New results released from WHI: What do they mean for patients?
Risks of long-term combination hormone therapy outweigh benefits
Results from a follow-up study of women who were enrolled in the Women's Health Initiative (WHI) indicate that while many health effects of hormones are diminished after about three years after cessation of combined hormone therapy (CHT), risks for stroke, blood clots, and cancer remain elevated.1
The WHI is a major 15-year research program designed to address the most frequent causes of death, disability, and poor quality of life in postmenopausal women: cardiovascular disease, cancer, and osteoporosis. What is the bottom-line message for clinicians and their patients from the current three-year, post-intervention follow-up?
The widely shared information about the use of hormone therapy with estrogen plus progestin is unchanged, say researchers. The new results indicate that for prevention of chronic disease, the risks of estrogen plus progestin exceed the benefits.
"This follow-up study confirms earlier findings that combination hormone therapy should not be used to prevent disease in healthy post-menopausal women," says Michael Lauer, MD, director of the Division of Prevention and Population Sciences at the National Heart, Lung, and Blood Institute (NHLBI), which sponsors the WHI. "It's remarkably powerful and simple."
The principal findings from the two WHI hormone therapy trials — which studied 27,347 postmenopausal women on estrogen plus progestin, estrogen-alone, or placebo — found that the overall risks of long-term use of hormone therapy outweigh the benefits.2,3 Both of those trials were stopped early because of increased health risks and failure to prevent heart disease, a key question of the studies.
Check the results
After the estrogen plus progestin arm of the WHI trial was stopped in 2002, many women stopped taking CHT because of the increased risks of cardiovascular disease and breast cancer noted in the study results. The current follow-up study was designed to give information to women to help them understand how drug cessation might affect their future health.
To conduct the follow-up study, researchers randomly assigned 15,730 postmenopausal women ages 50-79 who participated in the WHI estrogen-plus-progestin trial to receive a combination of estrogen plus progestin (CHT) or placebo. All women in the follow-up study were examined at least once a year by a WHI clinician and received an annual breast examination and mammogram, with biopsies performed as needed.
In the follow-up study, the researchers found the annualized event rates for all cancers was higher during the post-intervention follow-up for the CHT group [1.56% per year (n = 281)] than the placebo group [1.26 % per year (n = 218)]. This finding suggests a greater risk of invasive breast cancer and other cancers in the CHT group. Rates of colorectal cancer did not differ significantly between the two groups, while rates of endometrial cancer were lower in the CHT group. Though the risk of breast cancer remained elevated during the follow-up, the risk was less than that experienced toward the end of the trial period, researchers report.
The risk of cardiovascular events after the intervention was comparable between the two groups, with an annualized rate of 1.97% in the CHT group (343 events) and 1.91% in the placebo arm (323 events). This finding suggests the increased risks found during the trial period weakened after study drugs were stopped.
Researchers found the risk of fractures in the post-intervention follow-up was similar among women in both groups for each type of fracture considered: hip, vertebral, and other osteoporotic fractures.
The researchers developed a global index, which is a summary of the risks and benefits, including outcomes for coronary heart disease, invasive breast cancer, stroke, pulmonary embolism, endometrial cancer, colorectal cancer, hip fracture, and death due to other causes. The global index indicates the risks of CHT exceed the benefits for chronic disease prevention.
Consider risks, benefits
The results in the follow-up study are fully consistent with the current guidelines, says Gerardo Heiss, MD, professor of epidemiology in the School of Public Health at the University of North Carolina at Chapel Hill. Women are encouraged to use hormones only if needed for menopausal symptoms, and for the shortest time possible. They should adopt and maintain a healthy lifestyle, such as engaging in regular physical activity, maintaining a healthy body weight, consuming a diet low in saturated fat, and refraining from smoking. The findings do offer guidance to those women who used CHT in the past for prolonged periods of time to continue in prevention and screening activities, Heiss says.
The latest news about the women in the WHI adds to the confusion, but it adds little to what clinicians know about the women for whom HT is most appropriate: those women close to menopause, says Susan Wysocki, RNC, NP, FAANP, president and CEO of the National Association of Nurse Practitioners in Women's Health. There were no age breakdowns given in this latest release, she points out.
"Since the WHI was first released, clinicians have learned that age since menopause does make a difference," states Wysocki. "It is a shame that this latest report did not give us more information about this early menopausal group."
Clinicians now are awaiting the age-specific follow-up analyses of both the estrogen-plus- progestin and the estrogen-alone WHI clinical trials focusing on cardiovascular outcomes, says Andrew Kaunitz, MD, professor and associate chair in the Obstetrics and Gynecology Department at the University of Florida College of Medicine — Jacksonville.
Although increased risks for heart disease, stroke, and blood clots attributable to combined hormone therapy are no longer present after stopping the drug regimen, cardiovascular disease remains the leading cause of death among all women, advises the NHLBI.4 One in three female adults has some form of cardiovascular disease, according to the American Heart Association.5
Women need to take action to prevent cardiovascular disease even after stopping hormone therapy by choosing healthy lifestyles: refraining from smoking; engaging in regular exercise; having checkups for risk factors such as high blood pressure, high blood cholesterol, and diabetes; and treating these risk factors as needed.
If a woman stops hormone therapy, she loses some protection against fractures, so clinicians should counsel on strategies to prevent or reduce osteoporosis and fracture risk in consultation with a provider of health care. Women also should continue to monitor their risk for cancers, including breast cancer and lung cancer, says the NHLBI.
References
- Heiss G, Wallace R, Anderson GL, et al. Health risks and benefits 3 years after stopping randomized treatment with estrogen and progestin. JAMA 2008; 299:1,036-1,045.
- 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.
- Women's Health Initiative Steering Committee. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: The Women's Health Initiative randomized controlled trial. JAMA 2004; 291:1,701-1,712.
- Women's Health Initiative. Questions and Answers about the Health Risks and Benefits of Estrogen and Progestin 3 Years after Stopping Randomized Treatment. Accessed at www.whi.org/faq/faq_eplusp_3yr.php.
- American Heart Association. Women and Cardiovascular Diseases — Statistics. Fact sheet. Accessed at www.americanheart.org.
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