In patients with ST-segment elevation acute myocardial infarction (AMI), several studies have examined the role of glycoprotein (GP) IIb/IIIa receptor inhibition as adjunctive pharmacotherapy for percutaneous coronary intervention (PCI) and as part of a combined fibrinolytic/antiplatelet regimen. In the ReoPro and Primary PTCA Organization and Randomized Trial (RAPPORT), the use of abciximab as adjunctive therapy during primary angioplasty for AMI reduced the composite endpoint of death, recurrent MI and urgent revascularization at 30 days by approximately 50% compared with controls (5.8% versus 11.2%, respectively; p = 0.03).1 Then, the Intracoronary Stenting and Antithrombotic Regimen (ISAR-2) trial demonstrated a similar reduction with abciximab in the composite endpoint of death, recurrent MI and urgent revascularization at 30 days in patients undergoing primary stenting (5.0% versus 10.5%, respectively; p = 0.038).2 The Abciximab Before Direct Angioplasty and Stenting in Myocardial Infarction Regarding Acute and Long-term Follow-up (ADMIRAL) trial, which also examined abciximab as an adjunct to stenting, demonstrated a 59% reduction at 30 days in the composite endpoint of death, recurrent MI or urgent target vessel revascularization (TVR) with abciximab compared with placebo in a high-risk population of patients (6.0% versus 14.6%, respectively; p = 0.01).3 Furthermore, the Stent Versus Thrombolysis for Occluded Coronary Arteries in Patients with Acute Myocardial Infarction (STOP-AMI) investigators demonstrated that stenting with abciximab was associated with improved recovery of microvascular function, reduced infarct size, better preservation of left ventricular (LV) function and a significant survival benefit compared to fibrinolysis with alteplase.4 Three small angiographic studies have assessed the effect of abciximab alone on restoring infarct vessel patency during AMI. In the Glycoprotein Receptor Antagonist Patency Evaluation (GRAPE) trial,5 a Thrombolysis in Myocardial Infarction (TIMI) 3 flow rate of 18% was achieved with abciximab at a mean of 45 minutes. Similar improvements in TIMI flow were observed in the abciximab-only arms of the Strategies for Patency Enhancement in the Emergency Department (SPEED) trial (TIMI 3 flow in 27% of patients at 60–90 minutes) and TIMI-14 (TIMI 3 flow in 32% of patients at 90 minutes) trials.6,7 The initial experience with GP IIb/IIIa antagonists suggests the potential for improved vessel patency when these agents are combined with full-dose fibrinolytic therapy. Abciximab, given soon after full-dose alteplase in the Thrombolysis and Angioplasty in Myocardial Infarction (TAMI-8) study, was associated with a pre-discharge infarct patency rate of 92% compared with 56% in controls, bleeding rates comparable to those in control patients and a reduction in recurrent ischemia.8 The addition of lamifiban (a small-molecule GP IIb/IIIa inhibitor) to full-dose alteplase or streptokinase was examined in the Platelet Aggregation Receptor Antagonist Dose Investigation for Reperfusion Gain in Myocardial Infarction (PARADIGM) study. Adjunctive lamifiban therapy was associated with more rapid and sustained resolution of electrocardiographic changes but no overall reduction in clinical events (death, reinfarction, refractory ischemia, non-elective revascularization, persistent/recurring ST-segment elevation, TIMI flow 9 Eptifibatide plus full-dose alteplase was assessed in the Integrilin to Minimize Platelet Aggregation and Coronary Thrombosis in Acute Myocardial Infarction (IMPACT-AMI) trial, demonstrating a 66% rate of TIMI 3 flow at 90 minutes compared with 39% for alteplase alone (p = 0.006) and a shorter median time to ST-segment recovery (65 minutes versus 116 minutes, respectively; p = 0.05). The study groups had similar rates of the composite endpoint of in-hospital death, reinfarction, stroke, revascularization procedures, new heart failure, pulmonary edema (43% versus 42%, respectively) and severe bleeding (4% versus 5%, respectively). Greater coronary patency was also observed on angiographic follow-up (79% versus 64%, respectively).10 Collectively, these studies suggest improvements in TIMI 3 flow associated with moderately increased bleeding when full-dose fibrinolytics are combined with GP IIb/IIIa inhibitors, but as would be expected from the small numbers of patients enrolled in these studies, no improvement in mortality benefit was shown. Table 1 describes phase-II trials supporting the combination of glycoprotein IIb/IIIa inhibitors with full-dose fibrinolytic agents.8–10 These preliminary studies set the stage for the next step in the evolution of pharmacologic reperfusion therapy — reduced-dose fibrinolytic and GP IIb/IIIa inhibition. TIMI-14 and SPEED, phase-II trials investigating this strategy, have been completed, as has Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO)-V, a phase-III trial that enrolled 16,588 patients.6,7,11 More recently, the phase-III Assessment of the Safety and Efficacy of a New Thrombolytic (ASSENT)-3 trial enrolled 6,095 patients in a comparison of varying doses of tenecteplase in combination with weight-adjusted heparin; with abciximab and weight-adjusted, low-dose heparin; or with enoxaparin (a low-molecular-weight heparin).12 These trials have provided crucial information defining the relationship between increasing doses of fibrinolytic agents, TIMI 3 flow at 60 and 90 minutes, and bleeding events within the context of GP IIb/IIIa receptor inhibition, reduced-dose fibrinolytics and unfractionated heparin (UFH) therapy. Two additional phase-II trials, Integrilin and Reduced Dose of Thrombolytic in Acute Myocardial Infarction (INTRO-AMI) and Integrilin and Tenecteplase in Acute Myocardial Infarction (INTEGRITI), are currently underway, but their results have yet to be reported in the peer-review literature.13–15 Table 2 describes phase-II trials supporting the combination of glycoprotein IIb/IIIa inhibitors with reduced-dose fibrinolytic agents.6,7,13–15 TIMI-14. The TIMI-14 study randomized a total of 888 patients presenting with ST-segment elevation MI to 100 mg accelerated-dose alteplase alone (control), standard-dose abciximab alone, or 7 escalating doses of alteplase (20–65 mg) or streptokinase (500,000 U to 1.5 MU) combined with full-dose abciximab.6 The optimal dose of combined fibrinolytic and abciximab therapy was found to be abciximab with alteplase p = 0.0009) and 90 minutes (77% versus 62%, respectively; p = 0.02). Major bleeding events occurred in 6% of patients who received alteplase alone, 3% of those who received abciximab alone, 10% of those treated with abciximab plus streptokinase, 7% of those in the abciximab plus alteplase with low-dose heparin group, and 1% of those in the abciximab plus alteplase with very low-dose heparin group. Approximately two-thirds of all bleeding events occurred at catheter access sites. The overall rate of intracranial hemorrhage (ICH) was 1.1%, with no important differences in this complication among the study groups.6 An additional 299 patients were assessed within a reteplase phase of this study that compared standard-dose, double-bolus reteplase (control arm) with standard-dose abciximab in combination with reduced doses of reteplase (5 U + 5 U or 10 U + 5 U). Control patients received standard-dose weight-adjusted heparin (70 U bolus plus 15 U/kg/h infusion). At 90 minutes, TIMI 3 flow rates were 70% for patients treated with 10 U + 10 U of reteplase alone, 73% for those who received reteplase 5 U + 5 U with full-dose abciximab, and 77% for those who received reteplase 10 U + 5 U with full-dose abciximab.16 Importantly, when the combination of reteplase 10 U + 5 U with abciximab was compared with reteplase monotherapy, a greater rate of complete (>= 70%) ST-segment resolution was observed at 90 minutes (68% versus 48%; p = 0.05), suggesting a more rapid and complete restoration of microvascular function. The overall rate of major bleeding events was 6%, with the majority of major bleeding occurring at the instrumentation access site, and the overall rate of ICH was 1.3%. No significant differences were observed between study groups in terms of major bleeding events, ICH, mortality, recurrent MI, severe pump failure or revascularization for recurrent ischemia.16,17 SPEED. The SPEED (GUSTO-V pilot) study also examined escalating doses of reteplase with full-dose abciximab in patients presenting with ST-segment elevation MI within the previous 12 hours, with all patients undergoing acute angiography (at a median of 62 minutes). The primary endpoint was the TIMI 3 flow rate at angiography 60 and 90 minutes after treatment began. The dose-finding phase included 304 patients who were randomized to receive standard-dose abciximab alone or in combination with one or two bolus doses (separated by 30 minutes) of reteplase (5 U, 7.5 U, 10 U, 5 U + 2.5 U, or 5 U + 5 U). Intravenous heparin (60 U) was given shortly after the first bolus dose of study drug, and additional weight-adjusted bolus doses or continuous infusion were given during angiography to maintain an activated clotting time (ACT) >= 200 seconds. This phase of the trial demonstrated a 62% TIMI 3 flow rate with the reteplase 5 U + 5 U double-bolus dose added to abciximab, which was significantly higher than the 27% TIMI 3 flow observed in patients who received abciximab alone (p = 0.001). Major bleeding rates in the dose-finding phase of this study were 3.3% for abciximab alone and 5.3% for abciximab and half-dose reteplase.7 A further 224 patients were then enrolled in a dose-confirmation phase in which the best regimen from the first phase (abciximab plus reteplase 5 U + 5 U) was compared with reteplase alone (10 U + 10 U). Two doses of heparin were tested in the abciximab plus reteplase 5 U + 5 U group: 60 U/kg and 40 U/kg. Patients in the reteplase-only group were given an initial 70 U/kg heparin bolus. This second phase of the study yielded a TIMI 3 flow rate of 54% at 60 minutes for the abciximab-reteplase 5 U + 5 U group, compared with 47% in the full-dose reteplase-only arm (p = 0.39). As with TIMI-14, the use of very low-dose heparin (40 U/kg) in the abciximab-reteplase 5 U + 5 U group was associated with a trend toward lower patency compared with patients in this study arm who received low-dose (60 U/kg) heparin (51% versus 61%, respectively; p = not significant). Major bleeding rates in the dose-confirmation phase were 9.8% for abciximab and half-dose reteplase and 3.7% for reteplase alone. Major bleeding rates were similar for standard and low-dose heparin. Adding reteplase to abciximab was associated with a trend toward increased major bleeding (p = 0.11), but no significant increase in the need for blood transfusions (p = 0.67) or minor bleeding (p = 0.95).7 A subgroup analysis was performed on 323 patients who underwent PCI at the time of their first angiography and 162 patients who did not receive early angiography. In these patients, combination therapy with reduced-dose reteplase and abciximab in SPEED was associated with several clinical advantages. Early PCI was performed less often in patients who received combination therapy compared to those who received abciximab alone (65% versus 82%, respectively), suggesting enhanced early reperfusion of epicardial and myocardial blood flow. Patients receiving combination therapy were stabilized before entry into the catheterization laboratory, as demonstrated by their arriving more frequently with patent infarct-related arteries. These patients experienced fewer instances of shock or cardiac arrest, and required less use of intra-aortic balloon pumping and temporary pacemakers. In patients receiving combination therapy with abciximab and reduced-dose reteplase, the TIMI 3 flow rate was 47% at 60 minutes. Following PCI, TIMI 3 flow was present in 86% of patients by 90 minutes after treatment.18 These studies served to provide the angiographic rationale for assessing the mortality benefits of combined antiplatelet therapy and reduced-dose fibrinolysis in the recently completed GUSTO-V clinical trial. ASSENT-3. The ASSENT-3 trial recently examined full-dose tenecteplase and enoxaparin (a low-molecular-weight heparin) compared with half-dose tenecteplase and standard-dose abciximab with weight-adjusted, low-dose heparin or full-dose tenecteplase in combination with weight-adjusted heparin in 6,095 patients with ST-segment elevation AMI. The primary endpoints were the composite of 30-day mortality, in-hospital reinfarction or in-hospital refractory ischemia (efficacy endpoint) and the composite of the efficacy endpoint plus in-hospital ICH or major bleeding complications (efficacy plus safety endpoint). The patients treated with tenecteplase plus unfractionated heparin had a significantly higher composite rate of 30-day mortality, in-hospital reinfarction or refractory ischemia (15.4%) compared to those who were treated with tenecteplase plus enoxaparin (11.4%; p = 0.0002) or tenecteplase plus abciximab (11.1%; p p = 0.0037, versus 14.2% tenecteplase/abciximab; p = 0.01416). The rate of in-hospital ICH was comparable for the three treatment arms in this trial (0.93% tenecteplase/heparin versus 0.88% tenecteplase/enoxaparin versus 0.94% tenecteplase/abciximab; p = 0.98). These findings suggest that combination therapy with tenecteplase plus enoxaparin or abciximab reduces the frequency of ischemic complications following ST-segment elevation AMI.12 An additional 1,000 patients have been randomized into a satellite study, ASSENT-3 Plus, which is evaluating the pre-hospital administration of tenecteplase with either heparin or enoxaparin.19 Ongoing research. Other studies are planned or currently underway to assess the combination of GP IIb/IIIa inhibitors and reduced-dose fibrinolytics, but data have not yet been published in peer-review journals. These include Tenecteplase and Integrilin Given for Event Reduction (TIGER), which is expected to compare full-dose tenecteplase with half-dose tenecteplase plus eptifibatide; Enoxaparin and TNK-tPA with or without GP IIb/IIIa Inhibitor as Reperfusion Strategy in ST-elevation MI (ENTIRE), which will examine TIMI flow rates following varying dosing regimens of tenecteplase, low-molecular-weight heparin (lovenox), abciximab and heparin; and Fibrinolytic and Aggrastat ST-Elevation Resolution (FASTER), which will examine three different dosing levels of tenecteplase administered in combination with tirofiban and heparin.19,20 The GUSTO-V Clinical Trial The GUSTO-V trial, which was completed in February 2001, was a phase-III, international, randomized, open-label study examining mortality in patients with acute ST-segment elevation MI treated with conventional reteplase and weight-adjusted heparin versus a combination of half-dose reteplase, full-dose abciximab and reduced-dose heparin. The primary hypothesis was that the combination of half-dose reteplase and abciximab would be either superior or non-inferior to reteplase alone in terms of mortality at 30 days after enrollment. This study was designed to determine whether the addition of abciximab would reduce the mortality ceiling presently experienced with second- and third-generation fibrinolytic monotherapy. It was hoped that this treatment strategy would significantly improve outcomes in patients with acute ST-segment-elevation MI and offer a new treatment paradigm for the management of AMI.11 Study design. The trial enrolled 16,588 patients in the first 6 hours of evolving ST-segment elevation MI from 820 hospitals in 20 countries. The primary endpoint of this study was all-cause mortality from randomization to 30 days. Secondary endpoints focused on the safety and long-term efficacy, including clinical and safety events at 30 days, combined 30-day mortality and nonfatal disabling stroke at 7 days or discharge, mortality at 1 year and reinfarction and complications of acute myocardial infarction.11 Patients were eligible for inclusion in the study if they presented with prolonged (>= 30 minutes) continuous ischemic chest pain with onset within 6 hours prior to randomization and had electrocardiographic changes consistent with ST-segment elevation MI or new left bundle branch block. Patients were excluded from enrollment in GUSTO-V if they were under 18 years of age, were scheduled for primary PCI, had active bleeding or puncture of a noncompressible vessel within 24 hours, had blood pressure higher than 180 mmHg systolic or 110 mmHg diastolic, had a history of cerebrovascular accident within the previous 2 years, weighed more than 120 kg, had a platelet count of 11 Methods. Patients were randomized to either half-dose reteplase (5 U bolus + 5 U bolus, 30 minutes apart) combined with standard-dose abciximab (0.25 mg/kg bolus followed by 0.125 µg/kg/min infusion to a maximum 10 µg/min for 12 hours) (n = 8,328) or standard-dose reteplase (10 U bolus + 10 U bolus, 30 minutes apart) (n = 8,260). Figure 1 describes the GUSTO-V trial schematic.11 Patients randomized to half-dose reteplase and abciximab received a reduced dose of heparin of 60 U/kg bolus (maximum, 5,000 U) followed by an infusion of 7 U/kg/h. Patients receiving standard doses of reteplase received a 5,000 U bolus of heparin followed by an infusion of 1,000 U/h for those >= 80 kg body weight and 800 U/h in patients 11 Coronary angiography and percutaneous coronary intervention were permitted at the discretion of the treating physician for clinical indications. Use of abciximab was permitted for patients in the reteplase-alone group if coronary intervention was performed within 24 hours, and was recommended if performed more than 24 hours after randomization.11 Results. At 30 days, all-cause mortality was 5.9% for the reteplase group compared with 5.6% for the combined reteplase and abciximab group (p = 0.43) (Figure 2).11 A similar nonsignificant trend toward lower mortality with combination therapy was seen at 24 hours (2.3% reteplase versus 2.2% combination) and at the time of discharge or day 7 (4.5% reteplase versus 4.3% combination). Thus, with respect to the primary mortality endpoint, combination therapy was not superior to conventional fibrinolytic therapy, but was established to be non-inferior to conventional fibrinolytic therapy by prespecified statistical criteria. Although a trend toward improved survival was observed in the combination therapy group, this difference was not significant in any subgroup defined by age, sex, weight or diabetic status.11 A significant effect of combination therapy on ischemic complications was observed. Compared to the patients who received reteplase alone, patients in the combination group had a lower rate of reinfarction at 7 days or discharge (3.5% reteplase versus 2.3% combination; p p p p p = 0.013) (Figure 3).11 Patients in the combination therapy arm had a lower composite of death (at 30 days), nonfatal reinfarctions at 7 days/discharge, and need for early PCI (19.4% reteplase alone versus 15.3% combination; p 21 Combination therapy was also associated with a lower rate of the composite of death (at 30 days), nonfatal reinfarctions at 7 days/discharge and need for urgent PCI (20.6% reteplase alone versus 16.2% combination; p 11 Patients in the combination therapy arm tended to have lower rates of 15 of the 17 prespecified nonfatal ischemic complications. Of these, combination therapy produced a significantly lower incidence than reteplase monotherapy of any complication (31.7% reteplase versus 28.6% combination; p p p = 0.004), ventricular septal defect (0.3% reteplase versus 0.2% combination; p = 0.049), sustained ventricular tachycardia (2.8% reteplase versus 2.2% combination; p = 0.020), ventricular fibrillation (3.5% reteplase versus 2.7% combination; p = 0.008) and second- or third-degree atrioventricular block (AVB) (3.3% reteplase versus 2.7% combination; p = 0.018).11 Patients in the combination abciximab plus reteplase group experienced more non-intracranial bleeding complications than those who received reteplase alone (13.7% reteplase versus 24.6% combination; p 11 Spontaneous hemorrhages occurred predominantly in the gastrointestinal tract. Rates of intracranial hemorrhage (0.6% reteplase versus 0.6% combination), nonfatal disabling stroke (0.3% reteplase versus 0.2% combination) and total strokes (0.9% reteplase versus 1.0% combination) were similar between groups, but patients in the combination therapy group did have a significantly greater incidence of severe thrombocytopenia (0.1% reteplase versus 1.2% combination; p p 11 Although combined treatment with reteplase and abciximab was not found to be superior to standard reteplase, it did fulfill the prespecified analysis criteria of non-inferiority and demonstrated that the combination of abciximab and reteplase produced a consistent reduction in key secondary complications of myocardial infarction, including reinfarction, ischemia and major arrhythmias. However, these advantages were partially offset by increased non-intracranial bleeding complications. Comparably low ICH and total stroke rates were seen in the two study arms, suggesting that the combination of abciximab and reduced-dose reteplase may reduce the secondary complications of myocardial infarction without increasing the risk of stroke and intracranial hemorrhage. Discussion and summary. The GUSTO-V trial validated the combined use of abciximab and reduced-dose reteplase as an alternative to fibrinolytic monotherapy in the management of AMI. The results of this trial have shown that management of ST-segment elevation MI with combined reteplase and abciximab treatment produces a 30-day mortality rate similar to that found with standard fibrinolytic therapy with reteplase alone. Though associated with an increase in non-intracranial bleeding complications, the combined reteplase and abciximab regimen produced no significant increase in intracranial hemorrhage or nonfatal disabling stroke, and the rate of most prespecified nonfatal complications of myocardial infarction up to 7 days was lower with the combination therapy than with reteplase alone. These findings suggest that non-weight-adjusted, half-dose reteplase in combination with full-dose abciximab and weight-adjusted heparin provides acceptable safety and an improved complication profile in the management of patients with ST-segment elevation myocardial infarction. One contributing factor to the lack of a significantly superior survival benefit with the combination therapy may be the unexpectedly low mortality rate in the reteplase monotherapy arm at 30 days. As shown in Figure 5, the 5.9% 30-day mortality rate observed in the reteplase group was considerably lower than the 7.5% mortality rate for reteplase alone reported in the GUSTO-III study of alteplase and reteplase.22 Within the limitations of cross-trial comparisons, this is the lowest mortality rate reported for a single fibrinolytic agent in any large trial of AMI.11 As shown in Figure 6, the ICH rates reported in GUSTO-V were also low compared to other major trials of fibrinolytic agents. This interpretation is supported by the 0.9% absolute difference in mortality among high-risk patients (e.g., those with anterior wall AMI) that favored the combination abciximab plus reteplase treatment group. The demonstration of non-inferiority in mortality rates combined with superiority in other efficacy parameters with manageable bleeding complications should provide compelling evidence that combination therapy is a viable additional treatment paradigm in the management of ST-segment elevation AMI.11,23–26 Acknowledgments. The authors wish to thank Eileen L. Sullivan, PharmD and Gordon Beck, RPh, for their assistance in preparing this manuscript.
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