Lotrafiban: an oral platelet glycoprotein IIb/IIIa blocker

Platelets play a major role in thrombus formation, as well as in the pathogenesis of atherothrombosis. Inhibition of platelet function is now emphasised more than ever for prevention and treatment of almost all vascular diseases, since thrombosis is established as the key pathogenic event causing acute ischaemic coronary and cerebrovascular syndromes. Although acetylsalicylic acid (aspirin) has been shown to reduce the incidence of myocardial infarction and stroke, its effect is weak and more effective antithrombotic agents are required to manage patients at high-risk for recurrent vascular events. Platelet glycoprotein IIb/IIIa receptor (GPIIb/IIIa) blockade represents a significant advance in interventional cardiology and treatment of acute ischaemic syndromes. The past several years have seen the introduction of many platelet GPIIb/IIIa blockers into the clinical arena targeting the unique platelet GPIIb/IIIa receptor for the adhesive proteins, fibrinogen and von Willebrand Factor. Platelet GPIIb/IIIa blockers administered intravenously have proven efficacious in mitigating arterial thrombosis in acute coronary syndromes (unstable angina and non-ST-elevation myocardial infarction) and percutaneous coronary interventions (PCI) such as balloon dilatation and stent implantation. Currently, orally-active platelet GPIIb/IIIa blockers are being developed to provide additional benefits for primary and secondary prevention of thrombosis as chronic treatment, especially in high-risk patients. Lotrafiban (SmithKline Beecham) is a member of the latest generation of orally-active platelet GPIIb/IIIa blockers undergoing Phase III clinical trials to test the relative effectiveness versus other oral platelet inhibitors for ischaemic conditions including unstable angina, restenosis after PCI and stroke. Lotrafiban is converted from an esterified prodrug by plasma and liver esterases to a peptidomimetic of the arginine-glycine-aspartic acid amino acid sequence. This sequence itself mimics the binding site of fibrinogen and von Willebrand Factor to the platelet GPIIb/IIIa receptor. Preliminary results of the clinical trial APLAUD (antiplatelet useful dose) show that lotrafiban is clinically safe and well-tolerated in patients with recent myocardial infarction, unstable angina, transient ischaemic attack (TIA), or stroke when added to aspirin therapy. With lotrafiban, a worldwide large-scale Phase III clinical trial BRAVO (blockage of the GPIIb/IIIa receptor to avoid vascular occlusion) is currently underway. In general, GPIIb/IIIa blockade seems clinically very promising. A number of unresolved issues, however, remain to be elucidated.     

Tirofiban: an investigational platelet glycoprotein IIb/IIIa receptor antagonist

The deposition of a platelet rich thrombus on an atherosclerotic plaque is a critical step in the development of unstable coronary syndromes. Currently available therapeutic agents such as aspirin and ticlopidine are relatively weak inhibitors of platelet aggregation. Recently, antagonists to platelet glycoprotein IIb/IIIa (GPIIb/IIIa), a platelet surface integrin whose activation and subsequent binding to fibrinogen is the final common step in the formation of platelet aggregates, have been utilised to treat unstable angina and myocardial infarction. Tirofiban is a novel, specific, low molecular weight GPIIb/IIIa receptor antagonist, which competitively inhibits the platelet fibrinogen receptor. Tirofiban is administered as an intravenous infusion with a mean half-life of 1.6 h. In healthy volunteers, the plasma concentration and half-life of tirofiban are unaffected by pre-treatment with aspirin, although aspirin increases the bleeding time prolongation caused by tirofiban. Tirofiban is excreted by both renal (37%) and non renal mechanisms. Three clinical trials, PRISM, PRISM PLUS, and RESTORE, have evaluated the safety and efficacy of tirofiban in unstable angina and in high-risk percutaneous transluminal coronary angioplasty (PTCA). When compared to heparin in the management of unstable angina, tirofiban decreased the odds of recurrent ischaemia, myocardial infarction, or death by 36% at 48 h, and death by 39% at 30 days. Similarly, the addition of tirofiban to heparin reduced the odds of recurrent ischaemic events for death at 7 days by 34%. RESTORE, a clinical trial evaluating the efficacy and safety of tirofiban in patients undergoing PTCA within 72 h of presentation with unstable angina or myocardial infarction, demonstrated a 38% reduction in a composite end-point at 48 h; the need for urgent PTCA and coronary artery bypass graft (CABG) at 30 days was reduced by 36%. Adverse side-effects, including major bleeding, were not significantly higher with tirofiban treatment. Tirofiban and other GPIIb/IIIa inhibitors represent a major advance in the treatment of unstable coronary syndromes and high-risk PTCA.     

Clinical trials with glycoprotein IIb/IIIa antagonists - No benefit without bleeding?

As the glycoprotein GPIIb/IIIa receptor is the final common pathway in platelet aggregation, antagonists of this receptor cause a profound inhibition of aggregation induced by any agonist. The short-term efficacy and safety of GPIIb/IIIa antagonists in patients undergoing coronary angioplasty was demonstrated with murine 7E3 Fab, but this antibody was immunogenic. Abciximab is a chimeric human-mouse monoclonal antibody that is less immunogenic. The first major trial with a GPIIb/IIIa antagonist was the EPIC trial with abciximab, which showed that abciximab reduced the ischemic complications of coronary balloon angioplasty and atherectomy in high-risk patients, but increased the risk of bleeding. Subsequent studies showed that using less concurrent heparin reduced bleeding. Abciximab also reduced the rate of revascularization. Further studies have shown that the benefits of abciximab extended to all patients undergoing angioplasty (EPILOG), including patients with unstable angina (CAPTURE) and acute myocardial infarction (RAPPORT). Clinical trials with eptifibatide and tirofiban have failed to demonstrate benefit, at the doses used, in angioplasty. Abciximab and eptifibatide, but not oral xemilofiban, improve the safety of the coronary stenting procedure. Short-term intravenous treatment with lamifiban, eptifibatide or tirofiban is beneficial in acute coronary syndromes (unstable angina, non-Q wave myocardial infarction). Orally active GPIIb/IIIa antagonists are being developed for use in acute coronary syndromes and myocardial infarction. However, no benefit has been shown with lefradafiban in acute coronary syndromes and sibrafiban and orbofiban are harmful. Eptifibatide, lamifiban and abciximab improve coronary patency in myocardial infarction, and long- term trials of GPIIb/IIIa antagonists are being conducted in acute myocardial infarction. Abciximab can cause thrombocytopenia, and all the GPIIb/ IIIa antagonists increase the incidence of bleeding, but there is no excess of intracranial hemorrhage. (c) 2001 Prous Science. All rights reserved.     

Xemilofiban Searle and Co

Xemilofiban is an orally-active antiplatelet agent (GPIIb/IIIa receptor antagonist) under development by Searle for the potential use in preventing thrombotic complications, following percutaneous transluminal coronary angioplasty (PTCA). It is in phase III clinical trials in the US for thrombosis and phase I trials in Japan for peripheral vascular disease. The potential cardiovascular benefits of xemilofiban are being evaluated in a worldwide, phase III trial, EXCITE (Evaluation of oral Xemilofiban in Controlling Thrombotic Events). Approximately 7200 patients who are undergoing angioplasty or stent placement will be enrolled. The trial will assess whether six months of treatment will reduce clot-related cardiac events, such as heart attack and death, and the need for revascularization procedures [268912]. Results of the phase II ORBIT trial in 549 angioplasty patients, demonstrated that four-week therapy with xemilofiban inhibited platelet aggregation by 50 to 80% [268911]. Phase I studies in Japan were completed in patients undergoing coronary revascularization, including stents and PTCA, for acute myocardial infarction (AMI) and for unstable angina [182809]. Sankyo is conducting the development in Japan, under a license agreement [181803]. Xemilofiban has been included in the ISIS-6 trial which will evaluate its efficacy and safety in heart attack patients following thrombolysis [182809]. Preliminary studies have shown that oral xemilofiban produces a rapid inhibition of ADP and collagen-induced platelet aggregation [182809]. Its mechanism of action results in potent inhibition of platelet aggregation in response to all stimuli. It acts as the ethyl ester prodrug of SC-54701, which is a potent (IC(50) = 0.035 mM) and selective inhibitor of GPIIb/IIIa. Xemilofiban is expected to be launched in 2000 for angioplasty, and a year later for unstable angina and AMI [220816].     

Section Review: Cardiovascular & Renal: Novel antiplatelet agents: The glycoprotein IIb/IIIa inhibitors

Platelets have been shown to play a significant role in the pathophysiology of acute coronary syndromes and the complications associated with percutaneous coronary intervention (abrupt closure and long-term restenosis). Recent efforts to inhibit platelets more fully have led to the discovery of a new class of platelet antagonists, the glycoprotein IIb/IIIa receptor inhibitors. These agents block the final common pathway for platelet aggregation and are, therefore, more potent than aspirin. Animal data and small clinical trials suggest that these platelet inhibitors may be beneficial in a variety of cardiovascular disease states; large, Phase III trials evaluating these agents in myocardial infarction, unstable angina, and percutaneous transluminal coronary angioplasty are in progress. This review will focus on the biology of the platelet glycoprotein IIb/IIIa receptor, its inhibitors developed to date, and the clinical trials (completed and in progress) in this area.     

Eptifibatide: a potent inhibitor of the platelet receptor integrin,glycoprotein IIb/IIIa

Platelet aggregation is intimately involved in the pathophysiology of acute coronary syndromes. Blockade of the platelet glycoprotein IIb/IIIa receptor, the mediator of platelet aggregation induced by all physiologic agonists, prevents arterial thrombosis in animal models far more effectively than aspirin. Eptifibatide (Integrilin ?) is a rapidly reversible competitive inhibitor of glycoprotein IIb/IIIa studied in a broad range of ischaemic coronary conditions, including percutaneous coronary intervention, ST-segment and non-ST-segment acute myocardial infarction and unstable angina. In each case, therapy with eptifibatide has reduced acute ischaemic complications without any increased risk of life-threatening bleeding or adverse events. Based on data from the Integrelin to Minimize Platelet Aggregation and Coronary Thrombosis (IMPACT) II study, a salutary benefit in the range of a 20 - 25% reduction in adverse clinical events can be expected in patients undergoing coronary intervention. Few significant pharmacological effects other than inhibition of platelet aggregation and the effect on bleeding time have been reported. Future research will focus on alternative doses, infusion regimens and combinations with other therapies to improve further cardiovascular outcomes.     

Eptifibatide: a potent inhibitor of the platelet receptor integrin, glycoprotein IIb/IIIa

Platelet aggregation is intimately involved in the pathophysiology of acute coronary syndromes. Blockade of the platelet glycoprotein IIb/IIIa receptor, the mediator of platelet aggregation induced by all physiologic agonists, prevents arterial thrombosis in animal models far more effectively than aspirin. Eptifibatide (Integrilintrade mark) is a rapidly reversible competitive inhibitor of glycoprotein IIb/IIIa studied in a broad range of ischaemic coronary conditions, including percutaneous coronary intervention, ST-segment and non-ST-segment acute myocardial infarction and unstable angina. In each case, therapy with eptifibatide has reduced acute ischaemic complications without any increased risk of life-threatening bleeding or adverse events. Based on data from the Integrelin to Minimize Platelet Aggregation and Coronary Thrombosis (IMPACT) II study, a salutary benefit in the range of a 20 - 25% reduction in adverse clinical events can be expected in patients undergoing coronary intervention. Few significant pharmacological effects other than inhibition of platelet aggregation and the effect on bleeding time have been reported. Future research will focus on alternative doses, infusion regimens and combinations with other therapies to improve further cardiovascular outcomes.     

Targeting the platelet integrin GPIIb/IIIa

The platelet integrin GPIIb/IIIa plays an essential role in thrombus formation through interactions with adhesive ligands and has emerged as a primary target for the development of anti-thrombotic agents. Receptor activation is under strict control, with activators, inhibitors, and signalling mechanisms controlling its conformation. Structural biology research has produced high-resolution images defining the ligand binding site at the atomic level. Successful blockade of this ligand binding has validated GPIIb/IIIa as a therapeutic target in cardiovascular medicine. GPIIb/IIIa inhibitors were the first rationally designed anti-platelet agents and have been used effectively in a wide variety of clinical scenarios including unstable angina, myocardial infarction, and high risk percutaneous coronary interventions with and without intracoronary stenting. Three inhibitors (abciximab, eptifibatide, and tirofiban) are currently licensed for human use. Surprisingly, oral GPIIb/IIIa antagonists have not been successful and there is an unmet need for effective anti-GPIIb/IIIa drugs that cause less bleeding problems and that can be orally applied. Here we review our current knowledge about GPIIb/IIIa structure, signalling pathways and receptor function, the benefits and limitations of current GPIIb/IIIa blockers and we take a look forward how the lessons learned from the mixture of success and failure of GPIIb/IIIa blocker development can be transformed in new and better GPIIb/IIIa blockers.     

Abciximab (Reopro): a clinically effective glycoprotein IIb/IIIa receptor blocker

Acute coronary syndromes are responsible for the deaths of tens of thousands of patients every year. Rupture of coronary atheromatous plaques with resultant luminal thrombosis is the cause in most cases. Although great steps forward have been taken in the management of acute myocardial infarction (MI) and unstable angina (UA), new therapeutic strategies are required to reduce further the incidence and risk of these events. At present, aspirin, nitrates and heparin are the conventional treatments for unstable angina. Aspirin, in combination with a thrombolytic agent or with percutaneous transluminal coronary angioplasty (PTCA), has been shown to be effective in reducing mortality in acute MI. Heparin is conventionally used in all PTCA procedures, whereas its efficacy in enhancing the therapeutic role of thrombolytic agents remains uncertain and may depend on the thrombolytic agent used. PTCA, which is also an effective therapy for stable angina, can be complicated by intimal dissection and thrombosis in a minority of cases, with vessel restenosis leading to recurrent symptoms in approximately 30% of cases. A number of new agents are being evaluated in both acute coronary syndromes and PTCA. These can be classified as adenosine diphosphate (ADP) receptor antagonists, Factor Xa inhibitors (low-molecular weight heparin [LMWH], direct thrombin inhibitors, new thrombolytic agents and glycoprotein IIb/IIIa receptor blockers. Of the latter, the most studied is abciximab, the Fab fragment of the chimeric monoclonal antibody, 7E3. This is a potent inhibitor of platelet aggregation. Four major clinical studies of PTCA in high-risk patients have demonstrated clear efficacy of abciximab in reducing acute ischaemic complications, mainly by reducing the frequency of MI and the need for repeat revascularisation. Unlike other glycoprotein IIb/IIIa receptor blockers, both short- and long-term efficacy have been demonstrated. Its impact on the rate of restenosis after PTCA is unclear. Abciximab's role in an era of intracoronary stent implantation is undergoing further study (with encouraging early results). Its role in other situations, such as the early (non-angioplasty) management of unstable angina and its ability to enhance the efficacy of thrombolytic agents, is under active investigation.     

Abciximab (Reopro): a clinically effective glycoprotein IIb/IIIa receptor blocker

Acute coronary syndromes are responsible for the deaths of tens of thousands of patients every year. Rupture of coronary atheromatous plaques with resultant luminal thrombosis is the cause in most cases. Although great steps forward have been taken in the management of acute myocardial infarction (MI) and unstable angina (UA), new therapeutic strategies are required to reduce further the incidence and risk of these events. At present, aspirin, nitrates and heparin are the conventional treatments for unstable angina. Aspirin, in combination with a thrombolytic agent or with percutaneous transluminal coronary angioplasty (PTCA), has been shown to be effective in reducing mortality in acute MI. Heparin is conventionally used in all PTCA procedures, whereas its efficacy in enhancing the therapeutic role of thrombolytic agents remains uncertain and may depend on the thrombolytic agent used. PTCA, which is also an effective therapy for stable angina, can be complicated by intimal dissection and thrombosis in a minority of cases, with vessel restenosis leading to recurrent symptoms in approximately 30% of cases. A number of new agents are being evaluated in both acute coronary syndromes and PTCA. These can be classified as adenosine diphosphate (ADP) receptor antagonists, Factor Xa inhibitors (low-molecular weight heparin [LMWH], direct thrombin inhibitors, new thrombolytic agents and glycoprotein IIb/IIIa receptor blockers. Of the latter, the most studied is abciximab, the Fab fragment of the chimeric monoclonal antibody, 7E3. This is a potent inhibitor of platelet aggregation. Four major clinical studies of PTCA in high-risk patients have demonstrated clear efficacy of abciximab in reducing acute ischaemic complications, mainly by reducing the frequency of MI and the need for repeat revascularisation. Unlike other glycoprotein IIb/IIIa receptor blockers, both short- and long-term efficacy have been demonstrated. Its impact on the rate of restenosis after PTCA is unclear. Abciximab’s role in an era of intracoronary stent implantation is undergoing further study (with encouraging early results). Its role in other situations, such as the early (non-angioplasty) management of unstable angina and its ability to enhance the efficacy of thrombolytic agents, is under active investigation.     

The antithrombotic efficacy of lotrafiban (SB 214857) in canine models of acute coronary thrombosis

In patients with acute coronary syndromes, inhibition of platelet aggregation with parenteral alpha(IIb)/beta(III) antagonists has proven effective at preventing nonfatal myocardial infarction and repeat percutaneous coronary interventions. Paradoxically, the efficacy observed for acute indications and parenteral agents has not extended to oral agents and chronic prevention of secondary thrombotic events, despite robust antithrombotic properties in preclinical thrombosis models. This report documents the preclinical data of Lotrafiban, an oral alpha(IIb)/beta(III) antagonist that recently failed in a phase III clinical trial (BRAVO) for the prevention of secondary thrombosis. Lotrafiban was characterized in a dog circumflex artery electrical injury model, and a cyclic flow reduction model ("Folts"). The data demonstrate that both oral (1.0-50.0 mg/kg) and intravenous (0.1-0.8ug/kg/min) administration of lotrafiban produced dose-related inhibition (45%-95%) of ex vivo platelet aggregation. In the electrical injury model, the dose-related inhibition correlated with a significant reduction in the frequency of coronary occlusion, size of the developing thrombus, and the extent of left ventricular ischemic damage. Effects on blood flow and bleeding time were also dose related. The combination of low dose lotrafiban (0.1ug/kg/min) and aspirin (5.0 mg/kg) generated additive antithrombotic effects, approximating the antithrombotic efficacy of a 2-4 fold higher dose of lotrafiban while only modestly prolonging the bleeding time. For purposes of comparison, the ADP receptor antagonist clopidogrel was also assessed in the electrical injury model. Clopidogrel (5.0-10.0 mg/kg, iv.) significantly reduced the resulting left ventricular infarct areas, but lacked the overall efficacy of lotrafiban. In the "Folts" model, lotrafiban inhibited cyclic blood flow reductions (CFR's) by 100% in animals insensitive to the antithrombotic effects of aspirin. Overall, the preclinical data demonstrated that alpha(IIb)/beta(III) antagonism with lotrafiban was a well tolerated and effective strategy for attenuating acute arterial thrombosis. The lack of a correlation between these preclinical data and the outcome of the clinical trial BRAVO are unexplained. However, the combined evidence suggests that these acute canine thrombosis studies may not completely capture the pathology reflected in chronic human atherothrombotic disease.     

Platelet glycoprotein IIb/IIIa receptor antagonists

The molecular understanding of platelet function, together with an appreciation of the role of platelet thrombus in the pathogenesis of acute coronary syndromes (ACS) and abrupt vessel closure following coronary intervention, lead to the development of the class of agents now referred to as platelet glycoprotein IIb/IIIa (GP IIb/IIIa) inhibitors. Currently three parenteral GP IIb/IIIa inhibitors are licensed for use in patients undergoing coronary intervention or as empirical therapy in non-ST elevation ACS (unstable angina and non-Q wave myocardial infarction). Clinical trials using these agents in patients undergoing coronary interventions have demonstrated a consistent reduction in ischaemic end points at 30 days that is sustained during long-term follow-up. Similar benefits have been found in patients with ACS who are managed medically or who proceed to revacularisation. Studies using prolonged platelet inhibition using oral GP IIb/IIIa inhibitors in patients following coronary intervention or with ACS have produced disappointing results. Further investigation with existing and newer oral agents are ongoing. The use of GP IIb/IIIa inhibitors in combination with fibrinolytic agents for optimal reperfusion in patients with acute ST-elevation myocardial infarction (MI) is an active area of interest. Angiographic outcomes with this approach have been encouraging and clinical outcome data are awaited. Beyond efficacy, GP IIb/IIIa inhibitors have proven to be safe for clinical use. Haemorrhagic complications and thrombocytopenia are the most common adverse events, though infrequent. Unresolved issues regarding drug dosing, monitoring of effect, duration of therapy, head-to-head comparisons of agents, and use of adjunctive therapies are the subject of ongoing studies.     

Role of platelet glycoprotein polymorphisms in cardiovascular diseases

Atherothrombosis is the leading cause of death in western countries. Major complications of atherothrombotic disease, which are responsible for a large burden of morbidity and mortality, are acute coronary syndromes, ischemic stroke, and peripheral occlusive disease. Plaque rupture, platelet adhesion, aggregation, and thrombosis may lead to unstable angina and may progress to myocardial infarction as well as to ischemic stroke. Platelet membrane glycoprotein receptors mediate crucial reactions in acute thrombosis and chronic processes of atherogenesis. The platelet glycoprotein GP IIb/IIIa, which is the most abundant platelet receptor, also represents the drug target of a novel class of anti-platelet drugs, which includes abciximab, tirofiban, and eptifibatide. The genes encoding the three major platelet glycoprotein receptors (GP Ib/IX/V, GP Ia/IIa, and GP IIb/IIIa) are subject to considerable genetic variability. This paper reviews how polymorphisms in the platelet glycoprotein receptors affect platelet function, susceptibility to atherothrombosis and its major complications including myocardial infarction, stroke, and complications following percutaneous coronary interventions, and individual variability of drug response. Recent data on platelet glycoprotein receptor polymorphisms as modifiers of drug action and as predictors of drug response offer the perspective of individualized drug treatment. Prospective studies will show whether this approach is useful or not. As the data reviewed here show clearly, future clinical trials should routinely take into account genetic susceptibility factors and modifiers, both for study design and for predefined patient stratification.Abbreviations ACS Acute coronary syndrome - CI Confidence interval - DCA Directional coronary atherectomy - GP Glycoprotein - MACE Major adverse cardiac event - MI Myocardial infarction - PCI Percutaneous coronary intervention - PTCA Percutaneous transluminal coronary angioplasty - RR Relative risk - SCD Sudden cardiac death - VWF Von Willebrand factor     

Recent advances in antiplatelet agents

Platelet aggregation plays a key role in the pathogenesis of thromboembolic diseases such as myocardial infarction, stroke, unstable angina and peripheral artery disease. Until recently, aspirin was the only antiplatelet agent available to prevent or treat these events. Over the past several years, there has been a substantial expansion in the antiplatelet armamentarium as well as in the understanding of the clinical importance of antiplatelet therapy in limiting the complications of thrombosis. Aspirin was one of the first agents to be adopted and it remains as the standard therapy with the higher amount of available clinical information. Following aspirin, ADP receptor antagonists like ticlopidine and clopidogrel as well as phosphodiesterase inhibitors dipyridamole and cilostazol have been introduced. Glycoprotein (GP) IIb/IIIa receptor antagonists like eptifibatide, tirofiban and abciximab are the newer antiplatelet agents which act at the end of the common pathway of platelet aggregation. Although results of clinical studies with the first oral GPIIb/IIIa antagonists were disappointing, agents of the new generation might expand the potential application of GPIIb/IIIa targeted therapy. This review will highlight recent advances in the development of aspirin, phosphodiesterase inhibitors, ADP receptor antagonists and the platelet glycoprotein IIb/IIIa inhibitors. The emphasis of this paper has been placed on the chemical aspects of these agents.     

Bleeding complications with glycoprotein IIb/IIIa inhibitors

The new class of antiplatelet drugs, the GPIIb/IIIa inhibitors, has proven to be effective in acute coronary syndromes including unstable angina and myocardial infarction as well as adjunct therapy for coronary interventions for preventing morbidity and mortality. As these drugs inhibit the final common pathway of platelet activation, effectively blocking the platelet aggregation response, potential bleeding is a concern with their use. The risk of bleeding has been demonstrated to be higher in patients treated with combination drug therapy (heparin, aspirin, thienopyridines, thrombolytics, oral anticoagulants), when antithrombotic drugs are not given on an individual weight basis and with late removal of vascular access sheaths. The early clinical trials have defined modifications in patient management that have effectively reduced bleeding. Pooled data from the more recent clinical trials, mostly in coronary intervention enrolling over 27,000 patients, show a bleeding rate of 3.6% in the drug group and 2.3% in the placebo group. Although this is acceptable, several unresolved issues remain to be addressed regarding the GPIIb/IIIa inhibitors. Thrombocytopenia occurs infrequently with all GPIIb/IIIa inhibitors but can be severe. The use of these drugs by oral administration presents new challenges with determining optimal dosing, drug-drug interactions and long-term effects. Incorporating point-of-care monitoring may enable better titration of these drugs to avoid bleeding complications. GPIIb/IIIa inhibitors are destined to become a mainstay therapy for cardiovascular treatment and over time these issues should be resolved.     

Future therapies for the prevention and treatment of venous and arterial thrombosis

The incidence of thrombosis as a complication of invasive surgery, in cancer patients, as a cause or complication of stroke, acute myocardial infarction (AMI), thrombolysis, unstable angina (UA) or angioplasty is substantial. To better serve this patient population in the prevention and prophylaxis of thrombosis, new types of anticoagulant drugs are under development by the pharmaceutical industry. The goal of these efforts are orally-active anticoagulants with specificity and pharmacokinetic properties that could translate into better control of anticoagulation and thrombosis and less bleading liability compared to the currently used anticoagulants: heparin, the low molecular weight heparins and warfarin. Various approaches for which there is a great deal of activity include: tissue factor/Factor VIIa inhibitors, Factor Xa inhibitors, thrombin inhibitors, glycoprotein IIb/IIIa antagonists. There is also interest in Factor IXa inhibitors, thrombin receptor antagonists and inhibitors of plasminogen activator inhibitor-1.     

Platelet glycoprotein IIb/IIIa receptor antagonists

The molecular understanding of platelet function, together with an appreciation of the role of platelet thrombus in the pathogenesis of acute coronary syndromes (ACS) and abrupt vessel closure following coronary intervention, lead to the development of the class of agents now referred to as platelet glycoprotein IIb/IIIa (GP IIb/IIIa) inhibitors. Currently three parenteral GP IIb/IIIa inhibitors are licensed for use in patients undergoing coronary intervention or as empirical therapy in non-ST elevation ACS (unstable angina and non-Q wave myocardial infarction). Clinical trials using these agents in patients undergoing coronary interventions have demonstrated a consistent reduction in ischaemic end points at 30 days that is sustained during long-term follow-up. Similar benefits have been found in patients with ACS who are managed medically or who proceed to revacularization. Studies using prolonged platelet inhibition using oral GP IIb/IIIa inhibitors in patients following coronary intervention or with ACS have produced disappointing results. Further investigation with existing and newer oral agents are ongoing. The use of GP IIb/IIIa inhibitors in combination with fibrinolytic agents for optimal reperfusion in patients with acute ST-elevation myocardial infarction (MI) is an active area of interest. Angiographic outcomes with this approach have been encouraging and clinical outcome data are awaited. Beyond efficacy, GP IIb/IIIa inhibitors have proven to be safe for clinical use. Haemorrhagic complications and thrombocytopenia are the most common adverse events, though infrequent. Unresolved issues regarding drug dosing, monitoring of effect, duration of therapy, head-to-head comparisons of agents, and use of adjunctive therapies are the subject of ongoing studies.     

Glycoprotein IIb/IIIa antagonists in acute ischaemic stroke: current status and future directions

Glycoprotein (GP) IIb/IIIa receptors on the surface of platelets play a critical role in thrombosis. Intravenous GP IIb/IIIa antagonists abciximab, tirofiban and eptifibatide have demonstrated efficacy in acute coronary syndromes when combined with heparin, aspirin, clopidogrel and percutanous coronary interventions. Results have been less consistent in acute ischaemic stroke. Preclinical data support the potential benefit of these agents both in the microcirculation and in aiding clot lysis. While phase I and II trials of abciximab as the sole agent employing dosages comparable with those used in coronary syndromes were promising, the pivotal phase III trial was abandoned because of an unfavourable benefit-to-risk ratio. New preliminary platelet inhibition measurements from our group suggest that cardiac dosages were likely to be too high for stroke patients. Exploration of lower dosages of abciximab and potentiation with time-limited weight-based heparin along with platelet aggregation inhibition measurement is continuing on a smaller scale. At present, the most common usage of GP IIb/IIIa antagonists in stroke are as adjunctive agents to thrombolysis by intravenous and intra-arterial routes. Substantial progress is likely to require a better understanding of the mechanism of actions and unique pharmacology of GP IIb/IIIa antagonists in ischaemic stroke.     

Glycoprotein IIb/IIIa receptor antagonists: clinical pharmacology in cardiovascular diseases of aging.

The aging process is accompanied by a series of anatomical and physiological cardiovascular changes, including a generalised loss of vascular compliance, neuroendocrine alterations and endothelial dysfunction. Superimposed on this, there is an age-related increase in common cardiovascular disorders, such that the majority of deaths and much disability in older populations are caused by coronary artery disease. Most acute vascular events are mediated by thrombosis in which the formation of platelet aggregates forms an integral part. Research over recent years has led to the characterisation of the platelet glycoprotein (GP) IIb/IIIa receptor as the ultimate mechanism by which activated platelets cross-link by binding fibrinogen and other ligands. This knowledge has resulted in novel pharmacological strategies targeting this receptor which have proven to be potent inhibitors of thrombosis. The prototype drug, abciximab, is a chimeric monoclonal antibody directed against GP IIb/IIIa. Synthesis of new drugs has followed, based on the identification of the molecular sequences to which GP IIb/IIIa is attracted. This includes the emergence of oral agents which can be used for long term therapy. Clinical trials with these agents in the setting of percutaneous coronary interventions and unstable ischaemic syndromes have demonstrated a beneficial effect on thrombosis-related end-points. Trials of GP IIb/IIIa antagonists for direct percutaneous transluminal coronary angioplasty (PTCA) in acute myocardial infarction have also shown benefit, while their use in combination with fibrinolytic drugs is currently being evaluated. Other potential indications including neurovascular disease and primary haematological disorders are also being explored.