Hormone replacement study yields surprising cardiac conclusion
BY RUTHANN RICHTER
An unexpected finding has emerged from the first large-scale trial to examine the effects of hormone replacement therapy on women's cardiac outcomes. Postmenopausal women with known heart disease who took estrogen plus progestin did not decrease their risk of heart attack or coronary death compared with women who were not on hormone therapy, according to the results of the national, multicenter trial, in which Stanford researchers played a key role.
Contrary to researchers' expectations, the newly published data showed that the women on hormone therapy had a greater risk of heart attack in the first year of treatment than their untreated counterparts. By the third year of treatment, their risk was lower than that of the untreated women. When considered together, the earlier and later risk levels balanced out, so that the number of women who had heart attacks or died of heart-related causes over the four years of the study was roughly the same for those on hormone therapy and those not taking hormones, the researchers found.
"These results will force us to rethink our recommendations about the use of hormone replacement therapy for the management of heart disease," said William Haskell, a professor of medicine with the Stanford Center for Research in Disease Prevention and a principal investigator on the study.
In light of the new results, Haskell said, the researchers don't recommend that women start hormone replacement therapy specifically for the purpose of preventing heart attacks. However, women who are already taking estrogen plus progestin could decide to continue, given the apparent decrease in the risk of heart attack after several years of treatment, he said.
The findings of the study, known as HERS (Heart and Estrogen/progestin Replacement Study), were reported in the Aug. 19 Journal of the American Medical Association.
The study involved 2,763 women at 20 sites, including 153 women at Stanford. UCSF was the national coordinating site. Each of the women entering the randomized study had some evidence of heart disease, such as a previous heart attack, bypass surgery, angioplasty or coronary artery narrowing. The average age of the volunteers was 67. Half of the women received hormone replacement therapy, while the other half received an inert pill.
Observational studies, including some earlier studies conducted at Stanford, had led the researchers to expect that the women on hormone therapy would show some cardiac benefit. The controlled study did show an improvement in cholesterol levels among those in the treatment group. On average, blood levels of low-density lipoprotein cholesterol (the "bad" cholesterol) were 11 percent lower in treated women than in untreated women, while levels of high-density lipoprotein ("good") cholesterol were 10 percent higher in the treatment group.
At the same time, however, the study revealed that the women on hormone therapy had a 52 percent higher risk of suffering a heart attack during the first year of treatment. This risk, in relation to that of the untreated women, gradually decreased with time, so that by the fourth year, the women on therapy had a 33 percent lower risk than those not on treatment, said Dr. Mark Hlatky, professor and chair of health research and policy at Stanford, who served as the cardiologist for the Stanford clinical site and for the coordinating center at UCSF.
"I was certainly surprised by the result, which I thought would be positive, based on previous studies," Hlatky said.
"This is why it is so important to do controlled trials, because of these surprises. It's a distinct possibility that the reason there was an overall benefit is because there was an early risk, as well as a late benefit. We plan to follow the women longer to see if the late benefit becomes significant."
As expected, the women on hormone therapy had an increased risk of blood clots in the legs or lungs and a higher risk of gallbladder disease. These results fit with previous observational studies.
Hlatky said the researchers have speculated that the increased risk of blood clots may explain the initially high rate of heart attacks, since these clots may form in the blood vessels near the heart. It's also possible, he said, that it may take some time for the therapy's positive effects on cholesterol to translate into a protective effect on the heart.
In addition, said Haskell, previous observational studies suggesting heart benefits from hormone therapy may have been misleading because women who choose to go on the therapy may tend to be healthier to begin with and more likely to see their physicians regularly.
"Some of the difference we've seen in the observational studies may be due to selection bias that people who are on hormones have a generally healthier lifestyle and get more preventive care and hence have lower risk," Haskell said.
Hlatky noted that because all the women in the latest study had heart disease and were well beyond menopause when they began taking hormones, the results can't be extrapolated to younger, healthy women who are considering hormone replacement therapy.
"I think it would be very important to say that for women who don't have heart disease, who are going through menopause and making the decision about hormone therapy, this is not directly relevant to them because women in this study all had heart disease and on average were about 15 to 20 years older," Hlatky said.
It is important for women who are on hormone therapy or considering it to consult with their physicians and weigh all the pros and cons of hormone replacement, including postmenopausal symptoms, prevention of bone fractures and possible cancer risks, Haskell said. He noted that ongoing studies, including the federal Women's Health Initiative, are examining the effects of hormone therapy, including use of estrogen alone, on women who are younger and healthier than those in the HERS trial.
The HERS investigators will follow the women in their study for another two to four years to see if the trend toward a reduced heart attack risk continues with time, Haskell said.
Women who participated in the study at Stanford learned of the results at a meeting at Fairchild Auditorium on Aug. 18, the day before publication of the findings. Those who attended said they would support continued follow-up to further evaluate the risks and benefits of hormone replacement therapy, said Kathy Berra, the clinical trial coordinator at Stanford. "The HERS group is very committed to the advancement of knowledge in the care of postmenopausal women with heart disease," Berra said.
The study was sponsored by
Wyeth-Ayerst Research, an affiliate of American Home Products Corp.
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