EDITORIAL Observational Data and Clinical Trials Narrowing the Gap?

One of the signal events in epidemiology in the last decade is a mammoth randomizedtrial that failed to confirm an established epidemiologic finding. The observational finding was the protection provided by hormone replacement therapy against cardiovas-cular disease, and the trial was of course the Women’s Health Initiative.1 A protective effect had been consistently observed in cohort studies, supported by clinical evidence, and trusted by physicians and millions of their patients. According to the clinical trial, mortality from cardiovascular disease among the treated was, in fact, worse. In this issue of Epidemiology we publish an ambitious paper by Hernán (who also serves as one of our editors) et al,2 in which a new analysis of the Nurses ’ Health Study provides results consistent with the randomized trial. This paper is followed by 3 commentaries (by Hoover,3 Stampfer,4 and Prentice5) and responses from the authors.6,7 The questions raised are fundamental, and the stakes are high. Do the methods of Hernán et al narrow the gap between cohort studies and clinical trials? Have more conventional analyses of cohort studies been misleading? How much of the discrepancy between the trial and the cohort results is due to differences in study setting and populations, to differences in handling discontinuation of replacement hormones, or t