Abstract
Objective To assess the long term risks and benefits of hormone
replacement therapy (combined hormone therapy versus placebo, and oestrogen
alone versus combined hormone therapy).
Design Multicentre, randomised, placebo controlled, double blind
trial.
Setting General practices in UK (384), Australia (91), and New
Zealand (24).
Participants Postmenopausal women aged 50-69 years at randomisation.
At early closure of the trial, 56 583 had been screened, 8980 entered
run-in, and 5692 (26% of target of 22 300) started treatment.
Interventions Oestrogen only therapy (conjugated equine oestrogens
0.625 mg orally daily) or combined hormone therapy (conjugated equine oestrogens
plus medroxyprogesterone acetate 2.5/5.0 mg orally daily). Ten years of
treatment planned.
Main outcome measures Primary outcomes: major cardiovascular
disease, osteoporotic fractures, and breast cancer. Secondary outcomes: other
cancers, death from all causes, venous thromboembolism, cerebrovascular disease,
dementia, and quality of life.
Results The trial was prematurely closed during recruitment, after a
median follow-up of 11.9 months (interquartile range 7.1-19.6, total 6498 women
years) in those enrolled, after the publication of early results from the
women's health initiative study. The mean age of randomised women was 62.8 (SD
4.8) years. When combined hormone therapy (n=2196) was compared with placebo
(n=2189), there was a significant increase in the number of major cardiovascular
events (7 v 0, P=0.016) and venous thromboembolisms (22
v 3, hazard ratio 7.36 (95% CI 2.20 to 24.60)). There were
no statistically significant differences in numbers of breast or other cancers
(22 v 25, hazard ratio 0.88 (0.49 to 1.56)), cerebrovascular
events (14 v 19, 0.73 (0.37 to 1.46)), fractures (40
v 58, 0.69 (0.46 to 1.03)), and overall deaths (8
v 5, 1.60 (0.52 to 4.89)). Comparison of combined hormone
therapy (n=815) versus oestrogen therapy (n=826) outcomes revealed no
significant differences.
Conclusions Hormone replacement therapy increases cardiovascular and
thromboembolic risk when started many years after the menopause. The results are
consistent with the findings of the women's health initiative study and
secondary prevention studies. Research is needed to assess the long term risks
and benefits of starting hormone replacement therapy near the menopause, when
the effect may be different.
Trial registration Current Controlled Trials ISRCTN 63718836
Introduction
Although the use of hormone replacement therapy for control of moderate to severe
menopausal symptoms is well established, its long term use for disease prevention in
postmenopausal women is in dispute.1
2
3 Ten randomised controlled trials have
investigated the risks and benefits of hormone replacement therapy in postmenopausal
women.4
5
6
7
8
9
10
11
12
13 Three trials in the United States,4
7
12 two in the United Kingdom,8
9 and one in Estonia13 showed that such therapy does not protect against
development of cardiovascular disease and may increase the risk.
In the largest trial, and the only one designed to assess the prevention of
cardiovascular disease, the US women's health initiative study, women aged 50-79
years taking combined oestrogen and progestogen had a significantly increased risk
of stroke, pulmonary embolism, and breast cancer and a decreased risk of hip
fracture and colorectal cancer compared with women taking placebo.7 This study found that combined oestrogen and
progestogen therapy might increase coronary events in older women (aged 70-79) in
their first year of treatment.14 Overall,
the risks seen in the women's health initiative study were likely to outweigh the
benefits, and the combined oestrogen and progestogen arm of the trial was closed
prematurely after a mean of 5.2 years of follow-up. Later, the oestrogen only arm of
the trial in women who had had a hysterectomy was also closed prematurely, after an
average of 6.8 years of follow-up, as it showed an increased risk of stroke but no
overall difference in cardiovascular disease or breast cancer.12
In 1989 the UK Medical Research Council agreed that a randomised controlled trial to
assess the long term benefits and risks of hormone replacement therapy was a
priority. Successful feasibility trials were conducted, and, after extensive review,
funding from multiple sources was secured for the women's international study of
long duration oestrogen after menopause (WISDOM), which began recruitment in
1999.15
16 The women's health initiative study had
begun in 1997, enrolling women aged 50-79 for an expected average of 8.5 years of
follow-up. WISDOM was originally designed to investigate a younger age group (45-60
years old) to ensure the data were relevant to the normal use of hormone replacement
therapy, but this was later modified to 50-64 years and then extended to 69 years to
increase the likelihood of relevant events during the trial planned for 10 years
treatment with a further 10 years' follow-up (later modified to five years).16 The aim was to recruit 22 300
postmenopausal women and to assess the balance of long term risks and benefits of
hormone replacement therapy with particular emphasis on cardiovascular disease and
dementia. The design allowed for two main comparisons: combined oestrogen and
progestogen therapy versus placebo and, in women who had had a hysterectomy,
oestrogen alone versus combined oestrogen and progestogen therapy.
Recruitment began in the UK in 1999 and in Australia and New Zealand in 2000.
Recruitment was still under way when the MRC stopped the trial after the first
results of the combined oestrogen and progestogen arm of the women's health
initiative study were published in 2002. This paper presents the main clinical
outcomes for WISDOM after 6498 person years of follow-up for a median of 11.9
months.
Methods
Setting
Recruitment took place in general practice. In the UK participants were recruited
through 384 general practices from the MRC General Practice Research Framework.
In addition, 91 general practices in Australia and 24 in New Zealand
participated.
Participants
Full details of recruitment procedures and other methods are published
elsewhere.17 In each country we
identified women aged 50-69 years from practice registers. Where possible,
patients' notes were searched by a research nurse to exclude ineligible women.
Postmenopausal women (no menstrual period in the past 12 months or had undergone
hysterectomy) were eligible for the trial.
The exclusion criteria are described in full elsewhere.17 Main exclusion criteria were a history of breast
cancer; any other cancer in the past 10 years except basal and squamous cell
skin cancer; endometriosis or endometrial hyperplasia; venous thromboembolism;
gall bladder disease in women who had not had a cholecystectomy; and myocardial
infarction, unstable angina, cerebrovascular accident, subarachnoid haemorrhage,
transient ischaemic attack, or use of hormone replacement therapy within the
past six months. Women taking hormone replacement therapy at screening who were
prepared to enter the placebo controlled strata of the study agreed to stop the
therapy for three months before the run-in phase. During run-in they took
placebo so that at randomisation they had not taken hormone replacement therapy
for six months. Women who were, in the opinion of their general practitioner,
unlikely to be able to give informed consent or successfully complete trial
procedures were also excluded.
Eligible women and those whose notes were not available were contacted by post
and invited to attend a screening session with a research nurse at their
practice. In Australia patients were invited first to group sessions to learn
more about hormone replacement therapy and the trial before volunteering for
screening, whereas in the UK and New Zealand the research nurse discussed these
details at the interview. The strategy was to recruit the oldest women first.
Women completed a screening questionnaire, were provided with written
information, and, if, after consideration for two weeks, they were willing to
participate, provided written consent, and entered a 12 week run-in period
(figure⇓). All women took medication during
run-in: women who were willing to enter a placebo controlled randomisation took
placebo and women who had undergone a total hysterectomy and were willing only
to enter a comparison of two active treatments took oestrogen only. Four weeks
before the end of run-in, eligible women who had achieved 80% compliance were
invited to enter the trial and were randomised to treatment (figure⇓).
Flow of patients through the women's international study of long duration
oestrogen after menopause (WISDOM). (Trial closure was on 22 October
2002. Combined therapy=conjugated equine oestrogen 0.625 mg +
medroxyprogesterone acetate 2.5 mg orally daily. Oestrogen
therapy=conjugated equine oestrogen 0.625 mg orally daily)
Method of random allocation
Treatment was randomly allocated centrally with a computer based, stratified
block randomisation program. Stratification was based on hysterectomy status and
intended use of hormone replacement therapy. Women with a uterus or subtotal
hysterectomy (stratum 1 of the study) were randomised to combined oestrogen plus
progestogen or to placebo using a block size of 16. Women with no uterus and
unwilling to take placebo were randomised to either oestrogen only or combined
oestrogen and progestogen therapy (stratum 2) using a block size of 16, and
those willing to enter a placebo controlled comparison were randomised to
oestrogen, combined oestrogen plus progestogen, or placebo using a block size of
24 (stratum 3). Within each stratum there was equal probability of allocation to
any of the treatment arms.
As soon as the woman was randomised the appropriate treatment pack was issued
from the central store, labelled for the participant and dispatched to the
practice. Drugs were packed in foils containing tablets for 28 days. Within each
stratum the drug packaging for each arm of the trial was identical. Randomised
treatment was started if, at the end of run-in, the woman remained eligible and
willing to enter the trial.
Interventions
The oestrogen therapy was conjugated equine oestrogens (Premarin, Wyeth Ayerst
US), 0.625 mg orally daily. The combined therapy was conjugated equine
oestrogens as above plus medroxyprogesterone acetate 2.5 mg orally daily
(Prempro, Wyeth Ayerst US). Women with a uterus and within three years of their
last period, those aged 50-53, and older women with unacceptable breakthrough
bleeding took 5.0 mg medroxyprogesterone acetate (Premique, Wyeth Ayerst US).
Women with a uterus who experienced unacceptable spotting or bleeding with the
combined therapy containing 5.0 mg medroxyprogesterone acetate were offered open
label Premique cycle (Premarin 0.625 mg orally daily plus medroxyprogesterone
acetate 10 mg orally for the last 14 days of a 28 day cycle).
The planned median treatment duration of the trial was 10 years (range 9-12),
with treatment being co-terminous in all participants. As far as possible, the
trial was conducted in a double-blind manner, though full blindness could not be
maintained when vaginal bleeding triggered a code break and investigation for
possible pathology.
Data collection
Women were to be seen at 4, 14, 27, 40, and 52 weeks after start of treatment and
then at six month intervals. A final visit took place as soon as possible after
the closure of the trial. At the start of treatment and at each follow-up visit,
information was collected on all outcomes, adverse events, and other medical
history to check that patients remained eligible. The research nurse entered
data directly on to a customised Access database that incorporated extensive
checks for plausibility, consistency, and completeness. Data were sent by modem
link (UK) or via a standard File Transfer Program server site (Australia and New
Zealand) to the coordinating centre within one week of collection. A member of
the study team, who was blinded to treatment allocation, obtained any data
needed to confirm a clinical event from the general practice, hospital, or
coroner.
Main clinical outcome measures
Primary outcomes were major cardiovascular disease (defined as one or more of
unstable angina requiring hospitalisation, fatal or non-fatal myocardial
infarction, or sudden coronary death), osteoporotic fractures (all fractures
other than of the skull, face, cervical spine, fingers, or toes), and breast
cancer. Secondary outcomes were breast cancer mortality, other cancers, death
from all causes, venous thromboembolism (deep vein thrombosis, pulmonary
embolism, or retinal vein occlusion), cerebrovascular disease, and dementia.
Quality of life and psychological wellbeing were measured and are reported
separately. All outcomes were reviewed blind to treatment allocation. All
cardiovascular and cancer outcomes and 10% of fractures were reviewed by
independent assessors.
Participants were asked about symptoms and adverse events at each visit. Each
adverse event was assessed for seriousness according to defined criteria in the
protocol. Reporting of certain potential complications of hormone replacement
therapy—such as gallbladder disease, sudden loss of vision, or
diplopia—required the nurse to interrupt treatment temporarily.
Sample size
WISDOM was designed to detect a 25% reduction in the number of cases of coronary
heart disease (excluding unstable angina) and stroke over 10 years comparing
combined oestrogen and progestogen therapy with placebo in women aged 50-64
years at randomisation. A total sample size of 18 000, assuming
13 000 were taking combined therapy or placebo in strata 1 and 3,
provided 80% power at the 5% significance level.
The primary outcome was subsequently changed to exclude stroke and to include
unstable angina, and the age range at randomisation was extended to 69 years.
Other assumptions were modified. In particular, cardiovascular event rates were
reduced as these were falling faster than expected in the populations of the
countries involved and estimates of withdrawal rates were revised. The expected
maximum recruitment of 22 300 (16 000 for combined therapy
versus placebo) provided 80% power at the 5% significance level to detect a 29%
reduction from an expected probability of a primary outcome event in the placebo
group during the trial period of 39 per 1000 women randomised. This sample size
also had the power to detect a 20% reduction, from an expected probability of 95
per 1000 women, in all osteoporotic fractures and a 40% increase, from an
expected probability of 36 per 1000 women, in breast cancer.
The predicted withdrawal from randomised treatment was 36% (10% in the first year
of treatment, 7% in year 2, 4% in year 3, 3% in year 4, and 2% in years 5-10),
and the associated attenuation of observed differences between randomised groups
was taken into account in the power calculations. Based on feasibility studies
and current use of hormone replacement therapy, it was assumed that 20% of women
would be 65-69 years with 80% distributed equally across the three five-year age
bands 50-54, 55-59, and 60-64 years. Full details of the assumptions made for
the event rates in the placebo group are reported elsewhere.17
Statistical methods
Follow-up time for each participant was calculated for each outcome separately
from date of randomisation until the date of outcome, of death, of loss to
follow-up, or of trial closure, whichever occurred first. The outcomes of
interest were cardiovascular disease, cerebrovascular disease, venous
thromboembolism, fractures, cancer, and death. We adopted the intention-to-treat
principle when assessing treatment effects, with P<0.05 used to define
statistical significance. We classified participants according to randomisation
group and compared combined oestrogen plus progestogen therapy with placebo
(pooling data from women from strata 1 and 3), and combined therapy with
oestrogen only therapy (combining strata 2 and 3). Women from stratum 3 who were
randomised to combined therapy were thereby included in both comparisons.
To account for the prospective nature of the data, we calculated event rates (per
10 000 women-years) as the number of events divided by the relevant
accumulated person-time—that is, assuming a Poisson regression
(constant hazards) model. We calculated hazard ratios under the more flexible
Cox proportional hazards model, after graphically checking its assumptions.18 The results are reported as,
respectively, rates and hazard ratios for the effect of combined therapy versus
either placebo or oestrogen therapy (with 95% confidence intervals), with
associated likelihood ratio tests for significance.18 No adjustment was made for multiple a priori
testing.
Results
Recruitment
A total of 284 175 women aged 50-69 years were registered at the
participating practices (224 075 from the UK, 36 210 from
Australia, and 23 890 from New Zealand), of whom 226 282
were potentially eligible for the trial (figure⇑). When the trial closed on 22 October 2002, 155 204 women (68% of
those potentially eligible) had been invited to screening, 56 583 had
attended, and 4570 had agreed to attend but had not yet been interviewed. Of
those screened and eligible, 14 203 (29%) agreed to enter the run-in
phase, of whom 8980 had entered at the time of closure. At the end of run-in,
5692 participants remained eligible, gave consent, were randomised, and started
trial treatment (26% of the target of 22 300; 5250 from the UK, 319
from Australia, and 123 from New Zealand).
Baseline data
The participants' mean age was 62.8 years (SD 4.8), reflecting the strategy of
recruiting older women first. Women who had undergone a hysterectomy were, on
average, slightly younger and were more likely to have ever used hormone
replacement therapy and to have used it for a longer time than those women with
a uterus. Women who were not willing to accept placebo randomisation (stratum 2)
were more likely to have used hormone replacement therapy and to be using it at
screening (82%). Other characteristics were similar for the three strata. The
characteristics of the treatment groups for both the comparison groups of
combined therapy versus placebo and oestrogen therapy versus combined therapy
were also similar (table 1⇓).
Table 1
Characteristics of participants in WISDOM at randomisation by
treatment group. (Values are numbers (percentages) unless stated
otherwise
In the main treatment comparison (combined therapy versus placebo) 8% in each
group were using hormone replacement therapy at screening and 46-47% of those
screened were past users of hormone replacement therapy for a median of 3.8-4
years. Data from the screening interviews indicate that, with regard to major
risk factors for the primary outcomes, WISDOM participants were similar to women
screened in the participating practices (table 2⇓), although screened women had greater current use of hormone
replacement therapy (31%) than randomised women (21%). The mean number of years
since menopause (last menstrual period) in all women with a uterus was 13.8 (SD
6.7). The mean number of years since last menstrual period or hysterectomy with
or without oophorectomy in all women without a uterus (strata 2 and 3) was 18.5
(SD 7.5). In the main comparison of combined therapy versus placebo, which
included women with and without a uterus from strata 1 and 3, the mean years
from last menstrual period were 14.8 and 14.7 respectively.
Table 2
Characteristics of all women screened for WISDOM and those who
were randomised. (Values are numbers (percentages) unless stated
otherwise
Follow up
With the early closure of the trial the median follow-up time was 11.9 months
(interquartile range 7.3-19.6), with a total follow-up time of 6498 women years.
In women randomised to combined therapy or placebo, median follow-up was 12.8
(7.5-20.4) months, with a total of 5214 person-years; for women randomised to
combined therapy or oestrogen therapy the figures were 10.3 (6.4-16.8) months
and 1688 years, respectively. Five participants were lost to follow-up.
By 15 July 2002, when the results from the women's health initiative study were
disseminated, 725 women (12.7%) had withdrawn from randomised treatment; most
were in stratum 1 (369 taking combined therapy; 162 taking placebo) or stratum 3
(46 taking combined therapy; 50 taking oestrogen therapy, and 38 taking
placebo). Table 3⇓ gives the reasons for
withdrawal. An additional 368 women were taking a temporary interruption of
trial treatment at the time the women's health initiative reported; of these,
only 23 restarted randomised treatment before trial closure.
Table 3
Reasons for withdrawal from WISDOM before 15 July 2002.
(Values are numbers (percentages))
During follow-up of women randomised to combined therapy or placebo, trial
treatment was supplied for 73% of time at risk in women allocated to active
treatment (27% of time at risk was after withdrawal or during a temporary
interruption of treatment) and for 86% of time at risk in women allocated to
placebo. Corresponding proportions in women randomised between combined therapy
and oestrogen therapy were 83% and 84% respectively.
The treatment code was unblinded in only two of the 1971 women who had undergone
hysterectomy, but in women with a uterus the proportion unblinded was high,
mostly as a result of vaginal bleeding in those randomised to combined therapy,
where 712/1862 (38%) were unblinded, compared with 66/1859 (4%) of those
randomised to placebo (hazard ratio 13.4 (95% confidence interval 10.4 to 17.3),
P<0.001).
Clinical outcomes
The total number of events for all trial outcomes was low because the trial was
stopped early. There are no data on dementia because the first follow-up
assessment was planned for two years after randomisation.
Combined oestrogen and progestogen therapy versus placebo
Compared with those taking placebo, women taking combined therapy had
significantly increased rates of cardiovascular events (26.9 v
0 per 10 000 women-years, P=0.016) and venous thromboembolism (85.1
v 11.5 per 10 000 women-years, hazard ratio 7.36
(2.20 to 24.60), P<0.001) and a non-significant reduction in the rate of
osteoporotic fractures (155.3 v 226.2 per 10 000
women-years, hazard ratio 0.69 (0.46 to 1.03), P=0.07) (table 4⇓). Rates for cerebrovascular disease, breast
cancer, and other cancers were not significantly different in the two groups.
Table 4
Primary and secondary clinical outcomes in WISDOM by time of
follow-up and randomised treatment*
Cardiovascular events
The 11 cardiovascular events recorded were all in women randomised to hormone
replacement therapy (nine to combined therapy and two to oestrogen therapy). All
but two of these women were over 64 years of age at trial entry and had one or
more cardiovascular risk factors (three had a history of myocardial infarction
or angina, two had diabetes, four smoked, and eight had a body mass index
≥25).
Cerebrovascular events
There was no significant difference in cerebrovascular events with a rate of 73.4
(95% confidence interval 46.8 to 115.0) per 10 000 women-years in the
placebo group and 53.8 (31.9 to 90.9) in the combined therapy group (hazard
ratio 0.73 (0.37 to 1.46), P=0.38). When transient ischaemic attacks were
excluded the differences between the treatment groups were even smaller, with a
hazard ratio of 0.91 (0.39 to 2.14) for combined therapy versus placebo and
oestrogen therapy and 1.01 (0.21 to 5.02) for combined therapy versus oestrogen
therapy.
Oestrogen and progestogen versus oestrogen alone
The numbers of participants and the number of events in this comparison are much
smaller than for the comparison of combined oestrogen plus progestogen versus
placebo (table 4⇑). There is a suggestion in
the combined therapy group of an increase in cardiovascular events (47.8
v 23.6 per 10 000 women-years, hazard ratio 2.03
(0.37 to 11.09), P=0.40) and in venous thromboembolism (84.3 v
35.3 per 10 000 women-years, hazard ratio 2.39 (0.62 to 9.24),
P=0.19).
Adverse events
There were 15 deaths during the trial, with a non-significant increase in the
rate in the combined therapy group compared with placebo (30.7
v 19.2 per 10 000 women-years, hazard ratio 1.60
(0.52 to 4.89)). Serious adverse events by diagnostic category and treatment
group are listed in table 5⇓. There was no
excess of serious adverse events in either of the randomised comparisons.
Table 5
Numbers of serious adverse events among participants in WISDOM
by treatment group
Discussion
Data from WISDOM suggest that women starting or restarting combined oestrogen and
progestogen therapy an average of 15 years after menopause are at increased risk of
cardiovascular disease and venous thromboembolism, at least in the early years of
treatment. We found a trend towards a decreased risk of osteoporotic fracture and no
difference in the risk of stroke or cancers. The small numbers of events and the
brief follow-up periods inevitably mean that some of the results cannot be
confidently interpreted. However, we can comment on the results for early
cardiovascular and thromboembolic disease. In a direct comparison with combined
oestrogen and progestogen therapy, oestrogen only therapy may have similar, but
smaller, short term effects. These results are consistent with the findings of the
combined oestrogen and progestogen therapy arm of the women's health initiative
study and with secondary prevention trials, and support the conclusion that combined
oestrogen and progestogen therapy should not be given for cardiovascular disease
prevention in older postmenopausal women.4
7
8
9
Value of study
Despite the fact that WISDOM did not run to completion, this trial makes an
important contribution to the body of knowledge about hormone replacement
therapy started in older postmenopausal women of a mean age of 63 years. The
WISDOM population was recruited from women on general practice registers in
countries where health care is free or with low fees. The randomised women had a
similar health profile, with regard to the factors of interest in the trial, as
those in the same age range who were first screened. With the exception of a
history of breast cancer, a family history of venous thromboembolism, and other
exclusion factors that would have made them less likely to take hormone
replacement therapy, the WISDOM participants were similar to the registered
population and to the UK population of the same age range.19 A strength of the study is that participants are
likely to be representative of the general population of women of this age and
the results applicable to this older age group. Comparing the population in the
women's health initiative study, many of the women in WISDOM were similarly
overweight or obese and had many similar cardiovascular risk factors.7
12 The mean age at entry was also
similar. However, previous use of hormone replacement therapy was higher in
WISDOM than in the women's health initiative study (45% compared with 26% in
women with a uterus).
Comparison of results
For combined oestrogen and progestogen therapy, the WISDOM results are similar to
the findings in the early years of the women's health initiative trial.
Venous thromboembolism—The event rate in women taking
combined oestrogen and progestogen therapy in WISDOM was higher than that
reported in the early years of the women's health initiative trial, despite the
exclusion in WISDOM of those with previous events. The reason for this is not
clear but, in view of the small number of events, may be a chance finding. The
increased rate of venous thromboembolism with combined therapy was greatest in
the first year of the women's health initiative trial.7 It is possible that those with genetic predisposition to
thrombosis have early vulnerability to hormone replacement therapy.20
Cardiovascular disease—Although the number of
cardiovascular events observed was small, all occurred in the hormone
replacement therapy groups, at a rate of 27 per 10 000 women-years in
the combined therapy arm of WISDOM. This rate was smaller than the rate of 51
per 10 000 women-years in the first year of the combined therapy arm
of the women's health initiative study. The early increased risk of
cardiovascular events in both trials is compatible with the hypothesis that
administration of hormone replacement therapy, particularly combined oestrogen
and progestogen therapy, to women many years after menopause, who are likely to
have established atherosclerosis, may cause disruption of the plaque surface,
with subsequent platelet adhesion, clotting, and further arterial
narrowing.21 Most of the events in
WISDOM occurred in women over the age of 64, many of whom had cardiovascular
risk factors.
Fractures—The non-significant trend toward a reduced
risk of fractures after an average follow-up period of only one year is in
keeping with the significant reduction of fractures seen in the women's health
initiative study.7
12 Neither WISDOM nor the women's
health initiative study required an increased risk of fracture as an inclusion
criterion, and so the results suggest a potent preventive effect in an
unscreened population. As in the women's health initiative study, we found no
apparent difference between combined therapy and oestrogen therapy in their
effect on fracture prevention.
Cancer—We found no effect on cancer rates, including
breast cancer, but this must be interpreted with caution as the maximum
follow-up was three years (median one year). A decrease in the annual risk of
breast cancer of 7 per 10 000 cases compared with placebo after nearly
seven years of oestrogen therapy was reported in the women's health initiative
study, which approached statistical significance, but combined oestrogen and
progestogen therapy was associated with a significantly increased annual risk of
8 per 10 000 cases after five years.7
12
22 WISDOM was unable to shed light on
the relation between progestogen and breast cancer, although the data for all
outcomes suggested the greater safety of oestrogen only therapy, similar to the
results from the women's health initiative trial.
Death—The apparent but non-significant increase in
mortality in users of combined therapy versus placebo is not in keeping with a
recent meta-analysis of all randomised controlled trials of hormone replacement
therapy (including the women's health initiative), which showed no increased
mortality overall and a significantly reduced mortality in hormone users younger
than 60 years (odds ratio 0.67 (95% confidence interval 0.49 to 0.92)).23 The short follow-up time and small
number of deaths recorded in WISDOM do not allow robust conclusions.
Limitations of study
The follow-up period in WISDOM was short because of the early closure, and the
power of the study was greatly reduced by the curtailed recruitment, which also
led to relatively few women being in the younger age groups. No conclusions can
be drawn about the outcomes in relation to these age groups.
Implications of results
In WISDOM only two hormone replacement therapy regimens were studied, which
contained conjugated equine oestrogens and, when combined, medroxyprogesterone
acetate. The medical profession and the media must interpret and disseminate the
results of WISDOM with caution and responsibility. In 2002 unconsidered and
sometimes exaggerated responses to the first report from one arm of the women's
health initiative study caused great alarm and distress to women around the
world, with many suddenly stopping their hormone replacement therapy without
medical consultation and in some cases with adverse consequences.24
25
The results of WISDOM, like those of the women's health initiative study, help
test the hypothesis that starting long term hormone replacement therapy in
elderly, often asymptomatic, women in their 60s might reduce major morbidities,
in particular cardiovascular disease. With the exception of fractures, this does
not seem likely. However, currently, such women rarely start taking hormone
replacement therapy at these ages. Most women who start hormone replacement
therapy do so near the menopause to reduce menopausal symptoms and improve their
quality of life. Clinical and animal studies suggest that the effect of
oestrogen on the cardiovascular system and possibly the brain may be very
different and probably beneficial when used at or near the time of
menopause.26
27
28 In particular, a recent
meta-analysis of 23 randomised controlled trials of hormone replacement therapy
showed that it significantly reduced coronary heart disease in women starting
therapy younger than 60 years or within 10 years of menopause.29 The early termination of WISDOM before
large numbers of recently menopausal women could be recruited, means that the
“critical window hypothesis” could not be examined to see if
oestrogen has cardioprotective and neuroprotective effects.20
30 The risk:benefit equation for a
younger menopausal woman may be different from that seen in the mainly older
women in WISDOM and the women's health initiative study.
The publicity surrounding the first report from the first arm of the women's
health initiative study put great pressure on the funders of WISDOM to stop this
trial.15
31 Details of the more favourable
results from the oestrogen only arm and the reanalyses of the women's health
initiative study by age and years from menopause, which suggested different
results when hormone replacement therapy is started in early menopause, became
available only several years after the closure of WISDOM.32 A long term, randomised, placebo controlled trial of
hormone replacement therapy from menopause is still needed but presents great
problems in terms of funding, compliance, and continuance, especially in
symptomatic women.
Conclusions
The women's health initiative study and WISDOM have not answered the question
about long term benefits and risks of hormone replacement therapy in the large
majority of women who start therapy around menopause for symptom control.
However, they have shown that there is no overall disease prevention benefit,
and some potential risk, for women with few or no oestrogen deficiency symptoms
who start hormone replacement therapy many years after menopause. If there is a
menopausal window of therapeutic benefit its upper limit has not been well
defined and is likely to vary with arterial health and associated risk factors
such as obesity and metabolic syndrome.33
Both the women's health initiative study and WISDOM were specifically looking for
chronic disease prevention in older postmenopausal women who did not have
disabling menopausal symptoms. An increased quality of life associated with a
reduction in menopausal symptoms is the usual motivation for taking hormone
replacement therapy. Quality of life data from WISDOM will be published
separately, and these results should be considered alongside the main morbidity
and mortality outcome data described in this paper. Those helping women make
choices about treatment should consider both the results and limitations of the
women's health initiative study and WISDOM, particularly those that may be
influenced by the timing of starting hormone replacement therapy.
What is already known on this topic
-
Combined oestrogen and progestogen hormone replacement therapy
initiated many years after menopause in asymptomatic women
reduces fracture risk but increases thromboembolic, breast
cancer, and possibly cerebrovascular risk
-
Oestrogen only hormone replacement therapy started near the
menopause may decrease the risk of coronary heart disease,
breast cancer, diabetes, and osteoporotic fractures
What this study adds
-
This study confirms an early increase in thromboembolic and
cardiovascular risk in women starting hormone replacement
therapy at a mean of 63 years and 15 years after the
menopause
-
These uncommon serious events must be weighed against more common
improvements in quality of life
-
These results cannot be applied to symptomatic women starting
hormone replacement therapy near menopause, for whom
cardiovascular benefits have recently been described
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