A matter of life and death? The Heart Protection Study and protection of clinical trial participants

Clinical trials that demonstrate mortality reduction benefit from a particular therapy serve a crucial role in advancing medical care. The Heart Protection Study is one such trial, and it showed significant mortality reduction following 5 years of treatment with simvastatin compared with placebo in patients with arterial disease and/or diabetes. In this trial, by year 2 of follow-up, there was already a highly statistically significant advantage of simvastatin over placebo as regards major events (cardiac death, myocardial infarction, stroke, and revascularization). Despite these findings, the prespecified stopping rules that were contingent on proof of mortality reduction benefit were not invoked after interim analyses and the trial progressed to completion. The study raises issues concerning early termination of the trial based on benefit in major morbidity criteria even at the expense of being unable to answer the highly important question of mortality benefit. The study also engenders questions about whether interim data and analyses should be made available to physician-investigators, the trial participants, and the public. The issues are complex but need to be discussed to optimize the protection of study subjects in clinical trials.