Another Caution on Cardiovascular Risks From HRT

ADELAIDE, Australia, July 12 -- Once again, hormone replacement therapy started a decade or more past menopause has been found to increase the risk for cardiovascular and thromboembolic events, with no significant benefits in return.

The 12-month follow-up results of the Women's International Study of Long Duration [O]estrogen After Menopause (WISDOM) trial, reported online in the BMJ, came on the fifth anniversary of the report from the Women's Health Initiative, the clinical trial with similar findings that dashed hopes that HRT could be cardioprotective in postmenopausal women.

"Data from WISDOM suggest that women starting or restarting combined estrogen 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," wrote Alastair H. MacLennan, M.D., of the University of Adelaide, and colleagues in Britain and New Zealand.

Enrollment in the WISDOM study, originally planned to include 23,000 women, was stopped after fewer than 5,700 had started treatment, following publication of the initial WHI results. Similarly, the two studies in WHI trial were also halted early because of an excess number of thromboembolic events, and no evidence of a protective cardiovascular benefit.

Although the investigators found that compared with placebo, combined HRT significantly increased the risk of major cardiovascular events or venous thromboembolism, the trial did not answer the question of whether use of HRT for control of severe hot flashes and night sweats in early menopause has any long term benefits or detriments.

In an accompanying BMJ editorial, Helen Roberts, M.D., M.P.H., of the University of Auckland, in New Zealand, pointed out that "postmenopausal hormone therapy has come full circle." Originally used to treat menopausal symptoms, then becoming an agent to a prevent late coronary risks, HRT has gone back to its original purposes of hot flashes, night sweats, and vaginal dryness. "It is the best treatment we have at present for these symptoms."

Dr. Roberts noted that hot flashes and night sweats are mostly self limiting, and cited current recommendation that women use the lowest does need for relief for the shortest possible time.

"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," she wrote.

That sentiment was echoed by JoAnn Manson, M.D., Dr.P.H., of Boston's Brigham and Women's Hospital and Harvard, who was on the steering committee of the WHI, at a briefing to mark the WHI anniversary.

"When you combine the findings from the estrogen-plus-progestin trial and the estrogen-alone trial, there's a suggestion of a lower risk of heart disease in the women who were less than 10 years since onset of menopause," she said, "whereas there's an increased risk of heart disease for women who were more than 20 years past menopause, and a suggestion of a trend across time since menopause."

Dr. Manson and colleagues reported in the June 21 issue of the New England Journal of Medicine that estrogen reduced coronary calcium in women younger than 60 who took the hormone following a hysterectomy. (See Estrogen May Reduce Coronary Calcium in Women Younger than 60)

But they also said that the findings should not be construed as evidence that estrogen should be routinely used to reduce the risk of heart disease in older women.

At the WHI-anniversary briefing, Nieca Goldberg, M.D., of New York University's Women's Heart Program, agreed that "hormone therapy should never be given to a woman who has cardiovascular disease." Yet she noted that this represents a clinical problem for young women who have had heart attacks who are going through menopause because "there is nothing that we can prescribe that's as effective as hormone therapy" for their symptoms."

Before trial enrollment was halted, the WISDOM investigators enrolled 5,692 healthy women in the United Kingdom, Australia, and New Zealand. The mean t age was 63, and the mean time from menopause was 15 years.

Women with intact uteruses were randomly assigned to placebo or combined HRT with conjugated equine estrogens 0.625 mg plus medroxyprogesterone acetate 2.5/5.0 mg orally daily (Prempro). Women who had had hysterctomies were assigned to estrogen alone, combined therapy, or placebo. The mean follow-up was 11.9 months.

The primary endpoints were major cardiovascular disease, osteoporotic fractures, and breast cancer. Secondary outcomes were other cancers, death from all causes, venous thromboembolism, cerebrovascular disease, dementia, and quality of life.

The authors found in a comparison of combined HRT (2,196 patients) and placebo (2,189 patients) that there was a significant increase in major cardiovascular events among patients on the active drugs. There were seven events among patients on combined HRT, compared with none for patients on placebo (P=0.016). In addition, there were 22 cases of venous thromboembolism among patients on the combined therapies, compared with three among patients on placebo (hazard ratio 7.36, 95% confidence interval. 2.20 to 24.60).

There were no statistically significant differences in either numbers of breast or other cancers (22 for HRT versus 25 for placebo, hazard ratio 0.88, 95% CI, 0.49 to 1.56), cerebrovascular events (14 versus 19 respectively, HR 0.73, 95% CI, 0.37 to 1.46), fractures (40 versus 58, HR 0.69, 95% CI. 0.46 to 1.03), or overall deaths (eight versus five, HR, 1.60 (0.52 to 4.89).

There were also no significant differences in outcomes among patients on combined HRT compared with estrogen alone.