Intravenous glycoprotein IIb/IIIa inhibition in non-ST segment elevation acute coronary syndromes

Over recent years, substantial clinical trial evidence regarding glycoprotein IIb/IIIa inhibition for the medical management of non-ST segment elevation acute coronary syndromes has been compiled. Despite being recently advocated for the management of coronary instability within widely accepted guidelines, its use among patients presenting with acute coronary syndromes remains somewhat contentious. Within randomized placebo-controlled trials, uniform efficacy with the glycoprotein IIb/IIIa inhibitors has not been shown, whereas a disturbing excess in adverse events is evident within some trials. Currently, the basis for this heterogeneity of clinical evidence has not been adequately explained. However, evolving insights from clinical trials and basic research have further refined our understanding of glycoprotein IIb/IIIa antagonist therapy and the potential effects beyond the inhibition of the fibrinogen receptor. Likewise, appreciation of the pharmacokinetic characteristics of these agents provides putative explanations for the diverse findings of the randomized trials. Reexamination of the clinical trial data in light of this recent evidence provides a basis for interpreting the marginal results of glycoprotein IIb/IIIa inhibition in acute coronary syndromes. Consideration of these factors may facilitate the optimal clinical application of this class of agents to the management of coronary instability.     

Platelet glycoprotein IIb/IIIa inhibitor therapy in non-ST segment elevation acute coronary syndromes

Platelet glycoprotein (GP) IIb/IIIa inhibitors prevent fibrinogen binding and platelet aggregation. They decrease ischemic complications associated with non-ST segment elevation acute coronary syndromes and percutaneous coronary intervention. Meta-analyses of 6 randomized trials of parenteral GP IIb/IIIa inhibitors in patients with acute coronary syndromes suggest a significant reduction in death and myocardial infarction in high risk patients. These include patients undergoing early percutaneous coronary intervention or those with high TIMI risk score, elevated troponin values, or diabetes mellitus. Despite guideline recommendations supporting therapy for these indications, only a minority of appropriate candidates are being treated. The risk of major bleeding is small; thrombocytopenia can result from abciximab therapy. Optimal dosing strategies continue to evolve.     

Platelet glycoprotein IIb/IIIa inhibition in acute coronary syndromes

Acute coronary syndromes are a leading cause of hospitalization in industrialized countries. Current antithrombotic therapy focuses on relatively weak antiplatelet agents and heparin. The advent of inhibitors of the platelet glycoprotein IIb/IIIa receptor, the final common pathway for aggregation, provides a new therapeutic modality. Clinical trials with a total of more than 18,000 patients have clearly shown the benefits of intravenous IIb/IIIa blockade. Overall, at 30 days, 13 fewer deaths or myocardial infarctions occurred for every 1000 patients treated in these trials. This favorable outcome was extended to 6 months, resulting in 16 fewer such events per 1000 patients treated. Importantly, these benefits were not accompanied by an excessive occurrence in bleeding complications or thrombocytopenia. To further improve outcomes in this high-risk group of patients, strategies pertaining to prolonged periods of vessel passivation with oral formulations and early or delayed invasive approaches are being studied.     

Platelet glycoprotein IIb/IIIa inhibitors in acute coronary syndromes

Antagonists of the platelet fibrinogen receptor glycoprotein IIb/IIIa are potent inhibitors of platelet function and provide marked protection from ischemic events in patients undergoing PCI. These agents are also of benefit in patients with unstable angina or non-ST segment elevation myocardial infarction (MI) and provide a 9% reduction in the combined endpoint of 30-day death or MI. This benefit is most marked in patients undergoing early PCI or those at increased risk due to history of diabetes or elevation of the cardiac marker troponin. Based on these findings, the combined American Heart Association and American College of Cardiology guidelines on the management of unstable angina and non-ST segment elevation MI recommend intravenous GPIIb/IIIa in patients in whom PCI is planned particularly those with elevated troponin or diabetes. The use of these agents is associated with a slight increase in major bleeding and in rare instances thrombocytopenia that usually resolves quickly after therapy is discontinued.     

TARGET versus GUSTO-IV: appropriate use of glycoprotein IIb/IIIa inhibitors in acute coronary syndromes and percutaneous coronary intervention

Until recently, the selection of which glycoprotein IIb/IIIa inhibitor to use for patients with acute coronary syndromes or those undergoing percutaneous coronary intervention largely reflected physician preference, costs, and any evidence supporting the clinical indication. Clinicians often assumed a class effect for these agents: a benefit observed for one agent in one clinical setting (such as percutaneous coronary intervention) would confer benefit in another (such as non-ST-elevation acute coronary syndromes). The need for evidence to guide treatment selection motivated the design of the Do Tirofiban and ReoPro Give Similar Efficacy Trial (TARGET) and the Global Use of Strategies to Open occluded arteries (GUSTO-IV) trials with abciximab. This review examines the results from these and other recent trials of glycoprotein IIb/IIIa inhibition in acute coronary syndromes and percutaneous coronary intervention, presents a rationale for the lack of a consistent benefit with abciximab, and describes future directions for clinical investigation.     

Controversies surrounding platelet glycoprotein IIb/IIIa inhibitors in percutaneous coronary intervention and acute coronary syndromes

Platelet-dependent thrombosis is an important part of the pathophysiology of both percutaneous coronary interventions (PCI) and acute coronary syndrome (ACS). Data support the use of acute therapies that interfere with platelets to provide clinical benefit to patients presenting with acute cardiovascular disease. The discovery of platelet glycoprotein (GP) IIb/IIIa receptor antagonists has been a major advance in the pharmacotherapy for patients undergoing PCI and those presenting with ACS without ST-segment elevation. This article will cover the role of platelets in acute cardiovascular disease, as well as the discovery and development of the platelet GPIIb/IIIa inhibitors. The major focus of this article will be on examining key lessons from the trials in each of these areas as well as presenting a series of questions that still require answers from either ongoing or future research.     

Gp IIb/IIIa receptor antagonists in acute coronary syndromes with no ST elevation

Gp IIb/IIIa receptor antagonists have been the subject of much work in patients presenting with acute coronary syndrome with no ST elevation (ACS ST-). The initial studies (PRISM, PRISM-PLUS, PURSUIT, PARAGON, CAPTURE, GUSTO IV-ACS) were performed at the end of the 1990s and universally showed a significant reduction in an endpoint combining death and myocardial infarction, especially in patients with an elevation of troponin and treated by angioplasty. However, these studies were performed at a time when clopidogrel was not being used regularly for this indication. Four randomised studies have recently re-evaluated the significance of Gp IIb/IIIa blockers prescribed either on admission to coronary intensive care (ELISA-2, PRACTICE) or in the coronary angiography suite during angioplasty (ADVANCE, ISAR-REACT 2) in patients presenting with ACS ST- pre-treated with clopidogrel in association with aspirin and heparin. The results of these studies suggest that Gp IIb/IIIa blockers initiated at the start of angioplasty significantly reduce an endpoint combining death, myocardial infarction and the need for emergency revascularisation. On the other hand, studies in which Gp IIb/IIIa blockers are initiated in coronary intensive care have been negative, but they have only been carried out on small numbers. The results of the ACUITY study comparing bivalirudin and Gp IIb/IIIa blockers in this context have recently been published. Bivalirudin seems to compare well with Gp IIb/IIIa blockers in terms of ischemia, but it significantly reduces the occurrence of hemorrhagic events.     

The use of the glycoprotein IIb/IIIa receptor antagonists during percutaneous coronary intervention

Coronary thrombosis is the major cause of ischemic complications during percutaneous coronary interventions (PCI). The glycoprotein (GP) IIb/IIIa receptor plays a critical role in the process of platelet thrombus formation since it serves as the final common pathway for platelet aggregation. Presently, there are three commercially available intravenous GPIIb/IIIa inhibitors that block fibrinogen binding to its receptor. These agents significantly reduce the incidence of death and nonfatal myocardial infarction at 30 days in patients undergoing percutaneous coronary revascularization. In addition, the early benefits appear to be sustained at 6 months to 1 year. Increasing evidence shows that the predominant mechanism of benefit is due to a reduction in embolization to the microcirculation that occurs during PCI. While data regarding the comparative efficacy and cost-effectiveness of these agents are scarce, the magnitude of benefit appears to be greatest for abciximab. Furthermore, a mortality benefit has been demonstrated only for abciximab. Although high risk patients reap the greatest benefit from the use of these agents, it is clear that even patients who are classified as low-to-moderate risk still derive substantial benefit from their use. Finally, evidence indicates that the majority of patients with acute coronary syndromes without ST segment elevation who are scheduled to undergo PCI should be pretreated with a GPIIb/IIIa receptor antagonist.     

替罗非班对急性冠脉综合征患者血小板活化度的影响

目的:评价GPⅡb/Ⅲa受体拮抗剂(盐酸替罗非班)对急性冠脉综合征(ACS)患者血小板活化度的影响及临床安全性。方法:受试组患者为来自2005年1月～2008年1月我院就诊的急性非ST段抬高型心肌梗塞和不稳定型心绞痛ACS患者,共126例,接受盐酸替罗非班持续泵入24～48h,根据年龄、性别选取同期就诊的稳定型心绞痛冠心病患者112例作为对照组。应用流式细胞仪分别对受试组和对照组患者CD61、CD62p、活化的GPⅡb/Ⅲa(PAC-1)的表达情况进行分析。结果:受试组CD61、PAC-1指标应用替罗非班1.5～2h,10h,48h比用药前明显降低(P均0.01),而对照组在治疗前后无明显变化;CD61仅用药1.5h时两组间比较有显著差异(P0.001);受试组PAC-1水平在治疗1.5～2h,10h时明显下降(P0.05),在48h又出现明显升高(P0.05)。结论:急性冠脉综合征患者应用GPⅡb/Ⅲa受体拮抗剂可改善长期的临床预后,同时我们的研究也显示替罗非班治疗急性冠脉综合症是有效的和安全的。     

Low-molecular-weight heparins and glycoprotein IIb/IIIa antagonists in acute coronary syndromes

Traditional antithrombotic regimens for the management of acute coronary syndromes are far from optimal. There is considerable opportunity for improvement of standard treatment with unfractionated heparin and aspirin. The introduction of new antithrombotic drugs, such as low-molecular-weight heparins(LMWH), and more potent antiplatelet drugs, such as glycoprotein(GP) lIb/llla antagonists, has the potential to significantly improve clinical outcomes. The complementary anticoagulant/antiplatelet modes of action of LMWHs and GP lIb/Ila antagonists mean that combining these drugs in the medical management of patients with acute coronary syndromes, including those who undergo percutaneous coronary intervention, may offer enhanced clinical benefits. Until recently, there was a lack of clinical data to support this approach, but several recent trials have confirmed the safety and efficacy of combination therapy with the LMWH enoxaparin and a GP lIb/Illa antagonist in the management of patients with unstable angina/non-ST segment elevation myocardial infarction. The 2002 American College of Cardiology/American Heart Association guidelines on unstable angina/non-ST-segment elevation myocardial infarction reflect this new evidence.The combined use of a LMWH and a GP IIb/IIIa antagonist should now be viewed as safe and effective in the management of acute coronary syndromes. Definitive efficacy-powered superiority data will be available shortly.     

Evaluation of a selective strategy for glycoprotein IIb/IIIa inhibitors administration in non-ST segment elevation acute coronary syndromes

Aims

We evaluated the impact of a selective strategy for glycoprotein IIb/IIIa inhibitors administration in non ST-segment elevation acute coronary syndrome.

Patients and method

Between February 1st, 2007, and February 1st, 2009, 331 consecutive patients were prospectively included in the study. Criteria for upstream glycoprotein IIb/IIIa inhibitors administration were as follows: transient ST elevation greater than 1 mm, ST-segment depression greater than 2 mm, ischemic recurrence, TIMI risk score greater than 5. Global mortality and cardiovascular outcomes were assessed at Day 7 and Day 30.

Results

The overall use of glycoprotein IIb/IIIa inhibitors was 16%. The procedure was successfully applied in 98%. Compared with non eligible patients (group 1, n = 254), eligible patients (group 2, n = 77) had a higher risk profile, median age: 73 versus 66, p < 0.01, TIMI risk score: 4 versus 3, p < 0.001. Eligible patients (66%) actually received the treatment. Among the 26 eligible but untreated patients, 19% had major bleeding risk, 34% had an unfavourable risk-benefit ratio and 34% were not suitable for an invasive strategy. Cardiovascular events occurred in 5.1% at Day 7 (Group 1, 1.6%), and 6.0% at Day 30 (group 1, 2.4%). Overall mortality at Day 30 was 1.2% (0.4% in Group 1).

Conclusion

A strategy for glycoprotein IIb/IIIa inhibitors administration in non ST-segment elevation acute coronary syndrome restricted to 4 very high risk situations may be considered, without evidence for a loss of chance in intermediate risk patients, untreated although eligible for treatment according to the current guidelines.     

Patients with acute coronary syndromes without persistent ST elevation undergoing percutaneous coronary intervention benefit most from early intervention with protection by a glycoprotein IIb/IIIa receptor blocker.

BACKGROUND: Many patients with acute coronary syndromes are offered percutaneous coronary intervention. However, the appropriate indications for, and optimal timing of, such procedures are uncertain. We analysed timing of intervention and associated events (death and myocardial infarction) in the PURSUIT trial in which 9461 patients received a platelet glycoprotein IIb/IIIa inhibitor, eptifibatide, or placebo for 72 h. Other treatment was left to the investigators. 2430 patients underwent percutaneous coronary intervention within 30 days. Four groups were distinguished, who underwent percutaneous coronary intervention on day 1; on days 2 or 3; at 4 to 7 days; or between 8 until 30 days, for eptifibatide- and placebo-treated patients. RESULTS: The four groups treated with placebo demonstrated total 30-day events of 15.9% for day 1 percutaneous coronary intervention, 17.7%, 15.0% and 18.2%, respectively, for successive intervals of later intervention. Later intervention was associated with more pre-procedural events (2.2% to 13.7%, P=0.001) which was balanced by a decrease in procedure-related events (12.1 to 3.1%, P=0.001), while the overall 30-day event rates were similar. Eptifibatide-treated patients with percutaneous coronary intervention on day 1 had the lowest rate of 30-day events (9.2%, P<0.05 vs other groups). In this group, pre-procedural risk was only 0.3%, while percutaneous coronary intervention on eptifibatide treatment was associated with low procedural risk (7.2%). The total 30-day event rate for later percutaneous coronary intervention in patients receiving eptifibatide was 14.0 on days 2 and 3, 15.0% for days 4 to 7 and 17.4% for days 7 to 30, respectively. CONCLUSION: Patients treated with a platelet glycoprotein IIb/IIIa receptor blocker, and early percutaneous coronary intervention (within 24 h) had the lowest event rate in this post hoc analysis. Thus 'watchful waiting' may not be the optimal strategy. Rather an early invasive strategy with percutaneous coronary intervention under protection of a platelet glycoprotein IIb/IIIa receptor blocker should be considered in selected patients. Randomized trials are warranted to verify this issue.