The GUSTO-V Clinical Trial

Author(s): 

A. Michael Lincoff, MD

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 < 3, or a composite of these endpoints). This was possibly related to the relatively small sample size. However, bleeding events were moderately increased in lamifiban patients compared to those who received placebo (3.0% versus 1.7% for major bleeding; 13.7% versus 6.8% for intermediate bleeding; 16.1% versus 10.3% for blood transfusions; and 1.7% versus 0.9% for thrombocytopenia).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 <= 15 mg bolus and <= 35 mg infusion over 1 hour. This was then tested with low-dose heparin (60 U/kg bolus and infusion of 7 U/kg/h) or very low-dose heparin (30 U/kg bolus and infusion of 4 U/kg/h) against standard weight-adjusted accelerated alteplase within a dose-confirmation phase.

Significantly greater TIMI 3 flow rates were observed in the abciximab plus reduced-dose alteplase group compared with the alteplase-only control group at both 60 minutes (72% versus 43%, respectively; 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


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