JAMA-EXPRESS
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
Context Despite decades of accumulated observational evidence,
the balance of risks and benefits for hormone use in healthy postmenopausal
women remains uncertain.
Objective To assess the major health benefits and risks of the
most commonly used combined hormone preparation in the United States.
Design Estrogen plus progestin component of the Women's Health
Initiative, a randomized controlled primary prevention trial (planned
duration, 8.5 years) in which 16608 postmenopausal women aged 50-79 years
with an intact uterus at baseline were recruited by 40 US clinical centers
in 1993-1998.
Interventions Participants received conjugated equine estrogens,
0.625 mg/d, plus medroxyprogesterone acetate, 2.5 mg/d, in 1 tablet (n =
8506) or placebo (n = 8102).
Main Outcomes Measures The primary outcome was coronary heart
disease (CHD) (nonfatal myocardial infarction and CHD death), with invasive
breast cancer as the primary adverse outcome. A global index summarizing the
balance of risks and benefits included the 2 primary outcomes plus stroke,
pulmonary embolism (PE), endometrial cancer, colorectal cancer, hip
fracture, and death due to other causes.
Results On May 31, 2002, after a mean of 5.2 years of follow-up,
the data and safety monitoring board recommended stopping the trial of
estrogen plus progestin vs placebo 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. This report
includes data on the major clinical outcomes through April 30, 2002.
Estimated hazard ratios (HRs) (nominal 95% confidence intervals [CIs]) 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; PE,
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; and death due to other causes, 0.92
(0.74-1.14) with 331 cases. Corresponding HRs (nominal 95% CIs) for
composite outcomes were 1.22 (1.09-1.36) for total cardiovascular disease
(arterial and venous disease), 1.03 (0.90-1.17) for total cancer, 0.76
(0.69-0.85) for combined fractures, 0.98 (0.82-1.18) for total mortality,
and 1.15 (1.03-1.28) for the global index. Absolute excess risks per 10 000
person-years attributable to estrogen plus progestin were 7 more CHD events,
8 more strokes, 8 more PEs, 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.
Conclusions 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.
JAMA. 2002;288:321-333
The Women's Health Initiative (WHI) focuses on defining the risks and
benefits of strategies that could potentially reduce the incidence of heart
disease, breast and colorectal cancer, and fractures in postmenopausal
women. Between 1993 and 1998, the WHI enrolled 161 809 postmenopausal women
in the age range of 50 to 79 years into a set of clinical trials (trials of
low-fat dietary pattern, calcium and vitamin D supplementation, and 2 trials
of postmenopausal hormone use) and an observational study at 40 clinical
centers in the United States.1
This article reports principal results for the trial of combined estrogen
and progestin in women with a uterus. The trial was stopped early based on
health risks that exceeded health benefits over an average follow-up of 5.2
years. A parallel trial of estrogen alone in women who have had a
hysterectomy is being continued, and the planned end of this trial is March
2005, by which time the average follow-up will be about 8.5 years.
The WHI clinical trials were designed in 1991-1992 using the accumulated
evidence at that time. The primary outcome for the trial of estrogen plus
progestin was designated as coronary heart disease (CHD). Potential
cardioprotection was based on generally supportive data on lipid levels in
intermediate outcome clinical trials, trials in nonhuman primates, and a
large body of observational studies suggesting a 40% to 50% reduction in
risk among users of either estrogen alone or, less frequently, combined
estrogen and progestin.2-5
Hip fracture was designated as a secondary outcome, supported by
observational data as well as clinical trials showing benefit for bone
mineral density.6, 7
Invasive breast cancer was designated as a primary adverse outcome based on
observational data.3,
8 Additional clinical outcomes chosen as secondary outcomes that
may plausibly be affected by hormone therapy include other cardiovascular
diseases; endometrial, colorectal, and other cancers; and other fractures.3,
6, 9
The effect of hormones on overall health was an important consideration
in the design and conduct of the WHI clinical trial. In an attempt to
summarize important aspects of health benefits vs risks, a global index was
defined as the earliest occurrence of CHD, invasive breast cancer, stroke,
pulmonary embolism (PE), endometrial cancer, colorectal cancer, hip
fracture, or death due to other causes. Compared with total mortality, which
may be too insensitive, this index assigns additional weight to the 7 listed
diseases. Procedures for monitoring the trial involved semiannual
comparisons of the estrogen plus progestin and placebo groups with respect
to each of the elements of the global index and to the overall global index.
This report pertains primarily to estrogen plus progestin use among
healthy postmenopausal women, since only 7.7% of participating women
reported having had prior cardiovascular disease. During the course of the
WHI trial, the Heart and Estrogen/progestin Replacement Study (HERS)
reported its principal results.10
HERS was another blinded, randomized controlled trial comparing the same
regimen of estrogen plus progestin with placebo among women with a uterus;
however, in HERS, all 2763 participating women had documented CHD prior to
randomization. The HERS findings of no overall effect on CHD but an apparent
increased risk in the first year after randomization seemed surprising given
preceding observational studies of hormone use in women with CHD.3
Subsequent to HERS, some investigators reanalyzed their observational study
data and were able to detect an early elevation in CHD risk among women with
prior CHD11-13 but not in
ostensibly healthy women,14
prompting speculation that any early adverse effect of hormones on CHD
incidence was confined to women who have experienced prior CHD events.
The WHI is the first randomized trial to directly address whether
estrogen plus progestin has a favorable or unfavorable effect on CHD
incidence and on overall risks and benefits in predominantly healthy women.
METHODS
Study Population
Detailed eligibility criteria and recruitment methods have been published.1
Briefly, most women were recruited by population-based direct mailing
campaigns to age-eligible women, in conjunction with media awareness
programs. Eligibility was defined as age 50 to 79 years at initial
screening, postmenopausal, likelihood of residence in the area for 3 years,
and provision of written informed consent. A woman was considered
postmenopausal if she had experienced no vaginal bleeding for 6 months (12
months for 50- to 54-year-olds), had had a hysterectomy, or had ever used
postmenopausal hormones. Major exclusions were related to competing risks
(any medical condition likely to be associated with a predicted survival of
<3 years), safety (eg, prior breast cancer, other prior cancer within the
last 10 years except nonmelanoma skin cancer, low hematocrit or platelet
counts), and adherence and retention concerns (eg, alcoholism, dementia).
A 3-month washout period was required before baseline evaluation of women
using postmenopausal hormones at initial screening. Women with an intact
uterus at initial screening were eligible for the trial of combined
postmenopausal hormones, while women with a prior hysterectomy were eligible
for the trial of unopposed estrogen. This report is limited to the 16 608
women with an intact uterus at baseline who were enrolled in the trial
component of estrogen plus progestin vs placebo. The protocol and consent
forms were approved by the institutional review boards for all participating
institutions (see Acknowledgment).
Study Regimens, Randomization, and Blinding
Combined estrogen and progestin was provided in 1 daily tablet containing
conjugated equine estrogen (CEE), 0.625 mg, and medroxyprogesterone acetate
(MPA), 2.5 mg (Prempro, Wyeth Ayerst, Philadelphia, Pa). A matching placebo
was provided to the control group. Eligible women were randomly assigned to
receive estrogen plus progestin or placebo after eligibility was established
and baseline assessments made (Figure
1). The randomization procedure was developed at the WHI Clinical
Coordinating Center and implemented locally through a distributed study
database, using a randomized permuted block algorithm, stratified by
clinical center site and age group. All study medication bottles had a
unique bottle number and bar code to allow for blinded dispensing.
Initially, the design allowed women with a uterus to be randomized to
receive unopposed estrogen, estrogen plus progestin, or placebo. After the
release of the Postmenopausal Estrogen/Progestin Intervention (PEPI) trial
results15 indicating that
long-term adherence to unopposed estrogen was not feasible in women with a
uterus, the WHI protocol was changed to randomize women with a uterus to
only estrogen plus progestin or placebo in equal proportions. The 331 women
previously randomized to unopposed estrogen were unblinded and reassigned to
estrogen plus progestin. These women are included in the estrogen plus
progestin group in this report, resulting in 8506 participants in the
estrogen plus progestin group vs 8102 in the placebo group. Analysis of the
data excluding the women randomized before this protocol change did not
affect the results. Considerable effort was made to maintain blinding of
other participants and clinic staff. When required for safety or symptom
management, an unblinding officer provided the clinic gynecologist, who was
not involved with study outcomes activities, with the treatment assignment.
Follow-up
Study participants were contacted by telephone 6 weeks after randomization
to assess symptoms and reinforce adherence. Follow-up for clinical events
occurred every 6 months, with annual in-clinic visits required. At each
semiannual contact, a standardized interview collected information on
designated symptoms and safety concerns, and initial reports of outcome
events were obtained using a self-administered questionnaire. Adherence to
study interventions was assessed by weighing of returned bottles. The study
protocol required annual mammograms and clinical breast examinations; study
medications were withheld if safety procedures were not performed, but these
participants continued to be followed up. Electrocardiograms were collected
at baseline and at follow-up years 3 and 6.
Data Collection, Management, and Quality Assurance
All data were collected on standardized study forms by certified staff
according to documented study procedures. Study data were entered into a
local clinical center database developed and maintained by the Clinical
Coordinating Center and provided to each site in the form of a local area
network connected to the Clinical Coordinating Center through a wide area
network. Data quality was ensured through standard data entry mechanisms,
routine reporting and database checks, random chart audits, and routine site
visits.
Maintenance/Discontinuation of Study Medications
During the trial, some flexibility of the dosages of both estrogen and
progestin was allowed to manage symptoms such as breast tenderness and
vaginal bleeding. Vaginal bleeding was managed according to an algorithm
that accounted for the time since randomization, severity of the bleeding,
treatment assignment, and endometrial histology. Women who had a
hysterectomy after randomization for indications other than cancer were
switched to unopposed estrogen or the corresponding placebo without
unblinding. These women are included in the original randomization group for
analyses.
Permanent discontinuation of study medication was required by protocol
for women who developed breast cancer, endometrial pathologic state
(hyperplasia not responsive to treatment, atypia, or cancer), deep vein
thrombosis (DVT) or PE, malignant melanoma, meningioma, triglyceride level
greater than 1000 mg/dL (11.3 mmol/L), or prescription of estrogen,
testosterone, or selective estrogen-receptor modulators by their personal
physician. Medications were temporarily discontinued in participants who had
acute myocardial infarction (MI), stroke, fracture, or major injury
involving hospitalization, surgery involving use of anesthesia, any illness
resulting in immobilization for more than 1 week, or any other severe
illness in which hormone use is temporarily inappropriate.
Outcome Ascertainment
Cardiovascular Disease
Coronary heart disease was defined as acute MI requiring overnight
hospitalization, silent MI determined from serial electrocardiograms (ECGs),
or CHD death. The diagnosis of acute MI was established according to an
algorithm adapted from standardized criteria16
that included cardiac pain, cardiac enzyme and troponin levels, and ECG
readings. The primary analyses included both definite and probable MIs as
defined by the algorithm. Myocardial infarction occurring during surgery and
aborted MIs were included. An aborted MI was defined as chest pain and ECG
evidence of acute MI at presentation, an intervention (eg, thrombolysis)
followed by resolution of ECG changes, and all cardiac enzyme levels within
normal ranges. Silent MI was diagnosed by comparing baseline and follow-up
ECGs at 3 and 6 years after randomization. Coronary death was defined as
death consistent with CHD as underlying cause plus 1 or more of the
following: preterminal hospitalization with MI within 28 days of death,
previous angina or MI and no potentially lethal noncoronary disease, death
resulting from a procedure related to coronary artery disease, or death
certificate consistent with CHD as the underlying cause. Stroke diagnosis
was based on rapid onset of a neurologic deficit lasting more than 24 hours,
supported by imaging studies when available. Pulmonary embolism and DVT
required clinical symptoms supported by relevant diagnostic studies.
Cancer
Breast, colorectal, endometrial, and other cancers were confirmed by
pathological reports when available. Current data indicate that at least 98%
of breast, colorectal, and endometrial cancers and 92% of other cancers were
documented with pathological reports.
Fractures
Reports of hip, vertebral, and other osteoporotic fractures (including all
fractures except those of the ribs, chest/sternum, skull/face, fingers,
toes, and cervical vertebrae) were routinely ascertained. All fracture
outcomes were verified by radiology reports. Study radiographs were not
obtained to ascertain subclinical vertebral fractures.
This report is based on outcomes adjudicated by clinical center physician
adjudicators, as used for trial-monitoring purposes. Clinical center
physician adjudicators were centrally trained and blinded to treatment
assignment and participants' symptoms. Future communications will report
results based on centrally adjudicated outcomes and will include a broader
range of outcomes with more extensive explanatory analyses. Since this
report is presented before the planned study closeout, outcome information
is still being collected and adjudicated. Local adjudication is complete for
approximately 96% of the designated self-reported events. To date, agreement
rates between local and central adjudication are: MI, 84%; revascularization
procedures, 97%; PE, 89%; DVT, 84%; stroke, 94%; invasive breast cancer,
98%; endometrial cancer, 96%; colorectal cancer, 98%; hip fracture, 95%; and
specific cause of death, 82%. When related cardiovascular conditions are
combined (eg, when unstable angina or congestive heart failure is grouped
with MI), agreement rates exceed 94% for cardiovascular disease and 90% for
specific cause of death.
Statistical Analyses
All primary analyses use time-to-event methods and are based on the
intention-to-treat principle. For a given outcome, the time of event was
defined as the number of days from randomization to the first
postrandomization diagnosis, as determined by the local adjudicator. For
silent MIs, the date of the follow-up ECG applied. Participants without a
diagnosis were censored for that event at the time of last follow-up
contact. Primary outcome comparisons are presented as hazard ratios (HRs)
and 95% confidence intervals (CIs) from Cox proportional hazards analyses,17
stratified by clinical center, age, prior disease, and randomization status
in the low-fat diet trial.
Two forms of CIs are presented, nominal and adjusted. Nominal 95% CIs
describe the variability in the estimates that would arise from a simple
trial for a single outcome. Although traditional, these CIs do not account
for the multiple statistical testing issues (across time and across outcome
categories) that occurred in this trial, so the probability is greater than
.05 that at least 1 of these CIs will exclude unity under an overall null
hypothesis. The adjusted 95% CIs presented herein use group sequential
methods to correct for multiple analyses over time. A Bonferroni correction
for 7 outcomes as specified in the monitoring plan (described herein) was
applied to all clinical outcomes other than CHD and breast cancer, the
designated primary and primary adverse effect outcomes, and the global
index. The adjusted CIs are closely related to the monitoring procedures
and, as such, represent a conservative assessment of the evidence. This
report focuses primarily on results using the unadjusted statistics and also
relies on consistency across diagnostic categories, supportive data from
other studies, and biologic plausibility for interpretation of the findings.
Data and Safety Monitoring
Trial monitoring guidelines for early stopping considerations were based on
O'Brien-Fleming boundaries18
using asymmetric upper and lower boundaries: a 1-sided, .025-level upper
boundary for benefit and 1-sided, .05-level lower boundaries for adverse
effects. The adverse-effect boundaries were further adjusted with a
Bonferroni correction for the 7 major outcomes other than breast cancer that
were specifically monitored (CHD, stroke, PE, colorectal cancer, endometrial
cancer, hip fracture, and death due to other causes). The global index of
monitored outcomes played a supportive role as a summary measure of the
overall balance of risks and benefits. Trial monitoring for early stopping
considerations was conducted semiannually by an independent data and safety
monitoring board (DSMB). Aspects of the monitoring plan have been published.19
RESULTS
Trial Monitoring and Early Stopping
Formal monitoring began in the fall of 1997 with the expectation of final
analysis in 2005 after an average of approximately 8.5 years of follow-up.
Late in 1999, with 5 interim analyses completed, the DSMB observed small but
consistent early adverse effects in cardiovascular outcomes and in the
global index. None of the disease-specific boundaries had been crossed. In
the spring of 2000 and again in the spring of 2001, at the direction of the
DSMB, hormone trial participants were given information indicating that
increases in MI, stroke, and PE/DVT had been observed and that the trial
continued because the balance of risks and benefits remained uncertain.
In reviewing the data for the 10th interim analyses on May 31, 2002, the
DSMB found that the adverse effects in cardiovascular diseases persisted,
although these results were still within the monitoring boundaries. However,
the design-specified weighted log-rank test statistic for breast cancer (z
= -3.19) crossed the designated boundary (z = -2.32) and the global
index was supportive of a finding of overall harm (z = -1.62).
Updated analyses including 2 months of additional data, available by the
time of the meeting, did not appreciably change the overall results. On the
basis of these data, the DSMB concluded that the evidence for breast cancer
harm, along with evidence for some increase in CHD, stroke, and PE,
outweighed the evidence of benefit for fractures and possible benefit for
colon cancer over the average 5.2-year follow-up period. Therefore, the DSMB
recommended early stopping of the estrogen plus progestin component of the
trial. Because the balance of risks and benefits in the unopposed-estrogen
component remains uncertain, the DSMB recommended continuation of that
component of the WHI. Individual trial participants have been informed.
Baseline Characteristics
There were no substantive differences between study groups at baseline; 8506
women were randomized into the estrogen plus progestin group and 8102 into
the placebo group (Table
1). The mean (SD) age was 63.3 (7.1) years. Two thirds of the women who
reported prior or current hormone use had taken combined hormones and one
third had used unopposed estrogen.
Prevalence of prior cardiovascular disease was low and levels of
cardiovascular risk factors were consistent with a generally healthy
population of postmenopausal women. An assessment of commonly studied breast
cancer risk factors, both individually and combined using the Gail model,20
indicate that the cohort in general was not at increased risk of breast
cancer.
Follow-up, Adherence, and Unblinding
Vital status is known for 16 025 randomized participants (96.5%), including
449 (2.7%) known to be deceased. A total of 583 (3.5%) participants were
lost to follow-up or stopped providing outcomes information for more than 18
months. The remaining 15 576 (93.8%) provided recent outcome information (Figure
1).
At the time of this report, all women had been enrolled for at least 3.5
years, with an average follow-up of 5.2 years and a maximum of 8.5 years. A
substantial number of women had stopped taking study drugs at some time (42%
of estrogen plus progestin and 38% of placebo). Dropout rates over time (Figure
2) exceeded design projections, particularly early on, but compare
favorably with community-based adherence to postmenopausal hormones.21
Some women in both groups initiated hormone use through their own clinician
(6.2% in the estrogen plus progestin group and 10.7% in the placebo group
cumulatively by the sixth year). These "drop-in" rates were also greater
than expected.
At the time of this report, clinic gynecologists had been unblinded to
treatment assignment for 3444 women in the estrogen plus progestin group and
548 women in the placebo group, primarily to manage persistent vaginal
bleeding. During the trial, 248 women in the estrogen plus progestin group
and 183 in the placebo group had a hysterectomy.
Intermediate Cardiovascular Disease End Points
Blood lipid levels, assessed in an 8.6% subsample of fasting blood specimens
collected from women at baseline and year 1, showed greater reductions in
low-density lipoprotein cholesterol (-12.7%) and increases in high-density
lipoprotein cholesterol (7.3%) and triglycerides (6.9%) with estrogen plus
progestin relative to placebo (data not shown), consistent with HERS and
PEPI.10, 22
Systolic blood pressure was, on average, 1.0 mm Hg higher in women taking
estrogen plus progestin at 1 year, rising to 1.5 mm Hg at 2 years and beyond
(data not shown). Diastolic blood pressures did not differ.
Clinical Outcomes
Cardiovascular Disease
Overall CHD rates were low (Table
2). The rate of women experiencing CHD events was increased by 29% for
women taking estrogen plus progestin relative to placebo (37 vs 30 per
10 000 person-years), reaching nominal statistical significance (at the .05
level). Most of the excess was in nonfatal MI. No significant differences
were observed in CHD deaths or revascularization procedures (coronary artery
bypass grafting or percutaneous transluminal coronary angioplasty). Stroke
rates were also higher in women receiving estrogen plus progestin (41%
increase; 29 vs 21 per 10 000 person-years), with most of the elevation
occurring in nonfatal events. Women in the estrogen plus progestin group had
2-fold greater rates of venous thromboembolism (VTE), as well as DVT and PE
individually, with almost all associated CIs excluding 1. Rates of VTE were
34 and 16 per 10 000 person-years in the estrogen plus progestin and placebo
groups, respectively. Total cardiovascular disease, including other events
requiring hospitalization, was increased by 22% in the estrogen plus
progestin group.
Cancer
The invasive breast cancer rates in the placebo group were consistent with
design expectations. The 26% increase (38 vs 30 per 10 000 person-years)
observed in the estrogen plus progestin group almost reached nominal
statistical significance and, as noted herein, the weighted test statistic
used for monitoring was highly significant. No significant difference was
observed for in situ breast cancers. Follow-up rates for mammography were
comparable in the estrogen plus progestin and placebo groups. Colorectal
cancer rates were reduced by 37% (10 vs 16 per 10 000 person-years), also
reaching nominal statistical significance. Endometrial cancer incidence was
not affected, nor was lung cancer incidence (54 vs 50; HR, 1.04; 95% CI,
0.71-1.53) or total cancer incidence.
Fractures
This cohort experienced low hip fracture rates (10 per 10 000 person-years
in the estrogen plus progestin group vs 15 per 10 000 person-years in the
placebo group). Estrogen plus progestin reduced the observed hip and
clinical vertebral fracture rates by one third compared with placebo, both
nominally significantly. The reductions in other osteoporotic fractures
(23%) and total fractures (24%) were statistically significant (all
associated CIs exclude 1).
The global index showed a nominally significant 15% increase in the
estrogen plus progestin group (170 vs 151 per 10 000 person-years). There
were no differences in mortality or cause of death between groups (Table
3).
Time Trends
The Kaplan Meier estimates of cumulative hazards (Figure
3) for CHD indicate that the difference between treatment groups began
to develop soon after randomization. These curves provide little evidence of
convergence through 6 years of follow-up. The cumulative hazards for stroke
begin to diverge between 1 and 2 years after randomization, and this
difference persists beyond the fifth year. For PE, the curves separate soon
after randomization and show continuing adverse effects throughout the
observation period. For breast cancer, the cumulative hazard functions are
comparable through the first 4 years, at which point the curve for estrogen
plus progestin begins to rise more rapidly than that for placebo. Curves for
colorectal cancer show benefit beginning at 3 years, and curves for hip
fracture show increasing cumulative benefit over time. The difference in
hazard rates for the global index (Figure
4) suggests a gradual increase in adverse effects compared with benefits
for estrogen plus progestin through year 5, with a possible narrowing of the
difference by year 6; however, HR estimates tend to be unstable beyond 6
years after randomization. Total mortality rates are indistinguishable
between estrogen plus progestin and placebo.
Tests for linear trends with time since randomization, based on a Cox
proportional hazards model with a time-dependent covariate, detected no
trend with time for CHD, stroke, colorectal cancer, hip fracture, total
mortality, or the global index (Table
4). There was some evidence for an increasing risk of breast cancer over
time with estrogen plus progestin (z = 2.56 compared with a nominal
z score for statistical significance of 1.96) and a decreasing risk
of VTE with time (z = -2.45). These results must be viewed cautiously
because the number of events in each interval is modest, the data in later
years are still incomplete, and later year comparisons are limited to women
still at risk of their first event for that outcome.
Subgroup Analyses
Cardiovascular Disease
A small subset of women (n = 400; average follow-up, 57.4 months) in WHI
reported conditions at baseline that would have made them eligible for HERS,
ie, prior MI or revascularization procedures. Among these women with
established coronary disease, the HR for subsequent CHD for estrogen plus
progestin relative to placebo was 1.28 (95% CI, 0.64-2.56) with 19 vs 16
events. The remaining women, those without prior CHD, had an identical HR
for CHD (145 vs 106; HR, 1.28; 95% CI, 1.00-1.65). Few women with a history
of VTE were enrolled, but these data suggest a possibility that these women
may be at greater risk of future VTE events when taking estrogen plus
progestin (7 vs 1; HR, 4.90; 95% CI, 0.58-41.06) than those without a
history of VTE (144 vs 66; HR, 2.06; 95% CI, 1.54-2.76). For stroke, prior
history did not confer additional risk (1 vs 5 in women with prior stroke;
HR, 0.46; 95% CI, 0.05-4.51; 126 vs 80 with no prior stroke; HR, 1.47; 95%
CI, 1.11-1.95). No noteworthy interactions with age, race/ethnicity, body
mass index, prior hormone use, smoking status, blood pressure, diabetes,
aspirin use, or statin use were found for the effect of estrogen plus
progestin on CHD, stroke, or VTE.
Breast Cancer
Women reporting prior postmenopausal hormone use had higher HRs for breast
cancer associated with estrogen plus progestin use than those who never used
postmenopausal hormones (among never users, 114 vs 102; HR, 1.06; 95% CI,
0.81-1.38; for women with <5 years of prior use, 32 vs 15; HR, 2.13; 95% CI,
1.15-3.94; for women with 5-10 years of prior use, 11 vs 2; HR, 4.61; 95%
CI, 1.01-21.02; and for women with
10 years of prior use, 9 vs
5; HR, 1.81; 95% CI, 0.60-5.43; test for trend, z = 2.17). No
interactions between estrogen plus progestin and age, race/ethnicity, family
history, parity, age at first birth, body mass index, or Gail-model risk
score were observed for invasive breast cancer.
Further Analyses
Because a number of women stopped study medications during follow-up,
several analyses were performed to examine the sensitivity of the principal
HR estimates to actual use of study medications. Analyses that censored a
woman's event history 6 months after becoming nonadherent (using <80% of or
stopping study drugs) produced the largest changes to estimated effect
sizes. This approach increased HRs to 1.51 for CHD, to 1.49 for breast
cancer, to 1.67 for stroke, and to 3.29 for VTE. Analyses attributing events
to actual hormone use ("as treated," allowing for a 6-month lag) produced
more modest changes to these estimates. Analyses excluding women randomized
during the period when the unopposed-estrogen component was open to women
with a uterus and analyses stratifying by enrollment period did not
substantially affect the results. These analyses suggest that the
intention-to-treat estimates of HRs may somewhat underestimate the effect
sizes relative to what would be observed with full adherence to study
medications.
COMMENT
The WHI provides evidence from a large randomized trial that addresses
the important issue of whether most women with an intact uterus in the
decades of life following menopause should consider hormone therapy to
prevent chronic disease. The WHI enrolled a cohort of mostly healthy,
ethnically diverse women, spanning a large age range (50-79 years at
baseline). It is noteworthy that the increased risks for cardiovascular
disease and invasive breast cancer were present across racial/ethnic and age
strata and were not influenced by the antecedent risk status or prior
disease. Hence, the results are likely to be generally applicable to healthy
women in this age range. At the time the trial was stopped, the increases in
numbers of invasive breast cancers, CHD, stroke, and PE made approximately
equal contributions to harm in the estrogen plus progestin group compared
with placebo, which were not counterbalanced by the smaller reductions in
numbers of hip fractures and colorectal cancers.
Cardiovascular Disease
Even though the trial was stopped early for harm from breast cancer, a
sufficient number of CHD events had occurred by 5.2 years of average
follow-up to suggest that continuation to the planned end would have been
unlikely to yield a favorable result for the primary outcome of CHD. Even if
there were a reversal of direction toward benefit of a magnitude seen in the
observational studies (ie, a risk reduction of 55%) during the remaining
years, conditional power analyses indicate that less than 10% power remained
for showing potential benefit if the trial continued.
The WHI finding that estrogen plus progestin does not confer benefit for
preventing CHD among women with a uterus concurs with HERS findings among
women with clinically apparent CHD,10 with the
Estrogen Replacement for Atherosclerosis trial, in which estrogen plus
progestin did not inhibit progression,23
and with a trial in women with unstable angina that did not observe a
reduction in ischemic events.24
The finding of an increased risk after initiation of treatment in WHI is
similar to HERS. In HERS, after 4.1 and 6.8 years of follow-up, hormone
therapy did not increase or decrease risk of cardiovascular events in women
with CHD.25 The WHI extends
these findings to include a wider range of women, including younger women
and those without clinically apparent CHD, and indicates that the risk may
persist for some years.
Unlike CHD, the excess risk of stroke in the estrogen plus progestin
group was not present in the first year but appeared during the second year
and persisted through the fifth year. Preliminary analyses indicate that the
modest difference in blood pressure between groups does not contribute much
to an explanation of the increase in strokes (data not shown). The findings
in WHI for stroke are consistent with but somewhat more extreme than those
of HERS, which reported a nonsignificant 23% increase in the treatment
group.26 The results were
also more extreme than those of the Women's Estrogen and Stroke Trial of
estradiol (without progestin) in women with prior stroke, which found no
effect of estrogen on recurrent strokes overall but some increase in the
first 6 months.27 Trials of
the effect of estradiol on carotid intima-media thickness have yielded
conflicting results.28,
29 At least 1 observational study has suggested
that that use of estrogen plus progestin is associated with higher risk of
stroke than estrogen alone.14 In WHI, there
was no indication that excess strokes due to estrogen plus progestin were
more likely to occur in older women, in women with prior stroke history, by
race/ethnicity, or in women with high blood pressure at baseline. Therefore,
it appears that estrogen plus progestin increases the risk of strokes in
apparently healthy women.
Venous thromboembolism is an expected complication of postmenopausal
hormones, and the pattern over time in WHI is consistent with the findings
from HERS and several observational studies.30,
31
Cancer
The WHI is the first randomized controlled trial to confirm that combined
estrogen plus progestin does increase the risk of incident breast cancer and
to quantify the degree of risk. The WHI could not address the risk of death
due to breast cancer because with the relatively short follow-up time, few
women in the WHI have thus far died as a result of breast cancer (3 in the
active treatment group and 2 in the placebo group). The risk of breast
cancer emerged several years after randomization. After an average follow-up
of about 5 years, the adverse effect on breast cancer had crossed the
monitoring boundary. The 26% excess of breast cancer is consistent with
estimates from pooled epidemiological data, which reported a 15% increase
for estrogen plus progestin use for less than 5 years and a 53% increase for
use for more than 5 years.32
It is also consistent with the (nonsignificant) 27% increase found after 6.8
years of follow-up in HERS.33
With more common use of estrogen plus progestin, several epidemiological
studies have reported that estrogen plus progestin appears to be associated
with greater risk of breast cancer than estrogen alone.34-37
In the PEPI trial, women in the 3 estrogen plus progestin groups had much
greater increases in mammographic density (a predictor of breast cancer)
than women in the estrogen or placebo groups.38
In WHI, the HR for estrogen plus progestin was not higher in women with a
family history or other risk factors for breast cancer, except for reported
prior use of postmenopausal hormones. This may suggest a cumulative effect
of years of exposure to postmenopausal hormones.
Endometrial cancer rates were low and were not increased by 5 years of
estrogen plus progestin exposure. Close monitoring for bleeding and
treatment of hyperplasia may contribute to the absence of increased risk of
endometrial cancer.
The reduction in colorectal cancer in the hormone group is consistent
with observational studies, which have suggested fairly consistently that
users of postmenopausal hormones may be at lower risk of colorectal cancer.39
The mechanisms by which hormone use might reduce risk are unclear. Results
from other trials of postmenopausal hormones will help resolve the effects
of hormones on colorectal cancer.40
Fractures
The reductions in clinical vertebral fractures, other osteoporotic
fractures, and combined fractures supported the benefit for hip fractures
found in this trial. These findings are consistent with the observational
data and limited data from clinical trials41
and are also consistent with the known ability of estrogen (with or without
progestin) to maintain bone mineral density.42
The WHI is the first trial with definitive data supporting the ability of
postmenopausal hormones to prevent fractures at the hip, vertebrae, and
other sites.
Overall Risks and Benefits
At the end of the trial, the global index indicated that there were more
harmful than beneficial outcomes in the estrogen plus progestin group vs the
placebo group. The monitored outcomes included in the global index were
selected to represent diseases of serious import that estrogen plus
progestin treatment might affect, and do not include a variety of other
conditions and measures that may be affected in unfavorable or favorable
ways (eg, gallbladder disease, diabetes, quality of life, and cognitive
function). The data on these and other outcomes will be the subject of
future publications. All-cause mortality was balanced between the groups;
however, longer follow-up may be needed to assess the impact of the incident
diseases on total mortality.
The absolute excess risk (or risk reduction) attributable to estrogen
plus progestin was low. Over 1 year, 10 000 women taking estrogen plus
progestin compared with placebo might experience 7 more CHD events, 8 more
strokes, 8 more PEs, 8 more invasive breast cancers, 6 fewer colorectal
cancers, and 5 fewer hip fractures. Combining all the monitored outcomes,
women taking estrogen plus progestin might expect 19 more events per year
per 10 000 women than women taking placebo. Over a longer period, more
typical of the duration of treatment that would be needed to prevent chronic
disease, the absolute numbers of excess outcomes would increase
proportionately.
During the 5.2 years of this trial, the number of women experiencing a
global index event was about 100 more per 10 000 women taking estrogen plus
progestin than taking placebo. If the current findings can be extrapolated
to an even longer treatment duration, the absolute risks and benefits
associated with estrogen plus progestin for each of these conditions could
be substantial and on a population basis could account for tens of thousands
of conditions caused, or prevented, by hormone use.
Limitations
This trial tested only 1 drug regimen, CEE, 0.625 mg/d, plus MPA, 2.5 mg/d,
in postmenopausal women with an intact uterus. The results do not
necessarily apply to lower dosages of these drugs, to other formulations of
oral estrogens and progestins, or to estrogens and progestins administered
through the transdermal route. It remains possible that transdermal
estradiol with progesterone, which more closely mimics the normal physiology
and metabolism of endogenous sex hormones, may provide a different
risk-benefit profile. The WHI findings for CHD and VTE are supported by
findings from HERS, but there is no other evidence from clinical trials for
breast cancer and colorectal cancer, and only limited data from trials
concerning fractures.
Importantly, this trial could not distinguish the effects of estrogen
from those of progestin. The effects of progestin may be important for
breast cancer and atherosclerotic diseases, including CHD and stroke. Per
protocol, in a separate and adequately powered trial, WHI is testing the
hypothesis of whether oral estrogen will prevent CHD in 10 739 women who
have had a hysterectomy. The monitoring of this trial is similar to that for
the trial of estrogen plus progestin. At an average follow-up of 5.2 years,
the DSMB has recommended that this trial continue because the balance of
overall risks and benefits remains uncertain. These results are expected to
be available in 2005, at the planned termination.
The relatively high rates of discontinuation in the active treatment arm
(42%) and crossover to active treatment in the placebo arm (10.7%) are a
limitation of the study; however, the lack of adherence would tend to
decrease the observed treatment effects. Thus, the results presented here
may underestimate the magnitude of both adverse effects on cardiovascular
disease and breast cancer and the beneficial effects on fractures and
colorectal cancer among women who adhere to treatment.
The fact that the trial was stopped early decreases the precision of
estimates of long-term treatment effects. A longer intervention period might
have shown more pronounced benefit for fractures and might have yielded a
more precise test of the hypothesis that treatment reduces colorectal
cancer. Nonetheless, it appears unlikely that benefit for CHD would have
emerged by continuing the trial to its planned termination. The trial
results indicate that treatment for up to 5.2 years is not beneficial
overall and that there is early harm for CHD, continuing harm for stroke and
VTE, and increasing harm for breast cancer with increasing duration of
treatment. This risk-benefit profile is not consistent with the requirements
for a viable intervention for the primary prevention of chronic diseases.
Implications
The WHI trial results provide the first definitive data on which to base
treatment recommendations for healthy postmenopausal women with an intact
uterus. This trial did not address the short-term risks and benefits of
hormones given for the treatment of menopausal symptoms. On the basis of
HERS and other secondary prevention trials, the American Heart Association
recommended against initiating postmenopausal hormones for the secondary
prevention of cardiovascular disease.43
The American Heart Association made no firm recommendation for primary
prevention while awaiting the results from randomized clinical trials such
as WHI, and stated that continuation of the treatment should be considered
on the basis of established noncoronary benefits and risks, possible
coronary benefits and risks, and patient preference.
Results from WHI indicate that the combined postmenopausal hormones CEE,
0.625 mg/d, plus MPA, 2.5 mg/d, should not be initiated or continued for the
primary prevention of CHD. In addition, the substantial risks for
cardiovascular disease and breast cancer must be weighed against the benefit
for fracture in selecting from the available agents to prevent osteoporosis.
Author/Article Information
Writing Group for the Women's Health Initiative Investigators:
Jacques E. Rossouw, MBChB, MD, National Heart, Lung, and Blood Institute,
Bethesda, Md; Garnet L. Anderson, PhD, Ross L. Prentice, PhD, Andrea Z.
LaCroix, PhD, and Charles Kooperberg, PhD, Fred Hutchinson Cancer Research
Center, Seattle, Wash; Marcia L. Stefanick, PhD, Stanford University
Clinical Center, Stanford, Calif; Rebecca D. Jackson, MD, Ohio State
University Clinical Center, Columbus; Shirley A. A. Beresford, PhD, Fred
Hutchinson Cancer Research Center, Seattle, Wash; Barbara V. Howard, PhD,
MedStar Research Institute, Washington, DC; Karen C. Johnson, MD, MPH,
University of Tennessee, Memphis; Jane Morley Kotchen, MD, Medical College
of Wisconsin, Milwaukee; Judith Ockene, PhD, University of Massachusetts
Medical School, Worcester.
For Correspondence: Jacques E. Rossouw, MBChB, MD, Division of
Women's Health Initiative, National Heart, Lung, and Blood Institute, 6705
Rockledge Dr, One Rockledge Ctr, Suite 300, MS/7966, Bethesda, MD 20817
(e-mail: rossouw@nih.gov); Garnet L.
Anderson, PhD, Division of Public Health Sciences, Fred Hutchinson Cancer
Research Center, 1100 Fairview Ave N, MP-1002, PO Box 19024, Seattle, WA
98109-1024 (e-mail: garnet@whi.org).
Reprints: WHI Clinical Coordinating Center, Division of Public Health
Sciences, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N,
MP-1002, PO Box 19024, Seattle, WA 98109-1024.
Financial Disclosures: Dr LaCroix is an investigator on 2
osteoporosis studies separately funded by Merck and Pfizer. Dr Jackson is an
investigator on 1 osteoporosis study funded by Merck and 1 hormone study on
libido in women funded by Procter & Gamble Pharmaceuticals.
Author Contributions: Dr Anderson, as co–principal investigator of
the Women's Health Initiative Clinical Coordinating Center, had full access
to the data in the study and takes responsibility for the integrity of the
data and the accuracy of the data analyses.
Study concept and design: Rossouw, Anderson, Prentice.
Acquisition of data: Anderson, Prentice, LaCroix, Kooperberg,
Stefanick, Jackson, Beresford, Howard, Johnson, Kotchen, Ockene.
Analysis and interpretation of data: Rossouw, Anderson, Prentice,
LaCroix, Kooperberg, Stefanick, Jackson.
Drafting of the manuscript: Rossouw, Anderson, Prentice.
Critical revision of the manuscript for important intellectual
content: Rossouw, Anderson, LaCroix, Kooperberg, Stefanick, Jackson,
Beresford, Howard, Johnson, Kotchen, Ockene.
Statistical expertise: Anderson, Prentice, Kooperberg.
Obtained funding: Rossouw, Anderson, Prentice, Stefanick,
Beresford, Howard, Kotchen, Ockene.
Administrative, technical, or material support: Rossouw, Anderson,
Prentice, LaCroix, Kooperberg, Stefanick, Jackson, Beresford, Howard,
Johnson, Kotchen, Ockene.
Study supervision: Rossouw, Anderson, LaCroix, Stefanick, Jackson,
Beresford, Howard, Johnson, Kotchen, Ockene.
WHI Steering Committee: Clinical Centers: Marcia L.
Stefanick (chair), Stanford Center for Research in Disease Prevention,
Stanford University; Rebecca D. Jackson (vice chair), Ohio State University;
Catherine I. Allen, University of Wisconsin, Madison; Annlouise R. Assaf,
Brown University, Providence, RI; Tamsen Bassford, University of Arizona,
Tucson/Phoenix; Shirley A. A. Beresford, Fred Hutchinson Cancer Research
Center; Henry Black, Rush-Presbyterian-St Luke's Medical Center, Chicago,
Ill; Robert Brunner, University of Nevada, Reno; Gregory L. Burke, Wake
Forest University School of Medicine, Winston-Salem, NC; Bette Caan, Kaiser
Permanente Division of Research, Oakland, Calif; Rowan T. Chlebowski,
Harbor-UCLA Research and Education Institute, Torrance, Calif; David Curb,
University of Hawaii, Honolulu; Margery Gass, University of Cincinnati,
Cincinnati, Ohio; Jennifer Hays, Baylor College of Medicine, Houston, Tex;
Gerardo Heiss, University of North Carolina, Chapel Hill; Susan Hendrix,
Wayne State University School of Medicine/Hutzel Hospital, Detroit, Mich;
Barbara V. Howard, MedStar Research Institute, Washington, DC; Judith Hsia,
George Washington University, Washington, DC; F. Allan Hubbell, University
of California, Irvine, Orange; Karen C. Johnson, University of Tennessee,
Memphis; Howard Judd, University of California, Los Angeles; Jane Morley
Kotchen, Medical College of Wisconsin, Milwaukee; Lewis Kuller, University
of Pittsburgh, Pittsburgh, Pa; Dorothy Lane, State University of New York at
Stony Brook; Robert D. Langer, University of California, San Diego, LaJolla/Chula
Vista; Norman Lasser, University of Medicine and Dentistry of New Jersey,
Newark; Cora E. Lewis, University of Alabama at Birmingham; Marian Limacher,
University of Florida, Gainesville/Jacksonville; JoAnn Manson, Brigham and
Women's Hospital, Harvard Medical School, Boston, Mass; Karen Margolis,
University of Minnesota, Minneapolis; Judith Ockene, University of
Massachusetts Medical School, Worcester; Mary Jo O'Sullivan, University of
Miami, Miami, Fla; Lawrence Phillips, Emory University, Atlanta, Ga; Cheryl
Ritenbaugh, Kaiser Permanente Center for Health Research, Portland, Ore;
John Robbins, University of California, Davis, Sacramento; Robert Schenken,
University of Texas Health Science Center, San Antonio; Sylvia
Wassertheil-Smoller, Albert Einstein College of Medicine, Bronx, NY;
Maurizio Trevisan, State University of New York at Buffalo; Linda Van Horn,
Northwestern University, Chicago/Evanston, Ill; and Robert Wallace,
University of Iowa, Iowa City/Davenport; Program Office: Jacques E.
Rossouw, National Heart, Lung, and Blood Institute; Clinical Coordinating
Center: Andrea Z. LaCroix, Ruth E. Patterson, and Ross L. Prentice, Fred
Hutchinson Cancer Research Center.
Data and Safety Monitoring Board: Janet Wittes (chair), Eugene
Braunwald, Margaret Chesney, Harvey Cohen, Elizabeth Barrett-Connor, David
DeMets, Leo Dunn, Johanna Dwyer, Robert P. Heaney, Victor Vogel, LeRoy
Walters, and Salim Yusuf.
Funding/Support: The National Heart, Lung, and Blood Institute
funds the WHI program. Wyeth-Ayerst Research provided the study medication
(active and placebo).
Acknowledgment: The WHI Steering Committee gratefully acknowledges
the dedicated efforts of the WHI participants and of key WHI investigators
and staff at the clinical centers and the Clinical Coordinating Center. A
full listing of the WHI investigators can be found at
http://www.whi.org.
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