Results of the Women's Health Initiative, reported in the July 17 issue of The Journal of the American Medical Association, indicate that Prempro, the combination of conjugated equine estrogen (0.625 mg/day) and medroxyprogesterone acetate (2.5 mg/day), is associated with an increased overall health risk. Although the absolute risk was low, investigators stopped this arm of the study and suggested discontinuing this therapy.

"During one year, for every 10,000 women taking estrogen plus progestin, we would expect seven more women would have heart attacks (than in the placebo group), eight more women with strokes, eight more women with breast cancer, and 18 more women with blood clots," investigator Denise E. Bonds, MD, MPH, from Wake Forest University Baptist Medical Center in Winston-Salem, N.C., says in a news release.

Despite the low absolute risk (2.5%) and the positive effect of six fewer cases of colorectal cancer and five fewer hip fractures per 10,000 women treated with Prempro, Bonds says that "the balance of risks significantly outweighed the benefits."

This randomized, controlled, primary prevention trial taking part at 40 U.S. clinical centers from 1993-1998 enrolled 16,608 postmenopausal women aged 50-79 years with an intact uterus at baseline. Although the study has a planned duration of 8.5 years, the study's Data and Safety Monitoring Board discontinued the Prempro treatment arm after a mean follow-up period of 5.2 years.

For women on this combination hormone, the test statistic for invasive breast cancer exceeded the stopping boundary for this adverse effect (hazard ratio 1.26; 95% confidence interval 1.00-1.59), and the global index statistic suggested that risks exceeded benefits. Mortality was not increased in the Prempro treatment arm, but the absolute excess risk of adverse events was 19 per 10,000 person years. Most adverse outcomes occurred within one to two years, except for breast cancer risk, which was not increased until four years.

Women in other groups in the study, including women taking estrogen alone, women on a low-fat diet, women taking calcium and vitamin D supplementation, and those on observation alone are advised to continue with their assigned treatment.

"The risk-benefit profile found in this trial is not consistent with the requirements for a viable intervention for primary prevention of chronic diseases, and the results indicate that [Prempro] should not be initiated or continued for primary prevention of coronary heart disease," the authors write.

In an accompanying editorial, Suzanne W. Fletcher, MD, MSc, and Graham A. Colditz, MD, DrPH, from Harvard Medical School in Boston, call the methods "strong" and the findings "surprising" but "consistent with the growing body of literature." Because results were similar across subgroups, they suggest that there is no subgroup appearing to benefit from Prempro.

"To date, estrogen alone may be safer than the combination estrogen/progestin," they write. "We recommend that clinicians stop prescribing this combination for long-term use. Primum non nocere applies especially to preventive health care. ... The WHI provides an important health answer for generations of healthy postmenopausal women to come -- do not use estrogen/progestin to prevent chronic disease."

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