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.     

Current strategies with eptifibatide and other antiplatelet agents in percutaneous coronary intervention and acute coronary syndromes

Antiplatelet and anticoagulation therapies are essential for the prevention of thromboembolic-induced myocardial ischaemia in non-ST-elevation acute coronary syndromes and the ischaemic complications of percutaneous coronary intervention. Although heparin, direct thrombin inhibitors and oral platelet activation inhibitors provide substantial benefit, only glycoprotein (GP) IIb/IIIa inhibitors block the final common pathway leading to platelet aggregation, and the American College of Cardiology/American Heart Association guidelines recommend GP IIb/IIIa inhibitors as an integral component of care in these patients. Abciximab, eptifibatide and tirofiban all act through the GP IIb/IIIa receptor; however, variations in clinical outcomes among patients receiving these agents may be related to their structural and pharmacological differences, as well as to patient demographics. Data indicate that eptifibatide, at the current recommended dosing schedule, achieves the highest level of consistent platelet inhibition compared with current doses of abciximab and tirofiban.     

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.     

Inhibitors of platelets glycoprotein IIb/IIIa (GP IIb/IIIa) receptor: rationale for their use in clinical cardiology

The glycoprotein IIb/IIIa (GP IIb/IIIa) receptor is the most important receptor involved in platelet aggregation. A stable GP IIb/IIIa inhibition is required when a massive platelet activation triggers thrombosis. Three GP IIb/IIIa inhibitors are currently approved for clinical use: abciximab, tirofiban and integrilin. Their different pharmacodynamic and pharmacokinetic properties reflect a different efficacy in platelet inhibition.     

Intracoronary use of GP IIb/IIIa inhibitors in percutaneous coronary interventions

The glycoprotein (GP) IIb/IIIa receptor is critical to the process of platelet aggregation and thrombus formation as it serves as the final common pathway for platelet aggregation. For this reason, the development of GP IIb/IIIa inhibitors that block fibrinogen binding to the receptor has become an attractive strategy for antiplatelet therapy with an expected strong and specific effect. Presently, there are three commercially available GP IIb/IIIa inhibitors: abciximab, eptifibatide and tirofiban. All three drugs are commonly administered intravenously, and large-scale clinical trials have demonstrated a clear clinical benefit and good safety profile in patients at high risk, especially those undergoing percutaneous coronary interventions (PCI). Recently, several studies tested the intracoronary (IC) route for GP IIb/IIIa inhibitors in order to verify its safety and its possible superiority as compared to the intravenous (IV) route. The majority of the studies testing the IC route were conducted using abciximab and in patients with STEMI with better results in terms of myocardial reperfusion and infarct size and also promising results in terms of clinical outcome. On the IC administration of eptifibatide and tirofiban only some, even if promising, data are available. Larger and randomized studies are warranted to confirm the superiority of the IC route of administration of the GP IIb/IIIa inhibitors to the IV one in patients with coronary artery disease undergoing PCI.     

Ongoing clinical trials of anti-platelet agents in the management of acute ischaemic coronary syndromes

Acute ischaemic coronary syndromes, the clinical sequelae of thrombosis over a fissured atherosclerotic plaque within the coronary circulation, are the leading cause of death and hospitalisation in Western countries. Platelets are fundamental for the initiation and continuation of thrombosis, and currently available anti-platelet agents such as aspirin significantly improve the clinical outcome of patients with these syndromes. Therapeutic success with available therapy is however not universal, and adverse clinical event rates remain high. Several new classes of agents with a variety of anti-platelet actions are currently under development. Those which inhibit the final common pathway of platelet aggregation, the glycoprotein (GP) IIb/IIIa receptor, appear to show the most promise. Much clinical trial evidence already exists supporting the use of GP IIb/IIIa receptor antagonists in the management of acute ischaemic coronary syndromes. Several clinical studies are underway to further refine this knowledge base, and to assess their efficacy in a variety of novel applications.     

Oral beclomethasone dipropionate: a topically active corticosteroid for the treatment of gastrointestinal graft-versus-host disease following allogeneic hematopoietic cell transplantation

The success of intravenous platelet glycoprotein (GP) IIb/IIIa receptor blockers as potent antithrombotic therapies has ignited interest in the research and development of oral agents with the intention of extending the initial clinical benefits proven with intravenous GP IIb/IIIa blockers to long-term care with the use of oral agents. Nonetheless, results of the recently published Blockade of the Glycoprotein IIb/IIIa Receptor to Avoid Vascular Occlusion (BRAVO) trial support the disappointing results of the earlier published studies, which revealed that the use of oral GP IIb/IIIa inhibitors was associated with an unacceptable increased mortality. Further research to elucidate the mechanism of this increased fatality risk is warranted before any further clinical studies with the oral GP IIb/IIIa inhibitors can be ethically justified.     

Is there a role for oral blockade of platelet glycoprotein IIb/IIIa receptors in coronary and cerebrovascular disease?

The success of intravenous platelet glycoprotein (GP) IIb/IIIa receptor blockers as potent antithrombotic therapies has ignited interest in the research and development of oral agents with the intention of extending the initial clinical benefits proven with intravenous GP IIb/IIIa blockers to long-term care with the use of oral agents. Nonetheless, results of the recently published Blockade of the Glycoprotein IIb/IIIa Receptor to Avoid Vascular Occlusion (BRAVO) trial support the disappointing results of the earlier published studies, which revealed that the use of oral GP IIb/IIIa inhibitors was associated with an unacceptable increased mortality. Further research to elucidate the mechanism of this increased fatality risk is warranted before any further clinical studies with the oral GP IIb/IIIa inhibitors can be ethically justified.     

Antiplatelet mechanism of 2-chloro-3-(4-hexylphenyl)-amino-1,4-naphthoquinone (NQ304), an antithrombotic agent

The effects of 2-chloro-3-(4-hexylphenyl)-amino-1,4-naphthoquinone (NQ304), an antithrombotic agent, on aggregation, binding of fibrinogen to glycoprotein IIb/IIIa and intracellular signals were investigated using human platelets. NQ304 inhibited thrombin-, arachidonic acid- and thapsigargin-induced aggregation of washed human platelets with the IC50 values of 22.2+/-0.7, 6.5+/-0.2, and 7.6+/-0.1 microM, respectively. NQ304 significantly inhibited fluorescein isothiocyanate-conjugated fibrinogen binding to human platelet surface glycoprotein IIb/IIIa receptor by 75%, but failed to inhibit the fibrinogen binding to purified glycoprotein IIb/IIIa receptor. This result suggests that NQ304 inhibit platelet aggregation by suppression of an intracellular pathway that involves exposure of the glycoprotein IIb/IIIa receptor, rather than by direct inhibition of fibrinogen-glycoprotein IIb/IIIa binding. NQ304 significantly inhibited thrombin-induced increase in intracellular Ca2+ mobilization at the dose of 30 microM and ATP secretion in a dose-dependent manner. It also inhibited thrombin- and arachidonic acid-induced thromboxane A2 formation in human platelet dose-dependently. In conclusion, the antiplatelet mechanism of NQ304 may be due to the reduction of the thromboxane A2 formation, inhibition of adenosine triphosphate release and intracellular calcium mobilization.     

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.     

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.     

Low molecular weight heparins combined with platelet glycoprotein IIb/IIIa inhibitors in the management of acute coronary syndromes

Clinical trials of several platelet glycoprotein (GP) IIb/IIIa receptor inhibitors have demonstrated an unequivocal benefit of this potent antithrombotic therapy in high-risk patients with acute coronary syndromes (ACS) as well as in those undergoing percutaneous coronary intervention. In all of these major trials, however, GP IIb/IIIa inhibitors were used in combination with unfractionated (UF) heparin. Low molecular weight heparins (LMWH) have several advantages over UF heparin therapy, making them attractive alternatives for use in combination with GP IIb/IIIa inhibitors. In the INTegrelin and Enoxaparin Randomized assessment of Acute Coronary syndrome Treatment (INTERACT) study, combination therapy using the GP IIb/IIIa inhibitor eptifibatide (Integrilin) and the LMWH enoxaparin (Lovenox) in patients with high-risk non-ST-segment elevation ACS, resulted in improved outcomes compared to the currently recommended therapy of UF heparin, with better safety results. It is anticipated that the LMWHs may soon replace the traditional UF heparin for combination therapy with GP IIb/IIIa inhibitors in the medical stabilisation of patients with ACS. Results of other ongoing studies of LMWH combinations with other GP IIb/IIIa inhibitors and in the setting of percutaneous coronary intervention are awaited.     

Platelet glycoprotein IIb/IIIa antagonists in clinical trials for the treatment of coronary artery disease

There is a growing understanding of the central role that platelets play in coronary artery disease. The glycoprotein IIb/IIIa receptor has recently been identified as the final common pathway for platelet aggregation and hence has been the focus of many clinical trials to influence various aspects of coronary artery disease. In this report we give an overview of these clinical trials.     

Oral Glycoprotein IIb/IIIa Inhibitors

Despite their promise as orally active potent inhibitors of platelet aggregation, the oral platelet glycoprotein IIb/IIIa inhibitors have failed to provide a reduction in late ischemic events. In fact, with five large-scale randomized trials now complete, including over 42000 patients, these agents have been associated with a surprising, yet consistent, excess in mortality. Peculiarly, this fatality risk has occurred in the absence of a commensurate increase in other ischemic end-points. While these findings have curtailed the further clinical development of this class of potent platelet inhibitors, the obvious dissociation between platelet suppression and adverse outcome requires further clarification. Multiple putative explanations for this excess in ischemic events with oral glycoprotein IIb/IIIa inhibitors have been proposed, but definitive data implicating a specific mechanism are currently not available. While the lack of concurrent aspirin may account for some of this effect, it is unlikely to fully explain the mortality excess. Potential mechanisms include partial agonist activity leading to increased expression of platelet-leukocyte adhesion molecules, sub-optimal inhibition of platelet aggregation, genetic polymorphisms, especially phospholipase A₂ polymorphism, and promotion of cardiac myocyte apoptosis via activation of caspase 3. Definitive elucidation of these adverse mechanisms will be required if further clinical development of the oral platelet glycoprotein IIb/IIIa inhibitors is to be pursued.     

Platelet glycoprotein IIb/IIIa antagonists in clinical trials for the treatment of coronary artery disease

There is a growing understanding of the central role that platelets play in coronary artery disease. The glycoprotein IIb/IIIa receptor has recently been identified as the final common pathway for platelet aggregation and hence has been the focus of many clinical trials to influence various aspects of coronary artery disease. In this report we give an overview of these clinical trials.     

Low molecular weight heparins combined with platelet glycoprotein IIb/IIIa inhibitors in the management of acute coronary syndromes

Clinical trials of several platelet glycoprotein (GP) IIb/IIIa receptor inhibitors have demonstrated an unequivocal benefit of this potent antithrombotic therapy in high-risk patients with acute coronary syndromes (ACS) as well as in those undergoing percutaneous coronary intervention. In all of these major trials, however, GP IIb/IIIa inhibitors were used in combination with unfractionated (UF) heparin. Low molecular weight heparins (LMWH) have several advantages over UF heparin therapy, making them attractive alternatives for use in combination with GP IIb/IIIa inhibitors. In the INTegrelin and Enoxaparin Randomized assessment of Acute Coronary syndrome Treatment (INTERACT) study, combination therapy using the GP IIb/IIIa inhibitor eptifibatide (Integrilin^®) and the LMWH enoxaparin (Lovenox^®) in patients with high-risk non-ST-segment elevation ACS, resulted in improved outcomes compared to the currently recommended therapy of UF heparin, with better safety results. It is anticipated that the LMWHs may soon replace the traditional UF heparin for combination therapy with GP IIb/IIIa inhibitors in the medical stabilisation of patients with ACS. Results of other ongoing studies of LMWH combinations with other GP IIb/IIIa inhibitors and in the setting of percutaneous coronary intervention are awaited.     

Platelet glycoprotein IIb/IIIa inhibitors during percutaneous coronary interventions: a pharmacological and clinical review

One of the most significant advances of the last decade has been the development of platelet glycoprotein (GP) IIb/IIIa receptor inhibitors. A large series of randomised, controlled clinical trials of these agents have shown a significant reduction in ischaemic events, not only in acute coronary syndrome patients, but also in patients who undergo elective percutaneous coronary interventions. Even though the use of oral antiplatelet and antithrombotic therapies in addition to percutaneous coronary interventions have had a significant impact in clinical outcomes after acute coronary syndromes, the use of GP IIb/IIIa inhibitors provide additional protection against recurrent ischaemia and has been identified as the pivotal mediator of platelet aggregation, making it a logical target for the control of platelet response to vascular injury. A series of key trials performed over the last few years with GP IIb/IIIa inhibitors in patients undergoing percutaneous coronary intervention, have shown a reduction in the risk of short-term death and non-fatal myocardial infarction. The pharmacology and molecular basis of GP IIb/IIIa receptor inhibition and the use of these agents in patients undergoing percutaneous coronary intervention (during acute coronary syndromes and in elective procedures) and their safety issues will be reviewed. A special emphasis has been made on the role of these agents in diabetic patients and their beneficial effect in reducing peri-procedural creatine kinase myocardial band fraction elevation and associated complications.     

Platelet glycoprotein IIb/IIIa inhibitors during percutaneous coronary interventions: a pharmacological and clinical review

One of the most significant advances of the last decade has been the development of platelet glycoprotein (GP) IIb/IIIa receptor inhibitors. A large series of randomised, controlled clinical trials of these agents have shown a significant reduction in ischaemic events, not only in acute coronary syndrome patients, but also in patients who undergo elective percutaneous coronary interventions. Even though the use of oral antiplatelet and antithrombotic therapies in addition to percutaneous coronary interventions have had a significant impact in clinical outcomes after acute coronary syndromes, the use of GP IIb/IIIa inhibitors provide additional protection against recurrent ischaemia and has been identified as the pivotal mediator of platelet aggregation, making it a logical target for the control of platelet response to vascular injury. A series of key trials performed over the last few years with GP IIb/IIIa inhibitors in patients undergoing percutaneous coronary intervention, have shown a reduction in the risk of short-term death and non-fatal myocardial infarction. The pharmacology and molecular basis of GP IIb/IIIa receptor inhibition and the use of these agents in patients undergoing percutaneous coronary intervention (during acute coronary syndromes and in elective procedures) and their safety issues will be reviewed. A special emphasis has been made on the role of these agents in diabetic patients and their beneficial effect in reducing peri-procedural creatine kinase myocardial band fraction elevation and associated complications.     

Antiplatelet Mechanism of 2‐Chloro‐3‐(4‐hexylphenyl)‐amino‐1,4‐naphthoquinone (NQ304), an Antithrombotic Agent

Abstract: The effects of 2‐chloro‐3‐(4‐hexylphenyl)‐amino‐1,4‐naphthoquinone (NQ304), an antithrombotic agent, on aggregation, binding of fibrinogen to glycoprotein IIb/IIIa and intracellular signals were investigated using human platelets. NQ304 inhibited thrombin‐, arachidonic acid‐ and thapsigargin‐induced aggregation of washed human platelets with the IC₅₀ values of 22.2±0.7, 6.5±0.2, and 7.6±0.1 μM, respectively. NQ304 significantly inhibited fluorescein isothiocyanate‐conjugated fibrinogen binding to human platelet surface glycoprotein IIb/IIIa receptor by 75%, but failed to inhibit the fibrinogen binding to purified glycoprotein IIb/IIIa receptor. This result suggests that NQ304 inhibit platelet aggregation by suppression of an intracellular pathway that involves exposure of the glycoprotein IIb/IIIa receptor, rather than by direct inhibition of fibrinogen‐glycoprotein IIb/IIIa binding. NQ304 significantly inhibited thrombin‐induced increase in intracellular Ca²⁺ mobilization at the dose of 30 μM and ATP secretion in a dose‐dependent manner. It also inhibited thrombin‐ and arachidonic acid‐induced thromboxane A₂ formation in human platelet dose‐dependently. In conclusion, the antiplatelet mechanism of NQ304 may be due to the reduction of the thromboxane A₂ formation, inhibition of adenosine triphosphate release and intracellular calcium mobilization.     

Pharmaceutical thrombosis prevention in cardiovascular disease

Cardiovascular diseases are a leading cause of morbidity and mortality in modern society. As a result of this, great efforts have been made to establish regimens for prophylaxis and treatment of such disorders. Pharmacological intervention is also a prerequisite for the success of other therapeutic approaches, e.g. coronary angioplasty. Prevention of platelet aggregation is a goal that can be achieved by counteracting various receptors on the platelet surface. The main attentions for such interventions are focused on inhibiting the glycoprotein IIb/IIIa receptor. So far, they are limited to intravenous usage. Adenosine diphosphate receptor inhibitors are available for intravenous and oral usage. Their effect is, at least partly, also exerted via the counteraction of adenosine diphosphate-mediated activation of the glycoprotein IIb/IIIa complex. An oral direct thrombin inhibitor is under clinical evaluation. This review focuses on atherothrombotic disorders, but recent advances within new fields of anticoagulation (i.e., treatment of severe septic shock and a novel approach to prevent thromboembolic disorder during surgery) should not be overlooked.