Drug Criteria & Outcomes
HRT, calcium with vitamin D in postmenopausal women? An update on the Women’s Health Initiative
By Kathryn Kollefrath, PharmD Candidate
Auburn (AL) University Harrison School of Pharmacy
In 1991, the Women's Health Initiative (WHI) was established to address cardiovascular disease, cancer, and osteoporosis in postmenopausal women. It was a 15-year, multimillion-dollar project that included 161,808 women aged 50-79 years.
Over its 15-year course, recommendations for diet and medication therapies have been made from the data collected in the ongoing trials. Now, in 2006, more updates and conclusions have been made regarding medication therapy in various diseases concerning postmenopausal women.
A large component of this massive project was several randomized controlled clinical trials concerning hormone replacement therapy (HRT), dietary modifications, and calcium plus vitamin D supplementation. Investigators specifically assessed the risks and benefits of these interventions and their ability to delay mortality and improve morbidity.
The estrogen plus progestin therapy, which was one of the HRT trials, was stopped in 2002 after approximately five years of treatment because the results were showing an increased risk of stroke and breast cancer with therapy.
At that time, it was unknown whether the estrogen-alone trial would have similar effects. However, in 2004, results were emerging that demonstrated an increased risk of stroke with estrogen-only therapy as well. This trial, therefore, was discontinued after an average of seven years of follow-up and approximately one year earlier than the planned stop date. This trial included 10,739 women ages 50-79 years that had undergone a hysterectomy. They were randomized to receive 0.625 mg of daily conjugated equine estrogen (CEE) (n = 5,310) or placebo (n = 5,429). From this trial, stroke, venous thrombosis, breast cancer, and coronary heart disease risks were assessed.
During the trial, there were 168 strokes in the CEE group vs. 127 in the placebo group. The majority of strokes, 84.5% in the CEE group and 74.8% in the placebo group, were ischemic; however, there was no significant difference in ischemic stroke based on age, race, ethnicity, years postmenopause or bilateral oophorectomy, prior history of CVD or hormone use, body mass index, hypertension, diabetes mellitus, smoking, Framingham risk score, vasomotor symptoms, or concurrent statin or aspirin use.
Although these results strengthened previous findings implicating estrogen, not progestin, as the more likely cause of stroke, the overall effects of estrogen alone or estrogen plus progestin are similar in that both increase the incidence of ischemic stroke in postmenopausal women.
Because estrogen-only HRT showed an increase in ischemic stroke, it is not surprising that the results in the venous thrombosis (VT) trial also showed that estrogen only-therapy increased the risk of VT. During this seven-year trial, VT occurred in 111 (2%) women who were assigned to receive CEE, and in 86 (1.6%) women who were taking placebo. Of the VTs that occurred, 85 (75%) in the CEE group were deep vein thrombosis (DVT) compared to 59 (67%) in the placebo group, and 27 (24%) and 28 (33%) events in the CEE and placebo group, respectively, were thought to be procedure-related. Therefore, estrogen-alone HRT showed an increase risk of VT, again suggesting that estrogen is the most likely cause, not the progestin.
Coronary Heart Disease
In February 2006, the effects of CEE on coronary heart disease were published in Achieves of Internal Medicine. It showed that estrogen-only HRT neither increased nor decreased the risk of coronary heart disease in postmenopausal women. There were 201 (3.8%) coronary events, which were defined as nonfatal myocardial infarction or coronary death, compared to 217 (4%) reported among women taking placebo. The difference between these groups was not statistically significant. Also, one year into this seven-year study, women taking CEE had a greater increase from baseline in high-density lipoprotein (HDL) and triglyceride (TG), but decreased low-density lipoprotein (LDL) and total cholesterol compared to placebo.
The data from this seven-year study showed that CEE offers no more coronary protection than placebo.
Breast Cancer and Mammography
One outcome that differed from the estrogen plus progestin trial was released in April of 2006. This arm focused on the effects of estrogen-only HRT in breast cancer and mammography screening. The study showed that 104 (2%) women in the CEE group and 133 (2.5%) women in the placebo group were diagnosed with breast cancer and that 36% vs. 28%, respectively, had abnormal mammograms.
This difference was primarily in the assessment of abnormal findings during routine mammograms where a higher percentage in the CEE group required short interval follow-up. There was no statistical difference in suspicious abnormalities or ones that were suggestive of malignancy between the two groups. Therefore, after seven years of treatment, estrogen alone did not seem to increase a women's risk of breast cancer; however, it did increase the frequency of mammography screening due to the increase in short interval follow-up recommended after abnormal results.
Calcium and Vitamin D
Not only did the WHI assess the outcomes of HRT, but also the risks and benefits of calcium plus vitamin D supplementation in postmenopausal women. In a randomized, double-blind, placebo-controlled trial, patients received 500 mg of elemental calcium as calcium carbonate with 200 IU of vitamin D3 twice daily (n = 18,176) or placebo (n = 18,106). The results of this study were released in February 2006, after seven years.
One aspect of the trial compared whether calcium plus vitamin D could be used as primary prevention of colorectal cancer, as previous studies had indicated. The WHI found no statistically significant difference between the calcium plus vitamin D group and placebo. There were 168 (0.92%) cases of colorectal cancer reported in the prevention group vs. 154 (0.85%) reported in the placebo group and there was no difference in tumor characteristics, screenings, or symptoms. Daily supplementation with calcium plus vitamin D for seven years had no effect on the incidence of colorectal cancer among postmenopausal women.
Another outcome the WHI assessed was whether calcium with vitamin D prevented hip and other fractures in healthy postmenopausal women. Although the hip bone mineral density was slightly higher (1%) in patients taking calcium plus vitamin D, there was no statistical difference in fracture among either group. The results also showed that the calcium with vitamin D group had a higher incidence of kidney stones compared to placebo, 449 (2.5%) patients and 381 (2.1%) patients, respectively. This was the only significant difference found between the groups when assessing safety and tolerability.
It is estimated that 17% of all women will experience a hip fracture during their lifetime, which may lead to disability and a decreased quality of life. Heart disease, breast cancer, and colon cancer are the first-, second-, and third-leading causes of death, respectively, in postmenopausal women. More than 240,000 women die each year of heart attacks; this accounts for 22% of all deaths among U.S. women. The number of deaths from breast cancer and colon cancer are equally as astounding with more than 46,000 and 28,000, respectively. Currently, it still is recommended that physicians take careful consideration and assess the potential risks vs. benefits before prescribing estrogen-only HRT.
Although the results from this project did not show the outcomes that health care practitioners had hoped for, they did make the medical world more aware of postmenopausal symptoms and diseases and the need for better treatment.
- Women's Health Initiative Background and Overview. Available at: www.nhlbi.nih.gov/whi/factsht.htm. Accessed July 10, 2006.
- The Women's Health Initiative participant web site.WHI Clinical Coordinating Center at the Fred Hutchinson Cancer Research Center. Available at: www.whi.org. Accessed July 10, 2006.
- Hendrix S, Wassertheil S, Johnson K, et al. Effects of conjugated equine estrogen on stroke in the Women's Health Initiative. Circulation 2006;113:2,425-2,434.
- Curb JD, Prentice RL, Bray PF, et al. Venous thrombosis and conjugated equine estrogen in women without a uterus. Arch Intern Med 2006;166:772-780.
- Hsia J, Langer R, Manson J, et al. Conjugated equine estrogens and coronary heart disease: The Women's Health Initiative. Arch Intern Med 2006;166:357-365.
- Stefanick M, Anderson G, Margolis K, et al. Effects of conjugated equine estrogen on breast cancer and mammography screening in postmenopausal women with hysterectomy. JAMA 2006;295:1,647-1,657.
- Wactawski-Wende J, Kotchen J, Anderson G, et al. Calcium plus vitamin D supplementation and the risk of colorectal cancer. N Engl J Med 2006;354:684-696. Erratum in: N Engl J Med 2006;354:1,102.
- Jackson R, LaCroix A, Gass M, et al. Calcium plus vitamin D supplementation and the risk of fractures. N Engl J Med 2006;354:669-683. Erratum in: N Engl J Med 2006;354:1,102.