Estrogen hormone replacement therapy does not reduce the risk of stroke or death in postmenopausal women who have already had a stroke or a transient ischemic attack (TIA), according to a report from the first randomized, controlled clinical trial of estrogen therapy for secondary prevention of cerebrovascular disease.
Previous observational studies have suggested that estrogen replacement therapy may reduce the risk of stroke and death in postmenopausal women. However, it was not clear whether the apparent benefits of estrogen among women in those studies were due to the hormone therapy or other factors.
The new randomized, double-blind, placebo-controlled study, called the Women's Estrogen for Stroke Trial (WEST), was designed to resolve this question. The study, led by Ralph I. Horwitz, M.D., of the Yale University School of Medicine, was funded by the National Institute of Neurological Disorders and Stroke (NINDS) and will be published in the October 25, 2001, issue of The New England Journal of Medicine.*
"The good news is that we have taken a lot of guesswork out of treating women with strokes. The benefits from estrogen that we hoped for are not there to balance the risks," says John R. Marler, M.D., NINDS Associate Director for Clinical Trials.
Based on this finding, the investigators say, estrogen therapy should not be prescribed for the purpose of preventing a second stroke or death in postmenopausal women. Postmenopausal women who are already taking estrogen or who wish to take it for other reasons should seek the advice of their personal physicians to decide whether to continue or start therapy.
Estrogen has rarely been prescribed specifically for stroke prevention, says Lawrence M. Brass, M.D., of the Yale University School of Medicine, principal neurologist on the study. However, it has been widely prescribed for prevention of osteoporosis (thinning of the bones) and relief of menopausal symptoms such as hot flashes.
The researchers enrolled 664 postmenopausal women with an average age of 71 years who had experienced an ischemic stroke or a TIA within the previous 90 days. Ischemic strokes and TIAs result from blockages in the vessels that supply blood to the brain. Participants were given a number of initial assessments, including the NIH Stroke Scale (NIHSS) of neurological impairment and the Barthel index of functional ability in activities of daily living.
In addition to the usual best care for patients who have had a stroke, women in the trial received either oral estrogen (estradiol 17-beta at the standard replacement dose of 1 mg daily) or a matching placebo. Patients were studied for an average of 2.8 years. They stopped receiving the estrogen or placebo if they had a stroke.
The researchers found that there was no significant difference in the incidence of stroke or death in the women who were randomly assigned to receive estrogen instead of placebo. However, they found that the incidence of death due to stroke was higher in the estrogen group and that the non-fatal strokes in that group were associated with slightly worse neurological and functional impairments at 1 month after stroke.
The risk of stroke within the first 6 months after enrollment in the study was also higher among women in the estrogen group. There were no significant differences between treatment groups in the number of TIAs or non-fatal heart attacks. However, participants receiving estrogen were more likely to experience gynecologic complications, particularly vaginal bleeding.
While this is the first controlled clinical trial to evaluate estrogen for stroke prevention, the results are similar to findings from the Heart and Estrogen/Progestin Replacement Study (HERS), the first placebo-controlled randomized clinical trial of hormone replacement therapy for prevention of heart disease in postmenopausal women who had pre-existing heart disease.
The HERS results, published in 1998, showed that treating these women with a combination of estrogen and progestin did not reduce heart attacks or death from heart disease. That study also found no reduction in strokes among women who received the study drug.
Additional information about the benefits and risks of hormone replacement therapy is expected from the Women's Health Initiative (WHI), a long-term prospective study of more than 27,000 healthy postmenopausal women that is examining whether estrogen or an estrogen/progestin combination can help prevent heart disease. Results from the first 2 years of the WHI study suggest a small increase in the number of heart attacks, strokes, and blood clots in women receiving the hormone therapy.
While the WEST study provides important information about the use of estrogen in women with existing cerebrovascular disease, many questions remain to be answered, according to the investigators. They are planning additional analyses of their data to look at the effects of estrogen on cognition and physical function. The study results also may change researchers' understanding of how estrogen affects blood vessels and lead to new research in that area, says Dr. Horwitz.
The NINDS is a component of the National Institutes of Health in Bethesda, Maryland, and is the nation's primary supporter of biomedical research on the brain and nervous system. The Institute is celebrating its 50th anniversary this year.
*Viscoli, C. M.; Brass, L.M..; Kernan, W.N.; Sarrel, P.M.; Suissa, S.; Horwitz, R.I. "Estrogen Replacement after Ischemic Stroke: Report of the Women's Estrogen for Stroke Trial (WEST)." The New England Journal of Medicine, October 25, 2001, Vol. 345, No. 17, pp. 1243-1249.
This release will be posted on the NINDS website at http://www.