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Hormone Replacement Therapy
July 2002 The Women’s Health Initiative (WHI) study was established to assess the major health benefits and risks of the most commonly used combined hormone preparation in the United States. The preparations studied were Prempro 2.5 (conjugated equine estrogen plus progestin) and Premarin 0.625 (conjugated equine estrogen). The primary outcomes studied were the subsequent development of coronary heart disease (CHD) and/or invasive breast cancer. Besides these two primary outcomes, the study also evaluated the incidence of stroke, pulmonary embolism (PE), endometrial cancer, colorectal cancer, hip fracture, and death due to other causes. After a mean follow-up of 5.2 years, the trial of estrogen plus progestin (Prempro 2.5) vs. placebo was halted on May 31, 2002 because the test statistic for invasive breast cancer exceeded the stopping boundary for this adverse effect and the global index statistic showed risks exceeding benefits. A full study report appeared in the July 17, 2002, issue of the Journal of the American Medical Association (JAMA), and is also available on the JAMA web site at www.jama.com. The WHI population study group comprised 16,608 healthy women ages 50 to 79. The data indicates that for every 10,000 women taking the hormone combination for one year, as compared to 10,000 women not taking the hormone combination, there will be: 8 more invasive breast cancers 8 more pulmonary embolism (PE) 8 more strokes 7 more coronary heart disease (CHD) events 6 fewer colorectal cancers 5 fewer hip fractures
The increased breast cancer risk did not appear in the first four years of use. Risks for blood clots were greatest during the first 2 years of hormone use. The excess risk of stroke appeared in the second year and persisted through the fifth year. The increased risk for CHD began immediately and persisted beyond 5 years. The reduced colorectal cancer emerged after 3 years of hormone use. The improvement of hip fractures showed increasing cumulative benefit over time. The absolute excess risk of events for patients treated with Prempro 2.5 included in the global index was 19 per 10,000 person years. Overall health risks exceeded benefits from use of Prempro 2.5 for an average 5.2 years follow up among healthy postmenopausal U.S. women. Mortality was not affected. This trial tested only one drug regimen, Prempro 2.5 mg/day, in postmenopausal women with an intact uterus. The results do not necessarily apply to lower dosages of these drugs, to other formulations of oral estrogens and progestins, or to estrogens and progestins administered through the transdermal route.
Practitioner Alert Hormone Replacement Therapy (HRT) July 2002
The study arm comparing Premarin 0.625 mg/day to placebo in women with hysterectomy has not been terminated. The above findings have not been substantiated in the Premarin alone group. The study is scheduled to be finished in March 2005, by which time the average follow up will be about 8.5 years. Results from this study indicate Prempro 2.5 mg/day should not be initiated or continued for the primary prevention of CHD. In addition, the risks for cardiovascular disease and breast cancer must be weighed against the benefit for fracture in selecting from the available agents to prevent osteoporosis.
Recommendations:
1. Women who have been on the Prempro for a number of years should discuss their individual situation with their physicians. For an individual woman, a decision about continued hormone use should take into account her individual risk for specific conditions that may be harmed or benefited by hormone use. 2. Prempro should not be initiated or continued for the primary prevention of CHD. Greater attention should be paid to the use of statins and aspirin in the prevention of CHD. 3. The substantial risks for cardiovascular disease and breast cancer must be weighed against the benefit for fracture and colorectal cancer, while also keeping in mind the available agents to prevent osteoporosis and methods to screen for colorectal cancer. 4. With respect to women on short-term use of combination hormone therapy for relief of menopausal symptoms, this was not the focus of this study. It may be reasonable for women to continue use for this purpose, since the benefits are likely to outweigh the risks. Short-term use of combined estrogen/progestin therapy for relief of menopausal symptoms remains a personal, individualized decision, made after consultation between a woman and her hysician, taking into account her individual benefits and risks from such use. When discontinuing hormonal replacement therapy, there are no controlled studies supporting an optimal method to accomplish this. After hormone replacement therapy (HRT) is discontinued, hot flashes often return in about 4 days, depending on the type and route of estrogen therapy. There are two methods of tapering the HRT described in the Prescriber’s Letter. This can be found at www.prescribersletter.com. There are several non-hormonal alternatives for treating hot flashes also listed for women with debilitating vasomotor symptoms. The following Web site offers women suggestions or alternatives to HRT (hormone replacement therapy) for the treatment of hot flashes, difficulty sleeping, and vaginal dryness, along with ways to reduce their risk for osteoporosis and heart disease. These recommendations are from The North American Menopause Society at http://www.menopause.org/alternatives_hrt.html
References
1. Writing Group for the Women’s Health Initiative Investigators. Risks and Benefits of Estrogen Plus Progestin in Healthy Postmenopausal Women. JAMA 2002; 288: 321-333. www.jama.com. Accessed 7/12/70. 2. O’Mara Neeta Bahal. Discontinuation of Hormone Replacement Therapy. Prescriber’s Letter. www.prescribersletter.com. Accessed 7/12/02. 3. ACOG. Statement on the Estrogen Plus Progestin Trial of The Women’s Health Initiative. ACOG News Release. www.acog.com. Accessed 7/12/02 4. Alternatives to Hormone Replacement Therapy: Suggestions from The North American Menopausal Society. http://www.menopause.org/alternatives_hrt.html. Accessed 7/16/02.
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