NOTE: Since this advisory was written, results of the estrogen-alone study have been published.
On March 1, 2004, the National Institutes of Health (NIH) informed study participants that they should stop study medications in the trial of conjugated equine estrogens (Premarin™, Estrogen-alone) versus placebo in the Women's Health Initiative (WHI). Women will continue to be followed for several more years, including ascertainment of outcomes and mammogram reports.
NIH informed participants, who now have an average age of almost 70 years and have been followed for approximately 7 years, that the current results show that estrogen alone does not appear to affect (either decrease or increase) coronary heart disease. At the same time, estrogen alone appears to increase the risk of stroke and decrease the risk of hip fracture, and does not increase the risk of breast cancer during the time period of this study. The current results indicate that the increased risk of stroke is similar to that found in the trial of Estrogen plus Progestin when it was stopped after 5.6 years of follow up. NIH believes that an increased risk of stroke is not acceptable in a prevention trial in healthy women, especially if estrogen does not affect coronary heart disease.
With an average of nearly 7 years of follow-up completed, the study results are not likely to change if the trial continues for one more year. Thus, the NIH believes that enough data have been obtained to provide an overall assessment of the risks and benefits of the use of estrogen in this trial.
The WHI investigators are analyzing the results of the estrogen-alone trial, and plan to publish the data in a peer-reviewed journal in the next two months. The results of the estrogen-alone trial will include an additional three months of data, and the numbers will change somewhat from those in the current data. To avoid confusion and misinterpretations arising from incomplete data, NIH will not be releasing the current data.
Women in the WHI who were older than 65 years of age on enrollment also had the opportunity to participate in an ancillary study known as the WHI Memory Study (WHIMS). WHIMS researchers are analyzing data from this study and, like the estrogen-alone study investigators, are expected to publish results in a peer-reviewed journal in the next two months. Preliminary data suggest that for the WHIMS participants who were on estrogen alone when compared to the women who were taking the placebo, there was a trend toward increased risk of probable dementia and/or mild cognitive impairment.
Almost 11,000 women with a prior hysterectomy aged 50-79 at baseline participated in the WHI estrogen-alone trial, which was designed to find out whether estrogen prevents heart disease in healthy older women. Hip fractures were the major secondary outcome, and breast cancer the major possible risk. The trial was designed to assess the long-term effects of estrogen alone on overall health in terms of both benefits and risks.
The WHI trial of conjugated equine estrogens and medroxy-progesterone acetate (Prempro™, Estrogen plus Progestin) in women with a uterus was stopped in July 2002 after 5.6 years of follow-up because of an increased risk of breast cancer, and because the risks of breast cancer, coronary heart disease, strokes, and blood clots outweighed the benefits on hip fracture and colorectal cancer. In 2003, WHIMS reported an increased risk of dementia in participants aged 65 and older.
As a result of these findings, the Food and Drug Administration has requested that manufacturers of all postmenopausal hormone therapies (Estrogen alone as well as Estrogen plus Progestin) amend their labels to include a "Black Box" warning stating that:
- Estrogens and progestins should not be used for the prevention of cardiovascular disease
- Other doses of CEE and MPA, and other combinations of estrogens and progestins were not studied in the WHI and, in the absence of comparable data, these risks should be assumed to be similar.
- Because of these risks, estrogens with or without progestins should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman.
In February 2004, the FDA additionally requested that manufacturers should include WHIMS data in the existing Black Box that contains WHI data on cardiovascular risks. WHIMS found an increased risk of developing probable dementia in postmenopausal women age 65 years of age or older during 4 years of treatment with oral conjugated estrogens plus medroxyprogesterone acetate compared to placebo. It is unknown whether this finding applies to younger postmenopausal women taking estrogen alone. FDA also advised manufacturers to add the WHIMS data to the clinical studies section, and to specify the lowest effective dose of their drug (or state that the lowest effective dose has not been determined).
In addition to the "black box" warning, the FDA requested that Indications and Usage read as follows:
Current Labeling: Indications and Usage
- Treatment of moderate to severe vasomotor symptoms associated with the menopause.
- Treatment of moderate to severe symptoms of vulvar and vaginal atrophy associated with menopause. When prescribing solely for the treatment of symptoms of vulvar and vaginal atrophy, topical vaginal products should be considered.
- Prevention of postmenopausal osteoporosis. When prescribing solely for the prevention of postmenopausal osteoporosis, therapy should only be considered for women at significant risk of osteoporosis and non-estrogen medications should be carefully considered.
NIH has notified the FDA of the decision to stop the trial of estrogen alone, and will provide the FDA with any additional information needed to consider the implications of the estrogen-alone data on the use of postmenopausal hormone therapy, including consideration of further changes in the label. In addition, the American College of Obstetricians and Gynecologists, the American Academy of Family Practice, the American College of Physicians, the North American Menopause Society, the American Society for Reproductive Medicine, and other professional organizations have been notified of the decision to stop and the reasons for doing so.
Until such time as the final data are available, and the FDA and the physician groups have had an opportunity to consider revisions to practice guidelines, the NIH advises physicians to follow the current FDA guidance.
Additional information on menopausal hormone therapy, including the WHI estrogen-plus-progestin study, can be found on the websites of the NIH, National Heart, Lung, and Blood Institute (NHLBI), and the FDA.