Acute Coronary Syndromes

Integrating GP IIb/IIIa Inhibition into Treatment Strategies for Acute ST-Elevation Myocardial Infarction (PART I)

David E. Kandzari, MD and Matthew T. Roe, MD, MHS
David E. Kandzari, MD and Matthew T. Roe, MD, MHS
Overview. Against the background of established clinical benefit in non-ST segment elevation acute coronary syndromes (ACS) and elective percutaneous revascularization, recent trials examining the role of glycoprotein (GP) IIb/IIIa inhibition in acute myocardial infarction (AMI) have been based on the rationale that effective platelet inhibition is fundamental to reperfusion strategies designed to restore myocardial perfusion, limit infarct size, and improve survival. Despite advances in the care of high-risk patients with acute ST-elevation MI, limitations of current standard therapies underscore the need for further improvement. Although primary angioplasty and stenting achieves successful reperfusion in more than 90% of cases, limited availability, time delays, and procedural inexperience are shortcomings associated with this treatment strategy.1 In spite of these limitations, transfer of AMI patients to an institution capable of performing primary percutaneous coronary intervention (PCI) may yield improved outcomes compared with prompt administration of fibrinolytic therapy. Compared with fibrinolytic therapy, a strategy that allowed up to 3 hours delay for transfer to hospitals performing primary PCI in the DANAMI-2 trial was still associated with significant reductions in the 30-day occurrence of death, recurrent infarction, or disabling stroke (13.7% vs. 8.0% for the composite endpoint; p = 0.0003).2 Alternatively, fibrinolytic therapy is limited by the failure to achieve normal antegrade Thrombolysis in Myocardial Infarction (TIMI) grade 3 flow in 40% or more of patients, early and late reocclusion of the infarct vessel in approximately 10% and 30% of patients, respectively, and iatrogenic hemorrhagic risks, including intracranial bleeding in approximately 1% of patients.3–7 Although TIMI 3 flow may be initially achieved in approximately half of patients receiving fibrinolytic therapy alone, appraisal of impaired microvascular flow, reocclusion, and intermittent (or incomplete) patency have unveiled the “illusion of reperfusion,” with most patients experiencing incomplete epicardial and/or microvascular perfusion following fibrinolytic therapy.8 In spite of results from contemporary trials evaluating fibrinolytic therapy with low-molecular-weight heparins or direct thrombin inhibitors, a “ceiling of reperfusion” has been achieved with standard fibrinolytic and antithrombotic therapy (Figure 1).9–14 Despite the development of 1) newer-generation, more fibrin-specific fibrinolytic agents and 2) novel antithrombin therapies, the current threshold of efficacy with pharmacologic therapies (~ 6% mortality, ~ %50 TIMI 3 flow; Figure 1) has motivated trials of adjunctive GP IIb/IIIa inhibition in acute MI with the intent of further improving the safety and efficacy. The purpose of this review is to present a rationale for the use of GP IIb/IIIa inhibitors as adjunctive therapy to fibrinolysis and primary angioplasty, examine the results from recent trials of GP IIb/IIIa inhibition in patients with acute MI, and describe future directions for clinical investigation. Role of GP IIb/IIIa in acute coronary syndromes. The pathogenesis of ACS is characterized by atherosclerotic plaque rupture, platelet activation and aggregation, and resultant thrombus formation.15,16 In atherosclerotic coronary vessels, plaque rupture exposes the subendothelium, precipitating thrombus formation. Platelets first adhere to the subendothelium by binding to class I glycoproteins. In the presence of thrombin and other agonists such as adenosine or epinephrine, platelet activation occurs, effecting a conformational change in the GP IIb/IIIa receptor and platelet degranulation. This releases serotonin, adenosine diphosphate (ADP), and other vasoactive substances, which stimulate further platelet activation and recruitment. The conformational change in the GP IIb/IIIa receptor allows binding of fibrinogen and von Willebrand factor, producing platelet aggregation and thrombus formation. The subsequent clinical presentation is determined by whether the thrombotic mass is occlusive, sub-occlusive, or non-obstructive, and is influenced by collateral flow, baseline left ventricular function, amount of jeopardized myocardium, diabetes, and other factors. As a result, patients may experience severe angina with ST-segment elevation, non-ST elevation MI, or unstable angina without elevations of cardiac markers. The role of the GP IIb/IIIa receptor as the final common pathway for platelet aggregation made its inhibition a pivotal transition from bench work to clinical practice.17,18 In 1983, Coller and coworkers first reported a murine monoclonal antibody that blocked the IIb/IIIa receptor.19 These findings led to the engineering of a chimeric monoclonal antibody, abciximab (ReoPro), which was first studied in patients undergoing high-risk PCI.20 Since then, several other inhibitors that mimic the arginine-glycine-aspartic acid (RGD) binding sequences of the GP IIb/IIIa receptor have also undergone extensive clinical investigation. These include the synthetic cyclic heptapeptide eptifibatide (Integrilin) as well as peptidomimetics such as tirofiban (Aggrastat) and lamifiban (Ro 44-9883). Despite differences in pharmacodynamics, the common role of these drugs is to inhibit platelet function by occupying the fibrinogen binding site. GP IIb/IIIa inhibition and PCI in ST-elevation myocardial infarction. Recent trials have established evidence supporting GP IIb/IIIa inhibition as adjunctive therapy for primary PCI in acute ST-segment elevation myocardial infarction. Addition of GP IIb/IIIa blockade to PCI for ST-elevation myocardial infarction has substantially lowered the incidence of recurrent ischemic events and improved early survival, ventricular function, and vessel patency. Observations from early studies evaluating the use of GP IIb/IIIa inhibitors prior to primary PCI yielded TIMI 3 flow rates that exceeded previously reported rates of reperfusion with aspirin and heparin and were comparable to full-dose streptokinase.21 Based on the clinical observation that abciximab exhibited intrinsic anticoagulant and clot-dissolving activity,22,23 the GRAPE investigators showed that rates of TIMI grade 2/3 flow occurred in approximately 40% patients treated with abciximab prior to angioplasty.24 More recently, nearly one-third of patients randomized to abciximab alone in the TIMI 14 (32%) and SPEED (27%) trials experienced grade TIMI 3 flow at 90 minutes.25,26 Although treatment with GP IIb/IIIa inhibitors alone is not ideally suited to achieve early reperfusion, such observations reaffirm the potential of abciximab to restore infarct-artery patency prior to mechanical revascularization. Aside from epicardial artery patency, pivotal trials demonstrating improved clinical outcomes with abciximab in unstable angina patients undergoing PCI also lead to studies extending the role of GP IIb/IIIa inhibitors in percutaneous revascularization for acute MI. Among the 893 patients in the EPIC trial27 with evolving myocardial infarction or unstable angina, abciximab was associated with an approximate 30% reduction in death, nonfatal myocardial infarction, or recurrent ischemic complications at 30 days (7.0% vs. 12.8%, 95% confidence interval 0.5–1.1). For the 64 AMI patients undergoing primary or rescue angioplasty,28 treatment with abciximab resulted in an 83% reduction in 30-day death, reinfarction or urgent revascularization. (26.1% vs. 4.5%; p = 0.06). Similarly, in the RAPPORT trial, patients with acute infarction given abciximab in the catheterization laboratory before primary angioplasty experienced significant reductions in 30-day and 6-month death, reinfarction, or urgent revascularization (5.6% vs. 11.2% at 30 days; p = 0.03).29 In the ISAR-2 trial,30 a total of 401 AMI patients within 48 hours of symptom onset for whom rescue or primary PCI were planned were randomized to abciximab bolus plus infusion or control. Abciximab as an adjunct to coronary stenting improved 30-day clinical outcomes (5.0% vs. 10.5%; p = 0.038 for the composite of death, reinfarction, or target lesion revascularization). At one year, although the absolute reduction in the composite endpoint was maintained with abciximab therapy, this early benefit no longer remained statistically significant, largely due to the accrual of restenotic events and the need for repeat revascularization. More recently, the ADMIRAL study demonstrated that abciximab improved early and late TIMI 3 flow (post-PCI TIMI 3 flow, 95.1% for abciximab vs. 86.7% for placebo; p = 0.04; Figure 2), was associated with higher left ventricular ejection fraction (57.0 ± 10.4% vs. 53.9 ± 10.4%; p GP IIb/IIIa inhibition in AMI: Improving myocardial perfusion and downstream microvascular function. New angiographic techniques, including the TIMI myocardial blush score, as well as noninvasive diagnostic tests (e.g., continuous ST segment monitoring, contrast echocardiography) have been used to show that epicardial TIMI flow grade 3 may be an incomplete measure of reperfusion success.34 Although many events can be identified by angiography, such as side branch occlusion or the no-reflow phenomenon, a substantial number of “angiographically silent” events occur at the level of myocardial perfusion. Persistent ST-segment elevation following primary PCI, for example, is associated with reduced left ventricular function and increased mortality.35,36 Despite epicardial vessel patency, disrupted microvascular function and inadequate myocardial perfusion are often the result of thromboembolic debris. To date, a number of studies examining the potential benefit of myocardial perfusion with GP IIb/IIIa antagonists have demonstrated improvements in distal microcirculatory flow. In the TIMI 14 study, patients treated with combined abciximab and fibrinolytic therapy experienced more rapid and complete restoration of epicardial flow as well as angiographically-evident thrombus.37 However, when comparing all patients with 60-minute TIMI 3 flow, combination therapy also resulted in more complete ST-segment resolution.38 Since these findings were independent of the fibrinolytic agent used, an additional mechanism by which abciximab improved myocardial perfusion was proposed; by preventing microvascular obstruction from platelet thromboemboli and the proaggregatory effects of fibrinolysis, abciximab may improve myocardial and microvascular perfusion in addition to epicardial flow. In the single-center open label randomized STOP-AMI trial, the combination of stenting plus abciximab was shown to enhance myocardial salvage and markedly improve event-free survival at 30 days and 1 year compared with accelerated t-PA.39 Similarly, among 162 AMI patients randomized to primary PCI with abciximab or a pharmacologic strategy of reduced-dose alteplase with full-dose abciximab, coronary stenting plus abciximab resulted in significantly greater myocardial salvage and infarct size measured by nuclear imaging at 11 days post-infarction.40 Although 6-month survival tended to favor patients randomized to the invasive strategy, overall survival did not significantly differ in this modest-sized study. Neumann et al. also explored the effects of abciximab on myocardial recovery and coronary flow following stenting in AMI patients.41 In that study, 200 patients within 48 hours of onset of AMI in whom a primary or rescue stent strategy was planned were randomized to a bolus plus 12-hour infusion abciximab regimen or control. Patients treated with abciximab had a lower composite rate of in-hospital death, reinfarction or urgent TVR (9.2% vs. 2.0%; p NOTE: SEE "PART II" OF THIS ARTICLE FOR CONTINUATION
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