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.
NHLBI
Overview of Main Findings Marcia Stefanick, Ph.D.
Stanford
Breast Cancer Rowan Chlebowski, M.D.
Harbor-UCLA
Garnet
Anderson, Ph.D.
Fred Hutchinson Cancer
Osteoporosis and Fractures Jane Cauley, Ph.D.
U. Pittsburgh
Garnet Anderson, Ph.D.
Fred Hutchinson Cancer
Other WHI/NIH
Representatives
Barbara Alving, M.D.
NHLBI
(WHI Director)
Rebecca Jackson, M.D.
OHSU
(Osteoporosis)
Leslie Ford, M.D.
NCI
(Cancer)
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
medroxyprogesterone. Initially,
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
JAMA 2002;288:321-333
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:
- CHD: 1.29 (1.02-1.63) with 286 cases
- Breast cancer: 1.26 (1.00-1.59) with
290 cases;
- Stroke: 1.41 (1.07-1.85) with 212
cases;
- Pulmonary embolism: 2.13 (1.39-3.25) with 101
cases
- Colorectal cancer: 0.63 (0.43-0.92)
with 112 cases
- Endometrial cancer: 0.83 (0.47-1.47)
with 47 cases
- Hip fracture: 0.66 (0.45-0.98) with
106 cases
- Death due to other causes: 0.92 (0.74-1.14)
with 331 cases
- Total mortality: 0.98 (0.82-1.18)
- Global index: 1.15 (1.03-1.28).
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.
Abstract: http://jama.ama-assn.org/cgi/content/abstract/288/3/321
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
NEJM 2003;349:523-534
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.
- A total of 335 cases of CHD were included in
this final analysis, and with 188 vs 147 cases the HR was 1.24 (95% CI
1.00 - 1.54) for E+P compared to placebo
- This corresponds to an excess of 6 cases CHD
for every 10,000 women treated for one year, on average.
- In adherent women the HR for CHD was 1.50
(1.14-1.97)
- The elevation in risk was most
apparent at one year with a HR of 1.81 (1.09 - 3.01); the risks of CHD for
years 2 through 6+ were 1.34, 1,27, 1.25, 1,45, and 0.70
- In year 6 and beyond, increased rates in the
placebo group resulted in an apparent risk reduction
- E+P did not increase or decrease the risks for
angina, CABG or PTCA, and congestive heart failure
- No subgroup (e.g., by age, years since
menopause, presence of symptoms, BMI) with lowered risk of CHD on E+P
could be identified
- Higher base-line levels of
low-density lipoprotein cholesterol were associated with an
excess risk of CHD among women who received E+P, but higher base-line
levels of C-reactive protein, other biomarkers, and other
clinical characteristics did not significantly modify the
treatment-related risk of CHD
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.
Abstract: http://content.nejm.org/cgi/content/short/349/6/523
Breast Cancer
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
JAMA 2003:289;3243-3253
- After a mean follow-up of 5.6 years, the hazard
ratios (95% confidence intervals) for breast cancer associated with E+P
compared to placebo were as follows:
- Total breast cancer (245 vs 185 cases),
HR 1.24 (1.02-1.50), weighted P<.001*
- Invasive breast cancer (199 vs 150
cases), HR 1.24 (1.01-1.54), weighted P
= .003
- In situ breast cancer (47 vs 37 cases),
HR 1.18 (0.77-1.82), weighted P
= 0.09.
- The invasive breast cancers
diagnosed in the E+P group were similar to those in the placebo group in
respect of histology (including proportions of ductal and lobular
cancers), estrogen and progestin receptor status, and grade of malignancy
- However, the cancers in the E+P group were
larger (mean [SD], 1.7 cm [1.1] vs 1.5 cm [0.9], respectively; P = .04) and were at
more advanced stage (regional/metastatic 25.4% vs 16.0%, respectively;
P = .04) compared with those
diagnosed in the placebo group.
- For all study periods after the baseline
examination, the percentages of women with abnormal mammograms
were substantially higher in the E+P group than in the placebo group
- In adherent participants, the HR for invasive
breast cancer was 1.49 (1.13-1.96), P
<.001
- The findings were statistically consistent
across multiple subgroups (e.g., by age, BMI, Gail Risk Assessment
category)
- Women with no prior menopausal hormone use had
a HR for invasive breast cancer of 1.09 (0.86-1.39), while women with
<5 years prior use had a HR of 1.70 (0.99-2.91), and those with >5
years prior use had a HR of 2.27 (1.00-5.15), weighted P value for interaction = 0.15
- In the placebo group, women with no prior
menopausal hormone use appeared to have somewhat higher risk of breast
cancer compared to women with prior use
- On the other hand, the risk from E+P emerged
later in women with no prior use; their HRs for invasive breast cancers
were 0.48, 0.65, and 0.96 in years 1 through 3, and 1.45, 1.61, and 1.24
in years 4 through 6+. In women
with prior use, the HRs were 0.90, 1.10, 3.09, 2.16, 3.56, and 1.99 in
years 1 through 6+.
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
Abstract: http://jama.ama-assn.org/cgi/content/abstract/289/24/3254
Stroke
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
JAMA 2003:289;2673-2684
- All strokes were centrally adjudicated by
stroke-trained neurologists for this report
- 151 participants in the E+P and 107 in the
placebo groups had strokes.
- For combined ischemic and
hemorrhagic strokes, the HR for estrogen plus progestin vs placebo was
1.31 (95% CI, 1.02-1.68); with adjustment for adherence, the HR
was 1.50 (95% CI, 1.08-2.08).
- The excess risk for stroke appeared in the
second year after randomization and persisted thereafter
- Overall 79.8% of strokes were ischemic; the HR
for ischemic stroke was 1.44 (95% CI, 1.09-1.90)
- There was no effect of E+P on hemorrhagic
stroke, HR 0.82 (95% CI, 0.43-1.56)
- Although E+P raised systolic blood pressure
slightly (between 1 and 2 mm Hg), this did not explain the excess risk
- The excess risk of all stroke was apparent in
all age groups, in all categories of baseline stroke risk, and
in women with and without hypertension, prior history of
cardiovascular disease, or prior use of hormones
- Use of statins or aspirin did not modify the
increased risk of stroke due to E+P
- Years since menopause and presence or absence
of hot flashes and/or night sweats did not modify the effect of E+P on
stroke risk
- Higher levels of inflammatory factors (IL-6,
CRP, and E-selectin) predicted stroke, but did not modify the effect of
E+P on stroke risk.
- Other risk factors for stroke,
including smoking, blood pressure, diabetes, lower use of
vitamin C supplements, higher white blood cell count, and higher
hematocrit levels also did not modify the effect of E+P on
stroke risk
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.
Abstract: http://jama.ama-assn.org/cgi/content/abstract/289/20/2673
DEMENTIA
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
JAMA 2003:289;2651-2662
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.
- Overall, 61 women were diagnosed
with probable dementia, 40 (66%) in the estrogen plus progestin
group compared with 21 (34%) in the placebo group.
- The HR for probable dementia was
2.05 (95% CI, 1.21-3.48)
- In adherent women the HR for probable dementia
was 3.22 (95% CI, 1.25-8.29)
- Absolute rates were 45 vs 22 per
10 000 person-years, P =
.01; on average, this increased risk would result in an
additional 23 cases of dementia per 10 000 women per year
of treatment with E+P.
- Alzheimer disease was the most common
classification of dementia in both study groups
- Age, education, and baseline 3MSE score related
to risk of probable dementia, but did not modify the effect of E+P
- Prior use of hormones, statins, or aspirin did
not modify the effect of E+P
- Mild cognitive impairment did not differ
between E+P and placebo groups (HR, 1.07; 95% CI, 0.74-1.55; 63
vs 59 cases per 10 000 person-years; P = .72)
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.
Abstract: http://jama.ama-assn.org/cgi/content/abstract/289/20/2651
COGNITIVE FUNCTION
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
JAMA 2003:289;2663-2672
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).
- 3MSE mean total scores in both
groups increased slightly over time (mean follow-up of 4.2
years), probably due to the “learning effect” of repeated administration
- Women in the estrogen plus progestin group
had smaller average increases in total scores compared with
women receiving placebo (P =
.03), but these differences were not clinically important
- Re-analysis after removing women by censoring
them after adjudicated dementia, mild cognitive impairment, or
stroke, and nonadherence to study protocol, did not alter the
findings
- Prior hormone therapy use and duration of prior
use did not affect the interpretation of the results, nor did
timing of prior hormone therapy initiation with respect to the
final menstrual period
- More women in the estrogen plus progestin group
had a substantial and clinically important decline (
2 SDs) in 3MSE total score (6.7%)
compared with the placebo group (4.8%) (P = .008)
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.
Abstract: http://jama.ama-assn.org/cgi/content/abstract/289/20/2663
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
NEJM
2003:348;1839-54
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.
- E+P treatment compared to placebo did not have
any effects on general health, vitality, mental health,
depressive symptoms, or sexual satisfaction
- E+P treatment was associated with a
statistically significant but small and not clinically meaningful
benefits for sleep disturbance, physical functioning, and
bodily pain after one year (for sleep disturbance the mean benefit was 0.4
point on a 20-point scale, for physical functioning 0.8 point on a
100-point scale, and for bodily pain it was 1.9 points on a 100-point
scale)
- These small benefits were no longer apparent at
three years, and there were no significant benefits in terms of any of the
other quality-of-life outcomes, in the subgroup with data at 3
years
- The findings were similar in women aged 50-59
and in older women, and there were no differences in any subgroup (e.g.,
by body mass index, race or ethnicity, presence of menopausal symptoms, or
previous use of hormone therapy)
- Among 574 women aged 50 to 54 years with
moderate-to-severe vasomotor symptoms at base line, E+P
improved vasomotor symptoms and resulted in a small benefit for
sleep disturbance but no benefit for the other quality-of-life outcomes
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.
Abstract: http://content.nejm.org/cgi/content/abstract/NEJMoa030311v1
FRACTURES
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.
- 733 women in the E+P group and 896 in the placebo group
experienced a fracture, HR 0.76 (95% CI 0.69-0.83)
- On average, 10,000 women treated for one year with E+P would
experience 47 fewer osteoporotic fractures than women on placebo
- 52 women in the E+P group and 73 in the placebo group experienced
a hip fracture, HR 0.72 (95% CI 0.47-0.96)
- On average, 10,000 women treated for one year with E+P would
experience 5 fewer hip fractures than women on placebo
- The HRs in adherent women were similar to those in the groups
overall; HR for total fracture was 0.71 (95% CI, 0.64-0.81), and HR for
hip fracture was 0.63 (95% CI, 0.38-1.06)
- The effect of E+P on fractures did not differ significantly by
age, years since menopause, BMI, BMD, prior hormone use, or fracture risk
score
- For hip fracture, E+P reduced the risk more markedly in the
subgroup of women with a baseline calcium intake of >1200 mg/day than
in women with a lower intake (P
for interaction = 0.02); however, this was not true for total fracture
- E+P lowered the risk of hip fracture in women with baseline BMIs
of <25 and 25-<30, but not in women with a BMI of >30, but
the interaction of therapy with baseline BMI was not statistically
significant; E+P reduced the risk of total fracture to a similar degree
across all groups of baseline BMI
- Total hip BMD increased by 3.7% after 3 years, compared to 0.14% in
the placebo group, p<0.0001
- The HR for the global index ranged from 1.20 in the lowest
fracture risk tertile to 1.03 in the highest tertile (the global index
includes coronary heart disease, stroke, pulmonary embolism, hip fracture,
breast cancer, colorectal cancer, endometrial cancer, and death from other
causes)
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
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 hazard ratio (HR) for invasive ovarian cancer in
women assigned to estrogen plus progestin relative to placebo was 1.58
(95% CI: 0.77-3.24) with 32 cases.
- The HR for endometrial cancer was 0.81 (95% CI:
0.48-1.36) with 58 cases.
- No appreciable differences were found in the
distributions of tumor histology, stage or grade for either cancer site
- The HR for cervical cancer was 1.44 (95% CI 0.47-4.42)
with 13 cases, and the Pap smear results yielded slightly more mild
displasia, low grade squamous intra-epithelial lesions, or atypia than the
placebo arm and fewer normal results (p<0.0001)
- The incidence of other gynecologic cancers (uterus,
other gynecologic organs) was low and did not differ by treatment arm
- More women on E+P required endometrial biopsies (33% vs
6%, p<0.0001)
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.
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JA. The evolution of the Women's Health Initiative: perspectives
from the NIH. Journal of the
American Medical Women's Association 1995;50:50-55.
- Prentice R, Rossouw JR, Johnson, SR, Freedman LS, McTiernan A.
"The role of randomized controlled trial's in assessing the benefits
and risks of long-term hormone replacement therapy: example of the Women’s
Health Initiative." Menopause,
1996;3:71-76.
- Prentice RL, Anderson G, CummingsS, Freedman LS, Furberg C,
Henderson M, Johnson SR, Kuller L, Manson J, Oberman A, Prentice RL,
Rossouw JE. Design of the Women's Health Initiative Clinical Trial and
Observational Study. Controlled
Clinical Trials 1998;19:61-109.
- Shumaker SA, Reboussin BA, Espeland MA, Rapp SR, McBee WL, Dailey
M, Bowen D, Terrell T, Jones BN. The Women's Health Initiative Memory Study (WHIMS): a trial
of the effect of estrogen therapy in preventing and slowing the
progression of dementia. Control
Clin Trials 199819:604-21.
- Writing Group for the Women's Health Initiative Investigators. Risks
and Benefits of Estrogen Plus Progestin in Healthy Postmenopausal Women.
JAMA 2002;288:321-333.
- Rapp S, Espeland M, Hogan P, Jones B, Dugan E. Baseline
experience with Modified Mini Mental State Exam: The Women’s Health
Initiative Memory Study (WHIMS). Aging
and Mental Health 2003;7(3):217-223.
- Rapp S, Espeland M, Shumaker S, Henderson V, Brunner R, Manson J,
Gass M, Stefanick M, Lane D, Hays J, Johnson K, Coker L, Dailey M, Bowen
D. Effect of Estrogen Plus Progestin on Global Cognitive
Function in Postmenopausal Women: The Women's Health Initiative Memory
Study: A Randomized Controlled Trial. JAMA 2003;289:2663-2672.
- Shumaker S, Legault C, Thal L, Wallace R, Ockene J, Hendrix S,
Jones III B, Assaf A, Jackson R, Kotchen JM, Wassertheil-Smoller S,
Wactawski-Wende J. 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. JAMA
2003;289:2651-2662.
- Wassertheil-Smoller S, Hendrix S, Limacher M, Heiss G, Kooperberg
C, Baird A, Kotchen T, Curb JD, Black H, Rossouw J, Aragaki A, Safford M,
Stein E, Laowattana S, Mysiw WJ. Effect
of Estrogen Plus Progestin on Stroke in Postmenopausal Women: The Women's
Health Initiative: A Randomized Trial. JAMA 2003;289:2673-2684.
- Jennifer Hays, Judith K. Ockene, Robert L. Brunner, Jane M.
Kotchen, JoAnn E. Manson, Ruth E. Patterson, Aaron K. Aragaki, Sally A. Shumaker,
Robert G. Brzyski, Andrea Z. LaCroix, Iris A. Granek, Barbara G. Valanis;
for the Women's Health Initiative Investigators. Effects of Estrogen
plus Progestin on Health-Related Quality of Life. NEJM 2003:348;1839-54
- Rowan T. Chlebowski, Susan L.
Hendrix, Robert D. Langer, Marcia L. Stefanick, Margery Gass, Dorothy
Lane, Rebecca J. Rodabough, Mary Ann Gilligan, Michele G. Cyr, Cynthia A.
Thomson, Janardan Khandekar, Helen Petrovitch, Anne McTiernan; for the WHI
Investigators. Influence of Estrogen Plus Progestin on Breast Cancer
and Mammography in Healthy Postmenopausal Women: The Women's Health
Initiative Randomized Trial. JAMA. 2003;289:3243-3253
- JoAnn E. Manson, Judith Hsia, Karen C. Johnson,
Jacques E. Rossouw, Annlouise R. Assaf, Norman L. Lasser, Maurizio
Trevisan, Henry R. Black, Susan R.
Heckbert, Robert Detrano, Ora L. Strickland, Nathan D. Wong, John R.
Crouse, Evan Stein, Mary Cushman; for the Women's Health Initiative
Investigators. Estrogen plus Progestin and the Risk of Coronary Heart
Disease. NEJM 2003;349:523-534
- Jane A. Cauley, John Robbins, Zhao Chen, Steven
R. Cummings, Rebecca Jackson, Andrea Z. LaCroix, Meryl LeBoff, Cora E.
Lewis, Joan McGowan, Joan Neuner, Mary Pettinger, Marcia L. Stefanick,
Jean Wactawski-Wende, Nelson Watts; For the Women’s Health Initiative
Investigators. The Effects of Estrogen Plus Progestin on the Risk of
Fracture and Bone Mineral Density. The Women’s Health Initiative Clinical
Trial. JAMA 2003: 290;1729-1738 (In
addition to this publication, Committee Members and Consultants also
received the pre-publication manuscript to this publication.)
- Garnet L. Anderson, Howard Judd, Andrew M.
Kaunitz, David H. Barad, Shirley A.A. Beresford, Mary Pettinger, James
Liu, S. Gene McNeeley, Ana Maria Lopez. Gynecologic Cancers and Associated
Diagnostic Procedures in the Women’s Health Initiative Randomized Trial of
Estrogen Plus Progestin. JAMA 2003:290;1739-1748 (In
addition to this publication, Committee Members and Consultants also
received the pre-publication manuscript to this publication.)
Further information
on the WHI Program can be found at http://www.whi.org/
and at http://www.nhlbi.nih.gov/whi/