Platelet glycoprotein IIb/IIIa inhibitors

Glycoprotein (GP) IIb/IIIa inhibitors including abciximab, eptifibatide and tirofiban have been studied extensively as short-term adjuncts to short-term heparin and indefinite aspirin in patients with acute coronary syndrome or undergoing percutaneous coronary interventions on native vessels. The drugs provide a small advantage in the composite endpoint of death, myocardial infarction, and need for revascularization at 30 days (1-2% of treated patients) at the expense of an increase in major and potentially fatal bleeding complications (1% of treated patients over heparin plus aspirin alone). Highest-risk patients appear to benefit the most; clopidogrel should also be considered in these patients. Patients undergoing percutaneous interventions on bypass grafts do not benefit. Whether one GP IIb/IIIa inhibitor is superior to another is incompletely clarified. Abciximab causes severe immune-mediated thrombocytopenia (<20,000/microl) in 0.7% of cases; this is more often than eptifibatide or tirofiban (0.2%). Pseudothrombocytopenia should be differentiated. Effective use of GP IIb/IIIa inhibitors for acute coronary syndrome and percutaneous coronary interventions requires discerning clinical judgment. The value of GP IIb/IIIa inhibitors is not established in other forms of vascular disease.     

Noncardiac applications of glycoprotein IIb/IIIa inhibitors

Platelet activation and aggregation have become increasingly recognized as the primary processes involved in the cascade that leads to thrombus formation in atherosclerotic vascular disease. Glycoprotein IIb/IIIa receptor inhibitors (GPI) favorably impact thrombus formation and distal embolization by inhibiting the final common pathway of platelet aggregation. Glycoprotein IIb/IIIa inhibitors have been used effectively in a wide variety of clinical scenarios including unstable angina, non‐ST segment elevation myocardial infarction, ST segment elevation myocardial infarction, and low and high risk percutaneous coronary interventions with and without intracoronary stenting, however there is limited data regarding the use of these potent antiplatelet agents in the setting of extracardiac vascular disease. This article will review the non‐cardiac applications of glycoprotein IIb/IIIa inhibitors in the setting of acute ischemic stroke, carotid and vertebral angioplasty and stenting, acute critical limb ischemia, and percutaneous interventions in peripheral arterial occlusive disease. Catheter Cardiovasc Interv 2004;62:530–538. © 2004 Wiley‐Liss, Inc.     

Clinical trials of glycoprotein IIb/IIIa inhibitors

Glycoprotein (GP) IIb/IIIa inhibitors were developed to block platelet aggregation and potentially to abolish thrombus formation. Clinical trials have demonstrated that GP IIb/IIIa inhibitors are more potent antithrombotic agents than aspirin and heparin alone. GP IIb/IIIa inhibitors reduce short- and long-term complications of percutaneous revascularization. These agents also are effective as adjuncts to various treatment strategies for the management of patients with unstable angina (UA) or non-Q-wave myocardial infarction (NQMI). Furthermore, recent clinical trials with a small number of patients suggest that GP IIb/IIIa inhibitors in combination with low-dose fibrinolytics are safe and effective for the treatment of ST segment elevation myocardial infarction. The clinical trials of GP IIb/IIIa inhibitors summarized here examined different patient populations managed under different strategies. Moreover, these agents have different indications for clinical use and varying safety profiles.     

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.     

Thrombocytopenia after treatment with platelet glycoprotein IIb/IIIa inhibitors

Abciximab, eptifibatide, and tirofiban are the three drugs approved by the US Food and Drug Administration designed to block platelet aggregation by binding glycoprotein IIb/IIIa. Results from large therapeutic trials demonstrate that all three agents induce thrombocytopenia in approximately 1% to 5% of cardiac patients. Thrombocytopenia is typically rapid in onset and antibody mediated. In vitro evidence suggests abciximab-induced thrombocytopenia is associated with antibodies directed to murine sequences within the chimeric anti-IIb/IIIa molecule. In addition, abciximab, eptifibatide, and tirofiban also function as mixed agonist-antagonists in vivo, inducing neoepitopes within the glycoprotein IIb/IIIa receptor that may react with pre-existing or induced antibodies. Screening for the development of these antibodies may reduce the incidence of thrombocytopenia associated with these agents, but it may limit their chronic usage.     

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.     

Synthetic inhibitors of platelet glycoprotein IIb/IIIa in clinical development

Activation of the platelet glycoprotein (GP IIb/IIIa) receptor on the platelet surface is the final pathway of platelet aggregation, regardless of the initiating stimulus. Inhibitors of GP IIb/IIIa receptors include monoclonal antibodies (abciximab) against this receptor and peptidic and nonpeptidic synthetic specific receptor blockers. Abciximab exchanges between and binds to platelets for as long as 2 weeks, whereas synthetic GP IIb/IIIa inhibitors inhibit ex vivo platelet aggregation for only a few hours after the end of infusion, but some have the advantage of also being orally active. In the secondary prevention of atherothrombosis, large-scale trials were successfully conducted with aspirin, dipyridamole, ticlopidine, and clopidogrel. In the first large-scale trials with GP IIb/IIIa inhibitors, abciximab was investigated. In aggregate, synthetic GP IIb/IIIa inhibitors, combined with aspirin and heparin, were shown to reduce ischemic events in patients with high- and low-risk coronary intervention, stents, unstable angina, and non-Q-wave infarction. With short-term use of synthetic GP IIb/IIIa inhibitors, there is no suppression of clinical evident restenosis 6 months after the end of treatment. With the doses currently used, bleeding occurs more often with the synthetic GP IIb/IIIa inhibitors (used for 3 days) than with abciximab (used for 12 hours), but there are no direct comparisons between these drugs.     

Alveolar hemorrhage associated with platelet glycoprotein IIb/IIIa receptor inhibitors

Platelet glycoprotein IIb/IIIa receptor inhibitors have been shown to improve outcomes in percutaneous coronary interventions. Their use with multiple anticoagulants has been associated with increased bleeding complications. Among these, alveolar hemorrhage is a rare and potentially fatal complication. Six patients with this complication were identified over a four-year period. Patient characteristics, possible risk factors, pathophysiology, prevention and potential treatment options are discussed.     

Use of platelet glycoprotein IIb/IIIa inhibitors and spontaneous pulmonary hemorrhage

BACKGROUND: The use of platelet glycoprotein (GP) IIb/IIIa inhibitors in patients undergoing percutaneous coronary intervention has resulted in an impressive reduction in adverse events. Pulmonary hemorrhage is a rare but potentially lethal complication of antithrombotic and antiplatelet therapy. We analyzed the incidence of spontaneous pulmonary hemorrhage following the use of platelet GP IIb/IIIa inhibitors. METHODS: The medical records of 1,020 consecutive patients who received GP IIb/IIIa inhibitors and underwent PCI at our institution between August 1997 and December 1999 were reviewed. RESULTS: Diffuse pulmonary hemorrhage developed in 7 patients (0.68%), two of whom died. Five of 7 patients with pulmonary hemorrhage had activated clotting times > 250 seconds during the procedure. Activated partial thromboplastin time measured at the time of pulmonary hemorrhage was elevated in all patients (mean, 85 seconds; range, 69 95 seconds). All patients had history of congestive heart failure and had elevated pulmonary capillary wedge pressure and/or left ventricular end-diastolic pressure at the time of the index procedure. Six patients also had evidence of baseline radiographic abnormalities. CONCLUSION: Diffuse pulmonary hemorrhage is a potentially disastrous complication of GP Ilb/Illa antagonists. No specific predictors can be identified, but evidence of pulmonary congestion, baseline pulmonary abnormalities and use of higher heparin dosages may predispose patients to this serious complication.     

The use of glycoprotein IIb/IIIa inhibitors in patients with coronary artery disease

Platelet membrane glycoprotein IIb/IIIa inhibitors, a new class of potent antiplatelet agents, have been used in the treatment of acute coronary syndromes as well as in the prevention of complications after percutaneous coronary interventions. Approximately 50,000 patients with coronary artery disease have been enrolled in randomized studies of glycoprotein IIb/IIIa inhibitors. The purpose of this article is to review the pharmacology of glycoprotein IIb/IIIa inhibitors, the results of the clinical trials using these agents, and their current use in percutaneous coronary interventions and the treatment of acute coronary syndromes.