Looking for the Pony in the HERS Data

Abstract

One of the great public health advances of the last century was the development of the randomized, controlled clinical trial, which is designed to control for known and unknown differences in persons who take or do not take medication (by the use of randomization), and for the effects of patient and provider expectation (by the use of double-blind placebo control). See p 917 The late Reuel A. Stallones was fond of teaching that clinical trials are done during a narrow window of opportunity when there is enough evidence for benefit to justify the time and expense of the trial, but not so much evidence that it would be unethical to deprive participants of the “active” treatment by assigning them to placebo. This window is particularly difficult to achieve when the medication has been in use for many years, its benefit has been demonstrated repeatedly in epidemiological studies and in clinical practice, and when the thought leaders and major medical organizations have already recommended its widespread use. Such was the case with hormone replacement therapy (HRT) and the prevention of heart disease. At the beginning of the Heart and Estrogen/progestin Replacement Study (HERS), a secondary prevention trial of estrogen in postmenopausal women with heart disease, several experts opined that this trial was unnecessary at best and unethical at worst, given the consistency of the observational data, which certainly looks very impressive in a meta-analysis, and the plethora of potential cardioprotective mechanisms for estrogen that have been demonstrated in vivo and in vitro. It was therefore more than a bit of a shock when the HERS trial results showed no overall benefit to HRT and a completely unexpected early excess of cardiovascular events.1 The reaction of the research and clinical community to these results has been one of disbelief and denial …