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WHI Estrogen/Progestin Study Halted

Preliminary results showed increased risks for breast cancer and cardiovascular disease among postmenopausal women on combination hormone therapy, prompting shutdown of this major clinical trial.

The Women's Health Initiative (WHI), an NIH-sponsored, multicenter effort begun in 1993, has been conducting 2 randomized, placebo-controlled trials of hormone therapy (HT) in postmenopausal women: an estrogen-only study for women who have had a hysterectomy (n=10,739) and an estrogen/progestin (E+P) study for women with a uterus (n=16,608). The active treatment regimen in the E+P study was 0.625 mg of conjugated equine estrogen plus 2.5 mg of medroxyprogesterone acetate daily.

On July 9, 2002, the NIH announced that the E+P study was being halted after a mean of 5.2 years of follow-up, rather than the planned 8.5 years, because those on active treatment had an increased risk for breast cancer in excess of the safety threshold and had an increased risk for cardiovascular disease. Among active-treatment recipients, 166 cases of breast cancer developed, compared with 122 among placebo recipients (hazard ratio, 1.26; 95% CI, 1.00-1.59). Active treatment resulted in 164 coronary events, 127 strokes, and 151 venous thromboembolic events, and placebo treatment resulted in 122, 85, and 67 events, respectively (combined HR, 1.22; 95% CI, 1.09-1.36). On the other hand, active treatment resulted in fewer cases of colorectal cancer (45 vs. 65) and fewer hip fractures (44 vs. 62) than did placebo treatment.

The increase in breast cancer was not apparent until after a mean of 4 years of follow-up and was associated with duration of prior use of postmenopausal HT. No increased risk was evident among women who had never used HT prior to the study. Because of an estimated absolute excess risk of 19 total adverse events per 10,000 person years with E+P treatment, long-term use of this combination of hormones cannot be recommended for prevention of cardiovascular disease in healthy postmenopausal women.

Comment: Although the absolute risks associated with active treatment in the WHI E+P study were small, they outweighed the even smaller benefits. Much information is still needed, including the risk-benefit profile for estrogen alone, outcomes with other types of hormone preparations, and the long-term risk associated with short-term use of HT. The ongoing WHI estrogen-only study should help determine how progestin influenced the E+P study results. In the meantime, women should discuss their individual needs and risk profiles with their healthcare providers. There are effective alternative therapies for lowering cardiovascular and osteoporosis risk; we can no longer expect one regimen to be a panacea.

— Marian C. Limacher, MD

Dr. Limacher, an Associate Editor of Journal Watch Women's Health, is the principal investigator from the University of Florida Clinical Center for the Women's Health Initiative.

Published in Journal Watch Women's Health August 7, 2002

Citation(s):

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 Jul 17; 288:321-33.

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