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.     

Meta-analysis of randomized trials of glycoprotein IIb/IIIa inhibitors in high-risk acute coronary syndromes patients undergoing invasive strategy

It is still unknown whether upstream administration of glycoprotein (Gp) IIb/IIIa inhibitors, aiming at cooling the culprit lesion before angioplasty, is superior to its selective downstream administration in high-risk patients with acute coronary syndromes (ACSs) undergoing coronary angioplasty. Therefore, the aim of the present study was to perform a meta-analysis of randomized trials comparing upstream to downstream administration of Gp IIb/IIIa inhibitors in high-risk patients with ACS undergoing early invasive strategy. We obtained results from all randomized trials on this issue. The literature was scanned by formal searches of electronic databases from January 1990 to March 2010. The following key words were used: "randomized trial," "myocardial infarction," "ACS," "coronary angioplasty," "upstream," "downstream," "Gp IIb/IIIa inhibitors," "abciximab," "tirofiban," and "eptifibatide." Primary and secondary clinical end points were mortality and myocardial infarction at 30 days, respectively. Major bleeding complications were assessed as a safety end point. Seven randomized trials were included in the meta-analysis, involving 19,929 patients (9,981 or 50.0% in the upstream Gp IIb/IIIa inhibitors group and 9,948 or 50% in the downstream Gp IIb/IIIa inhibitors group). Upstream Gp IIb/IIIa inhibitors did not decrease 30-day mortality (2.0% vs 2.0%, p = 0.84) or recurrence of myocardial infarction (7.0% vs 7.6%, p = 0.11) but were associated with higher risk of major bleeding complications (1.8% vs 1.3%, p = 0.0002). In conclusion, this meta-analysis shows that in high-risk patients with ACS undergoing an early invasive strategy, upstream administration of Gp IIb/IIIa inhibitors does not improve clinical outcome compared to a downstream selective administration, and it is associated with an increased risk of major bleeding complications. Therefore, a strategy of upstream Gp IIb/IIIa inhibitors cannot be recommended.     

Role of glycoprotein IIb/IIIa inhibitors in the management of acute coronary syndromes

Antiplatelet therapy is a cornerstone in the medical management of acute coronary syndromes. Three classes of antiplatelet drugs are available in this setting: acetylsalicylic acid, thienopyridines, and glycoprotein IIb/IIIa antagonists. During the last ten years, numerous clinical trials have been conducted in large populations of patients suffering from acute coronary syndromes. Further investigations are in progress. In the light of these results, the respective roles of the different antiplatelet drugs have been more precisely defined, in terms of class preference as well as in terms of the combination of several antiplatelet drugs and of antiplatelet drugs with other therapies, including non fractionated--or low molecular weight--heparin and non-invasive or invasive revascularisation procedures. In the present article, we review the results of the major published or non published trials that addressed the role of glycoprotein IIb/IIIa antagonists in the management of acute coronary syndromes. Based on these results, the current therapeutic guidelines for clinical practice issued by the American and European cardiology societies are given in the conclusion, with their level of evidence.     

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.     

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.     

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.     

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.     

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.     

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.     

Evaluating the benefits of glycoprotein IIb/IIIa inhibitors in heart failure at baseline in acute coronary syndromes

Background

We evaluated whether the use of glycoprotein IIb/IIIa receptor inhibitors, in addition to heparin and aspirin, imparts an incremental benefit in a subgroup of patients with acute coronary syndromes (ACS) who had congestive heart failure (CHF) symptoms at presentation.

Methods

We analyzed patients enrolled in the Platelet IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) trial, a randomized, double-blind, placebo-controlled study evaluating the use of eptifibatide versus placebo for patients with ACS without persistent ST-elevation. We compared the clinical characteristics and 30-day outcomes for 861 patients who had Killip class II or III CHF symptoms with those of 8558 patients who had no CHF symptoms.

Results

Odds ratios for the primary end point, 30-day death or non-fatal myocardial infarction, in the placebo group versus the eptifibatide group were similar for patients with and without CHF (odds ratio, 1.11; 95% CI, 0.8-1.5; odds ratio, 1.13; 95% CI, 1.0-1.3). However, adverse events were almost twice as frequent for patients with CHF compared with patients with no CHF (24.5% vs 14%).

Conclusions

Although patients with non-ST-segment elevation ACS who have CHF have markedly worse outcomes than patients without CHF symptoms, we did not find an incremental benefit from the use of eptifibatide in this seriously ill subgroup.     

Emergency coronary artery bypass grafting in patients with acute myocardial infarction treated with glycoprotein IIb/IIIa receptor inhibitors

Glycoprotein (GP) IIb/IIIa receptor inhibitors before primary angioplasty in patients with ST-elevation acute myocardial infarction (STEMI) are recommended by current guidelines. Thus, an increasing number of patients receive these drugs before coronary angiography, particularly if a between-hospital transfer is needed. However, when coronary anatomy is unsuitable for angioplasty, emergency coronary artery bypass grafting (CABG) under GP IIb/IIIa inhibitor treatment may be needed, with a potential increase in bleeding risk. Abciximab has a long duration of action, because of its high-affinity binding to GP IIb/IIIa receptors. Initial retrospective studies reported a higher incidence of major bleeding during emergency CABG after abciximab administration, leading to the recommendation of delaying surgery >12 h. However, data from the prospective trials on abciximab do not confirm the increase in bleeding risk, and current evidence shows that emergency surgery can be performed safely soon after abciximab cessation. Monitoring of activated clotting time during surgery and platelet transfusion in case of postoperative relevant bleeding are the only measures needed. No data are available on emergency surgery in patients with STEMI treated with eptifibatide or tirofiban. However, their short-lasting effects and the results of trials on non-ST-elevation acute coronary syndromes suggest that they could even reduce postoperative bleeding by preventing platelet consumption during cardiopulmonary bypass. In conclusion, the early administration of GP IIb/IIIa inhibitors, in particular of abciximab, in patients with STEMI in whom primary angioplasty is planned should not be discouraged because of the potential bleeding risk in case of emergency CABG.     

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 inhibitors in coronary artery disease

BACKGROUND: Inhibition of platelet activity at the injured coronary plaque is a target for novel therapeutic strategies. One of these mechanisms is the blockade of the platelet surface membrane glycoprotein (GP) IIb/IIIa receptor, which binds circulating fibrinogen or von Willebrand factor and crosslinks platelets as the final common pathway to platelet aggregation. Intravenous agents directed against this receptor include the chimeric monoclonal antibody fragment abciximab, the peptide inhibitor eptifibatide and nonpeptide mimetics tirofiban and lamifiban. RESULTS: During percutaneous coronary intervention, an absolute reduction of 1.5-6.5% in the 30-day risk of death, myocardial infarction or repeat urgent revascularization has been observed, with some variability in treatment effect among the agents tested. Treatment effect is achieved early with every modality of revascularization and maintained over the long-term up to 3 years. Increased bleeding risk may be minimized by reduction and weight adjustment of concomitant heparin dosing. In the acute coronary syndromes without ST segment elevation, absolute 1.5-3.2% reductions in 30-day rates of death or myocardial infarction have been achieved with 2- to 4-day courses of eptifibatide or tirofiban. Clinical benefit accrues during the period of drug infusion and is durable. Treatment effect may be enhanced among patients undergoing early coronary revascularization, with evidence of stabilization before intervention and suppression of postprocedural ischemic events. CONCLUSION: Thus, blockade of the platelet GP IIb/IIIa receptor reduces ischemic complications when used as an adjunct to percutaneous coronary intervention or the management of acute ischemic syndromes.