Estrogen–progestin Replacement Does Not Increase Stroke Risk

Researchers with the Heart & Estrogen–progestin Replacement Study (HERS) found that the hormone therapy did not significantly increase or decrease the risk of stroke or transient ischemic attacks (TIAs), sometimes called “ministrokes,” in women who received it.

“HERS is the first clinical trial of postmenopausal hormone therapy to examine whether such therapy affects the risk of TIAs and stroke. The bottom line is that the decision to use or not use hormone therapy should be based on its known risks and benefits, and not on any presumed effect on stroke risk,” says Joel A. Simon, M.D., the paper’s lead author and a scientist at the University of California, San Francisco, as well as a physician at the Veterans Affairs Medical Center.

An editorial in today’s Circulation calls the findings “surprising” when one considers the well-documented role of estrogen as a vasoprotectant, and that hormone replacement therapy is known to reduce various fats in the blood. Also, animal studies have suggested that estrogen can protect against strokes, say Todd Tolbert, M.D., and Suzanne Oparil, M.D., of the University of Alabama at Birmingham, the editorial’s authors.

Stroke is a leading cause of death and disability, particularly among older women, many of whom use the estrogen–progestin combination to treat the symptoms of menopause and for the prevention of osteoporosis.

Previous studies that assessed the therapy’s stroke risk had yielded mixed results. Some showed a benefit, some found no benefit, and the highly regarded Framingham Heart Study suggested an increased risk of stroke, at least among cigarette smokers. None of these studies, however, was a randomized, controlled clinical trial.

The HERS trial was primarily designed to examine whether the estrogen–progestin combination would prevent a recurrent heart attack or hospitalization for unstable (worsening) angina in postmenopausal women with heart disease. However, HERS also included a number of secondary goals, one of which was to determine the therapy’s impact on stroke and TIAs.

In 1993 and 1994, researchers enrolled 2,763 postmenopausal women with known heart disease in the HERS trial, which was conducted at 20 medical centers across the United States. Half the women received the estrogen–progestin combination and half took a placebo.

The women were followed for an average of 4.1 years and the heart results were reported in 1998.

“The overall heart attack findings were that postmenopausal hormone therapy caused an increase in coronary events during the first year of the study and then subsequent decreases, so that when the study ended, there was no difference between the two groups,” Simon says.

The stroke study found that 149 of the HERS participants suffered a total of 165 strokes, of which 26 were fatal. Eighty-five percent were ischemic strokes, caused by a blockage in a carotid artery, which carries blood to the brain; 8 percent were hemorrhagic strokes, which result from a bleeding or burst blood vessel. Researchers could not determine the type of stroke in the remaining participants.

After analyzing the data, the HERS team found that the estrogen–progestin therapy did not significantly increase or decrease the risk of strokes or TIAs. Nor did the therapy affect the risk of either ischemic or hemorrhagic strokes when examined separately.

By the end of HERS, 7 percent of the women on the hormone therapy suffered a stroke compared to 5 percent of those receiving a placebo. “That was not a statistically significant difference, and could have resulted from chance,” Simon says.

He cautions that the HERS findings may not apply to women taking estrogen without progestin or to postmenopausal women taking the combination therapy who do not have heart disease. The HERS team also looked at the risk factors for stroke and found an increased risk of stroke with older age, high blood pressure, diabetes, current cigarette smoking, and a form of irregular heart beat called atrial fibrillation.

The researchers continue to follow the women who participated in HERS as part of what is known as HERS II. “We have another two to three years of observations,” Simon says. “We should be able to update this paper in another year or so to see whether these findings have changed.”

Co-authors are Judith Hsia, M.D.; Jane A. Cauley, Dr.P.H.; Cynthia Richards, M.D.; Fran Harris, M.S.; Josephine Fong, M.S.; Elizabeth Barrett-Connor, M.D.; and Stephen B. Hulley, M.D.