The National Heart, Lung, and Blood Institute stops trial of estrogen plus progestin due to increased breast cancer risk and lack of overall benefit.
The National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health (NIH) has stopped a large clinical trial years ahead of its scheduled completion. The purpose of the trial was to assess the risks/benefits of estrogen and progestin in healthy menopausal women due to an increased risk of invasive breast cancer. When the Data Safety Monitoring Board made the decision to break the code for the blinded, randomized, controlled study, researchers were surprised to learn of increased risks among those taking estrogen compared to those taking placebos.
The trial, a component of the Women's Health Initiative (WHI), found increases in coronary heart disease, stroke, and pulmonary embolism in study participants taking estrogen plus progestin compared to those taking placebos. While there are benefits of the combination hormone therapy — including fewer cases of hip fractures and colon cancer and the prevention of endometrial cancer — the harm was deemed greater than the benefit. The study, scheduled to run until 2005, was halted after an average follow-up of 5.2 years.
A separate WHI study of estrogen alone in women who had a prior hysterectomy continues, unchanged. At this point, the balance of risks and benefits of estrogen alone is still uncertain.
"We have long sought the answer to the question: Does postmenopausal hormone therapy prevent heart disease and, if it does, what are the risks? The bottom-line answer from WHI is that this combined form of hormone therapy is unlikely to benefit the heart. The cardiovascular and cancer risks of estrogen plus progestin outweigh any benefits — and a 26 percent increase in breast cancer risk is too high a price to pay, even if there were a heart benefit. Similarly, the risks outweigh the benefits of fewer hip fractures," says NHLBI Director Claude Lenfant, MD.
He adds, "Menopausal women who might have been candidates for estrogen plus progestin should now focus on well-proven treatments to reduce the risk of cardiovascular disease, including measures to prevent and control high blood pressure, high blood cholesterol, and obesity. This effort could not be more important as heart disease remains the number one killer of American women."
The WHI's estrogen plus progestin trial involved 16,608 women ages 50 to 79 who have an intact uterus. One objective was to examine the effect of estrogen plus progestin on the prevention of heart disease and hip fractures, and search for any associated change in risk for breast and colon cancer. The study did not address the short-term risks and benefits of using hormones for the treatment of menopausal symptoms.
"Women with a uterus who are currently taking estrogen plus progestin should have a talk with their doctor to see if they should continue. If they are taking this hormone combination for short-term relief of symptoms, it may be reasonable to continue since the benefits are likely to outweigh the risks. Longer term use or use for disease prevention must be re-evaluated given the multiple adverse effects noted in WHI," says Jacques Rossouw, MD, acting director of the WHI. According to Rossouw, the adverse effects of estrogen plus progestin apply to all women, irrespective of age, ethnicity, or prior disease status.
Marcia Stefanick, PhD, chair of the WHI Steering Committee and associate professor of medicine, Stanford University, Palo Alto, Calif., comments, "When the estrogen-only trial is completed, a comparison of the results of these two trials may provide a better idea of the roles of estrogen, compared to estrogen plus progestin, in health and disease."
Women enrolled in the estrogen plus progestin study were randomly assigned to a daily dose of estrogen plus progestin (0.625 mg of conjugated equine estrogens plus 2.5 mg of medroxyprogesterone acetate) or to a placebo.
In 2000 and again in 2001, WHI investigators complied with a recommendation from the study's Data and Safety Monitoring Board (DSMB) to inform participants of a small increase in heart attacks, strokes, and blood clots in women who take hormones. The DSMB's May 31, 2002, recommendation to stop the trial was based on an increased breast cancer risk, supported by the evidence of health risks exceeding any benefits. Since then, WHI and its investigators have sent letters to participants informing them about the results and advising them to stop taking the study medications. All WHI participants, including those in other studies, have received a newsletter summarizing the findings and explaining the risks and benefits.
Dr. Rossouw stresses the importance of understanding how the risk to an individual can be low, but the risk to the population at large can be great: "The WHI results tell us that during one year, among 10,000 postmenopausal women with a uterus who are taking estrogen plus progestin, eight more will have invasive breast cancer, seven more will have a heart attack, eight more will have a stroke, and 18 more will have blood clots, including eight with blood clots in the lungs, than will a similar group of 10,000 women not taking these hormones. This is a relatively small annual increase in risk for an individual woman. Individual women who have participated in the trial and women in the population who have been on estrogen and progestin should not be unduly alarmed. However, even small individual risks over time, on a population-wide basis, add up to tens of thousands of serious adverse health events."
The National Cancer Institute (NCI) continues to recommend that all women age 40 and older be screened for breast cancer with mammography every one to two years.
According to Leslie Ford, MD, associate director for clinical research in NCI's Division of Cancer Prevention, "The reduction in colorectal cancer risk in the WHI is intriguing, but the balance of harm versus benefit does not justify any woman beginning or continuing to take estrogen plus progestin for this purpose. NCI has a number of clinical trials underway investigating new methods to detect and prevent both colorectal cancer and breast cancer that will provide critical information to help women make important health decisions."
The study revealed these findings for the estrogen plus progestin group compared to the placebo:
- A 41 percent increase in strokes
- A 29 percent increase in heart attacks
- A doubling of rates of venous thromboembolism (blood clots)
- A 22 percent increase in total cardiovascular disease
- A 26 percent increase in breast cancer
- A 37 percent reduction in cases of colorectal cancer
- A one-third reduction in hip fracture rates
- A 24 percent reduction in total fractures
- No difference in total mortality (of all causes)
The Women's Health Initiative is sponsored by NHLBI in collaboration with four other components of the NIH — the National Cancer Institute, the National Institute of Arthritis and Musculoskeletal and Skin Diseases, the National Institute on Aging, and the Office of Research on Women's Health.
For more information about the study's findings, visit www.whi.org. More information on breast cancer, including prevention and early detection, is available from the NCI's Cancer Information Service at (800) 4-CANCER and at www.cancer.gov.