Combination hormone therapy raises women's stroke risk

February 14, 2003

PHOENIX, Feb. 14. - Combined hormone replacement therapy (HRT) increased the risk of stroke for postmenopausal women of all ages, whether or not they had hypertension. Researchers reported these findings, which are based on women studied in the Women's Health Initiative, today at the American Stroke Association's 28th International Stroke Conference. The American Stroke Association is a division of the American Heart Association.

Information on subgroup analysis by age, race, hypertension status and baseline risk were not detailed when this major hormone study was halted last summer.

"Estrogen plus progestin increased the risk of stroke in older and younger postmenopausal women, in those with and without high blood pressure and in those with no prior history of cardiovascular disease (CVD). Our finding is that this is absolutely not a strategy for primary prevention of cardiovascular disease," says Sylvia Wassertheil-Smoller, Ph.D., professor of epidemiology and social medicine and head of the division of epidemiology and biostatistics at Albert Einstein College of Medicine in New York.

Smoller is a principal investigator of the Women's Health Initiative (WHI), a multi-part study that enrolled more than 160,000 post menopausal women at 40 U.S. medical centers between 1993 and 1998. The randomized controlled primary prevention trial of combined hormone therapy included 16,608 women. The WHI included two strategies of hormone replacement therapy: estrogen alone in postmenopausal women without a uterus and combined therapy of estrogen plus progestin in those with a uterus. Progestin was used in addition to estrogen therapy for those with a uterus to lessen the increased risk of cancer in the lining of the uterus that's associated with using estrogen alone.

In the summer of 2002, researchers ended the estrogen-plus-progestin trial early because, after 5.2 years of the planned 8.5 years of follow-up, health risks seemed to exceed benefits in healthy women.

Using results from the halted WHI trial and other recent trials, the American Heart Association advised physicians to avoid prescribing combination HRT solely to prevent CVD.

"These results fill a critical gap in our knowledge about stroke risk and hormone replacement therapy," says Lawrence Brass, M.D., professor of neurology at Yale University Medical Center in New Haven, Conn. and a member of the American Heart Association's Stroke Council executive committee. "Not only do these findings demonstrate that the combination therapy tested is not effective for primary prevention of stroke and ischemic heart disease, it also allows for women and their physicians to make a more informed decision about risk and benefit when hormone replacement therapy is considered for other conditions."

The current study is a subanalysis of the 8,506 women ages 50-79 who received the combined hormone therapy and 8,102 women in the same age range on placebo. Overall, there were 133 strokes in the treatment group, compared to 93 in the placebo group.

The increased risk of stroke associated with estrogen plus progestin therapy extended across age groups: estrogen plus progestin conferred a 70 percent higher risk in women ages 50-59 compared to placebo controls in that age group, and a 26 percent higher risk in those between ages 70 and 79 compared to the same age group controls, (although this difference was not statistically significant).

The adverse effect of the combination hormones on stroke risk was apparent both in women with high blood pressure and in those without hypertension who had still had a 28 percent higher risk than did the placebo controls. The increased risk associated with the hormone combination was found in women who had no prior history of heart or blood vessel disease; these women had a 40 percent higher risk of stroke on estrogen progestin than did similarly healthy women on placebo, she says.

"We were astonished," Smoller says in describing the findings. "It really shows that things that are 'accepted wisdom' really can be quite turned around by clinical trials."

Earlier observational studies showed that women who took hormone replacement therapy after menopause had less heart and blood vessel disease. However, these looked at women already taking hormones and compared them to those who were not. Observational studies are open to selection bias. For instance, healthier women might have been more likely to be taking hormones.

WHI is a prospective trial and a more expensive but scientifically more rigorous study design in which subjects volunteer for a study and then they are randomly assigned to the therapy or non-therapy arms and followed over time, she says. The randomization avoids the selection bias that occurs in observational studies.

"We've absolutely resolved some important questions, but there are many questions that still need resolving, such as: what is the mechanism by which estrogen plus progestin increases cardiovascular risk? We are in fact addressing that question by looking at blood biomarkers and genetic factors," she says.
Co-authors are Susan Hendrix, D.O.; Gerardo Heiss, M.D., Ph.D.; and Marian Limacher, M.D. The National Heart, Lung, and Blood Institute funded the WHI. Wyeth-Ayerst Research provided the study medication. Abstract 36
(This news release contains updated data from the abstract)

For information Feb.13 - 15 call:
Carole Bullock or Bridgette McNeill
at the Phoenix Civic Plaza
(602) 514-7881

American Heart Association

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