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GP IIb/IIIa Inhibition in Acute
Coronary Syndromes

A. Michael Lincoff, MD

Department of Cardiovascular Medicine, The Cleveland Clinic Foundation,
Cleveland, OH, USA

   Thrombosis plays a major role in the pathogenesis of the acute ischemic syndromes of unstable angina and acute myocardial infarction. Rupture of the atherosclerotic plaque is the initiating event, exposing thrombogenic lipids and other subendothelial components, resulting in platelet adhesion, activation, and aggregation, thrombin generation and fibrin deposition, with formation of occlusive thrombus.

   Aggregating platelets form the core of the growing thrombotic mass, with upstream and/or downstream propagation. Pathologic or angioscopic examinations have revealed the presence of characteristic platelet-rich ("white") thrombus at the site of plaque rupture, with proximal and distal extension of fibrin- and erythrocyte-rich ("red") clot (1, 2). Thrombus which becomes occlusive or sub-occlusive or embolizes the coronary vessel may lead to unstable angina or myocardial infarction.

   Management of the acute coronary syndromes is guided to a great extent by initial electrocardiographic findings, which in turn correlate with the extent of coronary occlusion. Patients presenting with ST segment elevation on electrocardiogram will usually be found to have complete coronary occlusion on angiography, and many of these patients will ultimately develop AQ-wave myocardial infarction.@ Initial therapy in this group is aimed at prompt recanalization of the affected coronary vessel by fibrinolytic therapy or primary angioplasty to arrest the wavefront of myocardial necrosis, preserve left ventricular function, and diminish mortality. Patients with acute coronary syndromes without ST segment elevation represent a group in whom thrombotic coronary occlusion is usually subtotal or intermittent, and the majority will be experiencing unstable angina or be found on the basis of elevated myocardial enzymes to have suffered Anon-Q wave myocardial infarction.@ In these patients, fibrinolytic therapy has been demonstrated to offer no clinical benefit (3, 4), and initial management is directed at anticoagulation to prevent further thrombus propagation, as well as reduction of myocardial oxygen demand to reduce ischemia.

   Arterial thrombosis involves both the coagulation cascade (primarily thrombin) and platelets. Thrombin is a central mediator of clot formation through its activation of platelets, conversion of fibrinogen to fibrin, and activation of factor XIII, leading to fibrin cross-linking and clot stabilization. Thrombin molecules are bound to fibrin within the evolving mural coronary thrombus, becoming exposed during endogenous or exogenous thrombolysis; moreover, thrombolytic agents lead to thrombin generation directly or indirectly through the activation by plasmin of prothrombin and factors V and X 5. Enhanced thrombin activity at the site of plaque rupture thus serves as a powerful stimulus for thrombosis and rethrombosis. Platelet activity, however, appears to play a particularly important role in the acute ischemic syndromes. Platelets initiate the formation of thrombus at the plaque rupture site, then act further to render the thrombus resistant to endogenous or exogenous clot lysis, delay reperfusion, and promote cyclic patency and reocclusion.

   The central role of platelet activity in the development of ischemic complications in these settings is highlighted by several studies demonstrating unequivocal clinical benefit derived from aspirin therapy in patients with unstable angina (6-9) or undergoing percutaneous coronary revascularization (3, 10). Yet aspirin is a relatively weak platelet inhibitor, acting on only one (cyclooxygenase, thromboxane-synthetase) of several important pathways to platelet activation and aggregation (11). Strategies for more profound inhibition of platelet activity at the injured coronary plaque focus on the integrin glycoprotein (GP) IIb/IIIa receptor on the platelet surface membrane, which binds circulating fibrinogen or von Willebrand factor and cross-links adjacent platelets as the final common pathway to platelet aggregation (12). Pharmacologic compounds directed against GP IIb/IIIa block this receptor, prevent binding of circulating adhesion molecules, and potently inhibit platelet aggregation (13). Intravenous agents of this class include the chimeric Fab monoclonal antibody fragment abciximab (ReoPro, Centocor, Malvern, PA), a peptide inhibitor eptifibatide (Integrilin, COR Therapeutics, South San Francisco, CA), and non-peptide mimetics tirofiban (Aggrastat, Merck, White House Station, NJ), and lamifiban (Hoffman-La Roche, Basel, Switzerland). These agents have been extensively evaluated in placebo-controlled randomized trials in the settings of unstable ischemic syndromes and percutaneous coronary revascularization.

   The traditional mainstays of antithrombotic therapy for non-ST-segment elevation acute ischemic syndromes have been aspirin and heparin. Recent expansions in this armamentarium include the thienopyridine platelet inhibitors, low molecular weight heparins, and glycoprotein IIb/IIIa inhibitors.

   The antiplatelet effect of aspirin appears to be mediated principally or exclusively through inhibition of the synthesis of thromboxane A2. Thromboxane A2 is released by platelets in response to a number of agonists, amplifying the platelet response leading to aggregation. Across the spectrum of diseases of the vascular wall (coronary artery, cerebrovascular, and peripheral vascular), aspirin has been demonstrated to consistently reduce the risk of adverse ischemic endpoints (3). Among patients with unstable angina in four placebo-controlled trials, aspirin in doses ranging from 75 to 1320 mg per day was associated with consistent reductions in the risk of progression to death or myocardial infarction by 30-50% (6-9).

   Unfractionated heparin is an indirect thrombin inhibitor, exerting its anticoagulant effect by complexing with antithrombin and converting this circulating cofactor from a slow to a rapid inactivator of thrombin, factor Xa, and to a lesser extent, factors XIIa, XIa, and IXa. In contrast to the experience with aspirin, evidence for clinical benefit derived from heparin in the setting of coronary ischemic syndromes has not met the same degree of rigor. Large-scale, placebo-controlled randomized trials have not been carried out for most indications, and optimal approaches for dosing and the incremental efficacy of heparin to that of full dose aspirin remain controversial. In the setting of unstable angina, heparin appears to prevent death or myocardial infarction in the acute phase, but the durability of this benefit is unclear (9, 14).

   The thienopyridines ticlopidine and clopidogrel selectively and irreversibly inhibit ADP-induced platelet activation. A systematic overview of 39 placebo-controlled trials of ticlopidine in patients with vascular disease demonstrated a significant 33% reduction in the risk of ischemic endpoints, a treatment effect which was not significantly different from that produced by aspirin regimens (25-30%) (3). In the CAPRIE trial clopidogrel was found to be modestly superior to aspirin with regard to the long-term suppression of ischemic events in patients with vascular disease(15). More recently, the efficacy of the combination of clopidogrel and aspirin in reducing long-term ischemic complications among patients with acute coronary syndromes without ST-segment elevation was demonstrated in the CURE trial. Among 12,562 patients randomized to aspirin alone versus aspirin plus clopidogrel and followed for 6-12 months, the composite endpoint of cardiovascular death, myocardial infarction, or stroke was reduced from 11.47 to 9.28% (p = 0.0005). In the last several years, a regimen of clopidogrel or ticlopidine for 2 to 4 weeks has assumed an important role in combination with aspirin in the prevention of subacute thrombosis following coronary stent implantation.

   Low molecular weight heparins offer several potential advantages over unfractionated heparin. Their primary action is directed against Factor X, with less inactivation of thrombin; inhibition higher in the coagulation cascade than unfractionated heparin may limit the Arebound@ phenomenon by preventing thrombin generation. Low molecular weight heparins generally have better bioavailability than unfractionated heparin when administered subcutaneously, do not require therapeutic monitoring, and are thus more suitable for long-term administration. Randomized trials have demonstrated that one low-molecular weight heparin, enoxaparin, is superior to unfractionated heparin in preventing ischemic complications during the medical phase (prior to revascularization) of management of patients with acute ischemic syndromes without ST segment elevation (16). Issues of optimal dosing and anticoagulation monitoring in the catheterization laboratory remain to be clarified.

   Three roles for GP IIb/IIIa inhibitors in the setting of unstable angina or non-Q-wave myocardial infarction have been evaluated in clinical trials. First, these agents may be administered as an adjunct to percutaneous coronary revascularization in patients with acute ischemic syndromes, and data for this indication may be derived from subgroup analyses of patients enrolled in the large GP IIb/IIIa interventional trials. Second, the CAPTURE trial investigated the role of abciximab administered as pretreatment for 24 hours prior to coronary angioplasty to stabilize patients with refractory unstable angina. Third, the efficacy of these agents as empiric therapy, with or without revascularization, among patients with unstable ischemic syndromes has been evaluated.

   As an adjunct to percutaneous coronary revascularization, the clinical efficacy of GP IIb/IIIa receptor blockade is marked, with reductions in the 30-day risk of death, myocardial infarction, or repeat urgent intervention of as much as 50-60% among patients undergoing revascularization for elective, urgent, or emergency indications. In the EPIC (17), EPILOG (18), and EPISTENT trials (19), abciximab therapy was associated with absolute 4.5-6.5% (relative 35-58%) reductions in the 30-day composite endpoint. The magnitude of treatment effect was independent of the modality of revascularization (balloon angioplasty, directional atherectomy, or stenting). In IMPACT II and RESTORE, risk reductions with eptifibatide and tirofiban (absolute 1.5-2.5%) were less than in the abciximab trials and did not reach statistical significance. A higher dose of eptifibatide in ESPRIT among stented patients produced an absolute 3.7% risk reduction (20), intermediate between IMPACT II and EPISTENT. In the EPISTENT trial, mortality at one year was significantly reduced by 60% with the combination of abciximab with stenting relative to either therapy alone (21).

   Although clinical benefit of GP IIb/IIIa blockade during coronary intervention has been observed among all subgroups of patients, there is evidence of enhanced efficacy in certain settings. In particular, the composite endpoint rate was decreased from 13.1% to 3.8% (absolute 9.3% risk reduction, relative 71% risk reduction, p = 0.004) and the risk of death or myocardial infarction was diminished from 11.1% to 0.6% (absolute 10.5% risk reduction, relative 94% risk reduction, p <0.001) with abciximab among patients in the EPIC trial with unstable angina and ischemic electrocardiographic changes (22). Similar findings were observed among the subgroups with unstable angina in EPILOG and EPISTENT, wherein baseline (placebo group) event rates tended to be higher among those with unstable as compared with stable ischemia, with neutralization of that excess risk with abciximab therapy. Over 3-year follow-up in EPIC, mortality was significantly reduced by abciximab from 12.7% to 5.1% (p = 0.01) among the 555 highest risk patients enrolled with unstable angina or acute myocardial infarction (23).

   In the CAPTURE trial, patients with refractory unstable angina and angiography demonstrating a coronary lesion suitable for angioplasty were randomized to placebo or abciximab administered for 24 hours prior to and for 1 hour after intervention (24). The primary composite endpoint occurred in 15.9% of patients in the placebo group and 11.3% of patients in the abciximab group (29% relative risk reduction, p=0.012). Clinical benefit of abciximab began to accrue during the pre-treatment phase, with the preprocedural myocardial infarction rate reduced from 2.1% among control patients to 0.6% among those treated with abciximab (p=0.029).

   The GP IIb/IIIa inhibitors have also been evaluated in six large-scale, placebo-controlled trials among a total of over 23,000 patients with unstable angina: eptifibatide in PURSUIT (25), tirofiban in PRISM (26) and PRISM PLUS (27) trials, lamifiban in PARAGON -A and PARAGON-B (28), and abciximab in GUSTO IV (29). The largest of these trials was PURSUIT, in which treatment with eptifibatide rather than placebo among almost 11,000 patients was associated with an absolute 1.5% reduction (10% relative risk reduction) in the incidence of death or myocardial infarction at 30 days. The other four unstable angina trials, ranging in size from 1500 to 5200 patients, similarly demonstrated reductions in the risk of death or myocardial infarction ranging from 8-27%. The treatment effect of these agents appears to be greatest among those who undergo early percutaneous coronary revascularization, with clear evidence of stabilization during the period prior to intervention as well as suppression of postprocedural ischemic events. Patients with positive troponin markers of myocardial necrosis may derive enhanced benefit from GP IIb/IIIa therapy in this setting. More recently, the GUSTO-IV trial (29) failed to show efficacy of abciximab administered for 24 or 48 hours in a population of patients managed medically for unstable ischemic syndromes; reasons for the lack of benefit of abciximab in this setting are unknown, but may be related to inadequate platelet inhibition during prolonged infusion or the infrequent use of coronary revascularization in that trial. Oral glycoprotein IIb/IIIa inhibitors have not been shown to reduce ischemic events in patients with acute ischemic syndromes, and have even been associated with an increased mortality risk.

   The benefit of fibrinolytic therapy in the setting of acute myocardial infarction was unequivocally demonstrated by 5 major placebo-controlled, randomized trials, which used as their primary endpoints the reduction in short-term (3-5 week) mortality (30-34). Despite different entry criteria, thrombolytic agents, adjunctive therapies, and follow-up periods, the highly concordant results of these trials, demonstrated a pooled mortality reduction of 27% among over 28,000 patients. A further benefit was achieved with the Aaccelerated@ regimen of alteplase (t-PA) in the Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries (GUSTO) trial; a 1% absolute (14% relative) decrease in 30-day mortality was observed with this regimen compared with streptokinase (35), coupled with a higher rate of complete Thrombolysis in Myocardial Infarction (TIMI) grade 3 flow with accelerated t-PA (36). Other major advances in the acute therapy for myocardial infarction include the demonstration of the benefit of coadministration of aspirin with thrombolytic therapy: in the ISIS-2 study (31), aspirin resulted in highly significant reduction in 5-week mortality (23%) which was equivalent to that due to streptokinase (25%) and additive when streptokinase and aspirin were combined (42%). Moreover, a meta-analysis of 32 studies of aspirin showed the significant effects of this platelet inhibitor on reocclusion and recurrent ischemia, with an approximate halving of the frequency of these adverse endpoints (37).

   The role of heparin therapy among patients receiving thrombolytic therapy for acute myocardial infarction is controversial, with angiographic data suggesting that intravenous heparin may provide modest improvements in late infarct vessel patency and reduce reocclusion (38-40). Improvements in patency produced by heparin appear to be linked to the adequacy of anticoagulation, with a dose-response relationship observed between activated aPTT values and infarct vessel patency (41). Two large-scale studies (42-44) provided compelling evidence, however, that delayed subcutaneous heparin does not reduce mortality as an adjunct to thrombolysis and aspirin and likely increases bleeding complications. No definitive outcome data has been generated, however, supporting a reduction in clinical events with intravenous heparin therapy in this setting. Moreover, the therapeutic window for heparin appears to be narrow, with data suggesting that the risk of hemorrhagic complications (most importantly, hemorrhagic stroke) may be substantially increased with higher doses of intravenous heparin used as an adjunct to aspirin and thrombolytic agents (45, 46). Data from both the GUSTO-1 and GUSTO-2 studies suggests that the optimal level of anticoagulation with heparin among patients receiving thrombolytic therapy, associated with the lowest rates of death and bleeding complications, will target an aPTT of 55-75 seconds.

   The current Astate-of-the-art@ of reperfusion therapy for acute myocardial infarction continues to have important limitations. First, there is an apparent Aceiling@ of patency which may be achieved by pharmacologic reperfusion. A number of new fibrinolytic agents have been developed which differ from alteplase with regard to fibrin-specificity, resistance to inhibitors, or circulating half-life. Yet large-scale randomized mortality trials of these agents have failed to show any reduction in mortality with reteplase (47), tenectoplase (48), or lanoteplase as compared with the accelerated alteplase regimen. Second, with lanoteplase, lack of mortality reduction was accompanied by an increase in the incidence of intracranial hemorrhage (ICH). In fact, a general trend toward increasing ICH risk can be observed over time among all of the fibrinolytic trials; whereas in the early GISSI-2 trial, ICH was documented in 0.3-0.4% of patients (43), more recent trials have shown rates of ICH in the range of 0.6-1.1% (47, 48). This rise in ICH rates may be related in part to broader patient entry criteria for the trials, with increasing proportions of elderly and hypertensive patients, but also reflects the increasing Aaggressiveness@ of the antithrombotic therapy. Third, there is evidence that among a substantial proportion of patients with successful infarct-vessel recanalization, the quality of tissue level reperfusion is degraded by intermittent patency, frank reocclusion, or impaired tissue level reperfusion (49-53). Fourth, the mortality reduction derived from fibrinolytic therapy is critically dependent upon the time to reperfusion, with maximum survival benefit achieved if these agents can be administered within the first 1-2 hours of symptom onset (54).

   To overcome some of the limitations of fibrinolytic therapy, several groups of investigators have instead advocated direct coronary balloon angioplasty as a means of achieving infarct vessel patency.

   Randomized trials comparing fibrinolytic therapy to direct angioplasty have in general shown angioplasty to be associated with lower rates of mortality and hemorrhagic complications (55-58). Difficulties with the direct angioplasty approach include limited availability, the requirement for institutional and operator expertise, and the logistic barriers to mobilizing catheterization laboratory teams during night and weekend hours. Most importantly, the treatment effect of direct angioplasty, as with fibrinolytic therapy, is dependent upon the time to reperfusion. Analyses of the GUSTO IIb Angioplasty Substudy experience (59) as well as that of a high-volume community practice (60) have shown that maximal clinical benefit is achieved with a Adoor-to-balloon@ time of less than 60-90 minutes. Yet the mean time to catheter reperfusion exceeds 90-120 minutes in most published experiences. It is perhaps for these reasons that community- or registry-based comparisons of direct angioplasty and fibrinolysis have tended to show less difference in outcome between these two strategies than seen in randomized trials (61).

   A dichotomy therefore exists between two imperfect approaches to patients with acute myocardial infarction. Fibrinolytic therapy has the advantages of rapid administration, wide availability, and convenience; direct angioplasty may be more efficacious at expert institutions, carries less bleeding risk, and allows anatomic-based risk assessment. Combination of the mechanical and pharmacologic approaches has been hindered by trial data showing higher rates of ischemic and hemorrhagic complications among patients treated with routine adjunctive angioplasty after full-dose thrombolytic therapy (62-64).

   Recently, stent placement during acute myocardial infarction has been evaluated as a means of improving outcome following direct percutaneous revascularization (65-68). Although trials comparing stents to balloon angioplasty have consistently shown a reduction in the incidence of restenosis or the need for target vessel revascularization with stents, hard clinical endpoints have not been improved by stents. In the Stent-PAMI trial, rates of TIMI 3 flow tended to be lower in patients who received stents rather than PTCA (89 vs 93%, p = 0.10), and mortality at one-year trended to be higher with stenting (4.6 vs 2.7%, p = 0.27). This finding suggests that despite improving the angiographic result at the epicardial artery stenosis, stenting does not enhance the quality of tissue level reperfusion relative to balloon angioplasty. Possible etiologies of impaired microvascular perfusion include platelet-leukocyte aggregates (embolic from the epicardial stenosis or forming in situ), microvascular spasm, endothelial cell edema, perivascular edema, or loss of microvascular integrity due to myocardial necrosis. Some of these processes, particularly those related to platelet and leukocyte activity, may be modifiable by improved adjunctive pharmacologic therapy.

   Given the unequivocal efficacy of aspirin, with or without reperfusion therapy, in improving mortality and reducing reinfarction and recurrent ischemia among patients with acute ST segment elevation myocardial infarction, the potential role of GP IIb/IIIa inhibitors in this setting have been investigated as: 1) adjunctive therapy during Aprimary@ or direct percutaneous coronary revascularization, 2) a sole means of reperfusion, 3) adjunctive therapy to full-dose fibrinolytic agents, and 4) adjunctive therapy with reduced-dose fibrinolytic agents.

   GP IIb/IIIa Blockade as an Adjunct to Primary Coronary Intervention. Abciximab is the only GP IIb/IIIa inhibitor shown to effective in reducing ischemic complications as an adjunct to primary percutaneous revascularization (69-71). Periprocedural abciximab therapy was tested in RAPPORT (69) during primary balloon angioplasty and in the ISAR-2, ADMIRAL, and CADILLAC trials during stenting. The magnitude of reduction in acute ischemic events in these trials of acute MI (50-60% relative risk reductions) were similar to that observed in other PCI trials for more elective indications. In the Munich study, indices of microvascular flow were all significantly better among patients who had received abciximab, providing evidence that intense platelet inhibition by GP IIb/IIIa blockade may improve tissue level reperfusion (70). The apparent lesser treatment effect of abciximab in the CADILLAC trial seems related to the low risk profile of the patient population and the methods of ascertaining endpoints; that trial was designed primarily to assess the effect of stenting vs angioplasty on late target vessel revascularization.

   GP IIb/IIIa Blockade as Sole Reperfusion Therapy. Based upon preclinical evidence of platelet disaggregatory and clot dissolution properties of abciximab (72), investigators have proposed that coronary reperfusion may be achieved by potent GP IIb/IIIa inhibition alone without administration of exogenous plasminogen activators (or percutaneous coronary revascularization). In Phase II studies of patients treated with only abciximab, rates of TIMI 3 reperfusion 45-90 minutes after receiving only abciximab have ranged from 18-32% van den (73, 74), comparable to patency rates achieved with streptokinase (36). Thus, although GP IIb/IIIa antagonists likely have modest Athrombolytic@ properties, their optimal role in these patients will likely be as adjuncts to traditional reperfusion therapies.

   GP IIb/IIIa Blockade as an Adjunct to Full-Dose Fibrinolytic Therapy. Preclinical studies demonstrated that GP IIb/IIIa antagonists accelerate reperfusion and potently inhibit reocclusion and cyclic flow variations in animal models of coronary thrombolysis (75, 76). In the first clinical study (77), the highest doses of 7E3 Fab (the precursor to abciximab) were associated with reduced rates of recurrent ischemia and improved late coronary patency after administration of alteplase. In a subsequent dose-escalation trial (78), 90-minute angiography demonstrated improved rates of complete TIMI 3 patency among patients receiving the highest doses of eptifibatide with alteplase as compared with alteplase alone (66% vs 39%, p=0.006), and median time to ST-segment recovery by continuous electrocardiographic monitoring was reduced from 116 to 65 minutes (p = 0.05). Similar findings were obtained in dose-escalation study of lamifiban therapy with alteplase or streptokinase, with significant improvements in the speed and stability of reperfusion as assessed by continuous electrocardiographic monitoring (79).

   Bleeding complications were increased with higher doses of lamifiban in the latter trial (major bleeding in 15.2% vs 6.0% of patients receiving lamifiban and placebo, respectively, p = 0.059). A fourth trial of eptifibatide and full-dose streptokinase was terminated early due to a marked excess risk of hemorrhage with this combination (80).

   GP IIb/IIIa Blockade as an Adjunct to Reduced-Dose Fibrinolytic Therapy. The most recent series of GP IIb/IIIa trials in acute myocardial infarction focus on the hypothesis that by inhibiting platelet activation induced by exogenous plasminogen activators and directly disaggregating the platelet thrombus, administration of GP IIb/IIIa antagonists may achieve improved infarct vessel patency with reduced doses of fibrinolytic agents. The TIMI-14 trial randomized 888 patients with acute myocardial infarction to receive control therapy with accelerated alteplase (100 mg over 90 minutes) or full-dose abciximab alone or in combination with various doses of alteplase or streptokinase (74). In the dose-finding phase, the best regimen was abciximab with alteplase 50 mg as a bolus and 60 minute infusion: TIMI 3 patency rates at 90 minutes were 76% and 57% in the combined therapy and control alteplase arms, respectively. Patency improved with increasing duration of alteplase (bolus vs bolus plus 30 minute infusion vs bolus plus 60 minute infusion), and with low-dose (60 U/kg) rather than very low dose (30 U/kg) heparin dose regimens. In contrast, there was an apparent dose-related increase in bleeding complications with streptokinase in combination with abciximab, without evidence of a dose-related improvement in patency. In the SPEED trial, 304 patients with myocardial infarction were randomized to receive control therapy with abciximab only or abciximab with escalating doses of reteplase (73). The best regimen was abciximab with reteplase administered as two 5 U boluses 30 minutes apart (half the conventional dose), with a TIMI 3 patency rate at 60 minutes of 64%. As with TIMI 14, there was evidence of dimished efficacy with a heparin dose of 40 U/kg rather than 60 U/kg.

   The large-scale phase III GUSTO V trial was recently reported, investigating the efficacy of the combination of abciximab with reduced-dose fibrinolytic therapy in reducing mortality compared with conventional full-dose fibrinolytic therapy (81). A total of 16,588 patients were enrolled world-wide with acute myocardial infarction of less than 6 hours duration with ST-segment elevation or new left bundle branch block. Exclusion criteria included planned immediate direct angioplasty or uncontrolled hypertension. Patients were randomized to receive full-dose reteplase (10 U + 10 U double bolus) with aspirin and heparin (5000 U bolus plus 1000 U/hr for 24 hours) or half-dose reteplase (5U + 5 U double bolus) with full-dose abciximab, aspirin, and heparin (60 U/kg plus 7 U/kg-hr for 24 hours). Emergency angiography and revascularization were permitted for clinical evidence of failed pharmacologic reperfusion. The primary endpoint of the study was mortality at 30-days, which occurred in 5.91% of patients receiving full-dose reteplase therapy vs 5.62% of patients receiving combination abciximab plus half-dose reteplase (p = 0.45). This difference did not meet statistical significance for superiority of the combination therapy, but did meet formal criteria for the alternative hypothesis of non-inferiority. There was a trend toward greater mortality reduction among higher risk patients with anterior myocardial infarction (8.5 vs 7.6%, p = 0.17). Other prespecified endpoints were significantly reduced by combination therapy, including reinfarction (3.5 vs 2.3%, p<0.0001), urgent percutaneous revascularization within the first 6 hours (8.6 vs 5.6%, p<0.0001), recurrent ischemia (12.8 vs 11.3%, p = 0.004), sustained ventricular tachycardia (2.8 vs 2.2%, p = 0.02), ventricular fibrillation (3.5 vs 2.7%, p = 0.008), and 2-degree or 3-degree atrioventricular block (3.3 vs 2.7%, p = 0.02). Bleeding complications were increased somewhat among patients receiving combination therapy: severe bleeding from 0.5 to 1.1% (p <0.001) and moderate bleeding from 1.8 to 3.5% (p<0.001). There was no increase in the risk of intracranial hemorrhage (0.6% in both treatment groups) with combination therapy. Thus, the findings of GUSTO V establish an alternative form of pharmacologic reperfusion that may yield more stable infarct vessel patency and better facilitate mechanical revascularization than conventional fibrinolytic therapy alone.


1. Falk E. Coronary thrombosis: pathogenesis and clinical manifestations. Am J Cardiol 1991; 68:28B-35B.

2. Friedman MF, Van der Bovenkamp E. The pathogenesis of a coronary thrombus. Am J Pathol 1966; 48:19-44.

3. Antiplatelet Trialists' Collaboration. Collaborative overview of randomised trials of antiplatelet therapy - I: Prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. BMJ 1994; 308:81-106.

4. TIMI IIIB Investigators. Effects of tissue plasminogen activator and a comparison of early invasive and conservative strategies in unstable angina and non-Q-wave myocardial infarction. Results of the TIMI IIIB trial. Circulation 1994; 89:1545-1556.

5. Lee CD, Mann KG. Activation/inactivation of human coagulation factor V by plasmin. Blood 1989; 73:185-190.

6. Lewis HDJ, Davis JW, Archibald DG, et al. Protective effects of aspirin against acute myocardial infarction and death in men with unstable angina: results of the Veterans Administration Cooperative Study. N Engl J Med 1983; 309:396-403.

7. Cairns JA, Gent M, Singer J, et al. Aspirin, sulfinpyrazone, or both in unstable angina. N Engl J Med 1985; 313:1369-1375.

8. Theroux P, Ouimet H, McCans J, et al. Aspirin, heparin, or both to treat acute unstable angina. N Engl J Med 1988; 319:1105-1111.

9. RISC Group. Risk of myocardial infarction and death during treatment with low dose aspirin and intravenous heparin in men with unstable coronary artery disease. Lancet 1990; 336:827-30.

10. Schwartz L, Bourassa MG, Lesperance J, et al. Aspirin and dipyridamole in the prevention of restenosis after percutaneous transluminal coronary angioplasty. N Engl J Med 1988; 318:1714-1719.

11. Coller BS. Platelets and thrombolytic therapy. N Engl J Med 1990; 322:33-42.

12. Phillips DR, Charo IF, Parise LV, Fitzgerald LA. The platelet membrane glycoprotein IIb/IIIa complex. Blood 1988;


13. Lefkovits J, Ivanhoe R, Anderson K, Weisman H, Topol EJ. Platelet IIb/IIIa receptor inhibition during PTCA for acute myocardial infarction: insights from the EPIC trial (abstr). Circulation 1994; 90:I-564.

14. Holdright D, Patel D, Cunningham D, et al. Comparison of the effect of heparin and aspirin versus aspirin alone on transient myocardial ischemia and in-hospital prognosis in patients with unstable angina. J Am Coll Cardiol 1994; 24:39-45.

15. CAPRIE Steering Committee. A randomised, blinded trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 1996; 348:1329-39.

16. Antman EM, Cohen M, Radley D, et al. Assessment of the treatment effect of enoxaparin for unstable angina/non-Q-wave myocardial infarction. TIMI 11B-ESSENCE meta analysis. Circulation 1999; 100:1602-1608.

17. EPIC Investigators. Use of a monoclonal antibody directed against the platelet glycoprotein IIb/IIIa receptor in high-risk coronary angioplasty. N Engl J Med 1994; 330:956-961.

18. EPILOG Investigators. Platelet glycoprotein IIb/IIIa blockade with abciximab with low-dose heparin during percutaneous coronary revascularization. N Engl J Med 1997; 336:1689-1696.

19. EPISTENT Investigators. Randomised placebo-controlled and balloon-angioplasty-controlled trial to assess safety of coronaryt stenting with use of platelet glycoprotein IIb/IIIa blockade. Lancet 1998; 352:87-92.

20. ESPRIT Investigators. Novel dosing regimen of eptifibatide in planned coronary stent implantation (ESPRIT): a randomised, placebo-controlled trial. Lancet 2000; 356:2037-2044.

21. Topol EJ, Mark DB, Lincoff AM, et al. Enhanced survival with platelet glycoprotein IIb/IIIa blockade in patients undergoing coronary stenting: one year outcomes and health care economic implications from a multicenter, randomized trial. Lancet 1999; 354:2019-2024.

22. Lincoff AM, Califf RM, Anderson KM, et al. Evidence for prevention of death and myocardial infarction with platelet membrane glycoprotein IIb/IIIa receptor blockade by c7E3 Fab (abciximab) among patients with unstable angina undergoing percutaneous coronary revascularization. J Am Coll Cardiol 1997; 30:149-156.

23. Topol EJ, Ferguson JJ, Weisman HF, et al. Long-term protection from myocardial ischemic events in a randomized trial of brief integrin b3 blockade with percutaneous coronary intervention. JAMA 1997; 278:479-484.

24. CAPTURE Investigators. Randomised placebo-controlled trial of abciximab before and during coronary intervention in refractory unstable angina: the CAPTURE Study. Lancet 1997; 349:1429-1435.

25. PURSUIT Trial Investigators. Inhibition of platelet glycoprotein IIb/IIIa with eptifibatide in patients with acute coronary syndromes. N Engl J Med 1998; 339:436-443.

26. PRISM Study Investigators. A comparison of aspirin plus tirofiban with aspirin plus heparin for unstable angina. N Engl J Med 1998; 338:1498-1505.

27. PRISM PLUS Study Investigators. Inhibition of the platelet glycoprotein IIb/IIIa receptor with tirofiban in unstable angina and non-Q -wave myocardial infarction. N Engl J Med 1998; 338:1488-1497.

28. PARAGON Investigators. International, randomized, controlled trial of lamifiban (a platelet glycoprotein IIb/IIIa inhibitor, heparin, or both in unstable angina. Circulation 1998; 97:2386-2395.

29. GUSTO IV-ACS Investigators. Effect of glycoprotein IIb/IIIa receptor blocker abciximab on outcome in patients with acute coronary syndromes without early coronary revascularisation: the GUSTO IV-ACS randomised trial. Lancet 2001; 357:1915-1924.

30. Gruppo Italiano per lo Studio della Streptochinasi nell'Infarto Miocardico (GISSI). Effectiveness of intravenous thrombolytic treatment in acute myocardial infarction. Lancet 1986; 1:397-401.

31. ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. Randomized trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. Lancet 1988; 2:349-360.

32. ISAM Study Group. A prospective trial of intravenous streptokinase in acute myocardial infarction (I.S.A.M.). N Engl J Med 1986; 314:1465-1471.

33. AIMS Trial Study Group. Effect of intravenous APSAC on mortality after acute myocardial infarction: preliminary report of a placebo-controlled clinical trial. Lancet 1988; 1:545-549.

34. Wilcox RG, Olsson CG, Skene AM, et al. Trial of tissue plasminogen activator for mortality reduction in acute myocardial infarction. Anglo-Scandinavian Study of Early Thrombolysis (ASSET). Lancet 1988; 2:525-530.

35. GUSTO Investigators. An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction. N Engl J Med 1993; 329:673-682.

36. GUSTO Angiographic Investigators. The effects of tissue plasminogen activator, streptokinase, or both on coronary-artery patency, ventricular function, and survival after acute myocardial infarction. N Engl J Med 1993; 329:1615-1622.

37. Roux S, Christeller S, Ludin E. Effects of aspirin on coronary reocclusion and recurrent ischemia after thrombolysis: a meta-analysis. J Am Coll Cardiol 1992; 19:671-677.

38. Bleich SD, Nichols TC, Schumacher RR, Cooke DH, Tate DA, Teichman SL. Effect of heparin on coronary arterial patency after thrombolysis with tissue plasminogen activator in acute myocardial infarction. Am J Cardiol 1990; 66:1412-1417.

39. Col J, Decoster O, Hanique C, et al. Infusion of heparin conjuct to streptokinase accelerates reperfusion of acute myocardial infarction: results of a double blind randomized study (OSIRIS) (abstr). Circulation 1992; 86:I-259.

40. de Bono DP, on behalf of the European Cooperative Study Group (ECSG-6). Effect of early intravenous heparin on coronary patency, infarct size, and bleeding complications after alteplase thrombolysis: results of a randomised double blind European Cooperative Study Group (ECSG-6). Br Heart J 1992; 67:122-128.

41. Arnout J, Simoons M, de Bono D, Rapold HJ, Collen D, Verstraete M. Correlation between level of heparinization and patency of the infarct-related coronary artery after treatment of acute myocardial infarction with alteplase (rt-PA). J Am Coll Cardiol 1992; 20:513-519.

42. ISIS-3 (Third International Study of Infarct Survival) Collaborative Group. ISIS-3: a randomised comparison of streptokinase vs tissue plasminogen activator vs anistreplase and of aspirin plus heparin vs aspirin alone among 41,229 cases of suspected acute myocardial infarction. Lancet 1992; 339:753-770.

43. Gruppo Italiano per lo Studio dell Sopravvivenza nell'Infarto Miocardico. GISSI-2: A factorial randomized trial of alteplase versus streptokinase and heparin versus no heparin among 12,490 patients with acute myocardial infarction. Lancet 1990; 336:65-71.

44. International, Study Group. In-hospital mortality and clinical course of 20,891 patients with suspected acute myocardial infarction randomised between alteplase and streptokinase with or without heparin. Lancet 1990; 336:71-75.

45. GUSTO II Investigators. Randomized trial of intravenous heparin versus recombinant hirudin for acute coronary syndromes. The Global Use of Strategies To Open occluded coronary arteries (GUSTO) IIa investigators. Circulation 1994; 90:1631-1637.

46. Antman EM, for the TIMI 9A Investigators. Hirudin in acute myocardial infarction. Safety report from the thrombolysis and thrombin inhibition in myocardial infarction (TIMI) 9A trial. Circulation 1994; 90:1642-1630.

47. GUSTO III Investigators. A comparison of reteplase with alteplase for acute myocardial infarction. The Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO III) Investigators. NEJM 1997; 337:1118-1123.

48. ASSENT-2 (Assessment of the Safety and Efficacy of a New Thombolytic) Investigators. Single-bolus tenecteplase compared with front-loaded alteplase in acute myocardial infarction: the ASSENT-2 double- blind randomised trial. Lancet 1999; 354:716-722.

49. Granger CB, Califf RM, Topol EJ. Thrombolytic therapy for acute myocardial infarction, a review. Drugs 44 1992; 3:293-325.

50. Ito H, Tomooka T, Sakai N, et al. Lack of myocardial perfusion immediately after successful thrombolysis. A predictor of poor recovery of left ventricular function in anterior myocardial infarction. Circulation 1992; 85:1699-1705.

51. Grines CL, Topol EJ, Bates ER, Juni JE, Walton JA, O'Neill WW. Infarct vessel status after intravenous tissue plasminogen activator and acute coronary angioplasty: prediction of clinical outcome. Am Heart J 1988; 115:1-7.

52. Hackett D, Davies G, Chierchia S, Maseri A. Intermittent coronary occlusion in acute myocardial infarction. Value of combined thrombolytic and vasodilator therapy. N Engl J Med 1987; 317:1055-1059.

53. Lincoff AM, Topol EJ. Illusion of reperfusion. Does anyone achieve optimal reperfusion during acute myocardial infarction? Circulation 1993; 87:1792-1805 (Erratum 1993;88:1361-1374).

54. Fibrinolytic Therapy Trialists' (FTT) Collaborative Group. Indications for fibrinolytic therapy in suspected acute myocardial infarction: collaborative overview of early mortality and major morbidity results from all randomised trials of more than 1000 patients. Lancet 1994; 343:311-322.

55. Grines CL, Browne KF, Marco J, et al. A comparison of immediate angioplasty with thrombolytic therapy for acute myocardial infarction. New England Journal of Medicine 1993; 328:673-679.

56. GUSTO II Angioplasty Substudy Investigators. A clinical trial comparing primary coronary angioplasty with tissue plasminogen activator and recombinant hirudin for acute myocardial infarction. New Engl J Med 1997; 336:1621-1628.

57. Zijlstra F, Jan De Boer M, Hoorntje CA, Reiffers S, Reiber JHC, Suryapranta H. A comparison of immediate coronary angioplasty with intravenous streptokinase in acute myocardial infarction. N Engl J Med 1993; 328:680-684.

58. Gibbons RJ, Holmes DR, Reeder GS, Bailey KR, Hopfenspirger MR, Gersh BJ. Immediate angioplasty compared with the administration of a thrombolytic agent followed by conservative treatment for myocardial infarction. N Engl J Med 1993; 328:685-691.

59. Berger P, Ellis S, Holmes D, et al. Relationship between delay in performing direct coronary angioplsty and early clinical outcome in patients with acute myocardial infarction: results from the Global Use of Strategies to Open Occluded Arteries in Acute Coronary Syndromes (GUSTO IIb) trial. Circulation 1999; 100:14-20.

60. Brodie BR, Stuckey TD, Wall TC, et al. Importance of time to reperfusion for 30-day and late survival and recovery of left ventricular function after primary angioplasty for acute myocardial infarction. J Am Coll Cardiol 1998; 32:1312-1319.

61. Danchin N, Vaur L, Genes N, et al. Treatment of acute myocardial infarcion by primary coronary angioplsty or intravenous thrombolysis in the "real world". Circulation 1999; 99:2639-2644.

62. TIMI Research Group. Immediate vs. delayed catheterization and angioplasty following thrombolytic therapy for acute myocardial infarction. TIMI IIA results. JAMA 1988; 260:2849-2858.

63. SWIFT Trial Study Group. SWIFT trial of delayed elective intervention v conservative treatment after thrombolysis with anistreplase in acute myocardial infarction. Br Med J 1991; 302:555-560.

64. Topol EJ, Califf RM, George BS, et al. A randomized trial of immediate versus delayed elective angioplasty after intravenous tissue plasminogen activator in acute myocardial infarction. N Engl J Med 1987; 317:581-588.

65. Schomig A, Neumann F, Walter H, et al. Coronary stent placement in patients with acute myocardial infarction: comparison of clinical and angiographic outcome after randomization to antiplatelet or anticoagulant therapy. J Am Coll Cardiol 1997; 29:28-34.

66. Rodriguez A, Bernardi V, Fernandez M, et al. In-hospital and late results of coronary stents versus conventional balloon angioplasty in acute myocardial infarction (GRAMI trial). Am J Cardiol 1998; 81:1286-1291.

67. Antoniucci D, Santoro G, Bolognese L, Valenti R, Trapani M, Fazzini P. A clinical trial comparing primary stenting of the infarct-related artery with optimal primary angioplasty for acute myocardial infarction. Results from the Florence Randomized Elective Stenting in Acute Coronary Occlusions (FRESCO) trial. J Am Coll Cardiol 1998; 31:1234-1239.

68. Grines CL, Cox DA, Stone GW, et al. Coronary angioplasty with or without stent implantation for acute myocardial infarction. N Engl J Med 1999; 341:1949-1956.

69. Brener SJ, Barr LA, Burchenal JEB, et al. A randomized, placebo-controlled trial of platelet glycoprotein IIb/IIIa blockade with primary angioplasty for acute myocardial infarction. Circulation 1998; 98:734-741.

70. Neumann FJ, Blasini R, Schmitt C, et al. Effect of glycoprotein IIb/IIIa receptor blockade on recovery of coronary flow and left ventricular function after the placement of coronary artery stents in acute myocardial infarction. Circulation 1999; 98:2695-2701.

71. Montalescot G, Barragan P, Wittenberg O, et al. Platelet glycoprotein IIb/IIIa inhibition with coronary stenting for acute myocardial infarction. N Eng J Med 2001; 344:1895-1903.

72. Gold HK, Garabedian HD, Dinsmore RE, et al. Restoration of coronary flow in myocardial infarction by intravenous chimeric 7E3 antibody without exogenous plasminogen activators. Observations in animals and humans. Circulation 1997; 95:1755-1759.

73. SPEED Trial Investigators. Randomized trial of abciximab with and without low-dose reteplase for acute myocardial infarction. Circulation 2000; 101:2788-2794.

74. Antman E, Guigliano R, Gibson C, et al. Abciximab facilitates the rate and extent of thrombolysis results of the thrombolysis in myocaridal infarction (TIMI) 14 trial. Circulation 1999; 99:2720-2732.

75. Gold HK, Coller BS, Yasuda T, et al. Rapid and sustained coronary artery recanalization with combined bolus injection of recombinanat tissue-type plasminogen activator and monoclonal antiplatelet GPIIb/IIIa antibody in a canine preparation. Circulation 1988; 77:670-677.

76. Mickelson JK, Simpson PJ, Cronin M, et al. Antiplatelet antibody [7E3 F(ab')2] prevents rethrombosis after recombinant tissue-type plasminogen activator-induced coronary artery thrombolysis in a canine model. Circulation 1990; 81:617-627.

77. Kleiman NS, Ohman EM, Kereiakes DJ, et al. Profound platelet inactivation with 7E3 shortly after thrombolytic therapy for acute myocardial infarction: preliminary results of the TAMI 8 trial (abstr). Circulation 1991; 84:II-522.

78. Ohman EM, Kleiman NS, Gacioch G, et al. Combined acclerated tissue-plasminogen activator and platelet glycoprotein IIb/IIIa integrin receptor blockade with integrilin in acute myocardial infarction. Results of a randomized, placebo-contolled, dose-ranging trial. Circulation 1997; 95:846-854.

79. PARADIGM Investigators. Combining thrombolysis with the platelet glycoprotein IIb/IIIa inhibitor lamifiban: Results of the platelet aggregation receptor antagonist dose investigation and reperfusion gain in myocardial infarction (PARADIGM) trial. J Am Coll Cardiol 1998; 32:2003-2010.

80. Ronner E, van Kesteren H, Zijnen P, et al. Combined therapy with spreptokinase and Integrilin (abstr). J Am Coll Cardiol 1998; 31:191A.

81. GUSTO V Investigators. Reperfusion therapy for acute myocardial infarction with fibrinolytic therapy or combination reduced fibrinolytic therapy and platelet glycoprotein IIb/IIIa inhibition: the GUSTO V randomised trial. Lancet 2001; 357:1905-1914.


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2nd Virtual Congress of Cardiology

Dr. Florencio Garófalo
Steering Committee
Dr. Raúl Bretal
Scientific Committee
Dr. Armando Pacher
Technical Committee - CETIFAC

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