Hormone therapy: Make decisions on a balanced risk-to-benefit basis
Use new product labeling, recommendations for guidance
Family planning clinicians have found their care of postmenopausal women has changed dramatically since the July 2002 cessation of the estrogen/progestin arm of the Women’s Health Initiative (WHI). The estrogen/progestin arm of the landmark study was halted after findings showed that the overall health risk, particularly of cardiovascular disease and breast cancer, from taking estrogens with progestin was greater than the benefits of lowering the risk of colon cancer and bone fractures.
"The beneficial outcome of the WHI thus far is to have changed the nature of the conversation between health provider and consumer so that indications are more precise and decisions are being made on a balanced risk-to-benefit consideration," says Wulf Utian, MD, PhD, executive director of the Cleveland-based North American Menopause Society.
Clinicians now have new product labeling from the Food and Drug Administration (FDA) as well as updated recommendations from the U.S. Preventive Services Task Force (USPSTF) to help guide their use of hormonal steroids in postmenopausal women. Examine the following new information and integrate it into your daily practice.
As now approved by the FDA, estrogen products are indicated for use in relieving vasomotor symptoms of menopause such as hot flashes and night sweats; symptoms of vulvar and vaginal atrophy such as dryness, itching, and burning; and prevention of postmenopausal osteoporosis. In January, the FDA implemented new safety changes to labeling of all estrogen and estrogen with progestin products for use by postmenopausal women to incorporate information from the WHI study.
The new labeling information has been incorporated in physician prescribing information and patient information leaflets for Premarin, Prempro, and Premphase, all hormone products manufactured by Wyeth Pharmaceuticals of Collegeville, PA. However, the FDA is asking all manufacturers to update their labeling with WHI’s results because all estrogen and progestin products are believed to have similar risks. The agency is revising its formal guidances for the industry in two related areas: labeling for all estrogen and estrogen with progestin products for postmenopausal women, and recommendations for conducting clinical trials to develop new products for postmenopausal women.
The new product labeling features a boxed warning that reflects new risk information, and includes changes to the approved indications to emphasize individualized decisions for balancing the benefits and the potential risks involved. The boxed warning, the highest level of warning information in labeling, highlights the increased risks for heart disease, heart attacks, strokes, and breast cancer. This warning also emphasizes that these products are not approved for heart disease prevention.
Check label changes
Of the three approved indications, two have been revised to include consideration of other therapies:
- The indication for treatment of moderate to severe vasomotor symptoms associated with menopause has not changed.
- The indication for treatment of moderate to severe symptoms of vulvar and vaginal atrophy associated with menopause has been modified. When these products are being prescribed solely for the treatment of symptoms of vulvar and vaginal atrophy, topical vaginal products should be considered, advises the FDA.
- The indication for prevention of postmenopausal osteoporosis has been modified. When products are being prescribed solely for the prevention of postmenopausal osteoporosis, the new labeling advised that approved nonestrogen treatments should be carefully considered, and estrogens and combined estrogen-progestin products only should be considered for women with significant risk of osteoporosis that outweighs the risks of the drug.
Additional drugs that are FDA-approved for the prevention of postmenopausal osteoporosis include the bisphosphonates alendronate (Fosamax, manufactured by Merck & Co. of West Point, PA) and risedronate (Actonel, manufactured by Procter & Gamble Pharmaceuticals of Cincinnati), and the selective estrogen receptor modulator raloxifene (Evista, manufactured by Eli Lilly & Co. of Indianapolis). Calcitonin (Miacalcin, manufactured by Novartis Pharmaceuticals, East Hanover, NJ) carries an indication for treatment of the disease.
The new labeling also advises health care providers to prescribe estrogen and combined estrogen with progestin drug products at the lowest dose and for the shortest duration for the individual.
See new recommendation
The U.S. Preventive Services Task Force has issued a revised recommendation against the use of combined estrogen and progestin hormone replacement therapy for preventing cardiovascular disease and other chronic conditions in postmenopausal women. The independent panel also has concluded that the evidence is insufficient to recommend for or against the use of estrogen alone to prevent the chronic conditions in postmenopausal women who have had hysterectomies.
The new guideline is a change from the task force’s 1996 recommendation, which stated there was insufficient evidence to recommend for or against hormone therapy for all postmenopausal women. Task force members began reviewing information in 1999, and the recommendation was released in October 2002, states Heidi Nelson, MD, MPH, associate professor of medicine at the Oregon Evidence-based Practice Center at the Portland-based Oregon Health & Science University. The task force continued to update the report throughout the process even while the final paper was in press, says Nelson, who served as one of the leaders of the research teams involved with the review.
Two papers have been published containing the research reviewed by the task force. One article primarily addresses cardiovascular disease, while the other provides an overall summary of the risks and benefits of hormone therapy.1,2
The reviews did not examine the use of hormone therapy to treat menopausal symptoms or specific conditions such as osteoporosis. The USPSTF will not issue a recommendation about treating menopausal symptoms because it is not a prevention issue and therefore out of its scope, says Nelson. In October 2002, the panel gave unopposed estrogen for prevention of chronic conditions an "I" rating (insufficient evidence) because current evidence is not adequate to determine the overall benefit/harm balance, she states.
When more data become available, particularly from the WHI, the USPSTF likely will revisit this recommendation, says Nelson.
Review steroid use
What is the future for hormone therapy? For a number of years, there had been increasing off-label use of such medications for the prevention of cardiovascular disease, and some clinicians even were using it in the hope that it would prevent Alzheimer’s disease and cognitive decline, observes Margery Gass, MD, professor in the obstetrics/gynecology department of the University of Cincinnati and current president of the North American Menopause Society.
"The results of the WHI have demonstrated that hormone therapy does not prevent cardiovascular disease, and furthermore, has some serious side effects, [such as] invasive breast cancer, venous thrombolic events, cardiovascular disease [CVD], and stroke," says Gass. "Thus, it should no longer be used for prevention of CVD."
Preventive use of hormonal steroids at this time should be directed at osteoporosis only, pending data on coronary heart disease and Alzheimer’s, says Utian. In this instance, the latest FDA labeling requirements are clear, he states; clinicians should consider the risks and benefits of all options, decide on a therapy, and follow up appropriately. Estrogen-only or hormone therapy remains a viable option, and most certainly it is an option in younger women or women who cannot tolerate bisphosphonates, as well as for most women for up to five years of use, he maintains.
"The therapeutic role [of hormonal steroids] relates to the true estrogen deficiency symptoms, namely the vasomotor, vaginal atrophy, and possibly the enhanced quality of life components," he notes.
Clinicians now await the estrogen-only arm outcome of the WHI to determine whether the added continuous progestin was the culprit, observes Utian. Look for clinical practice to be "tremendously influenced" by that arm of the study, he predicts.
While it will be some years before information from the estrogen-only arm is available, look to the publication of detailed analyses of the estrogen/progestin arm of the WHI for further understanding, says Utian. These analyses, which will focus on the regimen’s impact on cardiovascular disease, cancer, osteoporosis, cholelithiasis, degenerative arthritis, sexual function, cognition and dementia, and quality of life, will be "crucial" since the initial published data3 did not provide the nuances that only such analyses can give, he states.
"In the interim, the last nail has not been driven into the hormone therapy coffin, and these products remain an essential component of contemporary practice," states Utian.
References
1. Humphrey LL, Chan BK, Sox HC. Postmenopausal hormone replacement therapy and the primary prevention of cardiovascular disease. Ann Intern Med 2002; 137:273-284.
2. Nelson HD, Humphrey LL, Nygren P, et al. Postmenopausal hormone replacement therapy: Scientific review. JAMA 2002; 288:872-881.
3. Writing Group for the Women’s Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: Principal results from the Women’s Health Initiative randomized controlled trial. JAMA 2002; 288:321-333.
Family planning clinicians have found their care of postmenopausal women has changed dramatically since the July 2002 cessation of the estrogen/progestin arm of the Womens Health Initiative (WHI). The estrogen/progestin arm of the landmark study was halted after findings showed that the overall health risk, particularly of cardiovascular disease and breast cancer, from taking estrogens with progestin was greater than the benefits of lowering the risk of colon cancer and bone fractures.
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