International Joint Efficacy Comparison of Thrombolytics - INJECT

Description:

Reteplase vs. streptokinase for mortality in acute MI.

Hypothesis:

To determine whether the effect of reteplase on survival was equivalent to a standard streptokinase regimen.

Study Design

Study Design:

Patients Screened: Not given
Patients Enrolled: 6,010
Mean Follow Up: 6 months
Mean Patient Age: 62
Female: 28

Patient Populations:

Chest pain at least 30 min duration characteristic of MI
Persistent ST elevation ≥ 1 mV in 2 of 3 inferior leads, in leads I and aVL, or ≥ 0.2 mV in two contiguous precordial leads, or left bundle branch block.

Exclusions:

Previous cerebrovascular event
Intracranial neoplasm, AVM, or aneurysm
Increased bleeding risk
Uncontrolled hypertension
Pregnancy or breastfeeding
Contraindication to streptokinase
Treatment with streptokinase or anistreplase within 12 months
Any investigational drug within 30 days
Previous enrollment in the study

Primary Endpoints:

35 day mortality

Drug/Procedures Used:

Streptokinase 1.5 M U or reteplase, two 10 MU boluses 30 min apart.

Concomitant Medications:

Aspirin, heparin

Principal Findings:

A total of 3004 patients were randomized to reteplase and 3006 to streptokinase.

At 35 days, 270 patients (9.02%) had died in the reteplase group compared to 285 (9.53%) in the streptokinase group. The 90% confidence limits for the difference between the two agents was -1.74% to 0.73%, and was interpreted as an indication that reteplase was therapeutically equivalent to streptokinase.

Six-month mortality rates were 11.02% for reteplase and 12.05% for streptokinase. A log-rank test comparing the mortality curves to six months was not significant (p=0.217).

The incidence of recurrent myocardial infarction was similar, but there were significantly fewer cases of atrial fibrillation, asystole, heart failure, and hypotension in the reteplase group.

Interpretation:

The INJECT trial indicated that reteplase was therapeutically comparable to streptokinase in terms of safety and efficacy; the subsequent GUSTO-III trial compared reteplase to alteplase (t-PA). INJECT is a modern example of an active-control design with an intention to demonstrate therapeutic equivalence (as opposed to superiority). It illustrates one approach to evaluating new agents when placebo-controlled trials are not ethical to perform.

References:

1. Lancet 1995;346:329-6. Final results

Clinical Topics: Anticoagulation Management, Arrhythmias and Clinical EP, Dyslipidemia, Heart Failure and Cardiomyopathies, Implantable Devices, EP Basic Science, SCD/Ventricular Arrhythmias, Lipid Metabolism, Acute Heart Failure

Keywords: Myocardial Infarction, Streptokinase, Chest Pain, Heart Failure, Recombinant Proteins, Bundle-Branch Block, Hypotension, Fibrinolytic Agents, Heart Arrest, Tissue Plasminogen Activator


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