Adjunctive therapies in the cath lab. Combination of tirofiban and alteplase in acute myocardial infarction

Primary angioplasty results in higher reperfusion rates than fibrinolysis in patients with acute myocardial infarction (MI). Two recent trials have shown improved rates of reperfusion when a reduced-dose thrombolytic is combined with the platelet glycoprotein IIb/IIIa receptor inhibitor abciximab. We present a case report of acute MI successfully treated with a combination of tirofiban and half-dose alteplase and eventual percutaneous coronary intervention.     

Overcoming thrombolytic resistance: rationale and initial clinical experience combining thrombolytic therapy and glycoprotein IIb/IIIa receptor inhibition for acute myocardial infarction.

OBJECTIVES: We sought to review the emerging data and the clinical rationale for combining glycoprotein (GP) IIb/IIIa inhibitors with thrombolytic therapy for acute myocardial infarction (AMI). BACKGROUND: Although thrombolytic therapy has been a major advance in the treatment of acute ST segment elevation MI, new single-bolus thrombolytic agents have been unable to break the "thrombolytic ceiling" in infarct-related artery (IRA) patency. METHODS: Recent literature on GPIIb/IIIa inhibitors in acute coronary syndromes was reviewed. RESULTS: A new approach toward improving current thrombolytic-antithrombotic regimens focuses on "targeted therapy" for each component of the occlusive coronary thrombus: fibrin, thrombin and platelets. For the fibrin component, front-loading and/or bolus dosing of plasminogen activators (PAs) has identified the currently available doses of tissue-type plasminogen activator (t-PA) and recombinant tissue-type plasminogen activator (r-PA). For the thrombin component, several recent trials have shown that lower doses of heparin improve the safety profile of the thrombolytic-antithrombotic regimen. For the platelet component, aspirin has been shown to be effective, but the GPIIb/IIIa inhibitors offer the potential for more effective platelet inhibition and improved clinical efficacy. The benefits of GPIIb/IIIa inhibition in reducing death, MI or urgent revascularization in the setting of percutaneous coronary intervention are well established. Emerging experimental and clinical data now suggest that combining GPIIb/IIIa inhibition with reduced-dose thrombolytic therapy may improve early IRA patency without increasing bleeding risk. CONCLUSIONS: Given the strong clinical and physiologic rationale, clinical investigation in acute ST segment elevation MI is currently focused on combining the potent GPIIb/IIIa receptor inhibitors with reduced-dose fibrinolytic agents in acute MI, with the goal of overcoming "thrombolytic resistance."     

Antiplatelet Therapy in AMI: Combining GP IIb/IIIa Inhibition with Reduced-dose Fibrinolytic Therapy

In the therapy of ST-segment elevation myocardial infarction (MI), the close relationship between early reperfusion of the infarct-related artery and improved outcomes has focused research on improving the speed and efficacy of pharmacologic reperfusion therapy. Recently, it has become appreciated that even among patients who achieve normal epicardial reperfusion after reperfusion therapy, myocardial and microvascular perfusion may be inadequate. Such patients are at increased risk for the development of death and congestive heart failure. The addition of glycoprotein (GP) IIb/IIIa antagonists to standard fibrinolytic therapy has been shown to improve both epicardial and myocardial reperfusion. This article focuses on emerging data regarding the combination of GP IIb/IIa antagonists and standard fibrinolytic agents for the treatment of acute ST-segment elevation MI.     

Glycoprotein IIb/IIIa inhibition in the setting of acute ST-segment elevation myocardial infarction

Glycoprotein (GP) IIb/IIIa inhibitors have been extensively studied in the setting of percutaneous coronary intervention (PCI) and in the management of non-ST-segment elevation acute coronary syndromes. However, the use of GP IIb/IIIa inhibitors is less well established in the setting of acute ST-segment elevation myocardial infarction (MI). Multiple nonrandomized studies suggest that combination therapy with GP IIb/IIIa inhibitors and thrombolytic agents leads to increased rates of TIMI 3 flow. However, two clinical trials involving over 22,000 patients demonstrated that combination therapy is associated with only modest reductions in major adverse cardiac events, does not reduce mortality, and is associated with an increase in bleeding. In the setting of primary PCI, four clinical trials involving over 3,000 patients demonstrated that GP IIb/IIIa inhibition results in a significant decrease in the need for urgent target vessel revascularization but not in reductions of death or recurrent MI. Thus, GP IIb/IIIa inhibition may provide only limited benefits in the setting of acute ST-segment elevation MI.     

Intracoronary administration of the combined fibrinolytic therapy a in patient with acute myocardial infarction and end-stage coronary heart disease - a case report

Classical thrombolytic treatment in acute myocardial infarction is able to reach reperfusion in 60-80% of patients, however in 5-10% of cases reoclusion occurs. Primary percutaneous coronary intervention (PCI) offers the potential for a higher rate of reperfusion and a lower rate of bleeding events. Recently, advances in platelet inhibition and PCI procedures have led to the combination of all the approaches. Facilitated PCI or the use of elective PCI after pharmacological reperfusion therapy can combine the best aspects of thrombolysis and mechanical revascularization in acute myocardial infarction. However, in some cases PCI cannot be performed. This paper describes a patient with acute myocardial infarction successfully treated with intracoronary infusion of alteplase and GP IIb/IIIa inhibitor.     

Prospective Use of Glycoprotein IIb/IIIa Receptor Blockers in the Emergency Department Setting

Platelets play a pivotal role in the pathophysiology of acute coronary syndromes (ACS) and thus are logical therapeutic targets for treatment of this disease process. Platelet glycoprotein (GP) IIb/IIIa receptor antagonists, which interrupt the final common pathway of platelet aggregation, have been proved to reduce the 30-day incidence of death, acute myocardial infarction (MI), and urgent revascularization in both high-risk and low-risk patients undergoing percutaneous intervention procedures. Three-year follow-up has indicated that these benefits appear durable. Recent large-scale randomized trials have demonstrated the value of GP IIb/IIIa receptor inhibitors in reducing the risk of death and MI in patients with unstable angina or those with MI with non–Q-wave abnormalities who are receiving pharmacologic management. In addition, emerging evidence suggests a future role for GP IIb/IIIa receptor inhibitors as an adjunct to low-dose fibrinolytic therapy in patients with acute MI. As the list of indications for GP IIb/IIIa receptor antagonists expands to encompass the full spectrum of ACS, there is increasing interest in the potential use of these agents in the emergency department setting. The integration of GP IIb/IIIa receptor inhibitors into ED protocols will ultimately depend largely on whether these drugs prove to be safe and effective regardless of the direction of ST-segment deviation, and irrespective of whether definitive therapy will be invasive or conservative. [Gibler WB, Wilcox RG, Bode C, Castaigne AD, Delooz H, Elich D, Fox KAA, Kereiakes DJ, Rupprecht H, Topol EJ: Prospective use of glycoprotein IIb/IIIa receptor blockers in the emergency department setting. Ann Emerg Med December 1998;32:712-722.]     

Update on the treatment with platelet antiaggregation agents]

Antiplatelet agents are primarily used to prevent and treat arterial thrombosis. Their mechanism of action is related to the interaction with metabolism of arachidonic acid, the increase of intraplatelet cAMP or the antagonism of ADP or GP IIb/IIIa receptors. 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 more recently clopidogrel have been introduced. In the CAPRIE study, clopidogrel was shown to be more effective than aspirin in the prevention of vascular events in patients with atherothrombotic disease. The newer antiplatelet agents are GP IIb/IIIa receptor antagonists like eptifibatide, tirofiban and abciximab, which act at the end of the common pathway of platelet aggregation. Their benefits after intravenous administration have been shown in the treatment of acute coronary syndrome and percutaneous coronary angioplasty. The potential application of GIIb/IIIa targeted therapy might theortically be expanded by the new class of oral GP IIb/IIIa antagonists. However, their performance in clinical trials has been disappointing.     

A Review of Clinical Trials with Eptifibatide in Cardiology

Glycoprotein (GP) IIb/IIIa receptor antagonists inhibit the binding of ligands to activated platelet GP IIb/IIIa receptors and, therefore, prevent the formation of platelet thrombi. Additional antithrombin therapy should be given in connection with GP IIb/IIIa administration. Eptifibatide is a small heptapeptide, which is highly selective and rapidly dissociates from its receptor after cessation of therapy. In clinical trials (IMPACT‐II and ESPRIT) concomitant administration of eptifibatide to patients undergoing percutaneous coronary intervention (PCI) reduced thrombotic complications. In the PURSUIT trial, in patients with non‐ST‐elevation acute coronary syndromes, eptifibatide, compared to placebo, significantly reduced the primary endpoint of death and nonfatal myocardial infarction at 30 days. In patients with STEMI eptifibatide has been studied as an adjunct to fibrinolysis and primary PCI; it improved epicardial flow and tissue reperfusion. Current studies are evaluating eptifibatide as upstream therapy in high‐risk patients with NSTE‐ACS, in the EARLY‐ACS and in comparison with abciximab in patients with primary PCI in the EVA‐AMI trial.     

Anti-thrombotic, anti-platelet and fibrinolytic therapy: current management of acute myocardial infarction

Significant advances in the treatment of patients with acute myocardial infarction (MI) have been obtained in recent times. In particular, thrombolytic therapy has been shown to preserve ventricular function and improve survival in patients with acute MI. Therapies now include third-generation thrombolytic agents, percutaneous transluminal coronary angioplasty (PTCA) and intracoronary stenting, and new anti-thrombotic therapies including anti-platelet treatment with glycoprotein (GP) IIb/IIIa inhibition and direct anti-thrombin agents. This review will focus on the use of GP IIb/IIIa antagonists and thrombin inhibitors as adjunctive therapies to thrombolytic treatment of patients with acute MI.     

Platelet Glycoprotein IIb/IIIa Integrin Blockade in Coronary Artery Disease: Current State of the Art

Platelets have been shown to play an important role in the pathogenesis of atherosclerosis, acute coronary syndromes, and ischemic complications after percutaneous coronary intervention. Fibrinogen binding via platelet surface glycoprotein (GP) IIb/IIIa receptors constitutes the "final pathway" in platelet aggregation leading to thrombus formation. The GP IIb/IIIa receptor inhibitors, a new class of antiplatelet agents that have emerged in recent years, show great promise in reducing complications of coronary angioplasty and acute coronary syndromes. This review will examine the biology of platelet GP IIb/IIIa receptors, the various classes of GP IIb/IIIa receptor antagonists, the results of the latest clinical trials, and their implications in current clinical practice.     

Bleeding complications of platelet glycoprotein IIb/IIIa inhibitor abciximab (ReoPro )

Studies of patients scheduled for percutaneous coronary intervention with acute coronary syndrome have shown that the addition of intravenous glycoprotein (GP) IIb/IIIa inhibitors to aspirin and heparin is associated with a reduction in death or myocardial infarction compared to therapy with aspirin and heparin alone. The principle safety issue with GP IIb/IIIa inhibitors is the risk of bleeding, as the potent antiplatelet effect of these drugs may adversely affect hemostasis. In addition, antagonists of GP IIb/IIIa may increase the risk of thrombocytopenia. We report a case of abciximab-induced severe thrombocytopenia which led to fatal intra-cranial hemorrhage.     

Intracoronary thrombolysis combined with platelet receptor IIb/IIIa inhibitor and followed by percutaneous coronary intervention for the treatment of acute myocardial infarction: two case reports

By using classical thrombolytic treatment in acute myocardial infarction, reperfusion can be obtained in 60-80% of patients. However, in only 30-55% of cases TIMI grade 3 flow is achieved. Primary percutaneous coronary intervention (PCI) offers the potential for a higher rate of reperfusion and a lower rate of bleeding events. Recently, advances in platelet inhibition and PCI procedures have led to the combination of all the approaches. Facilitated PCI or the use of elective PCI after pharmacological reperfusion therapy can combine the best aspects of thrombolysis and mechanical revascularization in acute myocardial infarction. We report two cases with acute myocardial infarction successfully treated with PCI following thrombolytic treatment combined with platelet receptor IIb/IIIa inhibitor.     

Thrombolysis and adjunctive therapies in acute myocardial infarction

Thrombolysis and percutaneous transluminal angioplasty represent the cornerstone of the pharmacologic treatment of and the interventional approach to patients with myocardial infarction (MI). They are very effective. However, they are hampered by some critical limitations. Therefore, alternatives to standard thrombolytic therapy have been developed. Platelet glycoprotein (GP) IIb/IIIa blockade is under investigation and seems very attractive. This review will focus on the use of GP IIb/IIIa antagonists and thrombin inhibitors as adjunctive therapies to the thrombolytic treatment of patients with acute MI.     

Antithrombotic therapy in the acute phase of unstable angina

Low molecular weight heparins appear to be a better choice in patients with unstable angina than unfractionated heparin. In addition, the excellent predictable dose-response makes them suitable to prevent ischemic complications of percutaneous coronary intervention. Although direct comparisons between LMWH and UH are limited, substantial evidence exists that patients receiving LMWH can be safely brought to cardiac catheterization. Therefore, previous concern regarding transitioning such therapy from the medical service to the cardiac catheterization laboratory should not impede the upstream use of thèse agents. Although UH remains an option in conjunction with GP IIB/IIIa inhibitors, there is substantial evidence that LMWH and GP IIb/IIIa inhibitor therapy can be used safely in combination. Although GP IIb/IIIa inhibitors are very potent to prevent ischemic events after percutaneous coronary interventions, their benefit in the medical management of unstable angina is much more modest. ADP receptor antagonists reduce major ischemic events in combination with aspirin in the medical management of unstable angina patients but also when PCI is planned. Their combination with GP IIB/IIIa receptor antagonist does not impair the benefit of GP IIb/IIIa antagonists. The development of biologic tools to monitor these antithrombotic regimen is highly warranted especially in high risk patients (chronic renal failure, elderly).     

Glycoprotein IIb/IIIa antagonists in the setting of rescue percutaneous coronary intervention

It is clear that survival and better outcomes after acute myocardial infarction (AMI) are dependent on rapid, complete, and sustained reperfusion of the affected myocardium. Thrombolytic therapy is currently the most common reperfusion strategy in AMI, however, a significant proportion of patients fail to reach reperfusion with this form of therapy. There is evidence from randomized trials that rescue percutaneous coronary intervention (PCI) for failed thrombolysis may convey better outcomes to patients when compared to a conservative management. Nevertheless, it is not surprising that in this inherently thrombogenic milieu, rescue PCI has a lower success rate and a high incidence of rethrombosis, which have a profoundly negative impact on the outcome of patients. Platelets are thought to play a central role in the pathophysiology of failed thrombolysis and in the thrombotic complications following PCIs. Therefore, platelet glycoprotein (GP) IIb/IIIa antagonist may be of benefit in the setting of rescue PCI. Two retrospective subgroup analyses have suggested that these potent antiplatelet agents may improve the outcome of patients undergoing rescue PCI after failed full-dose thrombolytic therapy. An increase in major bleeding, however, has also been noted. Therefore, in light of the lack of evidence deriving from randomized, placebo-controlled trials, careful consideration of several aspects relevant to this setting is needed before GP IIb/IIIa antagonists are administered in rescue percutaneous coronary procedures.     

Chemical structures and mode of action of intravenous glycoprotein IIb/IIIa receptor blockers: A review

Glycoprotein (GP) IIb/IIIa receptor antagonists compose a subcategory of antiplatelet medications that reduce thrombus formation through the blockade of key binding sites needed to stabilize the forming platelet aggregate. The GP IIb/IIIa receptors have been identified as a therapeutic target in reducing the occurrence of platelet-dependent thrombus formation. One advantage of GP IIb/IIIa receptor antagonists is that because GP IIb/IIIa is platelet-specific, inhibition of this receptor does not affect platelet adhesion. This may contribute to hemostasis without leading to ischemic damage. The platelet-specific pharmacological activity of GP IIb/IIIa receptor antagonists has allowed for its broad use in clinical settings. Based on clinical trials, GP IIb/IIIa receptor antagonists have been extensively studied and used in patients with acute coronary syndrome or during percutaneous coronary interventions. The goal of the present article is to provide a detailed review of the chemical structures and mode of action of currently used Food and Drug Administration-approved GP IIb/IIIa receptor antagonists in the United States.     

GP IIb/IIIa inhibitors during primary percutaneous coronary intervention for STEMI: New trial and registry data

Primary percutaneous coronary intervention (PCI) with adjunctive glycoprotein (GP) IIb/IIIa receptor inhibitor therapy administered in the cardiac catheterization laboratory is the optimal reperfusion strategy for patients with ST-elevation myocardial infarction. Most available data regarding these agents are from trials comparing abciximab to placebo alone. Noninferiority trials comparing small-molecule GP IIb/IIIa receptor inhibitors, such as tirofiban and eptifibatide with abciximab, have used markers for myocardial reperfusion as primary end points but are underpowered to detect significant differences in hard clinical outcomes. Such a trial would need to enroll a very large number of patients and thus make it practically impossible to perform. Registry data reveal that most patients undergoing primary PCI are treated with small-molecule GP IIb/IIIa receptor inhibitors in clinical practice, and no observed difference is observed in safety and efficacy when compared with patients treated with abciximab therapy.     

Glycoprotein IIb/IIIa inhibitors in acute ST segment elevation myocardial infarction

Limitations in the standard treatment of acute myocardial infarction have focused attention on inhibition of platelet activity by its final common pathway of activation, the glycoprotein IIb/IIIa receptor. Animal studies have suggested that a glycoprotein IIb/IIIa inhibitor could accelerate thrombolysis and prevent reocclusion after successful thrombolysis. Studies evaluating the use of a glycoprotein IIb/IIIa inhibitor alone without thrombolysis or percutaneous transluminal coronary revascularization do not suggest that isolated use of glycoprotein IIb/IIIa inhibitors restores TIMI 3 flow in a sufficient proportion of patients. Clinical studies evaluating the combination of thrombolytic therapy and glycoprotein IIb/IIIa inhibitors appear most promising, with evidence of improved angiographic outcomes. Reducing the dose of thrombolytic agents may result in reduction in bleeding risk. Current and future trials will investigate reduced-dose reteplase with abciximab and eptifibatide with reduced-dose alteplase. Available evidence suggests that glycoprotein IIb/IIIa inhibition may facilitate thrombolysis, thus adding a new element to future reperfusion regimens.     

Synthetic inhibitors of platelet glycoprotein IIb/IIIa in clinical development

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

Current perspectives on reperfusion therapy for acute ST-segment elevation myocardial infarction: integrating pharmacologic and mechanical reperfusion strategies

The therapeutic approach to patients with acute ST-segment elevation myocardial infarction (STEMI) has advanced rapidly over the past decade. Intravenous fibrinolytic therapy remains the most common form of reperfusion therapy worldwide, since fibrinolytics are associated with a dramatic reduction in mortality rates. However, primary percutaneous coronary intervention (PCI) is associated with improved outcomes and less bleeding complications compared with fibrinolytic therapy, but it is not widely available. Adjunctive therapies with intracoronary stents, glycoprotein (GP) IIb/IIIa inhibitors, and more potent antithrombin agents have shown great promise for the initial treatment of STEMI and have stimulated further investigation of combined pharmacological/mechanical reperfusion strategies that may be synergistic. Although the optimal combination of fibrinolytics, antiplatelet agents, antithrombins, and mechanical reperfusion at hospitals with and without primary PCI facilities remains elusive, results from recent studies suggest that such a combined approach may facilitate transfer of patients with STEMI from a referral hospital to an invasive hospital for definitive primary PCI after administration of a potent pharmacologic regimen designed to enhance early infarct-related artery reperfusion. Thus, as the reperfusion era continues to evolve, the ideal treatment strategy for patients with STEMI is being redefined to integrate pharmacologic and mechanical approaches to reperfusion.