Elsevier

The Lancet

Volume 357, Issue 9272, 16 June 2001, Pages 1905-1914
The Lancet

Fast track — Articles
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

https://doi.org/10.1016/S0140-6736(00)05059-5Get rights and content

Summary

Background

Plasminogen activator therapy for acute myocardial infarction is limited by lack of achievement of early, complete, and sustained reperfusion in a substantial proportion of patients. Many phase II trials have supported the potential of combined fibrinolytic therapy and platelet glycoprotein IIb/IIIa inhibition for improving reperfusion. We did a randomised, open-label trial to compare the effect of reteplase alone with reteplase plus abciximab in patients with acute myocardial infarction.

Methods

16 588 patients in the first 6 h of evolving ST-segment elevation myocardial infarction were randomly assigned standard-dose reteplase (n=8260) or half-dose reteplase and full-dose abciximab (n=8328). The primary endpoint was 30-day mortality, and secondary endpoints included various complications of myocardial infarction. Analysis was by intention to treat.

Findings

At 30 days, 488 (5·9%) of patients in the reteplase group had died, compared with 468 (5·6%) in the combined reteplase and abciximab group (odds ratio 0·95 [95% CI 0·83–1·08], p=0·43). There were fewer deaths or non-fatal reinfarctions with the combination than with reteplase alone, and there was less need for urgent revascularisation and fewer major non-fatal ischaemic complications of acute myocardial infarction. On the other hand, there were more non-intracranial bleeding complications in the combination group. The rates of intracranial haemorrhage and non-fatal disabling stroke were similar.

Interpretation

Although combined reteplase and abciximab was not superior to standard reteplase, the 0·3% absolute (5% relative) decrease in 30-day mortality fulfilled the criteria of non-inferiority. Combination therapy led to a consistent reduction in key secondary complications of myocardial infarction including reinfarction, which was partly counterbalanced by increased non-intracranial bleeding complications.

Introduction

Reperfusion therapy for acute myocardial infarction became the standard of care in the late 1980s,1, 2 and although there have been improvements in fibrinolytic therapy,3, 4, 5 pharmacological treatment has many limitations. Compared with standard plasminogen-activator therapy, several pilot studies that combined low-dose plasminogen activator and platelet glycoprotein IIb/IIIa antagonists have suggested better speed, durability, and completeness of myocardial reperfusion.6, 7, 8 To provide a meaningful assessment of combined therapy, a large-scale trial was necessary. GUSTO V was powered to detect a mortality difference between standard fibrinolytic therapy and the combination of reduced dose fibrinolytic and a IIb/IIIa receptor antagonist. Our aim was to find out whether the combination of half-dose reteplase and abciximab would be superior, or not inferior, to reteplase alone for mortality at 30 days after enrolment. Secondary endpoints included the composite of death and non-fatal disabling stroke, reinfarction, recurrent ischaemia, urgent revascularisation, intracranial haemorrhage and non-intracranial bleeding complications, and mortality at 1 year.

Section snippets

Patients

820 hospitals in 20 countries participated in the trial, and the protocol was approved by each centre's institutional review board. Each patient provided informed consent to participate. The inclusion criteria were: continuous symptoms of chest discomfort for at least 30 min and fewer than 6 h from onset to the time of randomisation, along with electrocardiographic criteria of ST-elevation myocardial infarction or new left-bundle branch block.3, 4, 5 Exclusion criteria were: age less than 18

Results

16 588 patients were enrolled from July 7, 1999, until February 16, 2001 (figure 1). Table 1 shows the demographic characteristics of the two treatment groups. 1088 (13–2%) of the patients assigned reteplase and 1149 (13–8%) of those assigned reteplase and abciximab were older than 75 years. The use of conjunctive medications did not differ between the groups–at discharge, 6327 (77%) of those on reteplase and 6388 (77%) of those on reteplase and abciximab were receiving (3-blockade; 4640 (56%)

Discussion

Since fibrinolytic therapy became the standard of care for acute myocardial infarction in the 1980s, limitations have been recognised, including the relatively late time taken to re-establishing coronary blood, clinical instability with respect to recurrent ischaemia and reocclusion, and the lack of reperfusion at the myocardial tissue level in a large proportion of patients.13, 14, 15 One of the obstacles to more effective reperfusion has been the known pivotal effect of platelets in

References (23)

  • DJ Moliterno et al.

    Effect of platelet glycoprotein IIb/IIIa integrin blockade on activated clotting time during percutaneous transluminal coronary angioplasty or directional atherectomy (The EPIC Trial)

    Am J Cardiol

    (1995)
  • Gruppo Italiano per lo Studio della Streptochinasi nell'Infarto Miocardio (GISSI)

    Effectiveness of intravenous thrombolytic treatment in acute myocardial infarction

    Lancet

    (1986)
  • Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17 187 cases of suspected acute myocardial infarction: ISIS-2

    Lancet

    (1988)
  • The GUSTO Investigators

    An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction

    N Engl J Med

    (1993)
  • The GUSTO-III Investigators

    An international, multicenter, randomized comparison of reteplase with alteplase for acute myocardial infarction

    N Engl J Med

    (1997)
  • Single-bolus tenecteplase compared with front-loaded alteplase in acute myocardial infarction: the ASSENT-2 double-blind randomised trial

    Lancet

    (1999)
  • The SPEED Group (Strategies for the Patency Enhancement in the Emergency Department)

    Randomized trial of abciximab with and without low-dose reteplase for acute myocardial infarction

    Circulation

    (2000)
  • EM Antman et al.

    Abciximab facilitates the rate and extent of thrombolysis: results of the Thrombolysis in Myocardial Infarction (TIMI) 14 trial

    Circulation

    (1999)
  • SJ Brener et al.

    INTRO AMI: marked enhancement of arterial patency with eptifibatide and low-dose t-PA in acute myocardial infarction

    Circulation

    (1999)
  • GI Barbash et al.

    Treatment of reinfarction after thrombolytic therapy for acute myocardial infarction: an analysis of outcomes and treatment choices in the GUSTO I and ASSENT 2 studies

    Circulation

    (2001)
  • V Hasselblad et al.

    Statistical methods for comparison to placebo in active-control trials

    Drug Inform J

    (2001)
  • Cited by (0)

    Members listed at end of paper

    View full text