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Causality and PsychopathologyFinding the Determinants of Disorders and their Cures$
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Patrick Shrout, Katherine Keyes, and Katherine Ornstein

Print publication date: 2011

Print ISBN-13: 9780199754649

Published to Oxford Scholarship Online: November 2020

DOI: 10.1093/oso/9780199754649.001.0001

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PRINTED FROM OXFORD SCHOLARSHIP ONLINE (oxford.universitypressscholarship.com). (c) Copyright Oxford University Press, 2021. All Rights Reserved. An individual user may print out a PDF of a single chapter of a monograph in OSO for personal use. date: 05 March 2021

Understanding the Effects of Menopausal Hormone Therapy: Using the Women’s Health Initiative Randomized Trials and Observational Study to Improve Inference

Understanding the Effects of Menopausal Hormone Therapy: Using the Women’s Health Initiative Randomized Trials and Observational Study to Improve Inference

Chapter:
5 Understanding the Effects of Menopausal Hormone Therapy: Using the Women’s Health Initiative Randomized Trials and Observational Study to Improve Inference
Source:
Causality and Psychopathology
Author(s):

Garnet L. Anderson

Ross L. Prentice

Publisher:
Oxford University Press
DOI:10.1093/oso/9780199754649.003.0009

Over the last decade, several large-scale randomized trials have reported results that disagreed substantially with the motivating observational studies on the value of various chronic disease–prevention strategies. One high-profile example of these discrepancies was related to postmenopausal hormone therapy (HT) use and its effects on cardiovascular disease and cancer. The Women’s Health Initiative (WHI), a National Heart, Lung, and Blood Institute–sponsored program, was designed to test three interventions for the prevention of chronic diseases in postmenopausal women, each of which was motivated by a decade or more of analytic epidemiology. Specifically, the trials were testing the potential for HT to prevent coronary heart disease (CHD), a low-fat eating pattern to reduce breast and colorectal cancer incidence, and calcium and vitamin D supplements to prevent hip fractures. Over 68,000 postmenopausal women were randomized to one, two, or all three randomized clinical trial (CT) components between 1993 and 1998 at 40 U.S. clinical centers (Anderson et al., 2003a). The HT component consisted of two parallel trials testing the effects of conjugated equine estrogens alone (E-alone) among women with prior hysterectomy and the effect of combined estrogen plus progestin therapy (E+P), in this case conjugated equine estrogens plus medroxyprogesterone acetate, among women with an intact uterus, on the incidence of CHD and overall health. In 2002, the randomized trial of E+P was stopped early, based on an assessment of risks exceeding benefits for chronic disease prevention, raising concerns among millions of menopausal women and their care providers about their use of these medicines. The trial confirmed the benefit of HT for fracture-risk reduction but the expected benefit for CHD, the primary study end point, was not observed. Rather, the trial results documented increased risks of CHD, stroke, venous thromboembolism (VTE), and breast cancer with combined hormones (Writing Group for the Women’s Health Initiative Investigators, 2002). Approximately 18 months later, the E-alone trial was also stopped, based on the finding of an adverse effect on stroke rates and the likelihood that the study would not confirm the CHD-prevention hypothesis.

Keywords:   Data and Safety Monitoring Board, Food and Drug Administration (FDA), Intent to treat (ITT), Menopausal hormone therapy

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