血小板糖蛋白Ⅱb/Ⅲa受体拮抗剂用于急性冠脉综合征经皮介入治疗的系统评价：随机对照试验的meta分析
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摘要
心血管疾病是工业化国家死亡的头号原因,预计到2020年在新兴国家也将如此。其中,冠状动脉疾病(Coronary artery disease, CAD)是最常见的表现,并且与高死亡率和高致残率有关。冠脉疾病的临床表现包括隐匿性缺血、稳定型心绞痛、不稳定型心绞痛、心肌梗死、心力衰竭和猝死。
引起冠脉疾病的动脉粥样硬化斑块分为硬斑块和软斑块。斑块的稳定性决定着冠脉疾病的严重程度。不稳定斑块破裂是急性冠脉综合征(Acute Coronary Syndrome, ACS)发病的病理基础。硬斑块不容易破裂,多见于中到重度冠脉狭窄导致的稳定型心绞痛；而软斑块则相对质软容易破裂,多见于不稳定型心绞痛(unstable angina, UA)。斑块破裂将导致不同程度的冠脉狭窄或堵塞,从而引起不同程度的冠状动脉病变。
急性冠脉综合征
冠脉疾病中,急性冠脉综合征(ACS)是以冠状动脉粥样硬化斑块破裂或侵蚀,继发完全或不完全闭塞血栓形成为病理基础的一组临床综合征,包括ST段抬高心肌梗死(ST-segment elevation myocardial infarction, STEMI)、非ST段抬高心肌梗死(non-ST-segment elevation myocardial infarction, NSTEMI)以及不稳定型心绞痛(UA),即使在现代治疗条件下,急性冠脉综合征患者的死亡率、心肌梗死率和再次入院率仍很高。
急性冠脉综合征代表了动脉粥样硬化的一种威胁生命的表现。它通常是由于破裂或侵蚀冠脉粥样硬化斑块诱发的急性血栓引起,合并或不合并血管痉挛,从而导致脉管血流突然性的严重减少。在动脉粥样硬化斑块破裂这一复杂的过程当中,炎症因子释放及炎症反应发生是一个关键的病理生理学因素。偶尔,急性冠脉综合征可以通过非粥样硬化性疾病引起,比如,动脉炎、外伤、动脉夹层、血栓栓塞、先天变异、滥用可卡因或是心导管检查引起的并发症。
急性冠脉综合征患者起病急、危险程度十分不均一。对其进行早期诊断、及时危险分层和合理的临床干预,是改善预后的关键。高龄、较快心率、低血压、前壁心肌梗死、既往有心力衰竭病史、既往有心肌梗死病史、初始血清肌酐水平较高以及Killip分级大于1级等都可成为急性冠脉综合征的临床高危指标。存在以上高危指标的患者应在住院期间检查代谢风险标志物,包括总胆固醇、低密度脂蛋白(low-density lipoproteins, LDL)胆固醇、高密度脂蛋白胆固醇、空腹甘油三酯以及血糖和肾功能等。一般情况下,LDL水平会在心肌梗死发病的最初几天内有所下降,因此,最好在患者入院后尽早进行检测。
经皮冠脉介入治疗
目前经皮冠状动脉介入治疗(Percutaneous Coronary Intervetion, PCI)是治疗急性冠脉综合征最有效、最常用的方法之一。90%以上的患者在进行PCI后能够获得TIMI3血流,同时,PCI可显著改善患者的近期以及远期临床预后。尤其对于高危ACS患者,PCI的临床受益更加明显。多个ACS治疗指南推荐尽早使用PCI治疗策略。
血小板糖蛋白Ⅱb/Ⅲa受体拮抗剂
然而,在ACS的发病过程及进行PCI的术中、术后都有冠脉内皮的破坏,使血管内膜下层暴露,血小板黏附、活化、脱颗粒并释放各种血管活性物质如ADP、5-羟色胺等,诱导血小板进一步聚集活化,血小板糖蛋白Ⅱb/Ⅲa(GPⅡb/Ⅲa)受体构象发生改变,暴露出纤维蛋白原结合位点,活化的血小板通过构象发生改变的糖蛋白Ⅱb/Ⅲa受体与纤维蛋白原相互交联,最终大量血小板聚集形成血栓,引起ACS缺血性并发症的发生,形成支架内血栓或附壁血栓,进而导致围手术期心肌梗死、死亡等不良心脏事件的发生。
由以上围术期急性冠脉综合征缺血性并发症的发病过程可见,血小板聚集扮演了重要的角色。血小板糖蛋白Ⅱb/Ⅲa(GP Ⅱ b/Ⅲa)属于整合素家族粘附受体,是血小板含量最丰富的膜糖蛋白,其配体主要是纤维蛋白原(Fg)、血管性血友病因子(vWF)、还有玻璃连接蛋白(VN)、纤维连接蛋白(FN)等。通过GPⅡb/Ⅲa受体拮抗剂阻断血小板聚集的最后共同通路,能有效改善急性冠脉综合征患者的心肌缺血,降低死亡率及心肌梗死发生率。并且GPⅡb/Ⅲa受体仅在血小板以及巨噬细胞谱系中发现,这一特点使得能够以其拮抗剂进行特异性治疗,而不用担心引起广泛的副作用。血小板GPⅡb/Ⅲa受体拮抗剂的出现是抗血小板药物发展史上里程碑式的事件。
目前获得批准上市应用于ACS及PCI中的GPⅡb/Ⅲa受体拮抗剂有三类：单克隆抗体Fab片段类(如阿昔单抗)、合成肽类(如依替巴肽)、非肽仿生物类(如替罗非班以及拉米非班)。近年来,以上药物应用于国内外临床实践,并在很多临床研究中证实了其疗效。
但是,关于血小板糖蛋白Ⅱb/Ⅲa受体拮抗剂在临床实践中的应用仍有许多细节问题。比如：
小分子血小板糖蛋白Ⅱb/Ⅲa受体拮抗剂与阿昔单抗的比较
与单克隆抗体Fab片段的阿昔单抗比较,依替巴肽、替罗非班、拉米非班等小分子GPIs与GPⅡb/Ⅲa的结合特异性更高、作用更强,且其结合是可逆的,一旦出现不良反应,立即停药后不良反应很快减轻,并且作为合成多肽,其本身几乎无抗原性,不会引起过敏反应,可以进行较长时间或反复的治疗。但目前在进行PCI的ACS患者中的临床研究以阿昔单抗居多,而有关小分子GPⅠs在此方面应用的研究并不多见,且研究结果存在差异。
GPⅠs初始剂量冠脉内给药与静脉内给药的比较
GPⅠs的常规用药方式为静脉快速推注起始剂量并继以≥12小时持续静脉输注。近几年有研究提出,以冠脉快速推注起始剂量再继以持续静脉输注,能够使冠脉血栓局部药物浓度高于静脉快速推注,从而更好地溶解已有血栓,并抑制进一步血栓形成,最终降低死亡、再次MI、再次TVR等不良心脏事件的发生。但现有研究样本量较小,有些为非随机和追溯性研究,且结果存在有分歧或不确定。
本研究根据循证医学的原则,运用Cochrane系统评价方法,对目前已发表的各种GPⅡb/Ⅲa受体拮抗剂在急性冠脉综合征患者的经皮冠脉介入治疗中应用的随机对照试验进行Meta分析,以期正确评估GPⅡb/Ⅲa受体拮抗剂作为急性冠脉综合征经皮介入治疗的辅助疗法,从而对患者进行围手术期心肌保护的疗效以及安全性,为临床医生在本类患者围手术期合理选择抗血小板药物及制定给药方案提供真实可靠的依据。
本研究分为两部分：第一部分为对小分子血小板糖蛋白Ⅱb/Ⅲa受体拮抗剂在急性冠脉综合征的经皮介入治疗中应用的疗效及安全性进行系统评价；第二部分为对冠脉注射GPⅡb/Ⅲa受体拮抗剂用于急性冠脉综合征的经皮介入治疗中的疗效及安全性进行系统评价。
第一部分小分子血小板糖蛋白Ⅱb/Ⅲa受体拮抗剂用于急性冠脉综合征经皮介入治疗的有效性及安全性的系统评价
目的系统评价小分子血小板糖蛋白Ⅱb/Ⅲa受体拮抗剂(GPIs)用于急性冠脉综合征(ACS)的经皮介入治疗(PCI)的疗效和安全性。
方法计算机检索PubMed、 EMBASE、OVID、中国生物医学文献数据库(CBM)、中国知网(CNKI)、中文科技期刊数据库(VIP),检索时间均从建库至2012年7月31日,并手工检索2012年1月到2012年7月国内已发表的有关论文,并用Goole学术搜索引擎等从互联网查找相关的文献,纳入小分子GPIs与安慰剂比较在ACS的PCI治疗中应用的所有随机对照试验(RCTs),并同时追索纳入研究的参考文献。由两名评价者独立选择研究、进行文献的逐步筛查,并按照Cochrane系统评价方法,由2名评价者独立对纳入研究的质量进行评价和资料提取,如有意见不一致的地方由双方讨论解决或由第三者判断,缺乏的数据和资料尽量与原作者联系予以补充,最后采用RevMan5.1软件对提取的数据进行Meta分析。
结果共纳入10个RCT,包括9518例进行PCI治疗的ACS患者。Meta分析结果显示：①与安慰剂相比,小分子GPIs能降低7天、30天及6个月的主要不良心脏事件(major adverse cardiovascular event, MACE)发生率：[OR=0.69,95%CI(0.51,0.93),P=0.01]、[OR=0.83,95%CI(0.71,0.98),P=0.03]、[OR=0.69,95%CI(0.49,0.96),P=0.03]；降低30天血运重建(target vessel revascularization, TVR)发生率[OR=0.3,95%CI(0.56,0.96),P=0.02]及6个月的再次心肌梗死(myocardial infarction, MI)发生率[OR=0.64,95%CI(0.50,0.81),P=0.0003]。但对于30天死亡率、6个月死亡率、30天MI及6个月TVR,两组的疗效相当,其差异无统计学意义：[OR=0.64,95%CI(0.40,1.04),P=0.07]、[OR=0.87,‘95%CI(0.57,1.32),P=0.52][OR=0.79,95%CI(0.62,1.00),P=0.05]、[OR=0.87,95%CI(0.74,1.03),P=0.10]。②与安慰剂相比,小分子GPIs伴随更多的轻微出血及严重出血事件：[OR=1.69,95%CI(1.27,2.24),P=0.0003]、[OR=1.46,95%CI(1.09,1.95),P=0.01]。但血小板减少症的发生率并没有统计学差异[OR=1.16,95%CI(0.63,2.16),P=0.63]。
结论小分子GPIs对于降低接受PCI治疗的ACS患者MACE发生率具有一定疗效,但也伴随更多出血事件的发生。其对MI、TVR及死亡率的影响,尚需更多高质量的RCT研究才能确定。
第二部分冠脉注射血小板糖蛋白Ⅱb/Ⅲa受体拮抗剂用于急性冠脉
综合征经皮介入治疗的有效性及安全性的系统评价
目的系统比较血小板糖蛋白Ⅱb/Ⅲa受体拮抗剂(GPIs)冠脉内应用与静脉内应用在急性冠脉综合征(ACS)经皮介入治疗(PCI)中的疗效和安全性。
方法计算机检索PubMed、EMBASE、OVID、中国生物医学文献数据库(CBM)、中国知网(CNKI)、中文科技期刊数据库(VIP),检索时间均从建库至2012年9月30日,并手工检索2012年1月到2012年9月期间国内已发表的有关论文,并用Goole学术搜索引擎等从互联网查找相关的文献,纳入冠脉内应用GPIs与静脉内应用GPIs比较在ACS的PCI治疗中应用的所有随机对照试验(RCTs),并同时追索纳入研究的参考文献。由两名评价者独立选择研究、进行文献的逐步筛查,并按照Cochrane系统评价方法,由2名评价者独立对纳入研究的质量进行评价和资料提取,如有意见不一致的地方由双方讨论解决或由第三者判断,缺乏的数据和资料尽量与原作者联系予以补充,最后采用RevMan5.1软件对提取的数据进行Meta分析。
结果共纳入10个RCTs,12篇文献,包括3553例进行PCI治疗的ACS患者。Meta分析结果显示：①与初始剂量常规静脉给药相比,GPIs初始剂量冠脉给药能降低给药后主要不良心脏事件(MACE)发生率、再次心肌梗死(MI)发生率、血运重建(TVR)发生率、心衰发生率：[OR=0.49,95%CI(0.32,0.75),P=0.0009]、[OR=0.60,95%CI(0.40,0.91),P=0.02]、[OR=0.52,95%CI(0.34,0.81),P=0.003]、[OR=0.52,95%CI(0.32,0.84),P=0.008];由于给予不同的GPIs, Meta分析显示不同研究结果间的异质性,亚组分析显示给予阿昔单抗及给予小分子GPIs的患者中,冠脉给药均可降低MACE发生率；但对于死亡率,两组的疗效相当,其差异无统计学意义：[OR=0.73,95%CI(0.52,1.01),P=0.06]。②与初始剂量静脉给药相比,GPIs初始剂量冠脉给药的轻微出血事件及严重出血事件发生率并无明显差异：[OR=0.94,95%CI(0.75,1.19),P=0.63]、[OR=1.18,95%CI(0.76,1.84),P=0.47]。
结论与常规静脉给药相比,GPIs初始剂量冠脉内给药能更好地改善接受PCI治疗的ACS患者的临床预后,且不增加出血事件发生率。
Cardiovascular disease is the number one cause of death in industrialized countries,and is expected that in2020it will also be the case in emerging countries. Coronary artery disease (CAD) is the most common manifestation, and is associated with high mortality and high morbidity. The clinical manifestations of coronary artery disease, including occult ischemia, stable angina, unstable angina pectoris, myocardial infarction, heart failure and sudden death.
Atherosclerotic plaque in the arteries which causes coronary artery disease can be divided into hard plaque and soft plaque. The stability of plaque determines the severity of coronary artery disease. Unstable plaque rupture is the pathological basis of the incidence of acute coronary syndrome (ACS). Hard plaque is not easy to break, so, it is more common in stable angina due to moderate to severe carotid artery stenosis; soft plaque is relatively soft and easy to break, more common in unstable angina (UA). Plaque rupture will lead to different degrees of coronary stenosis or blockage, causing varying degrees of coronary artery lesions.
Acute coronary syndrome
Acute coronary syndrome (ACS) is a set of clinical syndromes,whose pathological basis is coronary atherosclerotic palque rupture or erosion,and then complete or incomplete occlusive thrombus form,including ST-segment elevation myocardial infarction (STEMI), non-ST-segment elevation myocardial infarction(NSTEMI) and unstable angina (UA). Even in the modern treatment conditions, the mortality, myocardial infarction rate and the re-admission rate of patients with acute coronary syndrome are still very high.
Acute coronary syndrome represents the performance of atherosclerosis of life-threatening. It is usually caused by the coronary atherosclerotic plaque rupture or erosion induced acute thrombosis, with or without concomitant vasospasm, resulting in vascular blood flow suddenly severely reduced. During the complex process of atherosclerotic plaque rupture, the release of inflammatory cytokines and inflammatory response occurs are critical pathologic physiology factors. Occasionally, acute coronary syndrome can be caused by non-atherosclerotic diseases such as arteritis, trauma, arterial dissection, thromboembolism, congenital variation, cocaine abuse or cardiac catheterization complications.
These patients usually have a abrupt onset, the degree of risk varies.The key to improve the prognosis are early diagnosis、timely risk stratification and reasonable clinical intervention. Senior citizens, a rapid heart rate, low blood pressure, anterior myocardial infarction, previous history of heart failure, previous myocardial infarction, high initial serum creatinine level and Killip class>1,all of these can become acute coronary syndromeclinical risk indicators. Patients with these risk indicators should be checked metabolic risk markers during hospitalization, including total cholesterol, LDL (low-density lipoproteins, LDL) cholesterol, high-density lipoprotein cholesterol, fasting triglycerides, blood sugar and kidney function. In general, LDL levels decreased within the first few days of the onset of myocardial infarction, so, it is best to take early detection of patients after admission.
Percutaneous coronary intervention
Percutaneous coronary intervention (PCI) is one of the most effective and common treatment of ACS. During PCI, more than90%of patients can get TIMI3flow, also PCI can significantly improve the near-term and long-term clinical prognosis of the patients. Especially for high-risk patients with ACS, clinical benefit of PCI is more pronounced. Several ACS treatment guidelines recommend the early use of PCI treatment strategies.
Glycoprotein Ⅱb/Ⅲa inhibitors
However, during the pathogenesis of ACS and PCI intraoperative and postoperative have coronary endothelium damage, intimal exposed, platelet adhesion, activation and degranulation and the release of vasoactive substances such as ADP,5-serotonin, etc., to induce further platelet aggregation activation, platelet glycoprotein Ⅱb/Ⅲa (GPⅡb/Ⅲa) receptor conformational change, expose the fibrinogen binding sites of activated platelets, by the conformational change of the glycoprotein Ⅱb/Ⅲa receptorcross-linking with fibrinogen, and ultimately a large number of platelet aggregation, thrombosis, to cause ACS ischemic complications occurre, form stent thrombosis or mural thrombus, leading to the occurrence of adverse cardiac events, such as myocardial infarction and death. From these pathogenesis of acute coronary syndrome ischemic
complications,we can seen that, platelet aggregation plays an important role. Platelet glycoprotein Ⅱ b/Ⅲ a (GP Ⅱ b/Ⅲ a) is one member of integrin adhesion receptors family, is the most abundant platelet membrane glycoprotein,its ligands are fibrinogen (Fg), von Willebrand factor (vWF), glass connected proteins (VN), fibronectin protein (FN). GPⅡb/Ⅲa receptor antagonists by blocking the final common pathway of platelet aggregation, can effectively improve myocardial ischemia, reduce the incidence of mortality and myocardial infarction of patients with acute coronary syndrome. And the GPⅡb/Ⅲa receptor is only found in the platelet and macrophage lineage, this feature enables specific treatment of its antagonists, without fearing of causing a wide range of side effects. The appearance of platelet GPⅡb/Ⅲa receptor antagonists is the milestone event in the history of ainti platelet drug development.
The GP Ⅱ b/Ⅲ a receptor antagonists approved listing used in ACS and PCI are in three categories:monoclonal antibody Fab fragment (abciximab), synthetic peptides (such as eptifibatide), non-peptide biomimetic (such as tirofiban and lamifiban). In recent years, these drugs used in clinical practice, and have confirmed its efficacy in many clinical studies.
However, the application of platelet glycoprotein Ⅱ b/Ⅲ a receptor antagonist in clinical practice still has some detail questions.For example:
Small molecule platelet glycoprotein Ⅱ b/Ⅲa receptor antagonists compare with abciximab
Compared with the monoclonal antibody Fab fragment abciximab, small molecule GPI GP Ⅱ b/Ⅲ a receptor antagonists such as eptifibatide, tirofiban, and lamifiban,have a higher binding specificity, stronger role, and reversible combination, so,adverse reactions can be discontinued soon by immediately discontinued the drug, and as a synthetic peptide, themselves almost without antigen, do not cause allergic reactions, can be a long time or repeated treatment. However, clinical studies of GPI GP Ⅱ b/Ⅲ a receptor antagonists used during PCI in ACS patients most about abciximab, howerer, small molecule GPIs rare, and results differ.
GPIs initial dose intracoronary administration compared with intravenous administration
The GPIs conventional medication include bolus followed by≥12-hour continuous intravenous infusion. In recent years, studies have suggested that intracoronary bolus initial dose and then following the continuous infusion, coronary thrombosis local drug concentration would be higher than intravenous bolus, to better dissolve existing blood clots, and inhibit further thrombosis, and ultimately reduce death, re-MI and TVR and other adverse cardiac events. Sample sizes of existing researches are small, and some are non-randomized and retrospective studies, and there is disagreement or uncertainty.
In this study, we used Cochrane systematic review methods to make a Meta-analysis of randomized controlled trials of GPIIb/IIIa inhibitors for acute coronary syndrome patients undergoing percutaneous coronary intervention,in order to correctly assess the efficacy and safety,and to provide a reasonable choice of antiplatelet drugs and dosing regimens for clinicians.
The systematic review include two parts:Part Ⅰ:Systematic review for efficacy and safety of small molecular glycoprotein Ⅱb/Ⅲa inhibitors in percutaneous coronary intervention for acute coronary syndrome.Part Ⅱ:Systematic review for efficacy and safety of intracoronary glycoprotein Ⅱb/Ⅲa Inhibitors administration for acute coronary syndrome patients undergoing percutaneous coronary intervention.
PartⅠ Systematic review for efficacy and safety of small molecular glycoprotein Ⅱb/Ⅲa inhibitors in percutaneous coronary intervention for acute coronary syndrome.
Objective To systematically evaluate the efficacy and safety of small molecular glycoprotein Ⅱb/Ⅲa inhibitors(GPIs) in percutaneous coronary intervention(PCI) for acute coronary syndrome(ACS).
Methods A search was conducted in PubMed, EMBASE, OVID, CBM, CNKI and VIP for the randomized controlled trials (RCTs) of small molecular GPI versus placebo in PCI for ACS, from the date of their establishment to July31,2012, and the domestic relevant papers published in recent1year were also searched manually, the bibliographies of the included studies were searched too. According to the criteria of the Cochrane Handbook, two reviewers evaluated the quality of the included RCTs and extracted data independently, and then the extracted data were analyzed by using RevMan5.1software.
Results Ten RCTs involving9518ACS patients who treated with PCI were included. The results of meta-analysis showed that:①Compared with placebo, small molecular GPIs could decrease the major adverse cardiovascular event(MACE) in7days>30days and6months:[OR=0.69,95%CI (0.51,0.93), P=0.01],[OR=0.83,95%CI (0.71,0.98), P=0.03],[OR=0.69,95%CI (0.49,0.96), P=0.03]; the incidence of revascularization(TVR) in30days and re-infarction(MI) in6months were also been decreased:[OR=0.3,95%CI (0.56,0.96), P=0.02],[OR=0.64,95%CI (0.50,0.81), P=0.0003]. But for the mortality in30days and6months, the re-MI in30days and the TVR in6months, there were no significant differences in the two groups:[OR=0.64,95%CI (0.40,1.04), P=0.07],[OR=0.87,95%CI (0.57,1.32), P=0.52],[OR=0.79,95%CI (0.62,1.00), P=0.05],[OR=0.87,95%CI (0.74,1.03), P=0.10].②Compared with placebo, small molecular GPIs were associated with high risk of minor and major bleeding complications:[OR=1.69,95%CI (1.27,2.24), P=0.0003],[OR=1.46,95%CI (1.09,1.95), P=0.01]. However, the incidence of thrombocytopenia was not significantly different between the two groups[OR=1.16,95%CI (0.63,2.16), P=0.63].
Conclusion Small molecular GPIs have positive effect in PCI for ACS, however, they associate with high risk of bleeding complications. To evaluate the effect of small molecular GPIs for re-MI, TVR and mortality, more high-quality RCTs are needed.
Part II: Systematic review for efficacy and safety of intracoronary glycoprotein Ⅱb/Ⅲa Inhibitors administration for acute coronary syndrome patients undergoing percutaneous coronary intervention
Objective To systematiclly evaluate the efficacy and safety of intracoronary glycoprotein Ⅱb/Ⅲa inhibitors(GPIs) administration as compared to intravenous in percutaneous coronary intervention(PCI) for acute coronary syndrome(ACS).
Methods A search was conducted in PubMed、EMBASE、OVID、CBM、 CNKI and VIP for the randomized controlled trials (RCTs) of intracoronary GPIs administration versus intravenous in PCI for ACS,from the date of their establishment to September30,2012,and the domestic relevant papers published in regent1year were also searched manually,the bibliographies of the included studies were searched too.According to the criteria of the Cochrane Handbook,two reviewers evaluated the quality of the included RCTs and extracted data independently,and then the extracted data were analyzed by using RevMan5.1software.
Results10RCTs involving12articles and3553ACS patients who treated with PCI were included.The results of meta-analysis showed that:①Compared with intravenous administration, intracoronary GPIs administration could decrease the major adverse cardiovascular event(MACE)、the incidence of re-infarction(MI)-. revascularization(TVR) and heart failure:[OR=0.49,95%CI(0.32,0.75), P=0.0009]、[OR=0.60,95%CI (0.40,0.91), P=0.02]、[OR=0.52,95%CI (0.34,0.81), P=0.003].[OR=0.52,95%CI (0.32,0.84), P=0.008]. Meta-analysis of important covariables showed heterogeneity of in-dividual study results because of different GPIs.Subanalyses showed significant MACE reduction both in patients who had taken abciximab and tirofiban or eptifibatide.But for the mortality,there were no significant differences in the two groups:[OR=0.73,95%CI (0.52,1.01), P=0.06].②Compared with intravenous administration, intracoronary GPIs administration were not associated with any excess of minor nor major bleeding complications:[OR=0.94,95%CI(0.75,1.19), P=0.63].[OR=1.18,95%CI(0.76,1.84), P=0.47]。
Conclusion Compared with standard GPIs regimen of intravenous bolus, intracoronary administration showed significant benefits in clinical outcomes in ACS patients undergoing PCI,and did not increase the incidence of bleeding events.
引起冠脉疾病的动脉粥样硬化斑块分为硬斑块和软斑块。斑块的稳定性决定着冠脉疾病的严重程度。不稳定斑块破裂是急性冠脉综合征(Acute Coronary Syndrome, ACS)发病的病理基础。硬斑块不容易破裂,多见于中到重度冠脉狭窄导致的稳定型心绞痛；而软斑块则相对质软容易破裂,多见于不稳定型心绞痛(unstable angina, UA)。斑块破裂将导致不同程度的冠脉狭窄或堵塞,从而引起不同程度的冠状动脉病变。
急性冠脉综合征
冠脉疾病中,急性冠脉综合征(ACS)是以冠状动脉粥样硬化斑块破裂或侵蚀,继发完全或不完全闭塞血栓形成为病理基础的一组临床综合征,包括ST段抬高心肌梗死(ST-segment elevation myocardial infarction, STEMI)、非ST段抬高心肌梗死(non-ST-segment elevation myocardial infarction, NSTEMI)以及不稳定型心绞痛(UA),即使在现代治疗条件下,急性冠脉综合征患者的死亡率、心肌梗死率和再次入院率仍很高。
急性冠脉综合征代表了动脉粥样硬化的一种威胁生命的表现。它通常是由于破裂或侵蚀冠脉粥样硬化斑块诱发的急性血栓引起,合并或不合并血管痉挛,从而导致脉管血流突然性的严重减少。在动脉粥样硬化斑块破裂这一复杂的过程当中,炎症因子释放及炎症反应发生是一个关键的病理生理学因素。偶尔,急性冠脉综合征可以通过非粥样硬化性疾病引起,比如,动脉炎、外伤、动脉夹层、血栓栓塞、先天变异、滥用可卡因或是心导管检查引起的并发症。
急性冠脉综合征患者起病急、危险程度十分不均一。对其进行早期诊断、及时危险分层和合理的临床干预,是改善预后的关键。高龄、较快心率、低血压、前壁心肌梗死、既往有心力衰竭病史、既往有心肌梗死病史、初始血清肌酐水平较高以及Killip分级大于1级等都可成为急性冠脉综合征的临床高危指标。存在以上高危指标的患者应在住院期间检查代谢风险标志物,包括总胆固醇、低密度脂蛋白(low-density lipoproteins, LDL)胆固醇、高密度脂蛋白胆固醇、空腹甘油三酯以及血糖和肾功能等。一般情况下,LDL水平会在心肌梗死发病的最初几天内有所下降,因此,最好在患者入院后尽早进行检测。
经皮冠脉介入治疗
目前经皮冠状动脉介入治疗(Percutaneous Coronary Intervetion, PCI)是治疗急性冠脉综合征最有效、最常用的方法之一。90%以上的患者在进行PCI后能够获得TIMI3血流,同时,PCI可显著改善患者的近期以及远期临床预后。尤其对于高危ACS患者,PCI的临床受益更加明显。多个ACS治疗指南推荐尽早使用PCI治疗策略。
血小板糖蛋白Ⅱb/Ⅲa受体拮抗剂
然而,在ACS的发病过程及进行PCI的术中、术后都有冠脉内皮的破坏,使血管内膜下层暴露,血小板黏附、活化、脱颗粒并释放各种血管活性物质如ADP、5-羟色胺等,诱导血小板进一步聚集活化,血小板糖蛋白Ⅱb/Ⅲa(GPⅡb/Ⅲa)受体构象发生改变,暴露出纤维蛋白原结合位点,活化的血小板通过构象发生改变的糖蛋白Ⅱb/Ⅲa受体与纤维蛋白原相互交联,最终大量血小板聚集形成血栓,引起ACS缺血性并发症的发生,形成支架内血栓或附壁血栓,进而导致围手术期心肌梗死、死亡等不良心脏事件的发生。
由以上围术期急性冠脉综合征缺血性并发症的发病过程可见,血小板聚集扮演了重要的角色。血小板糖蛋白Ⅱb/Ⅲa(GP Ⅱ b/Ⅲa)属于整合素家族粘附受体,是血小板含量最丰富的膜糖蛋白,其配体主要是纤维蛋白原(Fg)、血管性血友病因子(vWF)、还有玻璃连接蛋白(VN)、纤维连接蛋白(FN)等。通过GPⅡb/Ⅲa受体拮抗剂阻断血小板聚集的最后共同通路,能有效改善急性冠脉综合征患者的心肌缺血,降低死亡率及心肌梗死发生率。并且GPⅡb/Ⅲa受体仅在血小板以及巨噬细胞谱系中发现,这一特点使得能够以其拮抗剂进行特异性治疗,而不用担心引起广泛的副作用。血小板GPⅡb/Ⅲa受体拮抗剂的出现是抗血小板药物发展史上里程碑式的事件。
目前获得批准上市应用于ACS及PCI中的GPⅡb/Ⅲa受体拮抗剂有三类：单克隆抗体Fab片段类(如阿昔单抗)、合成肽类(如依替巴肽)、非肽仿生物类(如替罗非班以及拉米非班)。近年来,以上药物应用于国内外临床实践,并在很多临床研究中证实了其疗效。
但是,关于血小板糖蛋白Ⅱb/Ⅲa受体拮抗剂在临床实践中的应用仍有许多细节问题。比如：
小分子血小板糖蛋白Ⅱb/Ⅲa受体拮抗剂与阿昔单抗的比较
与单克隆抗体Fab片段的阿昔单抗比较,依替巴肽、替罗非班、拉米非班等小分子GPIs与GPⅡb/Ⅲa的结合特异性更高、作用更强,且其结合是可逆的,一旦出现不良反应,立即停药后不良反应很快减轻,并且作为合成多肽,其本身几乎无抗原性,不会引起过敏反应,可以进行较长时间或反复的治疗。但目前在进行PCI的ACS患者中的临床研究以阿昔单抗居多,而有关小分子GPⅠs在此方面应用的研究并不多见,且研究结果存在差异。
GPⅠs初始剂量冠脉内给药与静脉内给药的比较
GPⅠs的常规用药方式为静脉快速推注起始剂量并继以≥12小时持续静脉输注。近几年有研究提出,以冠脉快速推注起始剂量再继以持续静脉输注,能够使冠脉血栓局部药物浓度高于静脉快速推注,从而更好地溶解已有血栓,并抑制进一步血栓形成,最终降低死亡、再次MI、再次TVR等不良心脏事件的发生。但现有研究样本量较小,有些为非随机和追溯性研究,且结果存在有分歧或不确定。
本研究根据循证医学的原则,运用Cochrane系统评价方法,对目前已发表的各种GPⅡb/Ⅲa受体拮抗剂在急性冠脉综合征患者的经皮冠脉介入治疗中应用的随机对照试验进行Meta分析,以期正确评估GPⅡb/Ⅲa受体拮抗剂作为急性冠脉综合征经皮介入治疗的辅助疗法,从而对患者进行围手术期心肌保护的疗效以及安全性,为临床医生在本类患者围手术期合理选择抗血小板药物及制定给药方案提供真实可靠的依据。
本研究分为两部分：第一部分为对小分子血小板糖蛋白Ⅱb/Ⅲa受体拮抗剂在急性冠脉综合征的经皮介入治疗中应用的疗效及安全性进行系统评价；第二部分为对冠脉注射GPⅡb/Ⅲa受体拮抗剂用于急性冠脉综合征的经皮介入治疗中的疗效及安全性进行系统评价。
第一部分小分子血小板糖蛋白Ⅱb/Ⅲa受体拮抗剂用于急性冠脉综合征经皮介入治疗的有效性及安全性的系统评价
目的系统评价小分子血小板糖蛋白Ⅱb/Ⅲa受体拮抗剂(GPIs)用于急性冠脉综合征(ACS)的经皮介入治疗(PCI)的疗效和安全性。
方法计算机检索PubMed、 EMBASE、OVID、中国生物医学文献数据库(CBM)、中国知网(CNKI)、中文科技期刊数据库(VIP),检索时间均从建库至2012年7月31日,并手工检索2012年1月到2012年7月国内已发表的有关论文,并用Goole学术搜索引擎等从互联网查找相关的文献,纳入小分子GPIs与安慰剂比较在ACS的PCI治疗中应用的所有随机对照试验(RCTs),并同时追索纳入研究的参考文献。由两名评价者独立选择研究、进行文献的逐步筛查,并按照Cochrane系统评价方法,由2名评价者独立对纳入研究的质量进行评价和资料提取,如有意见不一致的地方由双方讨论解决或由第三者判断,缺乏的数据和资料尽量与原作者联系予以补充,最后采用RevMan5.1软件对提取的数据进行Meta分析。
结果共纳入10个RCT,包括9518例进行PCI治疗的ACS患者。Meta分析结果显示：①与安慰剂相比,小分子GPIs能降低7天、30天及6个月的主要不良心脏事件(major adverse cardiovascular event, MACE)发生率：[OR=0.69,95%CI(0.51,0.93),P=0.01]、[OR=0.83,95%CI(0.71,0.98),P=0.03]、[OR=0.69,95%CI(0.49,0.96),P=0.03]；降低30天血运重建(target vessel revascularization, TVR)发生率[OR=0.3,95%CI(0.56,0.96),P=0.02]及6个月的再次心肌梗死(myocardial infarction, MI)发生率[OR=0.64,95%CI(0.50,0.81),P=0.0003]。但对于30天死亡率、6个月死亡率、30天MI及6个月TVR,两组的疗效相当,其差异无统计学意义：[OR=0.64,95%CI(0.40,1.04),P=0.07]、[OR=0.87,‘95%CI(0.57,1.32),P=0.52][OR=0.79,95%CI(0.62,1.00),P=0.05]、[OR=0.87,95%CI(0.74,1.03),P=0.10]。②与安慰剂相比,小分子GPIs伴随更多的轻微出血及严重出血事件：[OR=1.69,95%CI(1.27,2.24),P=0.0003]、[OR=1.46,95%CI(1.09,1.95),P=0.01]。但血小板减少症的发生率并没有统计学差异[OR=1.16,95%CI(0.63,2.16),P=0.63]。
结论小分子GPIs对于降低接受PCI治疗的ACS患者MACE发生率具有一定疗效,但也伴随更多出血事件的发生。其对MI、TVR及死亡率的影响,尚需更多高质量的RCT研究才能确定。
第二部分冠脉注射血小板糖蛋白Ⅱb/Ⅲa受体拮抗剂用于急性冠脉
综合征经皮介入治疗的有效性及安全性的系统评价
目的系统比较血小板糖蛋白Ⅱb/Ⅲa受体拮抗剂(GPIs)冠脉内应用与静脉内应用在急性冠脉综合征(ACS)经皮介入治疗(PCI)中的疗效和安全性。
方法计算机检索PubMed、EMBASE、OVID、中国生物医学文献数据库(CBM)、中国知网(CNKI)、中文科技期刊数据库(VIP),检索时间均从建库至2012年9月30日,并手工检索2012年1月到2012年9月期间国内已发表的有关论文,并用Goole学术搜索引擎等从互联网查找相关的文献,纳入冠脉内应用GPIs与静脉内应用GPIs比较在ACS的PCI治疗中应用的所有随机对照试验(RCTs),并同时追索纳入研究的参考文献。由两名评价者独立选择研究、进行文献的逐步筛查,并按照Cochrane系统评价方法,由2名评价者独立对纳入研究的质量进行评价和资料提取,如有意见不一致的地方由双方讨论解决或由第三者判断,缺乏的数据和资料尽量与原作者联系予以补充,最后采用RevMan5.1软件对提取的数据进行Meta分析。
结果共纳入10个RCTs,12篇文献,包括3553例进行PCI治疗的ACS患者。Meta分析结果显示：①与初始剂量常规静脉给药相比,GPIs初始剂量冠脉给药能降低给药后主要不良心脏事件(MACE)发生率、再次心肌梗死(MI)发生率、血运重建(TVR)发生率、心衰发生率：[OR=0.49,95%CI(0.32,0.75),P=0.0009]、[OR=0.60,95%CI(0.40,0.91),P=0.02]、[OR=0.52,95%CI(0.34,0.81),P=0.003]、[OR=0.52,95%CI(0.32,0.84),P=0.008];由于给予不同的GPIs, Meta分析显示不同研究结果间的异质性,亚组分析显示给予阿昔单抗及给予小分子GPIs的患者中,冠脉给药均可降低MACE发生率；但对于死亡率,两组的疗效相当,其差异无统计学意义：[OR=0.73,95%CI(0.52,1.01),P=0.06]。②与初始剂量静脉给药相比,GPIs初始剂量冠脉给药的轻微出血事件及严重出血事件发生率并无明显差异：[OR=0.94,95%CI(0.75,1.19),P=0.63]、[OR=1.18,95%CI(0.76,1.84),P=0.47]。
结论与常规静脉给药相比,GPIs初始剂量冠脉内给药能更好地改善接受PCI治疗的ACS患者的临床预后,且不增加出血事件发生率。
Cardiovascular disease is the number one cause of death in industrialized countries,and is expected that in2020it will also be the case in emerging countries. Coronary artery disease (CAD) is the most common manifestation, and is associated with high mortality and high morbidity. The clinical manifestations of coronary artery disease, including occult ischemia, stable angina, unstable angina pectoris, myocardial infarction, heart failure and sudden death.
Atherosclerotic plaque in the arteries which causes coronary artery disease can be divided into hard plaque and soft plaque. The stability of plaque determines the severity of coronary artery disease. Unstable plaque rupture is the pathological basis of the incidence of acute coronary syndrome (ACS). Hard plaque is not easy to break, so, it is more common in stable angina due to moderate to severe carotid artery stenosis; soft plaque is relatively soft and easy to break, more common in unstable angina (UA). Plaque rupture will lead to different degrees of coronary stenosis or blockage, causing varying degrees of coronary artery lesions.
Acute coronary syndrome
Acute coronary syndrome (ACS) is a set of clinical syndromes,whose pathological basis is coronary atherosclerotic palque rupture or erosion,and then complete or incomplete occlusive thrombus form,including ST-segment elevation myocardial infarction (STEMI), non-ST-segment elevation myocardial infarction(NSTEMI) and unstable angina (UA). Even in the modern treatment conditions, the mortality, myocardial infarction rate and the re-admission rate of patients with acute coronary syndrome are still very high.
Acute coronary syndrome represents the performance of atherosclerosis of life-threatening. It is usually caused by the coronary atherosclerotic plaque rupture or erosion induced acute thrombosis, with or without concomitant vasospasm, resulting in vascular blood flow suddenly severely reduced. During the complex process of atherosclerotic plaque rupture, the release of inflammatory cytokines and inflammatory response occurs are critical pathologic physiology factors. Occasionally, acute coronary syndrome can be caused by non-atherosclerotic diseases such as arteritis, trauma, arterial dissection, thromboembolism, congenital variation, cocaine abuse or cardiac catheterization complications.
These patients usually have a abrupt onset, the degree of risk varies.The key to improve the prognosis are early diagnosis、timely risk stratification and reasonable clinical intervention. Senior citizens, a rapid heart rate, low blood pressure, anterior myocardial infarction, previous history of heart failure, previous myocardial infarction, high initial serum creatinine level and Killip class>1,all of these can become acute coronary syndromeclinical risk indicators. Patients with these risk indicators should be checked metabolic risk markers during hospitalization, including total cholesterol, LDL (low-density lipoproteins, LDL) cholesterol, high-density lipoprotein cholesterol, fasting triglycerides, blood sugar and kidney function. In general, LDL levels decreased within the first few days of the onset of myocardial infarction, so, it is best to take early detection of patients after admission.
Percutaneous coronary intervention
Percutaneous coronary intervention (PCI) is one of the most effective and common treatment of ACS. During PCI, more than90%of patients can get TIMI3flow, also PCI can significantly improve the near-term and long-term clinical prognosis of the patients. Especially for high-risk patients with ACS, clinical benefit of PCI is more pronounced. Several ACS treatment guidelines recommend the early use of PCI treatment strategies.
Glycoprotein Ⅱb/Ⅲa inhibitors
However, during the pathogenesis of ACS and PCI intraoperative and postoperative have coronary endothelium damage, intimal exposed, platelet adhesion, activation and degranulation and the release of vasoactive substances such as ADP,5-serotonin, etc., to induce further platelet aggregation activation, platelet glycoprotein Ⅱb/Ⅲa (GPⅡb/Ⅲa) receptor conformational change, expose the fibrinogen binding sites of activated platelets, by the conformational change of the glycoprotein Ⅱb/Ⅲa receptorcross-linking with fibrinogen, and ultimately a large number of platelet aggregation, thrombosis, to cause ACS ischemic complications occurre, form stent thrombosis or mural thrombus, leading to the occurrence of adverse cardiac events, such as myocardial infarction and death. From these pathogenesis of acute coronary syndrome ischemic
complications,we can seen that, platelet aggregation plays an important role. Platelet glycoprotein Ⅱ b/Ⅲ a (GP Ⅱ b/Ⅲ a) is one member of integrin adhesion receptors family, is the most abundant platelet membrane glycoprotein,its ligands are fibrinogen (Fg), von Willebrand factor (vWF), glass connected proteins (VN), fibronectin protein (FN). GPⅡb/Ⅲa receptor antagonists by blocking the final common pathway of platelet aggregation, can effectively improve myocardial ischemia, reduce the incidence of mortality and myocardial infarction of patients with acute coronary syndrome. And the GPⅡb/Ⅲa receptor is only found in the platelet and macrophage lineage, this feature enables specific treatment of its antagonists, without fearing of causing a wide range of side effects. The appearance of platelet GPⅡb/Ⅲa receptor antagonists is the milestone event in the history of ainti platelet drug development.
The GP Ⅱ b/Ⅲ a receptor antagonists approved listing used in ACS and PCI are in three categories:monoclonal antibody Fab fragment (abciximab), synthetic peptides (such as eptifibatide), non-peptide biomimetic (such as tirofiban and lamifiban). In recent years, these drugs used in clinical practice, and have confirmed its efficacy in many clinical studies.
However, the application of platelet glycoprotein Ⅱ b/Ⅲ a receptor antagonist in clinical practice still has some detail questions.For example:
Small molecule platelet glycoprotein Ⅱ b/Ⅲa receptor antagonists compare with abciximab
Compared with the monoclonal antibody Fab fragment abciximab, small molecule GPI GP Ⅱ b/Ⅲ a receptor antagonists such as eptifibatide, tirofiban, and lamifiban,have a higher binding specificity, stronger role, and reversible combination, so,adverse reactions can be discontinued soon by immediately discontinued the drug, and as a synthetic peptide, themselves almost without antigen, do not cause allergic reactions, can be a long time or repeated treatment. However, clinical studies of GPI GP Ⅱ b/Ⅲ a receptor antagonists used during PCI in ACS patients most about abciximab, howerer, small molecule GPIs rare, and results differ.
GPIs initial dose intracoronary administration compared with intravenous administration
The GPIs conventional medication include bolus followed by≥12-hour continuous intravenous infusion. In recent years, studies have suggested that intracoronary bolus initial dose and then following the continuous infusion, coronary thrombosis local drug concentration would be higher than intravenous bolus, to better dissolve existing blood clots, and inhibit further thrombosis, and ultimately reduce death, re-MI and TVR and other adverse cardiac events. Sample sizes of existing researches are small, and some are non-randomized and retrospective studies, and there is disagreement or uncertainty.
In this study, we used Cochrane systematic review methods to make a Meta-analysis of randomized controlled trials of GPIIb/IIIa inhibitors for acute coronary syndrome patients undergoing percutaneous coronary intervention,in order to correctly assess the efficacy and safety,and to provide a reasonable choice of antiplatelet drugs and dosing regimens for clinicians.
The systematic review include two parts:Part Ⅰ:Systematic review for efficacy and safety of small molecular glycoprotein Ⅱb/Ⅲa inhibitors in percutaneous coronary intervention for acute coronary syndrome.Part Ⅱ:Systematic review for efficacy and safety of intracoronary glycoprotein Ⅱb/Ⅲa Inhibitors administration for acute coronary syndrome patients undergoing percutaneous coronary intervention.
PartⅠ Systematic review for efficacy and safety of small molecular glycoprotein Ⅱb/Ⅲa inhibitors in percutaneous coronary intervention for acute coronary syndrome.
Objective To systematically evaluate the efficacy and safety of small molecular glycoprotein Ⅱb/Ⅲa inhibitors(GPIs) in percutaneous coronary intervention(PCI) for acute coronary syndrome(ACS).
Methods A search was conducted in PubMed, EMBASE, OVID, CBM, CNKI and VIP for the randomized controlled trials (RCTs) of small molecular GPI versus placebo in PCI for ACS, from the date of their establishment to July31,2012, and the domestic relevant papers published in recent1year were also searched manually, the bibliographies of the included studies were searched too. According to the criteria of the Cochrane Handbook, two reviewers evaluated the quality of the included RCTs and extracted data independently, and then the extracted data were analyzed by using RevMan5.1software.
Results Ten RCTs involving9518ACS patients who treated with PCI were included. The results of meta-analysis showed that:①Compared with placebo, small molecular GPIs could decrease the major adverse cardiovascular event(MACE) in7days>30days and6months:[OR=0.69,95%CI (0.51,0.93), P=0.01],[OR=0.83,95%CI (0.71,0.98), P=0.03],[OR=0.69,95%CI (0.49,0.96), P=0.03]; the incidence of revascularization(TVR) in30days and re-infarction(MI) in6months were also been decreased:[OR=0.3,95%CI (0.56,0.96), P=0.02],[OR=0.64,95%CI (0.50,0.81), P=0.0003]. But for the mortality in30days and6months, the re-MI in30days and the TVR in6months, there were no significant differences in the two groups:[OR=0.64,95%CI (0.40,1.04), P=0.07],[OR=0.87,95%CI (0.57,1.32), P=0.52],[OR=0.79,95%CI (0.62,1.00), P=0.05],[OR=0.87,95%CI (0.74,1.03), P=0.10].②Compared with placebo, small molecular GPIs were associated with high risk of minor and major bleeding complications:[OR=1.69,95%CI (1.27,2.24), P=0.0003],[OR=1.46,95%CI (1.09,1.95), P=0.01]. However, the incidence of thrombocytopenia was not significantly different between the two groups[OR=1.16,95%CI (0.63,2.16), P=0.63].
Conclusion Small molecular GPIs have positive effect in PCI for ACS, however, they associate with high risk of bleeding complications. To evaluate the effect of small molecular GPIs for re-MI, TVR and mortality, more high-quality RCTs are needed.
Part II: Systematic review for efficacy and safety of intracoronary glycoprotein Ⅱb/Ⅲa Inhibitors administration for acute coronary syndrome patients undergoing percutaneous coronary intervention
Objective To systematiclly evaluate the efficacy and safety of intracoronary glycoprotein Ⅱb/Ⅲa inhibitors(GPIs) administration as compared to intravenous in percutaneous coronary intervention(PCI) for acute coronary syndrome(ACS).
Methods A search was conducted in PubMed、EMBASE、OVID、CBM、 CNKI and VIP for the randomized controlled trials (RCTs) of intracoronary GPIs administration versus intravenous in PCI for ACS,from the date of their establishment to September30,2012,and the domestic relevant papers published in regent1year were also searched manually,the bibliographies of the included studies were searched too.According to the criteria of the Cochrane Handbook,two reviewers evaluated the quality of the included RCTs and extracted data independently,and then the extracted data were analyzed by using RevMan5.1software.
Results10RCTs involving12articles and3553ACS patients who treated with PCI were included.The results of meta-analysis showed that:①Compared with intravenous administration, intracoronary GPIs administration could decrease the major adverse cardiovascular event(MACE)、the incidence of re-infarction(MI)-. revascularization(TVR) and heart failure:[OR=0.49,95%CI(0.32,0.75), P=0.0009]、[OR=0.60,95%CI (0.40,0.91), P=0.02]、[OR=0.52,95%CI (0.34,0.81), P=0.003].[OR=0.52,95%CI (0.32,0.84), P=0.008]. Meta-analysis of important covariables showed heterogeneity of in-dividual study results because of different GPIs.Subanalyses showed significant MACE reduction both in patients who had taken abciximab and tirofiban or eptifibatide.But for the mortality,there were no significant differences in the two groups:[OR=0.73,95%CI (0.52,1.01), P=0.06].②Compared with intravenous administration, intracoronary GPIs administration were not associated with any excess of minor nor major bleeding complications:[OR=0.94,95%CI(0.75,1.19), P=0.63].[OR=1.18,95%CI(0.76,1.84), P=0.47]。
Conclusion Compared with standard GPIs regimen of intravenous bolus, intracoronary administration showed significant benefits in clinical outcomes in ACS patients undergoing PCI,and did not increase the incidence of bleeding events.
引文
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[2][ESC guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation. The Task Force for the management of acute coronary syndromes (ACS) in patients presenting without persistent ST-segment elevation of the European Society of Cardiology (ESC)][J]. G Ital Cardiol (Rome),2012,13(3):171-228.
[3]Fernandez-Ortiz A, Pan M, Alfonso F, et al. Comments on the ESC guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation. A report of the Task Force of the Clinical Practice Guidelines Committee of the Spanish Society of Cardiology[J]. Rev Esp Cardiol,2012,65(2):125-130.
[4]Hamm C W, Bassand J P, Agewall S, et al. ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation:The Task Force for the management of acute coronary syndromes (ACS) in patients presenting without persistent ST-segment elevation of the European Society of Cardiology (ESC)[J]. Eur Heart J,2011,32(23):2999-3054.
[5]Muller C. New ESC guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation[J]. Swiss Med Wkly,2012,142:0.
[6]Mehilli J, Kastrati A, Schulz S, et al. Abciximab in patients with acute ST-segment-elevation myocardial infarction undergoing primary percutaneous coronary intervention after clopidogrel loading:a randomized double-blind trial[J]. Circulation,2009,119(14): 1933-1940.
[7]Nakagawa Y, Nobuyoshi M, Yamaguchi T, et al. Efficacy of abciximab for patients undergoing balloon angioplasty:data from Japanese evaluation of c7E3 Fab for elective and primary PCI organization in randomized trial (JEPPORT)[J]. Circ J,2009,73(1):145-151.
[8]Ndrepepa G, Kastrati A, Mehilli J, et al. One-year clinical outcomes with abciximab vs. placebo in patients with non-ST-segment elevation acute coronary syndromes undergoing percutaneous coronary intervention after pre-treatment with clopidogrel:results of the ISAR-REACT 2 randomized trial[J]. Eur Heart J,2008,29(4):455-461.
[9]Iversen A, Abildgaard U, Galloe A, et al. Intracoronary compared to intravenous bolus abciximab during primary percutaneous coronary intervention in ST-segment Elevation Myocardial Infarction (STEMI) patients reduces 30-day mortality and target vessel revascularization:a randomized trial[J]. J Interv Cardiol,2011,24(2):105-111.
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