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WISDOM trial results consistent with WHI findings
Postmenopausal hormone therapy increased risk for cardiovascular, thromboembolic events.
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Women who start or resume combination estrogen plus progestogen therapy a decade or more after menopause are at increased risk for cardiovascular events and venous thromboembolism, according to 12-month results from the Women’s International Study of Long Duration Oestrogen after Menopause.
These findings are consistent with the highly publicized findings from the Women’s Health Initiative study. WISDOM was stopped prematurely in October 2002, while recruitment was still ongoing, after just 11.9 months of treatment.
The long-awaited results from the WISDOM trial were published recently in the British Medical Journal — more than five years after the trial was halted. Alastair H. MacLennan, MbChB, MD, a WISDOM researcher, discussed the results with Endocrine Today.
“When HRT is commenced near menopause, it reduces the future burden of coronary calcification and arterial plaque … and is associated with a reduction of coronary events and death from all causes,” said MacLennan, professor of obstetrics and gynecology, University of Adelaide, Australia.
However, the researchers found that “when HRT is commenced many years after menopause, such as in WISDOM (15 years after) and in the Women’s Health Initiative (13 years after), no cardioprotection is seen and, in the first year of oral therapy, coronary events and thromboembolisms increased.”
Thus, the long-term use of combination HT among postmenopausal women is in dispute, according to the researchers.
An early end for WISDOM
The cessation and publicized results of the Women’s Health Initiative study prompted the subsequent cessation of WISDOM. After 12 months, 6,498 women were recruited for WISDOM, and 5,692 had started treatment. The researchers originally intended to recruit 23,000 postmenopausal women to assess the long-term benefits and risks of combined HT (Prempro, Wyeth) compared with placebo and estrogen-only therapy (Premarin, Wyeth). The women were slated to be followed for up to 10 years of treatment.
The major outcome measures were cardiovascular disease, such as myocardial infarction or sudden coronary death, osteoporotic fracture and breast cancer. The secondary outcome measures were other cancers, death, cerebrovascular disease and dementia, and VTEs, such as deep vein thrombosis and pulmonary embolism.
Consistent with WHI
The newly-released data are consistent with that of the Women’s Health Initiative study and secondary prevention trials. The researchers concluded that combined estrogen and progestogen therapy should not be given to older postmenopausal women for CVD prevention.
When the trial was stopped, the researchers recorded an increase in the number of major cardiovascular events in women who took combined HT (n=2,196) compared with placebo (n=2,189; 7 events vs. 0; P=.016). The rate of events was small; however, all occurred in the combination HT group (27 per 10,000 person-years).
Women who were postmenopausal for a decade or more may have established atherosclerosis, so administration of HT may disrupt the plaque surface and lead to platelet adhesion, clotting and arterial narrowing, according to the researchers.
The women randomly assigned to combined HT also had a higher number of VTEs (22 vs. 3; HR=7.36), which was a higher event rate than in the Women’s Health Initiative study.
Of note, there were no differences in the number of cancers, cerebrovascular events, fractures and overall deaths between the groups. Further, they found no differences when combination HT (n=815) and estrogen therapy (n=826) were combined.
Most of the adverse events in WISDOM occurred in women aged 64 years and older who may have already had cardiovascular risk factors. It is when women start HT in their 60s and 70s that these dangers arise, according to the researchers.
Critical therapeutic window
“The vast majority of HRT users commence therapy during the likely critical therapeutic window,” MacLennan said. “There is rarely a clinical indication to start HRT many years after menopause.”
Yet, the upper limit of this menopausal window of therapeutic benefit has not been well defined, according to the researchers. It may vary with arterial health and other risk factors, such as obesity and metabolic syndrome.
However, WISDOM and the Women’s Health Initiative study leave one major question unanswered — the long-term risk–benefit profile with HT. Additionally, younger women may have preventive benefits with HT, but “neither WISDOM nor the Women’s Health Initiative study addressed the generally healthy perimenopausal or early postmenopausal women with moderate-to-severe vasomotor symptoms for whom low-dose estrogen alone/combination estrogen plus progestogen therapy remains the gold standard of treatment,” JoAnn V. Pinkerton, MD, director of midlife health and professor of obstetrics and gynecology, University of Virginia Health System, wrote in a North American Menopause Society First to Know newsletter.
Postmenopausal HT has come full circle, according to Helen Roberts, MPH, senior lecturer, women’s health obstetrics and gynecology, University of Auckland, New Zealand, who wrote an accompanying editorial in the British Medical Journal.
“It was originally used to treat menopausal symptoms, and now the indications for use are again hot flashes, night sweats and vaginal dryness,” she said.
There is much to be explored surrounding HT and menopause. However, there are four major reasons why a long-term, randomized, controlled trial of HT will probably never be possible: huge cost, high withdrawal rates, possible irrelevance of the regimen at the end of the trial and the probability that study participants will not be representative of HT users, according to MacLennan and David W. Sturdee, MD, joint editors-in-chief of an editorial in Climacteric, the journal of the International Menopause Society.
Other findings from WISDOM should be published in the near future, including quality-of-life data, which should add to the risk–benefit–cost ratio, according to MacLennan. – by Katie Kalvaitis
Dr. Pinkerton is a consultant for Wyeth.
For more information:
- MacLennan AH, Sturdee DW. Long-term trials of HRT for cardioprotection – Is this as good as it gets? Climacteric. 2007;10:1-4.
- Roberts H. Hormone replacement therapy comes full circle. BMJ. 2007;335:219-220.
- Vickers MR, MacLennan AH, Lawton B, et al. Main morbidities recorded in women’s international study of long duration oestrogen after menopause (WISDOM): a randomized controlled trial of hormone replacement therapy in postmenopausal women. BMJ. 2007;doi:10.1136/bmj.39272.445428.80. Accessed Aug. 6, 2007.