS other than acute myocardial infarction or unstable angina. Data from 3,929 patients, including acute ST-segment elevation myocardial infarction, were finally included. 862 cases of myocardial infarction, 284 cases of non-ST-segment elevation myocardial infarction and 2,783 cases of unstable angina pectoris were divided into G1-DES group and G2-DES group according to the type of stent implantation. The follow-up period was 2 years, and the end-point events were as described above. The stent thrombosis reported in this study included definite and probable. Tendency score matching method was used to match 2,284 matched patients. Chi-square test, Kaplan-Meier method and multivariate Cox proportional hazard regression model were used to analyze and compare the incidence and risk factors of end-point events between the two groups. There was no significant difference in the incidence of MACE events (4.8% and 3.9% respectively, P = 0.302) between the G1-DES and G2-DES groups. TVR (5.5% and 3.5%, P = 0.019) / TLR (4.1% and 2.5%, P = 0.033) and cardiac mortality (0.5% and 1.40%, P = 0.032) were significantly different. There was no significant difference in the cumulative incidence of stent thrombosis between G1-DES and G2-DES (acute, subacute, late, very late and 2 years, respectively). Subacute in-stent thrombosis: 0.0% and 0.1%, P = 0.500; late in-stent thrombosis: 0.2% and 0.2%, P = 0.790; 2-year cumulative in-stent thrombosis: 0.7% and 0.5%, P = 0.826). Kaplan-Meier analysis showed that TLR survival rate was significantly increased (P = 0.038) in G2-DES group, but the survival rate of non-cardiogenic death was significantly decreased (P = 0.039). Case risk regression analysis showed that compared with G1-DES, (G2-DES was the protective factor (HR = 0.592,95% CI [0.370-0.947], P = 0.029) and there was no significant difference between the two groups in the risk of cardiac death and cumulative stent thrombosis (TV-MI: HR = 1.121, 95% CI [0.380-3.303], P = 0.836; and cardiac death: I IR = 2.469, 95.029). Accumulative stent thrombosis: HR = 1.197, 95% CI [0.471-3.041], P = 0.706. Study conclusions (1) There was no significant difference in MACE events between G1-DES and G2-DES in patients with acute coronary syndrome who received PCI treatment; (2) G2-DES was able to reduce the protection of target lesion reconstruction compared with G1-DES. Factors: (3) There was no significant difference between G1-DES and G2-DES in the risk of target-related myocardial infarction, cardiac death, and cumulative stent thrombosis.
【学位授予单位】：北京协和医学院
【学位级别】：博士
【学位授予年份】：2016
【分类号】：R541.4

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