The Women’s Health Initiative (WHI) Clinical Trial of Estrogen plus Progestin in Postmenopausal Women
Funded by the National Heart, Lung, and Blood Institute
Conducted by 40 Clinical Centers and a Clinical Coordinating Center
(Investigator list appended)
Speakers for WHI
Background and Future Directions Jacques Rossouw, M.D.
Overview of Main Findings Marcia Stefanick, Ph.D.
Breast Cancer Rowan Chlebowski, M.D.
Garnet Anderson, Ph.D.
Fred Hutchinson Cancer
Osteoporosis and Fractures Jane Cauley, Ph.D.
Garnet Anderson, Ph.D.
Fred Hutchinson Cancer
Other WHI/NIH Representatives
Barbara Alving, M.D.
Rebecca Jackson, M.D.
Leslie Ford, M.D.
Summary of the Women’s health initiative (wHI)
Rationale for WHI Trials of Hormone Therapy
The National Institutes of Health launched the WHI program in 1991 in response to concerns about unanswered questions of importance to women’s health. A number of clinical trials were designed to provide clear answers to promising but unproven prevention strategies. Two of these trials centered on the efficacy and safety of long term hormone therapy for prevention of chronic diseases.
While in prior decades these hormones were primarily used for the treatment of (FDA-approved) menopausal symptoms and vaginal atrophy, from the late 1980s and early 1990s long term hormone therapy was being used with increasing frequency for the prevention of fractures and coronary heart disease. For fracture prevention, this use was based on the proven (and FDA-approved) benefit for osteoporosis prevention, and on observational studies of fractures. For coronary heart disease prevention, this use was based on improvements in lipids found in clinical trials, observational studies, animal studies, and studies of mechanism. However, there was no clinical trial evidence proving that hormone therapy would prevent fractures, or prevent coronary heart disease, and these indications were not approved by the FDA. Similarly, there was no clinical trial evidence that any benefits would not be offset by harms. It was known that estrogen increased the risk of endometrial cancer (an effect which could be abrogated by progestins). It was suspected that hormone therapy increased the risk of breast cancer, based on observational and animal studies. At the time, the effect of hormones on stroke was unknown, as was the effect on venous thrombosis. In summary, the trials of hormone therapy were needed, because use of hormone therapy for the prevention of chronic disease was rising, and the diseases for which benefit was being assumed (or the harms which it could cause) were of considerable public health importance. The WHI trials were not designed to test the benefits and risks of short term hormone therapy at the time of menopause, but did include postmenopausal women in a wide age range in order to extend their generalizability.
Choice of Subjects and Drug Therapy
The age range of postmenopausal women included in these
trials was 50-79 to encompass the age range for which hormones were being
prescribed for prevention of chronic diseases.
The choice of estrogen was dictated by the knowledge that Premarin
(conjugated equine estrogen) was the most commonly prescribed hormone in the US
in the early 1990s, that most of the prescriptions were for the 0.625 mg daily
dose, and by the fact that most of the observational data suggesting benefit
for coronary heart disease were based on this drug at this dose. Premarin at this dose was also the most
commonly prescribed estrogen when used in combination with a progestin. The most commonly prescribed progestin was
medroxyprogesterone, typically as cyclic therapy of 10 mg for 10-12 days in the
month, or (increasingly) as continuous-combined therapy with daily 2.5 mg of
continous-combined therapy was prescribed as two separate pills, however from
1995 onwards the combination pill Prempro became the dominant combination
therapy. Compared to epidemiologic data
on Premarin alone, there was relatively little data on Premarin combined with
medroxyprogesterone. However, what data
existed appeared to support benefit for coronary heart disease of about the
same extent as for Premarin alone.
Observational data from
Design and Timeline of Randomized Controlled Clinical Trials of Hormone Therapy
The trials were designed to test whether hormone therapy would prevent coronary heart disease, and whether the benefits would outweigh the risks, when given for several years to generally healthy postmenopausal women aged 50-79. The primary outcome for benefit was coronary heart disease, and the main outcome for harm was breast cancer. A global index was constructed as a summary measure of overall benefit or harm. The monitored outcomes included in the global index were coronary heart disease, stroke, pulmonary embolism, hip fracture, breast cancer, colorectal cancer, endometrial cancer (in women with a uterus), and death from other causes.
A randomized controlled trial of estrogen (E-Alone) in 10,739 women who had had a hysterectomy enrolled participants in the period 1993-1998 and is planned to continue to 2005, after an average of 8.5 years of follow-up. The estrogen is Premarin (conjugated equine estrogen) 0.625 mg daily, compared to matching placebo. A separate randomized controlled trial of estrogen plus progestin (E+P) in 16,608 women who had an intact uterus had the same timeline and was also originally planned to continue to 2005. The drug used in the E+P trial was Prempro (conjugated equine estrogen 0.626 mg plus medroxyprogesterone 2.5 mg daily). However, this trial was stopped in July, 2002 after 5.2 years of follow up when the independent Data and Safety Monitoring Board concluded that the pre-designated boundary for harm from breast cancer had been crossed, and that there was overall harm as assessed by a summary measure of important clinical outcomes. Note that in 2000 and again in 2001 women in the E-Alone as well as women in the E+P trials were notified of an increased risk of coronary heart disease, stroke, and venous thrombosis in the active treatment arms.
Main Findings from the Completed E+P Trial
These findings are summarized below, and links to abstracts of published articles are provided. The first publication reported the major locally adjudicated outcomes as of April 30, 2002, representing an average of 5.2 years of follow-up. Subsequent publications include centrally adjudicated outcomes reported up to the closing of the trial on July 7, 2002 and represent an average of 5.6 years of follow up. These subsequent publications also provide more detailed subgroup analyses. The summary findings are reported here as hazard ratios (HR) with the traditional nominal confidence (CI) intervals; however, the various articles also report more conservative CIs adjusted for sequential monitoring and/or multiple outcomes, as appropriate.
Overall Risks and Benefits
Risks and Benefits of Estrogen Plus Progestin in Healthy Postmenopausal Women
Principal Results From the Women's Health Initiative Randomized Controlled Trial
Writing Group for the Women's Health Initiative Investigators
After a mean of 5.2 years of follow-up, the trial was stopped because because the test statistic for invasive breast cancer exceeded the stopping boundary for this adverse effect and the global index statistic supported risks exceeding benefits.
Hazard ratios (nominal 95% confidence intervals) were as follows:
Absolute excess risks per 10 000 person-years attributable to estrogen plus progestin were 7 more CHD events, 8 more strokes, 8 more pulmonary emboli, and 8 more invasive breast cancers, while absolute risk reductions per 10 000 person-years were 6 fewer colorectal cancers and 5 fewer hip fractures. The absolute excess risk of events included in the global index was 19 per 10 000 person-years.
Overall health risks exceeded benefits from use of combined estrogen plus progestin for an average 5.2-year follow-up among healthy postmenopausal US women. All-cause mortality was not affected during the trial. The risk-benefit profile found in this trial is not consistent with the requirements for a viable intervention for primary prevention of chronic diseases, and the results indicate that this regimen should not be initiated or continued for primary prevention of CHD.
Coronary Heart Disease
Estrogen plus Progestin and the Risk of Coronary Heart Disease
JoAnn E. Manson, M.D., Dr.P.H., Judith Hsia, M.D., Karen C. Johnson, M.D., M.P.H., Jacques E. Rossouw, M.D., Annlouise R. Assaf, Ph.D., Norman L. Lasser, M.D., Ph.D., Maurizio Trevisan, M.D., Henry R. Black, M.D., Susan R. Heckbert, M.D., Ph.D., Robert Detrano, M.D., Ph.D., Ora L. Strickland, Ph.D., Nathan D. Wong, Ph.D., John R. Crouse, M.D., Evan Stein, M.D., Mary Cushman, M.D., for the Women's Health Initiative Investigators
As noted above, this and all subsequent reports include the centrally adjudicated (rather than locally adjudicated) outcomes over the entire 5.6 year (rather than 5.2 year) duration of the trial.
Estrogen plus progestin does not prevent CHD, and may increase the risk of CHD among generally healthy postmenopausal women, especially during the first year after the initiation of hormone use. This treatment should not be prescribed for the prevention of cardiovascular disease.
Influence of Estrogen Plus Progestin on Breast Cancer and Mammography in Healthy Postmenopausal Women
The Women's Health Initiative Randomized Trial
Rowan T. Chlebowski, MD, PhD; Susan L. Hendrix, DO; Robert D. Langer, MD, MPH; Marcia L. Stefanick, PhD; Margery Gass, MD; Dorothy Lane, MD, MPH; Rebecca J. Rodabough, MS; Mary Ann Gilligan, MD, MPH; Michele G. Cyr, MD; Cynthia A. Thomson, PhD, RD; Janardan Khandekar, MD; Helen Petrovitch, MD; Anne McTiernan, MD , PhD; for the WHI Investigators
Relatively short-term E+P use increases the risk for breast cancers, which are diagnosed at a more advanced stage compared with placebo use, and also substantially increases the percentage of women with abnormal mammograms. The results suggest E+P stimulates breast cancer growth and delays breast cancer diagnosis. Apparent differences by prior hormone use status need further investigation.
* weighting, as specified in the design, varied linearly from zero at time of randomization to a maximum of 1 beginning at follow up year 10
Effect of Estrogen Plus Progestin on Stroke in Postmenopausal Women
The Women's Health Initiative: A Randomized Trial
Sylvia Wassertheil-Smoller, PhD; Susan Hendrix, DO; Marian Limacher, MD; Gerardo Heiss, MD; Charles Kooperberg, PhD; Alison Baird, MD, PhD, MPH; Theodore Kotchen, MD; J. David Curb, MD; Henry Black, MD; Jacques E. Rossouw, MD; Aaron Aragaki, MS; Monika Safford, MD; Evan Stein, MD, PhD; Somchai Laowattana, MD; W. Jerry Mysiw, MD; for the WHI Investigators
Estrogen plus progestin increases the risk of ischemic stroke in generally healthy postmenopausal women. Excess risk for all strokes attributed to estrogen plus progestin appeared to be present in all subgroups of women examined. Inflammatory factors appear to play a role in stroke, but did not modify the effect of E+P on stroke risk.
Estrogen Plus Progestin and the Incidence of Dementia and Mild Cognitive Impairment in Postmenopausal Women
The Women's Health Initiative Memory Study: A Randomized Controlled Trial
Sally A. Shumaker, PhD; Claudine Legault, PhD; Stephen R. Rapp, PhD; Leon Thal, MD; Robert B. Wallace, MD; Judith K. Ockene, PhD, MEd; Susan L. Hendrix, DO; Beverly N. Jones III, MD; Annlouise R. Assaf, PhD; Rebecca D. Jackson, MD; Jane Morley Kotchen, MD, MPH; Sylvia Wassertheil-Smoller, PhD; Jean Wactawski-Wende, PhD; for the WHIMS Investigators
The Women’s Health Initiative Memory Study (WHIMS) is an ancillary study to WHI funded by Wyeth. It enrolled women aged 65 and older who were participating in the WHI trial of E+P. WHIMS enrolled 92.6% of the 4894 WHI participants who were age-eligible and free of dementia in 39 of the 40 WHI clinical centers. WHIMS ascertained the incidence of probable dementia (primary outcome) and mild cognitive impairment (secondary outcome) through a structured clinical assessment. The mean (SD) time between the date of randomization into WHI and the last Modified Mini-Mental State Examination (3MSE) for all WHIMS participants was 4.05 (1.19) years.
E+P therapy increased the risk for probable dementia in postmenopausal women aged 65 years or older. In addition, estrogen plus progestin therapy did not prevent mild cognitive impairment in these women. These findings, in conjunction with previously reported WHI data, support the conclusion that the risks of estrogen plus progestin outweigh the benefits.
Effect of Estrogen Plus Progestin on Global Cognitive Function in Postmenopausal Women
The Women's Health Initiative Memory Study: A Randomized Controlled Trial
Stephen R. Rapp, PhD; Mark A. Espeland, PhD; Sally A. Shumaker, PhD; Victor W. Henderson, MD, MS; Robert L. Brunner, PhD; JoAnn E. Manson, MD, DrPH; Margery L. S. Gass, MD; Marcia L. Stefanick, PhD; Dorothy S. Lane, MD, MPH; Jennifer Hays, PhD; Karen C. Johnson, MD, MPH; Laura H. Coker, PhD; Maggie Dailey, PhD; Deborah Bowen, PhD; for the WHIMS Investigators
The study population for this report was essentially the same as that for the companion report on dementia, only excluding some 151 participants without a valid post-enrollment assessment of cognitive function. WHIMS participants completed an annual assessment of global cognitive function, as measured with the Modified Mini-Mental State Examination (3MSE).
Among postmenopausal women aged 65 years or older, estrogen plus progestin did not improve cognitive function when compared with placebo. While most women receiving estrogen plus progestin did not experience clinically relevant adverse effects on cognition compared with placebo, a small increased risk of clinically meaningful cognitive decline occurred in the estrogen plus progestin group.
QUALITY OF LIFE
Effects of Estrogen plus Progestin on Health-Related Quality of Life
Jennifer Hays, Ph.D., Judith K. Ockene, Ph.D., Robert L. Brunner, Ph.D., Jane M. Kotchen, M.D., M.P.H., JoAnn E. Manson, M.D., Dr.P.H., Ruth E. Patterson, Ph.D., R.D., Aaron K. Aragaki, M.S., Sally A. Shumaker, Ph.D., Robert G. Brzyski, M.D., Ph.D., Andrea Z. LaCroix, M.P.H., Ph.D., Iris A. Granek, M.D., Barbara G. Valanis, M.D., for the Women's Health Initiative Investigators
Quality-of-life measures were collected at base line and at one year in all women and at three years in a subgroup of 1511 women enrolled in the trial of E+P.
In this trial in postmenopausal women, estrogen plus progestin did not have a clinically meaningful effect on health-related quality of life. If present, symptoms of hot flashes and night sweats improved, but there were no clinically significant improvements in other domains of quality of life.
The effects of Estrogen Plus Progestin on the Risk of Fracture and Bone Mineral Density
The Women's Health Initiative Clinical Trial
Jane A. Cauley, Dr.PH; John Robbins, MD; Zhao Chen, PhD; Steven R. Cummings, MD; Rebecca Jackson, MD; Adrea Z. LaCroix, PhD; Meryl LeBoff MD; Cora E. Lewis, MD, MSPH; Joan McGowan, PhD; Joan Neuner, MD, MPH; Mary Pettinger MS; Marcia L. Stefanick, PhD; Jean Wactawski-Wende, PhD; Nelson B. Watts, MD; for the Women’s Health Initiative Investigators
JAMA 2003: 290;1729-1738
The trial was designed to test the effect of E+P on fractures in a population of postmenopausal women otherwise at low risk of fracture. All confirmed osteoporotic fractures that occurred during 5.6 years of the trial were included in this report. Hip fractures were designated as a secondary outcome of the trial, and were centrally adjudicated. Other osteoporotic fractures were locally adjudicated, using radiology reports to confirm initial self-report. Bone mineral density (BMD) was measured in a subset of women (n=1024) at baseline and years 1 and 3.
E+P increases BMD and reduces risk of osteoporotic fractures in healthy postmenopausal women. However, even in the highest fracture risk tertile there was no net benefit from treatment, as assessed by the global index. Given the overall unfavorable risk/benefit ratio and the availability of other agents to prevent and treat osteoporosis, E+P cannot be recommended for the prevention or treatment of osteoporosis.
Gynecologic Cancers and Associated Diagnostic Procedures in the Women’s Health Initiative Randomized Trial of Estrogen Plus Progestin
Garnet L. Anderson, PhD; Howard Judd, MD; Andrew M. Kaunitz, MD; David H. Barad, MD; Shirley A.A. Beresford, PhD; Mary Pettinger, MS; James Liu, MD; S. Gene McNeeley, MD; Ana Maria Lopez, MD; for the Women’s Health Initiative Investigators
JAMA 2003: 290;1739-1748
The effects of continuous combined E+P on gynecologic cancers have not previously been described in a clinical trial setting. The main outcome measures of this report were incident invasive cancer of the ovary and endometrium.
The data suggest that continuous combined E+P may increase the risk of ovarian cancer, but not that of endometrial cancer, over an average follow up period of 5.6 years. The increased rates of endometrial biopsy required to assess and manage vaginal bleed further limits the acceptability of this treatment.
WHI INVESTIGATORS AND SITES
Ross Prentice, Ph.D.
Fred Hutchinson Cancer
Catherine I. Allen, Ph.D.
University of Wisconsin, Madison
Annlouise Assaf, Ph.D.
The Memorial Hospital
of Rhode Island
Tamsen Bassford, M.D.
University of Arizona, Health
Shirley Beresford, M.D.
University of Washington
Henry R. Black, M.D.
Gregory Burke. M.D., MS
Wake Forest University
Robert Burnner, Ph.D.
University of Nevada
Bette Caan, Dr.PH
Kaiser Division of Research,
Rowan T. Chlebowski, M.D., Ph.D.
and Education Institute
David Curb, M.D.
University of Hawaii
Margery Gass, M.D.
University of Cincinnati
Jennifer Hays, Ph.D.
Baylor College of Medicine
Gerardo Heiss, M.D., Ph.D.
University of North Carolina,
Susan L. Hendrix, D.O.
Wayne State University
Barbara V. Howard, Ph.D.
MedStar Research Institute
Judith Hsia, M.D.
George Washington University
Allen Hubbell, M.D.
University of California, Irvine
Rebecca D. Jackson, M.D.
Ohio State University
Karen Johnson, M.D., M.P.H.
University of Tennessee, Memphis
Howard L. Judd, M.D.
Jane Morley Kotchen, M.D., M.P.H.
Medical College of Wisconsin
Lewis Kuller, M.D., DrPH
University of Pittsburgh
Dorothy Lane, M.D.
SUNY at Stony Brook
Robert D. Langer, M.D., M.P.H.
University of California, San Diego
Norman Lasser, M.D., Ph.D.
University of Medicine and
Dentistry of N.J.
Cora Beth Lewis, M.D., MSPH
University of Alabama, Birmingham
Marian C. Limacher, M.D.
University of Florida
JoAnn Manson, M.D., DrPH
Brigham & Women’s Health Hospital
Karen Margolis, M.D.
University of Minnesota
Judith K. Ockene, Ph.D.
University of Massachusetts
Mary Jo O’Sullivan, M.D.
University of Miami
School of Medicine
Cheryl Ritenbaugh, Ph.D
Kaiser Center for Health
John A. Robbins, M.D.
University of California, Davis
Robert S. Schenken, M.D.
University of Texas Health
Science Center, San Antonio
Marcia L. Stefanick, Ph.D.
Linda Van Horn, Ph.D., R.D.
Jean Wactawski-Wende, Ph.D.
SUNY at Buffalo
Robert B. Wallace, M.D.
University of Iowa
Sylvia Wassertheil-Smoller, Ph.D.
Albert Einstein College of Medicine
Lawrence Phillips, M.D.
Emory University School of Medicine