Glycoprotein Ⅱb/Ⅲa Inhibitors in Percutaneous Coronary Intervention for Acute Coronary Syndrome:Meta-analysis of Randomized Trials

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 syndromeAcute 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 interventionPercutaneous 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 inhibitorsHowever, 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 ischemiccomplications,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 abciximabCompared 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 administrationThe 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 interventionObjective 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.