Consideration of Early Stopping and Other Challenges in Monitoring the Heart and Estrogen/Progestin Replacement Study

The Heart and Estrogen-progestin Replacement Study (HERS) was the first major randomized blinded trial to test the widespread belief that hormone therapy would prevent fatal and non-fatal coronary heart disease (CHD). The main findings—CHD events were not prevented and thromboembolic events were increased—illustrates in a powerful way the evidence-based medicine principle that well-designed and executed randomized blinded trials are a necessary basis for drug treatments. The HERS Data and Safety Monitoring Board played an important role in a number of difficult decisions that led to more definitive conclusions, notably the decisions not to stop the trial early in the face of adverse experience in both primary and secondary disease outcomes. HERS, with its complex and unexpected findings, illustrates the value of designing flexible interim monitoring guidelines that allow for decisions based on the judgment of a diverse group of experts as to benefits and harms, ethical implications for participants, and the social obligation to have an optimal impact on policy and practice guidelines.