Monitoring antiplatelet therapy: What is the best method?

Platelet function tests measure different aspects of platelet function, which include adherence, activation, aggregation and secretion. Clinically, the goal of platelet function testing is to provide information about the platelet contribution to the risk of thrombotic or haemorrhagic events and the optimisation of antiplatelet therapy. The important clinical questions are whether an antiplatelet agent is having the desired effect on platelet inhibition (effectiveness) and whether the patient has sufficient residual platelet function to avoid bleeding (safety). The role of aspirin (acetylsalicylic acid) and thienopyridines is well established in the management of patients with coronary artery disease and in the setting of coronary interventions. The last several years have demonstrated the unequivocal effectiveness of intravenously administered platelet glycoprotein (GP) IIb/IIIa antagonists in the management of acute coronary syndromes and in the setting of percutaneous coronary interventions. With the increasing use of these GPIIb/IIIa antagonists, it is becoming more important clinically to measure platelet inhibition with these agents. This paper reviews major techniques and instrumentation for platelet monitoring and discusses the goals of the best method.     

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.     

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.     

Glycoprotein IIb-IIIa antagonists in non-ST elevation acute coronary syndromes and percutaneous interventions: from pharmacology to individual patient's therapy: Part 2: When and how to use various agents

Patients with high-risk characteristics admitted for non-ST elevation acute coronary syndromes benefit from an early invasive treatment, and in this case glycoprotein (GP) IIb/IIIa inhibitors appear effective in improving prognosis. There is however an ongoing debate on which of the currently available agents is the best in patients who are candidates for percutaneous coronary interventions. The dispute revolves on the optimal level of inhibition of platelet function and on whether the benefit is retained in the presence of pretreatment with thienopyridines. Especially the additional value of GP IIb/IIIa inhibition on top of an aggressive antithrombotic therapy (including aspirin, heparins, and clopidogrel) requires further clarification. Here we propose an algorithm for the practical use of available GPIIb/IIIa antagonists in relation with the patient's clinical presentation and concomitant use of other drugs and devices.     

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.     

Cangrelor: a novel P2Y12 receptor antagonist

Antiplatelet therapy is critical in the prevention of thrombotic complications of acute coronary syndrome and percutaneous coronary interventions. Current antiplatelet agents (aspirin, clopidogrel and glycoprotein IIb/IIIa antagonists) have demonstrated the capacity to reduce major adverse cardiac events. However, these agents have limitations that compromise their clinical utility. The platelet P2Y₁₂ receptor plays a central role in platelet function and is a focus in the development of antiplatelet therapies. Cangrelor is a potent, competitive inhibitor of the P2Y₁₂ receptor that is administered by intravenous infusion and rapidly achieves near complete inhibition of ADP-induced platelet aggregation. This investigational drug has been studied for use during coronary procedures and the management of patients experiencing acute coronary syndrome and is undergoing evaluation for use in the prevention of perioperative stent thrombosis.     

Prevention of platelet glycoprotein IIb/IIIa activation by 3,4-methylenedioxy-beta-nitrostyrene, a novel tyrosine kinase inhibitor

Binding fibrinogen to activated glycoprotein (GP)IIb/IIIa is the final common pathway of platelet aggregation and has become a successful target for antiplatelet therapy. In the present study, we found that a small chemical compound, 3,4-methyl-enedioxy-beta-nitrostyrene (MNS), exhibited potent and broad-spectrum inhibitory effects on human platelet aggregation caused by various stimulators. Moreover, addition of MNS to human platelets that had been aggregated by ADP caused a rapid disaggregation. We demonstrated that the antiaggregatory activity of MNS is due to inhibition of GPIIb/IIIa activation by measuring the binding amount of PAC-1 in platelets. In contrast, MNS is not a direct antagonist of GPIIb/IIIa, because MNS did not affect fibrinogen binding to fixed ADP-stimulated platelets. By investigating how MNS inhibits GPIIb/IIIa activation, we found that MNS potently inhibited the activity of tyrosine kinases (Src and Syk) and prevented protein tyrosine phosphorylation and cytoskeletal association of GPIIb/IIIa and talin, but it had no direct effects on protein kinase C, Ca2+ mobilization, Ca2+-dependent enzymes (myosin light chain kinase and calpain), and arachidonic acid metabolism, and it did not affect the cellular levels of cyclic nucleotides. Therefore, MNS represents a new class of tyrosine kinase inhibitor that potently prevents GPIIb/IIIa activation and platelet aggregation without directly affecting other signaling pathways required for platelet activation. Because MNS inhibits GPIIb/IIIa functions in a manner different from GPIIb/IIIa antagonists, this feature may provide a new strategy for treatment of platelet-dependent thrombosis.     

Antiplatelet therapies: platelet GPIIb/IIIa antagonists and beyond

Cardiovascular and cerebrovascular diseases continue to be leading causes of death throughout the world. Blood platelets play a pivotal role not only in haemostasis but also in the pathogenesis of thrombosis and atherosclerosis, platelet aggregation being an essential step in the formation of either an effective haemostatic plug or an intravascular thrombus. The benefits of various antiplatelet therapies ranging from aspirin, ticlopidine, Clopidogrel, and intravenous platelet GPIIb/IIIa antagonists in various thromboembolic disorders are well documented. Despite of the success of intravenous acute GPIIb/IIIa blockade when given in conjunction with heparin, chronic oral GPIIb/IIIa antagonists with or without aspirin failed in various cardiovascular settings. This review highlights the role of the various antiplatelet therapies in thrombotic disorders as well as future directions.     

Platelet glycoprotein IIb/IIIa receptor antagonists: current concepts and future directions

Platelets play a key role in the development of thrombosis. Glycoprotein (GP) IIb/IIIa antagonists are a new class of potent drugs that profoundly inhibit platelet function by blocking the key receptor involved in platelet aggregation. Several antiplatelet agents with varying characteristics have emerged in the past few years and have been evaluated in a variety of potential clinical settings. Clinical trials have established the effectiveness of these drugs in conditions where thrombosis plays a major contributing role such as unstable angina pectoris, myocardial infarction, and high-risk coronary intervention. Despite their potent antiplatelet effects, GP IIb/IIIa antagonists appear to be remarkably well tolerated, provided that the concomitant use of other anticoagulants such as heparin is managed carefully. Ongoing and future studies will further refine the role of GP IIb/IIIa antagonists, explore new applications, and further test their safety and cost effectiveness in the short and long term.     

Stroke: antithrombin versus antiplatelet therapy

The success of thrombolytic therapy for acute stroke has demonstrated that neurologic outcome can be improved with timely treatment. However, the severely restricted use of thrombolytics has reinforced the need to develop alternative and complementary therapies. Antithrombin and antiplatelet agents represent promising therapeutic approaches for stroke management. Antiplatelet therapy has modestly improved outcome in both acute stroke (aspirin) and in secondary stroke prevention (aspirin with or without dipyridamole; adenosine receptor antagonists), although bleeding and other adverse events associated with antithrombin therapy have largely negated their potential benefit. These findings have prompted innovative solutions to the pharmacokinetic and pharmacodynamic challenges that are crucial to advancing these strategies for acute, primary and secondary stroke therapy. Currently, inhibitors of the platelet surface glycoprotein IIb/IIIa (GP IIb/IIIa, fibrinogen) receptor are being examined in clinical trials while antithrombin therapies focus on thrombin antagonists and inhibitors as well as inhibitors of Factor Xa. Further advances in stroke treatment will include combination therapies. Additionally, the successful design of future drug therapies will result from a more complete understanding of the activity of these agents not only on platelet function and the coagulation cascade, but also for their effects on the endothelium and within the brain parenchyma. The sum of these activites will allow for the maintenance of cerebral blood flow, blood-brain barrier integrity and neuronal function.     

Stroke: antithrombin versus antiplatelet therapy

The success of thrombolytic therapy for acute stroke has demonstrated that neurologic outcome can be improved with timely treatment. However, the severely restricted use of thrombolytics has reinforced the need to develop alternative and complementary therapies. Antithrombin and antiplatelet agents represent promising therapeutic approaches for stroke management. Antiplatelet therapy has modestly improved outcome in both acute stroke (aspirin) and in secondary stroke prevention (aspirin with or without dipyridamole; adenosine receptor antagonists), although bleeding and other adverse events associated with antithrombin therapy have largely negated their potential benefit. These findings have prompted innovative solutions to the pharmacokinetic and pharmacodynamic challenges that are crucial to advancing these strategies for acute, primary and secondary stroke therapy. Currently, inhibitors of the platelet surface glycoprotein IIb/IIIa (GP IIb/IIIa, fibrinogen) receptor are being examined in clinical trials while antithrombin therapies focus on thrombin antagonists and inhibitors as well as inhibitors of Factor Xa. Further advances in stroke treatment will include combination therapies. Additionally, the successful design of future drug therapies will result from a more complete understanding of the activity of these agents not only on platelet function and the coagulation cascade, but also for their effects on the endothelium and within the brain parenchyma. The sum of these activities will allow for the maintenance of cerebral blood flow, blood-brain barrier integrity and neuronal function.     

Pharmacological control of platelet function.

Advancement in the understanding of the mechanisms of platelet activation, as well as the development of new techniques for studying platelet function, have led to the availability of new classes of platelet inhibiting drugs. Initially, characterization of arachidonic acid metabolism in platelets furthered an understanding of the utility of cyclooxygenase inhibitors, most notably aspirin. The discovery and characterization of platelet receptors such as the adenosine diphosphate (ADP) receptor and glycoprotein IIb/IIIa has been associated with the development of novel classes of anti-platelet drug, such as thienopyridine derivatives and glycoprotein IIb/IIIa receptor antagonists, respectively. Future development in receptor pathway inhibitors also includes glycoprotein Ib/IX as well as the potential use of platelet signaling pathway inhibitors.     

The role of antiplatelet therapy in the management of acute coronary syndromes

The benefit of aspirin use in the emergent care of acute coronary syndromes (ACS) has been well-established. Recent studies have further demonstrated the importance of antiplatelet therapy in the acute setting, primarily with the use of intravenous glycoprotein IIb/IIIa receptor inhibitors. Aspirin and the thienopyridines (ticlopidine and clopidogrel) are oral antiplatelet agents that interfere with platelet activation in complementary, but separate pathways. Combination therapy of aspirin with other antiplatelet agents has demonstrated a benefit for the management of ACS. This article reviews the pathophysiology of platelet activation in ACS, landmark trials regarding antiplatelet agents, and the current recommendations for the use of both intravenous and oral antiplatelet agents in the management of patients with ACS.     

The role of antiplatelet therapy in the management of acute coronary syndromes

The benefit of aspirin use in the emergent care of acute coronary syndromes (ACS) has been well-established. Recent studies have further demonstrated the importance of antiplatelet therapy in the acute setting, primarily with the use of intravenous glycoprotein IIb/IIIa receptor inhibitors. Aspirin and the thienopyridines (ticlopidine and clopidogrel) are oral antiplatelet agents that interfere with platelet activation in complementary, but separate pathways. Combination therapy of aspirin with other antiplatelet agents has demonstrated a benefit for the management of ACS. This article reviews the pathophysiology of platelet activation in ACS, landmark trials regarding antiplatelet agents, and the current recommendations for the use of both intravenous and oral antiplatelet agents in the management of patients with ACS.     

Acute and long-term antiplatelet therapy

Clinical presentations of atherothrombotic vascular disease, i.e., acute coronary syndromes, cerebrovascular events and events associated with peripheral arterial disease, are the major causes of mortality and morbidity worldwide. Platelet activation and aggregation play an important role in the progression and clinical presentation of atherothrombotic disease, and antiplatelet therapy improves outcome in patients with atherothrombotic vascular disease. Aspirin has been the cornerstone of antiplatelet therapy for many decades, but in recent years, adenosine diphosphate (ADP) receptor antagonists, mainly clopidogrel and ticlopidine, and glycoprotein (GP) IIb/IIIa (integrin alpha IIb beta 3) inhibitors have also shown similar effectiveness. This review briefly summarizes the major clinical trials and recommendations for the efficacy and safety of antiplatelet therapy in patients with established atherothrombotic disease.     

Intravenous glycoprotein IIb/IIIa antagonists: their benefits, problems and future developments

The intravenous Glycoprotein (GP) IIb/IIIa antagonists are potent antiplatelet agents that are particularly effective in patients who undergo percutaneous coronary intervention (PCI). Questions remain about their benefit in the setting of primary PCI, as well as in patients with acute coronary syndromes who do not undergo PCI. The dosing of these drugs is critical to their efficacy and for some agents may not yet be optimized. Differences in the level of platelet inhibition achieved with previous and current dosing strategies of these agents are discussed. In addition, the pharmacology of GPIIb/IIIa antagonists is more complex than initially appreciated. These drugs appear to have partial agonist properties and as a result may be prothrombotic at lower doses. Recent evidence also suggests that at least some of the GPIIb/IIIa antagonists may have anti-inflammatory as well as anti-thrombotic activity. Future research should clarify these issues. Because of the observed inter-individual variation in the response to GPIIb/IIIa antagonists, future trials of these agents should also look at individual tailoring of the dose to an optimum level of platelet inhibition. No definite clinical predictors of this inter-individual variation have been identified, but the Pl(A) polymorphism in GPIIIa appears to be associated with an adverse response to treatment with the oral GPIIb/IIIa antagonists in particular.     

Abciximab,eptifibatide, and tirofiban exhibit dose-dependent potencies to dissolve platelet aggregates

Platelet GPIIb/IIIa antagonists are not only used to prevent platelet aggregation, but also in combination with thrombolytic agents for the treatment of coronary thrombi. Recent data indicate a potential of abciximab alone to dissolve thrombi in vivo. We investigated the potential of abciximab, eptifibatide, and tirofiban to dissolve platelet aggregates in vitro. Adenosine diphosphate (ADP)-induced platelet aggregation could be reversed in a concentration-dependent manner by all three GPIIb/IIIa antagonists when added after the aggregation curve reached half-maximal aggregation. The concentrations chosen are comparable with in vivo plasma concentrations in clinical applications. Disaggregation reached a maximum degree of 72.4% using 0.5 microg/ml tirofiban, 91.5% using 3.75 microg/ml eptifibatide, and 48.4% using 50 microg/ml abciximab (P < 0.05, respectively). A potential fibrinolytic activity of the GPIIb/IIIa antagonists was ruled out by preincubation with aprotinin or by a plasma clot assay. A stable model Chinese hamster ovary (CHO) cell line expressing the activated form of GPIIb/IIIa was used to confirm the disaggregation capacity of GPIIb/IIIa antagonists found in platelets. Not only abciximab, but also eptifibatide and tirofiban have the potential to disaggregate newly formed platelet clusters in vitro. Because enzyme-dependent fibrinolysis does not appear to be involved, competitive removal of fibrinogen by the receptor antagonists is the most likely mechanism.     

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.     

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.