Component of HRT Trial Halted Due to Excessive Risks

BETHESDA, Md.--The estrogen plus progestin component of the Women's Health Initiative, a randomized controlled primary prevention trial, was halted based on a recommendation from the data and safety monitoring board saying overall health risks exceeded benefits. The trial, which was supposed to last eight years, was halted after a mean follow-up of just over five years because the incidence of invasive breast cancer exceeded the stopping boundary for this particular adverse event. In addition, the data and safety monitoring board noted that there was an increased incidence of coronary heart disease (CHD), stroke and pulmonary embolism. The Journal of the American Medical Association (JAMA) posted an early release of this report on its Web site (www.jama.com), although the findings are scheduled to appear in JAMA's July 17 issue (288, 3:321-33, 2002).

For the Women's Health Initiative, researchers from the National Heart, Lung and Blood Institute, a division of the National Institutes of Health (NIH), recruited a total of 16,608 postmenopausal women (aged 50 to 79 years) without hysterectomy at baseline from 40 clinical centers in the United States between 1993 and 1998. Subjects were randomized, and 8,506 received one tablet containing 0.625 mg/d of conjugated equine estrogens plus 2.5 mg/d of medroxyprogesterone acetate (as Prempro, from Philadelphia-based Wyeth Ayerst), while 8,102 received placebo. The 431 women who had a non-cancer-related hysterectomy after randomization were switched to another arm of the study to receive unopposed estrogen or the corresponding placebo without unblinding.

CHD was the primary outcome of the Women's Health Initiative, including fatal and nonfatal myocardial infarction. After a mean follow-up of 5.2 years, there were 286 cases of CHD, and researchers noted a 29-percent increase in the risk of coronary events in the treatment group compared to placebo, mostly in nonfatal myocardial infarction. There was also a 22-percent increased risk of total cardiovascular disease in the treatment group as compared to placebo.

Invasive breast cancer was defined as the primary adverse outcome of the trial. At the 5.2-year follow-up, there were 290 cases of breast cancer, indicating a 26-percent increased risk among the hormone group as compared to placebo.

The secondary outcomes included stroke, pulmonary embolism, cancer and fractures. At follow-up, there were 212 cases of stroke, 101 cases of pulmonary embolism, 112 cases of colorectal cancer, 47 cases of endometrial cancer, 106 cases of hip fracture and 331 cases of death from other causes. Researchers noted a higher incidence of stroke among the treatment group compared to placebo, with most of the elevations occurring in nonfatal events. Women in the treatment group also had a two-fold greater rate of venous thromboembolism, as well as deep vein thrombosis and pulmonary embolism individually. As for cancers other than breast cancer, hormone therapy seemed to reduce the risk of colorectal cancer rates by 37 percent, although endometrial cancer, lung cancer and total cancer incidence were not affected. Risk of fractures was also reduced in the hormone group as compared to placebo, with those receiving treatment exhibiting a one-third reduced risk for fracture. Specifically, osteoporitic fractures were reduced by 23 percent and total fractures were reduced by 24 percent in the treatment group.

"The risk-benefit profile found in this trial is not consistent with the requirements for a viable intervention for primary prevention of chronic diseases," the researchers concluded. "[A]nd the results indicate that this regimen should not be initiated or continued for primary prevention of CHD."

Earlier in the trial, specimens collected at baseline and one year indicated greater reductions in low-density lipoprotein (LDL or "bad") cholesterol levels, as well as increases in high-density lipoprotein (HDL or "good") cholesterol and triglyceride levels in the treatment group compared to placebo. However, systolic blood pressure was higher at this point in the women in the treatment group compared to placebo.

One drawback to this particular trial, as noted by the researchers, was the women's adherence. "The relatively high rates of discontinuation in the active treatment arm (42 percent) and crossover to active treatment in the placebo arm (10.7 percent) are a limitation of the study; however, the lack of adherence would tend to decrease the observed treatment effects," the authors wrote. "Thus, the results presented here may underestimate the magnitude of both adverse effects on cardiovascular disease and breast cancer and the beneficial effects on fractures and colorectal cancer among women who adhere to treatment."

The outcome of the Women's Health Initiative was not surprising to all. "This information is really not brand-new information," said Jane Guiltinan, ND, the dean of clinical affairs at Seattle's Bastyr University. "[W]e've known for a long time that estrogen replacement can increase the risk of breast cancer and clots and things like that. I think what's maybe most recent is the news that not only does hormone replacement not protect someone from cardiovascular disease, but it actually may increase the risk. But even that has been suspected for a couple of years now."

In terms of the future of menopause therapy, Guiltinan added, "From my point of view, each patient needs to make her own informed choice. What's good about this study is it gives women more information from which to make a decision. My sense is that more women will carefully consider whether they want to go on hormones and may give a more serious look at doing things like diet and exercise."

According to Guiltinan, there is a continuing arm of the Women's Health Initiative looking at diet and exercise in terms of menopause therapy, as well as chronic disease risk. And, researchers noted a parallel trial of estrogen therapy is ongoing in 10,739 women who have had a hysterectomy, with completion scheduled for March 2005.