Mega-trials and equivalence trials: Experience from the INJECT study

Abstract

As treatments for acute myocardial infarction have grown in number and effectiveness, the post-infarction mortality rate has fallen, and new therapies can provide only a small additional advantage in extending survival. To prove such an advantage of a new drug over its predecessors in the same drug class requires a trial of at least 20,000 patients. Proving 'equivalence' rather than superiority requires only 6000 patients. The INJECT trial was designed with the modest goal of determining whether the novel agent reteplase (recombinant plasminogen activator) has an effect on mortality equivalent to that of streptokinase. Between August 1993 and September 1994, 6010 patients were randomized to receive either reteplase (n = 3004) or streptokinase (n = 3006). Both treatment groups had similar rates of bleeding events, extension or recurrence of myocardial infarction, and in-hospital stroke followed by 6 months of disability. Reteplase recipients had a lower incidence of cardiac events in hospital and fewer allergic reactions, Although the number of diagnosed haemorrhagic strokes was higher in reteplase recipients, more patients receiving streptokinase had strokes of uncertain aetiology. At 35 days, the mortality rate associated with reteplase use was approximately 0.5% lower than that associated with streptokinase administration, and the upper limit of the 90% confidence interval for the difference between these rates was a superiority of streptokinase of 0.73%. Because the INJECT trial provided a probability of 0.95 that the mortality rate associated with reteplase use would be either lower than that with streptokinase administration or at most 0.73% worse, reteplase and streptokinase were proved equivalent according to the trial definition and limits.