VIGOUR Trials

Trial Publications

ASSENT-II This recent trial of 17,000 patients with acute myocardial infarction showed that tenecteplase (TNK) can be as effective as alteplase (t-PA) in reducing mortality. The practical advantage of tenecteplase is that it can be given in a single injection, rather than the standard 90-minute infusion of alteplase. Lancet 1999;354:716-722.

ASSENT-III Both enoxaparin and abciximab proved significantly superior to standard heparin when given with the thrombolytic agent tenecteplase in this international, randomized trial of 6095 pateints with acute myocardial infarction. Lancet 2001;358:605-613.

ASSENT-III Plus In this study of prehospital fibrinolysis, 1639 patients given tenecteplase were randomized to also receive enoxaparin or standard heparin. Compared with the main ASSENT-III trial, treatment began a median 45 minutes earlier. Patients given enoxaparin tended to have a lower rate of death or myocardial infarction at 30 days, but they also showed increased intracranial bleeding, especically among elderly patients.

GUSTO-I This "megatrial" of 41,021 patients with acute myocardial infarction set the standard for the modern clinical trial. The analysis of four thrombolytic treatments found that a regimen of alteplase and intravenous heparin was superior to streptokinase in reducing mortality. This trial established the superiority of alteplase over streptokinase in clinical practice. In addition, GUSTO-I was notable for its worldwide network of investigators, allowing rapid enrollment of this large number of patients. The GUSTO-I dataset has produced over 100 published manuscripts to date. N Engl J Med 1993;329:673-682.

GUSTO-I Angiographic Substudy. The key finding of this 2431-patient GUSTO-I substudy was that patterns in 90-minute infarct-artery patency mirrored patterns in outcomes; that is, alteplase resulted in both superior reperfusion and superior outcomes compared with other therapies. This finding provided hard evidence that better, more rapid reperfusion corresponds directly with favorable outcomes. N Engl J Med 1993;329:1615-1622.

GUSTO-IIa and -IIb GUSTO-II compared recombinant hirudin versus heparin in acute coronary syndromes. GUSTO-IIa (2564 patients) was stopped after higher rates of hemorrhagic strokes were found in patients given hirudin, but GUSTO-IIb continued the study at a lower dose of hirudin. This more-appropriate dose of hirudin was found to reduce rates of reinfarction. In addition, GUSTO-IIa highlighted the need for large numbers in a trial: since intracranial hemorrhage occurs very rarely, only a trial of this size would have recorded enough events to detect this potential problem. GUSTO-IIb was, at the time, the largest trial to date in non-ST-elevation acute coronary syndromes (n=12,142). GUSTO-IIa: Circulation 1994;90:1631-1637. GUSTO-IIb: N Engl J Med 1996;335:775-782.

GUSTO-IIb Angioplasty Substudy. Angioplasty was found to be superior to alteplase in reducing the rate of death, myocardial infarction, or stroke at 30 days, though this difference had narrowed by 6 months. This study helped establish angioplasty as an acceptable treatment alternative to thrombolytic therapy alone. N Engl J Med 1997:336:1621-1628.

GUSTO-III The third GUSTO trial was the first Phase III trial to evaluate reteplase versus alteplase. GUSTO-III studied 15,060 patients with acute myocardial infarction. Reteplase was associated with slightly higher rates of mortality and bleeding at 30 days. Designed as a superiority trial, GUSTO-III raised the question of how to define equivalence in a clinical trial. N Engl J Med 1997;337:1118-1123.

GUSTO-IV ACS This randomized trial of patients with acute coronary syndromes without ST-segment elevation had an unexpectedly negative result: two different doses of abciximab showed no advantage over placebo, at 30 days or 1 year, among the 7800 patients enrolled around the world. Initial results: Lancet 2001;357:1915-1924;1-year results: Circulation 2003;107:437-442.

GUSTO-V AMI This international randomized, open-label Phase III trial evaluated mortality 30 days after patients with acute myocardial infarction received half-dose reteplase plus abciximab or full-dose reteplase alone. Lancet 2001; 357: 1905-1914

HERO-II This international trial of 17,073 patients showed that bivalirudin, a direct thrombin inhibitor, did not offer a 30-day survival advantage over heparin when given with streptokinase for acute myocardial infarction. Early reinfarction was significantly reduced with bivalirudin, however, at the cost of increased bleeding. Lancet 2001;358:1855-1863.

PARAGON-A and -B These studies evaluated lamifiban, a platelet glycoprotein IIb/IIIa antagonist. PARAGON-A tested the benefit of two doses of lamifiban, alone and combined with heparin, in 2282 patients with unstable angina or non-Q-wave myocardial infarction. Lamifiban reduced adverse ischemic events at 6 months, beyond that of aspirin and heparin therapy alone. The follow-up, placebo-controlled PARAGON-B trial tested the effectiveness of lamifiban in reducing the incidence of death, myocardial infarction or severe, recurrent ischemia 30 days after presentation with an acute coronary syndrome. In all, 5225 patients were enrolled in 29 countries. PARAGON-A: Circulation 1998;97:2386-2395; PARAGON-B: Results from PARAGON-B were presented at the Annual Scientific Sessions of the American College of Cardiology, in March 2000.

SYMPHONY The recent SYMPHONY trial compared two doses of sibrafiban, an oral GP IIb/IIIa inhibitor, versus aspirin in 6000 patients with acute coronary syndromes. Sibrafiban showed no additional benefit over aspirin for secondary prevention of major ischemic events, and caused more dose-related bleeding. Lancet 2000;335:337-345.

2nd SYMPHONY This follow-up trial was to compare high- or low-dose sibrafiban plus aspirin versus aspirin alone in 8400 patients who had had an acute coronary syndrome event. Randomization in 2nd SYMPHONY was stopped early, after 6677 patients, when the negative results of SYMPHONY were announced. Results from this study were presented at the Annual Scientific Sessions of the American College of Cardiology, in March 2000. Circulation 2001;103:1727-1733.