Long-Term Hormone Replacement Therapy Increased Heart Disease
BMJ July 2007
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
Knock for long-term HRT in older women
Hormone replacement therapy should not be prescribed to older women who are many years past menopause because it likely to increase rather than reduce their risk of heart disease, experts say in the online version of this week's British Medical Journal.
Significantly, however, the authors support the view that HRT is a safe, short-term treatment for younger women in early menopause to relieve symptoms and improve quality of life.
In 2002, the Women's Health Initiative trial found that postmenopausal women taking HRT had more heart attacks and strokes than non-HRT users. The trial was halted early and millions of women around the world stopped taking HRT. But scientists now believe that these risks may only apply to older women who do not normally use HRT.
In 1999, another trial (WISDOM) began to assess the long-term risks and benefits of HRT after the menopause. This trial was stopped prematurely after the first WHI results appeared. But some findings that did emerge from the WISDOM study are published today, and provide new insights about HRT when it is initiated in older postmenopausal women.
The WISDOM team studied 5,692 healthy women registered at general practices in the UK, Australia and New Zealand with an average age of 63 years, 15 years after the menopause. Women received either a daily dose of combined hormone therapy (oestrogen and progestogen) or a placebo pill. Those who had had a hysterectomy were split between combined hormone treatment, oestrogen only and a placebo. All women were monitored for an average of 12 months and main outcomes such as cardiovascular disease, osteoporotic fractures, breast cancer and deaths, were recorded.
There was a significant increase in the number of major cardiovascular events (angina, heart attack or sudden coronary death) and blood clots (venous thromboembolisms) in the combined hormone therapy group compared to the placebo group. Rates for cerebrovascular disease, breast or other cancers, fractures and overall deaths were not significantly different in these two groups.
Nonetheless, the results found no overall disease prevention benefit, and some potential risk, for women who start hormone replacement therapy many years after menopause. However, the authors stress that these results cannot necessarily be applied to younger menopausal women starting hormone replacement therapy to relieve symptoms such as hot flushes and night sweats. For these women, recent studies suggest there may even be cardiovascular benefits of taking HRT around the time of menopause.
In order to assess conclusively the long-term benefits and risks among these women, lead researcher Professor Alastair MacLennan of the Women's and Children's Hospital, Adelaide, said that a long term, randomised, placebo-controlled trial of hormone replacement therapy from menopause was still needed. But she said this presented "great problems in terms of funding, compliance, and continuance, especially in symptomatic women".
In an accompanying editorial, Dr Helen Roberts at the University of Auckland said HRT had now "come full circle" with the evidence suggesting that its use be limited to the short-term relief of symptoms such as hot flushes, night sweats. She said: "Healthy women in early menopause are unlikely to face substantially increased risks when using hormones for a few years." However, she agreed that long-term use of HRT should not recommended.
By Michael Day
BMJ, doi:10.1136/bmj.39272.445428.80 (published 11 July 2007)
Hormone replacement therapy comes full circle
Further evidence on the early benefits and late risks does not change advice to menopausal women
The publication of the combined treatment arm of the women's health initiative study in July 2002 led to a dramatic fall in the use of hormone replacement therapy and a revision of the package insert for all hormone therapy preparations. This clinical trial randomised 16 608 women, aged 50-79 years, to 0.625 mg conjugated equine oestrogen and 2.5 mg medroxyprogesterone acetate or placebo.1 The study was stopped early, at an average follow-up of 5.2 years, because analysis did not find the expected benefit in preventing coronary heart disease. In addition, the global index score-which measures the balance between benefit and harm-showed that the benefits in preventing hip fracture and colorectal cancer were outweighed by the increased risk of breast cancer, stroke, and deep vein thrombosis.
This week's BMJ sees the publication of the women's international study of long duration oestrogen after menopause by Vickers and colleagues.2 This study was originally powered to detect a 25% reduction in the number of cases of coronary heart disease and aimed to recruit 22 300 women for 10 years' follow-up. The UK Medical Research Council stopped recruitment after the first publication from the women's health initiative, however, and 5692 women, age 50-69 years (mean age 63), entered the study. Median follow-up time was 11.9 months. Hormone preparations and doses were similar to those in the women's health initiative, although women who had vaginal bleeding triggered unblinding, and they were offered an increase in the dose of medroxyprogesterone acetate. Women who had no uterus and were unwilling to take placebo were randomised to either oestrogen only or combined treatment.
How do the results of this study compare with those from the women's health initiative? Owing to early closure of the study, the number of events was small and only two outcomes reached statistical significance. These were cardiovascular events and venous thromboembolism. All of the 11 cardiovascular events (comprising unstable angina, non-fatal myocardial infarction, or sudden coronary death) occurred in the women taking hormones; nine were using combined therapy. Compared with placebo, hormone use increased the risk of venous thromboembolism, and this risk was higher for those using combined therapy (hazard ratio 7.36; 95% confidence interval 2.20 to 24.60).
The table shows the results from the women's health initiative studies.3 Both these two studies and the study by Vickers and colleagues showed the expected increase in thromboembolism. None, however, found the expected benefit in preventing cardiovascular disease.
As in the women's health initiative trial, most women in the study by Vickers and colleagues were over the age of 65. None of these studies had the power to look at outcomes for younger women, who are the main users of hormones for symptom relief. Ongoing discussion concerns the "timing hypothesis" or "therapeutic window of opportunity." The proposal under debate, which comes from early primate studies, is that oestrogen may be cardioprotective if treatment is started before vasculature has been compromised. Subgroup analyses with small numbers and inadequate power in both women's health initiative hormone trials suggested a non-significant reduction in the risk of coronary heart disease in women aged 50-59 (oestrogen only trial) or in women who reached the menopause less than 10 years earlier (combined trial).4 Because these findings were in a similar direction, Roussouw and colleagues did a secondary analysis combining the data from both trials.4 They found that women who started taking hormone therapy closer to the menopause tended to have reduced risk of coronary heart disease rather than the increased risk seen in women more distant from the menopause. Again, however, this trend test did not meet the authors' criterion for statistical significance. The risk of stroke was raised regardless of years since menopause. Moreover, women aged 50-59 using combined therapy have a significantly increased risk of deep vein thrombosis.5
Roussouw and colleagues have asked the important question, "If early hormone use is cardioprotective, will this benefit continue?" and their comments suggest that the answer is "no." They say, "Age-related progression of atherosclerosis is likely to continue even in the face of hormone therapy. Even if ongoing imaging trials confirm a slowing of early atherosclerosis, it would be unwise to extrapolate such findings to clinical benefit with continued use into old age."4
Also, it has been calculated that, even if these were not subgroup analyses and even if the differences were significant, 1000 women each year would need to use hormone therapy to prevent one cardiovascular event.6
A recent surrogate outcome trial has now been published from the women's health initiative group. The coronary-artery calcium study looked at the effects of oestrogen on coronary artery calcification in women who were 50-59 years at randomisation in the oestrogen only arm of the original trial.7 Women taking oestrogen had a 42% reduction in coronary artery recalcification, supporting the likelihood of a potential cardioprotective effect in younger women. However, the accompanying editorial in the New England Journal of Medicine-by a cardiologist-reminds us that the vascular effects of oestrogen are complex: "It is important to emphasize that hormone replacement therapy should not be considered as a strategy to prevent cardiovascular disease and that there are proven therapies for cardiovascular disease that remain underused in women."8
So postmenopausal hormone therapy has come full circle.9 It was originally used to treat menopausal symptoms, and now the indications for use are again hot flushes, night sweats, and vaginal dryness. It is the best treatment we have at present for these symptoms. Hot flushes and night sweats are mostly self limiting, and current advice recommends short term use with the lowest dose needed for relief of symptoms. Healthy women in early menopause are at a low absolute risk whether they take hormones or not, and they are unlikely to face substantially increased risks when using hormones for a few years.9
Long term use of hormone replacement therapy to prevent chronic disease is no longer recommended, because available randomised evidence shows that the negative outcomes outweigh the positive benefits. Menopausal genitourinary symptoms, however, usually last a long time and require ongoing treatment. Current low dose vaginal oestrogen preparations have minimal systemic absorption, and recent position statements support long term use of these preparations as long as distressing symptoms remain.10
Helen Roberts, senior lecturer in women's health
Department of Obstetrics and Gynaecology, University of Auckland, Private Bag 92019, Auckland, New Zealand 1142
Main morbidities recorded in the women's international study of long duration oestrogen after menopause (WISDOM): a randomised controlled trial of hormone replacement therapy in postmenopausal women
Madge R Vickers, former head, MRC general practice research framework1, Alastair H MacLennan, professor, department of obstetrics and gynaecology2, Beverley Lawton, director women's health research centre3, Deborah Ford, senior statistician4, Jeannett Martin, former senior nurse manager1, Sarah K Meredith, senior clinical epidemiologist4, Bianca L DeStavola, reader in biostatistics5, Sally Rose, research fellow3, Anthony Dowell, professor3, Helen C Wilkes, senior statistician4, Janet H Darbyshire, director4, Tom W Meade, emeritus professor5
1 MRC General Practice Research Framework, Stephenson House, London NW1 2ND, 2 University of Adelaide, Women's and Children's Hospital, Adelaide SA 5006, Australia, 3 Department of Primary Health Care and General Practice, Wellington School of Medicine and Health Sciences, New Zealand, 4 MRC Clinical Trials Unit, London NW1 2DA, 5 Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London WC1E 7HT
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.
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.
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).
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).
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.
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.
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).
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.
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).
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).
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.
Data from WISDOM suggest that women starting or restarting combined oestrogen and progestogen therapy an average of 14 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.
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.