GP IIb/IIIa blockade in elective percutaneous coronary intervention

Cumulative scientific evidence gathered over the past ten years has confirmed the role of platelet GP IIb/IIIa inhibitors in reducing ischemic complications of patients undergoing percutaneous coronary intervention (PCI). Recently, mortality data available on more than 20,000 patients enrolled in randomized clinical trials suggest that GP IIb/IIIa blockade also improves short and long-term survival after PCI. Despite convincing arguments, GP IIb/IIIa inhibitors are still inconsistently administered in patients undergoing coronary intervention. The following review will discuss the scientific grounds and the principal controversies surrounding the use of these compounds in patients undergoing elective percutaneous coronary intervention.     

Optimal use of platelet glycoprotein IIb/IIIa receptor antagonists in patients undergoing percutaneous coronary interventions

Discovery of the central role of platelets in the pathogenesis of acute coronary syndromes (ACS) and ischaemic complications of percutaneous coronary interventions (PCI) has led to the widespread use of oral and parenteral platelet inhibitors to treat these conditions. Glycoprotein (GP) IIb/IIIa (also known as α(IIb)β(3)) receptors on the surface of platelets play an essential role in platelet aggregation and serve as a key mediator in the formation of arterial thrombus. When activated, GP IIb/IIIa receptors bind to fibrinogen, which serves as the 'final common pathway' in platelet aggregation. Of the numerous agents developed for modulating platelet activity, intravenous platelet GP IIb/IIIa receptor antagonists are the most potent. There are four agents in clinical use, including abciximab, eptifibatide, tirofiban and lamifiban, although lamifiban is not approved for use in the US. While all agents block fibrinogen binding to GP IIb/IIIa, they do so by different mechanisms. Abciximab is a humanized form of a murine monoclonal antibody directed against GP IIb/IIIa, eptifibatide is a synthetic, cyclic heptapeptide that contains a lysine-glycine-aspartic acid (KGD) sequence that mimics the arginine-glycine-aspartic acid (RGD) sequence found on GP IIb/IIIa, tirofiban is a non-peptide antagonist derived by optimization of the tyrosine analogue that structurally mimicks the RGD-containing loop of the disintegrin echistatin, and lamifiban is a synthetic, non-cyclic, non-peptide, low-molecular-weight compound. In clinical trials, use of these agents reduces ischaemic adverse cardiovascular events in patients with ACS undergoing PCI, but at a cost of increased bleeding.     

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.     

The therapeutic use of glycoprotein IIb/IIIa inhibitors in acute coronary syndromes

Acute coronary syndrome (ACS) embraces the clinical diagnoses of unstable angina and non-Q-wave myocardial infarction (NON-Q-MI). Conventional treatment for these conditions with aspirin, heparin and other anti-anginal drugs has its limitations. Treatment of acute symptoms with lytic therapy has not been beneficial. A large proportion of patients in this high-risk group will eventually need revascularisation due to ongoing symptoms. Platelet aggregation plays a crucial role in the pathogenesis of ACS and ischaemic complications of coronary intervention. The glycoprotein (GP) IIb/IIIa receptor, which belongs to a family of surface receptors called integrins, is the final step in this pathway. This has led to the development and use of GP IIb/IIIa inhibitors as potential therapeutic agents. Inhibitors developed so far include abciximab, a chimeric monoclonal antibody, and more recently, novel synthetic intravenous and orally administered competitive integrin blocking agents. To date, abciximab, tirofiban and eptifibatide are commercially available for clinical use. Completed clinical trials have looked at these agents as a primary treatment and as an adjunct to intervention for ACS; they have shown improvement over existing treatments, with reductions in the incidence of death, myocardial infarction (MI), refractory ischaemia and need for urgent revascularisation. Risk of bleeding and thrombocytopenia is low, and appears to be dose related and associated with concomitant treatment with high dose heparin. Cost benefit has been proven.     

Analysis of number needed to treat and cost of platelet glycoprotein IIb/IIIa inhibitors in percutaneous coronary interventions and acute coronary syndromes

This retrospective review and analysis of pivotal clinical trials compared acquisition costs and outcomes of platelet glycoprotein IIb/IIIa inhibitors. Absolute reduction in the number of deaths and nonfatal myocardial infarctions at 30 days, number of patients that need to be treated to prevent one event, and drug costs expended to prevent one event were assessed. In patients undergoing percutaneous coronary intervention (PCI), abciximab is the better value, especially in high-risk patients. In those with unstable angina and non-Q wave myocardial infarction, costs of eptifibatide and tirofiban were not significantly different, but the cost of tirofiban was more variable. These agents have the potential to be cost-effective if administered to populations at high risk for adverse outcomes of acute coronary syndromes or PCI. Prospective methods to identify these high-risk patients are being developed.     

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.     

Platelet glycoprotein IIb/IIIa inhibitors in percutaneous coronary intervention: focus on the pharmacokinetic-pharmacodynamic relationships of eptifibatide

Eptifibatide is a truncated derivative of the naturally occurring rattlesnake venom protein known as barbourin. It is a cyclic heptapeptide that mimics the tertiary structure found in the parent compound which allows it to bind receptors with the KGD (Lys-Gly-Asp) peptide recognition sequence. Specifically, eptifibatide is a competitive antagonist for the activated platelet glycoprotein IIb/IIIa receptor. Its mechanism of action involves preventing the binding and cross-linking of fibrinogen to the platelet surface. This binding site for fibrinogen is associated with five Ca2+ ions that help maintain the tertiary structure of the receptor and affect the affinity of other ligands such as eptifibatide.Arterial injury induced by percutaneous coronary interventions (PCI) such as balloon angioplasty and stenting, and the spontaneously occurring disease process known as the acute coronary syndrome (ACS), share a common underlying pathophysiology. In both situations, disruption of integrity of the arterial wall initiates a cascade of platelet activation, adhesion and aggregation. Ultimately, this process may proceed to arterial thrombosis unless controlled or modified. Advances in understanding how the platelet plays a pivotal role in this process have significantly enhanced therapy for patients with ACS and have resulted in important reductions in thrombotic complications from PCI procedures. Central to these advances has been evolving understanding of platelet-inhibiting pharmaceutical agents such as eptifibatide. The development of a rational administration regimen for eptifibatide parallels the growth in the understanding of the underlying mechanisms of platelet receptor functions. The binding of eptifibatide to the receptor involves displacement of receptor-associated Ca2+ from the activated binding site. Early in the clinical development of eptifibatide, this was poorly appreciated and resulted in an underestimation of the appropriate doses for this agent. Through a series of small clinical trials and laboratory studies, deficiencies in the early administration regimens were identified and a more effective dose schedule was determined. Modelling of the drug based on its two-compartment pharmacokinetics further defined the role of a newer double-bolus initiation of therapy verses the original single-bolus approach. In a large-scale clinical trial using this double-bolus followed by infusion regimen in PCI procedures, clinical efficacy was shown to be significantly improved over placebo and the earlier, low-dose regimens used in the original trials of eptifibatide.     

Risk-benefit analysis of platelet glycoprotein IIb/IIIa inhibitors in acute coronary syndromes

Four intravenous glycoprotein IIb/IIIa receptor inhibitors (GPIs) (abciximab, eptifibatide, tirofiban and lamifiban) have been tested extensively over the last decade for their efficacy and safety in patients with acute coronary syndromes (ACS). GPIs are well-established adjunct agents for patients undergoing percutaneous coronary intervention, and considerable effort has gone into evaluating these agents in patients who are not scheduled to undergo coronary revascularisation. In the current article, six major randomised clinical trials conducted in the latter patient population are reviewed. Based on a recent meta-analysis of these trials, GPIs reduced the incidence of death or myocardial infarction in patients not scheduled for early revascularisation, with the greatest reduction observed in patients at high risk of thrombotic complications. Major bleeding complications were more frequent in those receiving GPIs, however, the incidences of intracranial haemorrhage and stroke were similar in both treatment groups. Despite these risks, the benefits of GPI therapy in addition to conventional treatment, such as aspirin and heparin, should be considered for these high-risk patients.     

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.     

Therapeutic potential of GP IIb/IIIa receptor antagonists in acute myocardial infarction

The management of acute myocardial infarction (AMI) has changed dramatically over the last two decades, with the addition of fibrinolytic agents and primary coronary intervention (PCI). The more recent development of the glycoprotein (GP) IIb/IIIa antagonists, a new class of potent antiplatelet drugs, has the potential to considerably enhance the treatment of AMI patients. A number of recent studies have highlighted the potential incremental benefits with adjunctive IIb/IIIa-targeted therapy. In this review, we will discuss the pathophysiology of myocardial infarction (MI), the physiology and role of platelets in thrombosis and describe the currently available drugs. We will briefly summarise the results of recent clinical trials, discuss some key forthcoming trials and attempt to describe how GP IIb/IIIa antagonists may directly impact the immediate and near future day-to-day care of patients with AMI.     

Glycoprotein IIb/IIIa inhibitors: The resurgence of tirofiban

Glycoprotein (GP) IIb/IIIa inhibitors block platelet aggregation, reducing thrombotic events in acute coronary syndrome. They are most often utilized in patients who likely have an intracoronary thrombus. Tirofiban, eptifibatide, and abciximab are the three GP IIb/IIIa inhibitors approved for use in the United States. Each agent has unique pharmacological properties. They all have a rapid onset and are most often utilized in conjunction with heparin. Tirofiban, in particular, fell out of favor due to inferior dosing with its original Food and Drug Administration (FDA) approved indication, but has re-emerged in the market with a high-dose bolus regimen that is considered equally as effective as the FDA approved dosing regimens of other GP IIb/IIIa inhibitors. This review looks at pharmacological properties of all three agents, significant clinical trials associated with their use, and their place in current guidelines.     

Glycoprotein IIb/IIIa receptor therapy in percutaneous coronary intervention and non-ST-segment elevation acute coronary syndromes. Estimating the economic implications

In addition to efficacy and safety, cost is an important determinant of the use of glycoprotein IIb/IIIa (GPIIb/IIIa) therapy in patients with acute coronary syndromes (ACS) or undergoing percutaneous coronary intervention (PCI). In PCI, the average procurement cost of GPIIb/IIIa therapy ranges from $US400 to $US1500 (1999 values) per patient treated, depending on agent, dose and duration of infusion. Prospective economic substudies with abciximab and tirofiban have demonstrated subsequent cost savings that partially offset the procurement costs of the agents. The drug procurement costs per death or myocardial infarction (MI) prevented in PCI appear to vary from $US10,500 to $US37,000, depending on the agent. Abciximab has been proven to provide a survival benefit in the setting of PCI, including coronary stenting. Analyses of abciximab use yield cost-effectiveness ratios of $US2875 to $US14,765 per life-year or quality-adjusted life-year saved, which compares favourably with most widely accepted therapies. In non-ST-segment elevation ACS, drug procurement costs range from $US700 to $US1700 per patient treated, also depending on agent, dose and duration of infusion. Evidence of cost offsets from changes in subsequent resource utilisation are limited and seem contingent upon a conservative risk-stratification approach. Drug procurement costs have been calculated as $US32,000 to $US82,000 per death or MI prevented in the ACS trials. Cost-effectiveness ratios of $US16,000 per life-year saved for the US and Western European cohorts in the Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) trial are favourable. If these analyses prove correct, the cost effectiveness of GPIIb/IIIa receptor therapy for patients with non-ST-segment elevation ACS will also compare favourably with other widely accepted therapies in industrialised countries. More clinical and economic data are necessary to allow better selection of specific patients who will receive the most benefit from GPIIb/IIIa therapy in healthcare systems with limited resources.     

Intravenous glycoprotein IIb/IIIa inhibitors in acute coronary syndromes: lessons from recently conducted randomized clinical trials

The opportunity to completely inhibit platelet aggregation via the glycoprotein (GP)IIb/IIIa receptor represents a major innovation in antiplatelet therapy. Numerous trials conducted during the 1990s in patients undergoing percutaneous coronary intervention established GPIIb/IIIa inhibitors as a valuable component of treatment. Phase II trials in the medical management of acute coronary syndrome (ACS) patients also suggested beneficial effects, which encouraged six major phase III clinical trials to be conducted. In general, cardiac complications were reduced in those ACS patients who were not routinely scheduled for early revascularization. However, the treatment effect in the average patient is modest and overall 100 patients need to be treated in order to prevent one death or myocardial infarction. Given the current attention to healthcare costs, these agents may therefore be reserved for patients at suspected high risk of death or (re)infarction, including patients with diabetes mellitus and elevated cardiac troponins.     

Glycoprotein IIb/IIIa Antagonists

Mortality from ischemic cardiac disease in adults has been dramatically reduced by the development of novel therapies for inhibiting platelet function. Circulating platelets are maintained in a resting state and are activated at sites of vascular injury by exquisitely controlled mechanisms, thereby maintaining vascular integrity without causing intravascular thrombosis. As it became clear that platelets play a central role in arterial thrombosis, the processes of platelet activation, adhesion, and aggregation became logical targets for the development of antithrombotic agents.     

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.     

Update on glycoprotein IIb/IIIa: role in primary coronary intervention

Coronary artery diseases continue to be the most common causes of mortality and morbidity in the industrialized world, especially in the setting of acute myocardial infarction. Platelets play a crucial role in thrombosis and haemostasis, which can be either beneficial or deleterious, depending on the circumstances. Platelet hyperreactivity is a multifactor process depending on genetic polymorphism, pathological state and lifestyle; it contributes to the activation of the thrombotic cascade. Under pathophysiological conditions platelets activation plays a critical role in arterial thrombosis including platelets aggregation, the basis of destabilization of coronary plaque. Despite the benefits observed in outcome when primary angioplasty is compared with thrombolysis for the treatment of acute myocardial infarction there is still some room for improvement; unfortunately the restoration of an "optimal" epicardial flow is not always related to an "optimal" myocardial reperfusion. In the recent, past several studies have shown significant benefits with the administration of glycoprotein IIb/IIIa inhibitors. Thus, the aim of the present review is to perform an update on factors associated with platelets hyperactivity and on adjunctive glycoprotein IIb - IIIa inhibitors in primary angioplasty.     

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.