Methods and Applications of Statistics in Clinical Trials, Volume 1: Concepts, Principles, Trials, and Designs

Chapter 63

Postmenopausal Estrogen/Progestin Interventions Trial (PEPI)

Robert D. Langer

63.1 Introduction

During the 1980s, several observational studies of varying designs conducted in different populations found an association between the use of systemic estrogen by postmenopausal women and lower rates of coronary heart disease (CHD) and possibly stroke [1–4]. Because CHD was and remains the leading cause of death in women, there was substantial interest in this potential benefit. Nevertheless, there was cause for skepticism because studies that compared the characteristics of estrogen users to nonusers suggested a potential healthy user bias [5]. By the mid-1980s, some researchers and clinicians were calling for a clinical trial to test whether hormone replacement therapy (HRT) could prevent CHD, and a conference that explored this possibility was held under the auspices of the U.S. National Heart, Lung, and Blood Institute [6]. For a variety of reasons, including the fact that CHD rates are relatively low in women near the age of menopause, and the expectation that the estrogen effect on CHD was mediated principally by lipid benefits—a mechanism that takes years to become evident in generally healthy people—a trial with CHD as an endpoint was projected to require upward of 30,000 women followed for about 10 years. Given the magnitude of resources required, this idea was set aside pending more evidence. The concept of the Post-menopausal Estrogen/Progestin Interventions (PEPI) ...