Study Supports HRT Use for Short Term, but Little Benefit in Older Women

July 16, 2007 — Morbidity results of the WISDOM trial of HRT have finally been published, five years after the study was halted early following the cessation of the WHI study. The data show that hormone-replacement therapy (HRT) increases cardiovascular and thromboembolic risk when started many years after menopause and are consistent with the findings of the WHI study, say Dr Madge R Vickers (former head, Medical Research Council, UK) and colleagues in the report, published online July 11, 2007, in BMJ.
MacLennan — an obstetrician and gynecologist — explained that the reason it took so long to get WISDOM published was "because it was government funded; the governments took away the funding after the trial was stopped, and we had to get statisticians to do the work on their weekends, for no money." He is incredibly frustrated that the team has been unable to publish a second WISDOM paper, on quality of life, simultaneously with this one. "That one is the good-news paper, it shows improved quality of life in these women, which is much more common than the occasional adverse reaction. We hope to publish this paper within a few months."
WISDOM stopped just a year after it started
WISDOM was designed in 1989, around the same time as WHI, and was intending to recruit thousands of postmenopausal women from general practices in the UK, Australia, and New Zealand. The objective was to assess the long-term risks and benefits of combined HRT (Prempo, Wyeth-Ayerst) vs placebo and estrogen-only therapy (Premarin, Wyeth-Ayerst) vs combined HRT. Ten years of treatment were planned. However, WISDOM was prematurely closed during recruitment, after a median follow-up of just 11.9 months, following the very public cessation of the WHI study.
MacLennan told heartwire that the investigators "had wanted to run a much longer study of younger women and not include older women, but the funders demanded that we recruit older women first and leave the younger women until later so that there were enough events." As it turned out, the mean age of women who had been recruited at the time the study was stopped was 62.8 years.
Primary outcome measures were major cardiovascular disease, osteoporotic fractures, and breast cancer. Secondary outcomes were other cancers, death from all causes, cerebrovascular disease, dementia, and quality of life.
When combined HRT (n = 2196) was compared with placebo (n = 2189), there was a significant increase in the number of major cardiovascular events (seven with combined HRT vs zero in the placebo group, p = 0.016). There was also a significant increase in venous thromboembolism (22 vs three, hazard ratio 7.36).
There were no significant differences in numbers of breast or other cancers, cerebrovascular events, fractures, or overall deaths. In fact, there was "a remarkable reduction in osteoporotic fractures seen with HRT, even at one year, which was similar to that seen in WHI," MacLennan commented (40 fractures in combined HRT group vs 58 in placebo, HR 0.69, a nonsignificant trend).
Comparison of combined HRT (n = 815) vs estrogen therapy (n = 826) outcomes revealed no significant differences.
HRT "has come full circle"
"Despite the fact that WISDOM did not run to completion, this trial makes an important contribution to the body of knowledge about HRT therapy started in older postmenopausal women of a mean age of 63 years," say the investigators.
For combined HRT, the WISDOM results are similar to the findings in the early years of the WHI, they note, with the caveat that the event rate for venous thromboembolism (VTE) was higher, despite the exclusion in WISDOM of those with previous events. The reason for this is not clear, they say, but it could be due to chance. However, the increased risk of VTE was greatest in the first year of the WHI trial, so "it is possible that those with genetic predisposition to thrombosis have early vulnerability to HRT," they suggest.
"The early increased risk of cardiovascular events in both trials is compatible with the hypothesis that administration of HRT... to women many years after the menopause, who are likely to have established atherosclerosis, may cause disruption of the plaque surface, with subsequent platelet adhesion, clotting, and further arterial narrowing," they observe. Most of the events in WISDOM occurred in women over the age of 64, many of whom had cardiovascular risk factors, they add.
"What WISDOM says is that you cannot extend the indications of HRT to older women to reverse or reduce their risk of coronary heart disease," MacLennan commented.
In an accompanying editorial, Dr Helen Roberts (University of Auckland, New Zealand) says: "Postmenopausal HRT has come full circle. 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. 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."
No answer to "critical window" hypothesis
The WISDOM investigators explain that the early termination of the trial before large numbers of recently menopausal women could be recruited means that the "critical window" hypothesis could not be examined.
MacLennan says it is unfortunate that a trial will never be conducted to definitively prove or disprove the theory that starting HRT early in life, close to menopause, will reduce heart disease later on in life.
"But if you can never get your level 1 evidence, do you work with the best evidence you have, or do you wait for a trial that will never happen? We have laboratory, animal, and observational data that all point the same way. If you are under 60 and within 10 years of the menopause, you get cardiac benefit. The best surrogate outcomes are coronary artery calcium scores (CAC). If you take the estrogen-only arm from WHI and look at those women who were 80% or more compliant, you see a two-thirds reduction in the risk of atheroma, which is a good surrogate measure of future heart disease," he notes.
"The politically correct thing at the moment is to treat the 50% of women who have severe symptoms around the menopause, and don't let them be concerned that they are doing cardiac harm. They are not. They are probably doing cardiac benefit," he continues. "The original 2002 story was that they were doing cardiac harm, and the women were all scared to death."
Menopause docs vs epidemiologists
Last month, when WHI investigators published their analysis of CAC from the trial, chief of the National Heart, Lung, and Blood Institute WHI branch Dr Jacques E Roussouw was critical of the International Menopause Society (IMS), which at the time said it foresaw no problem with long-term use of HRT, including women continuing HRT until the age of 65.
MacLennan is editor of the IMS journal Climacteric, although he is not on the IMS council. Nevertheless, he supports its stance. Asked whether he would advise a woman to continue taking HRT until the age of 65, he replied: "It's hard to put a time limit on it. I don't say it is cardioprotective and I don't say it's not. However, I do say we don't have the data to know what happens after 65."
He says there is a simple split among doctors. "If you want to draw a line — anyone who makes a comment regarded as pro [HRT] is probably a practicing 'menopausologist' seeing patients. Anyone who has an anti view is almost always a nonpracticing epidemiologist or public-health doctor or someone outside the specialty — it's an interesting divide.
"The IMS wanted WHI to apologize for the scare they gave in 2002. They really made a mistake," he adds. "When asked if their findings applied to women of all age groups, they said 'yes.' It was only later that they analyzed it — when the damage had already been done — and they had data to show that the younger age group had a distinct advantage, particularly with estrogen-only therapy."
WISDOM was run and funded independently of industry. Wyeth Ayerst provided active drugs and matching placebo but had no other involvement in the trial. All authors have declared no direct conflicts of interest, as has the editorialist.
BMJ. Published online July 11, 2007.