Citing a Risk of Strokes, U.S. Stops Estrogen Study Early
The last major component of a landmark clinical trial investigating the effects of hormone replacement therapy for women has been terminated a year early because of a slightly increased risk of strokes, the National Institutes of Health announced Tuesday.
The trial -- part of the federally funded Women’s Health Initiative -- also showed that taking estrogen alone did not lower the risk of heart attacks. This was a primary reason for the trial in the first place, said Dr. Barbara Alving, director of the Women’s Health Initiative at the NIH.
The announcement was more discouraging news for long-term hormone replacement therapy. It follows the abrupt termination in 2002 of a larger segment of the Women’s Health Initiative in which 16,608 women took both estrogen and a second hormone, progestin.
The estrogen-plus-progestin trial was halted three years early after the trial’s safety monitoring board concluded that taking the two drugs conferred more risk than benefit.
The hormone combination slightly raised risks for strokes, blood clots, breast cancer and heart attacks, while slightly lowering the risk of fractures and colorectal cancer.
The estrogen-only trial studied 11,000 women who had undergone hysterectomies, and thus did not need to take progestin -- a hormone that protects against estrogen-induced uterine cancer.
The trial found fewer risks for women who took only estrogen, and the safety board was split over what to advise. Rates of breast cancer and heart disease were not detectably raised over the average of seven years that women took the hormones. Fracture rates were slightly reduced.
However, in addition to more strokes, preliminary data suggested that the risk for dementia and the deterioration of cognitive abilities was slightly raised in women taking estrogen compared with those taking a placebo.
Precise numbers were not released, but the NIH said that the stroke risk was similar to that found in the estrogen-progestin trial, which was an additional eight cases of stroke per 10,000 women each year.
Experts said that the new findings, which will be published in detail within two months, further weakened the rationale for hormone replacement therapy except for a limited time around menopause to treat acute symptoms such as hot flashes, or as a last-resort treatment for serious bone loss.
But they noted that the risks are slight, and that women could take their time and consult with their doctors before deciding what to do.
“Hormone replacement, including either estrogen and estrogen plus progestin, still has a place in the treatment of symptoms,” said Dr. Diana Petitti, director of research for Kaiser Permanente Southern California. “But as a global preventive agent, as an agent for preventing coronary heart disease, I think both drugs are on terminal life support.”
Some doctors disagree. Dr. Dan Mishell, professor and chair of obstetrics and gynecology at USC’s Keck School of Medicine, said that the estrogen-only findings should be considered good news, not bad, because breast cancer rates did not rise.
Women should still consider long-term estrogen therapy to help prevent fractures, he added, because estrogen is effective, relatively cheap and has fewer side effects than other bone-building drugs.
“Fractures are a big problem, one of the main reasons that women end up in nursing homes,” he said.
The Women’s Heath Initiative hormone trials began in the early 1990s to settle roiling debates about the risks and benefits of hormone therapy.
Based on previous studies, physicians were encouraging patients to take the hormones for the long haul after menopause to reduce their risk of heart disease and osteoporosis.
But some scientists believed the therapy’s benefits to the heart had not been properly proven and pushed for a large-scale clinical trial in which women would receive either hormones or a placebo.
Many scientists and doctors were shocked when the estrogen-plus-progestin portion of the Women’s Health Initiative failed to show any benefit to the heart. However, some held out hope that taking estrogen without progestin would be protective.
“This is just an example of how we have to be careful about letting things become ‘standard of care’ without data to support it,” said Dr. Susan Love, clinical professor of surgery at UCLA and an outspoken critic of long-term hormone therapy.
Dr. Elizabeth Barrett-Connor, professor in the department of family and preventive medicine at UC San Diego and a member of the study’s safety board, said she understood why the NIH decided to terminate the trial early.
However, she said she would have preferred the trial to run to completion to avoid the “rumors and second guessing” that an early termination could ignite. Another year of study also would have allowed researchers to glean the maximum possible data on the effect of estrogen on breast cancer.
In epidemiological studies, breast cancer risks often have not been detectable before five years or more have passed.
Dr. Howard Judd, principal investigator of the UCLA site of the Women’s Health Initiative, said: “We wanted it to be absolutely conclusive; no ifs, ands or buts.”
Alving, director of the Women’s Health Initiative, said that the NIH decided that little additional information would be gathered in the study’s remaining year and that the stroke risk was unacceptable for a trial of healthy women.
Other Women’s Health Initiative trials examining the health effects of low-fat diets, vitamin D and calcium supplements and other lifestyle patterns are continuing.
