In one of the biggest dilemmas facing cardiovascular clinical research, clinical trials are increasingly being required to show benefits on clinical end-points rather than surrogate end-points, while at the same time the incremental benefits of newer treatments are getting smaller. These two factors have a huge impact on sample size, which has led some investigators to design trials to show that the new treatment has an effect similar to that of the standard, rather than outright superiority. Recent examples of fibrinolytic trials that have demonstrated similar effects of two drugs are ASSENT (Assessment of the Safety and Efficacy of a New Thrombolytic)-2, GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries)-III, and COBALT (Continuous Infusion Versus Double-Bolus Administration of Alteplase) [1,2,3,4]. However, as discussed by several authors [5,6,7,8], there are issues with trials of this type that make them considerably less credible than superiority trials.