Stopping a Trial for Futility: The Cooperative New Scandinavian Enalapril Survival Study II

Abstract

The Cooperative New Scandinavian Enalapril Survival Study II (CONSENSUS II) trial was designed to test the hypothesis that enalapril, an angiotensin-converting enzyme inhibitor, would reduce the risk of death in patients with an acute myocardial infarction. A sequential stopping rule that allowed for both early acceptance and early rejection of the null hypothesis, in the spirit of stochastic curtailment, was developed specifically for this trial. Very early in the trial the Data and Safety Monitoring Committee noticed an excess of mortality in the enalapril group. When this trend persisted, the committee first recommended protocol modifications, then termination of recruitment, and finally termination of the trial. The main reason was futility, as well as the possibility of harm, particularly in certain subgroups. This trial provides useful lessons regarding futility analyses, flexible monitoring rules, and the sponsor’s role on both the Data Monitoring Committee and the Steering Committee.