A pill once vaunted to improve the health of post-menopausal women has turned out more bitter than sweet.
Because of findings strong enough to prompt its stoppage three years early, a major, nine-year-old clinical trial to evaluate the most commonly prescribed form of hormone-replacement therapy has shown that it boosts the risk of invasive breast cancer and other health problems.
The large, multi-site study - the first randomized prevention trial of its kind - is part of the Women's Health Initiative (WHI), whose 10-year-old clinical coordinating center and one of 40 clinical centers is housed in the Public Health Sciences Division at Met East.
Because of the results, leaders of the study are predicting that many women will stop using that form of HRT - a combination of the hormones estrogen and progestin, prescribed under the brand Prempro - for prevention of chronic disease.
Increases in heart disease
Besides invasive breast cancer, the researchers found increases in coronary heart disease, stroke and blood clots in study participants who took estrogen plus progestin compared to women taking placebo pills.
Noteworthy benefits of estrogen plus progestin, including fewer cases of hip fractures and colon cancer, did emerge from the study. But on balance, the harm was gauged as greater than the benefit.
The study, scheduled to run until 2005, was stopped this month after follow-up that averaged more than five years for each of the female participants.
The findings provide long-awaited answers to questions regarding the safety and effectiveness of the popular form of HRT, said Dr. Andrea LaCroix, co-principal investigator of the WHI clinical coordinating center.
'Solid information'
"We've watched one study after another saying what's good and bad about hormone replacement," she said. "We've been left with a lot of uncertainty. It's a delight when we finally reach the day when we have solid information and no longer have to wonder."
The report from WHI investigators on the study findings appeared in electronic form July 10 and in print on July 17 in The Journal of the American Medical Association.
The results showed that during one year, among 10,000 postmenopausal women with a uterus who are taking estrogen plus progestin, one can expect that eight more will have invasive breast cancer, seven more will have a heart attack, eight more will have a stroke, and 18 more will have blood clots, including eight with blood clots in the lungs, than will a similar group of 10,000 like women who are not taking these hormones.
Because these differences were not greater, the WHI researchers said women who participated in the trial and other women who have taken estrogen and progestin should not be unduly alarmed. But over the long term, they said, such risks can add up to tens of thousands of adverse events in the population, posing a serious public health issue.
Dr. Ross Prentice, principal investigator of the WHI Clinical Coordinating Center and PHS director, said the findings underscore the importance of such studies to address public-health issues that affect large segments of the population. About 6 million women in the United States take estrogen plus progestin for a variety of reasons, including menopausal-symptom relief and long-term prevention of heart disease and osteoporosis.
"This emphasizes the clear role for randomized trials to evaluate the safety and effectiveness of such interventions," he said. "The likely implication is that women will stop using - and physicians will stop prescribing - this therapy to prevent chronic disease."
'Women should talk to their doctors'
The center's Dr. Shirley Beresford, principal investigator of the WHI Seattle clinical center, agreed.
"This is a very important finding, and it's likely to change the way that providers think about prescribing medication for post-menopausal patients," said Beresford, also a professor of epidemiology at the University of Washington. "Women who are taking hormone replacement should talk to their doctors about these results. Only a doctor knows the health history of an individual woman, but many probably will stop taking this combination."
The decision to halt the estrogen-plus-progestin arm of the study was made by the National Heart, Lung and Blood Institute of the National Institutes of Health, the agency that funds the WHI, following a data review by an independent advisory committee charged with monitoring the results of the trial.
"Throughout the estrogen-plus-progestin trial, we placed a high priority on monitoring and maintaining participant safety, as well as on ensuring that all WHI participants were well informed about any potential risks associated with the study," said the center's Dr. Garnet Anderson, co-principal investigator of the WHI Clinical Coordinating Center and the biostatistician who led the analysis. "The trial was stopped at the first clear indication of overall increased risk."
She also noted that, at this point, there is no indication of increased risk for breast cancer for the estrogen-only WHI prevention trial.
The estrogen-plus-progestin trial involved 16,608 women age 50 to 79 years with an intact uterus. An important objective was to examine the effect of estrogen plus progestin on the prevention of heart disease and hip fractures, and any associated change in risk for breast and colon cancer. The study did not address the short-term risks and benefits of hormones for the treatment of menopausal symptoms.
Women enrolled in the estrogen-plus-progestin study were randomly assigned to a daily dose of estrogen plus progestin or to a placebo. Participants were enrolled in the study between 1993 and 1998 at 40 clinical sites across the country.
Insufficient magnitude of benefits
There were some benefits to the use of estrogen plus progestin - women on these hormones had fewer hip fractures and colon cancers - but the magnitude of these benefits was not sufficient to overcome the accumulated risks observed for other diseases.
In 2000 and again in 2001, WHI investigators complied with a recommendation from the study's Data and Safety Monitoring Board to inform participants of a small increase in heart attacks, strokes and blood clots in women taking hormones. The board, an independent advisory committee charged with reviewing results and ensuring participant safety, found that the actual number of women having any one of these events was small and therefore did not cross the statistical boundary established to ensure participant safety. As a result, the group recommended continuing the trial due to the still-uncertain balance of risks and benefits.
Anderson said during its May 31 meeting, the board reviewed WHI data through February 2002.
"At that time, with an average of five years of participant follow-up, the increased risk for heart disease, strokes and blood clots was still apparent," she said. "The (board) also discovered for the first time that breast-cancer rates were markedly increased among women assigned to the estrogen plus progestin group.
"Because this effect emerged suddenly, we wanted to be sure that it was not a random or temporary fluke in the data. We looked at additional data accumulated through April 30 and found that the picture had not changed. Compared to women on placebo, more women on estrogen plus progestin had been diagnosed with coronary heart disease, stroke, blood clots and breast cancer."
Unanimous recommendation
Based on these results, the board concluded that estrogen plus progestin produced harmful effects on women's health that exceeded the benefits generated by these hormones and unanimously recommended to the National Heart, Lung and Blood Institute that the study be stopped.
On July 8, participants began receiving letters informing them about the results and telling them that they should stop study medications. Participants will be contacted by their clinical centers for further counseling and will be asked to continue to provide information during clinic visits so that their health outcomes can be followed.
In addition, all WHI participants, including those in other study components, are receiving a newsletter with a summary of the findings and an explanation of risks and benefits.
Beresford said participants in the estrogen-plus-progestin study have not expressed alarm.
"They've clearly played a historic role in answering this very important question, since observational studies were not conclusive and in some cases were misleading," she said. "This is exactly why trials like this are necessary."
What the study found about HRT
Specific study findings for the estrogen-plus-progestin group compared to placebo include:
- A 41 percent increase (from .21 percent of participants to .29 percent) in strokes.
- A 29 percent increase (from .30 percent of participants to .37 percent) in heart attacks.
- A 111 percent increase (from .16 percent of participants to .34 percent) in venous thromboembolism (blood clots).
- A 22 percent increase (from 1.34 percent of participants to 1.57 percent) in total cardiovascular disease.
- A 26 percent increase (from .30 percent of participants to .38 percent) in breast cancer.
- A 37 percent reduction (from .16 percent of participants to .10 percent) in cases of colorectal cancer.
- A 33 percent reduction (from .15 percent of participants to .10 percent) in hip fractures.
- A 24 percent reduction (from 1.91 percent of participants to 1.47 percent) in total fractures.
- Virtually no difference (from .53 percent of participants to .52 percent) in total mortality (of all causes).
How do the study results translate to numbers of women?
The results showed that during one year, among 10,000 postmenopausal women with a uterus who are taking estrogen plus progestin, eight more will have invasive breast cancer, seven more will have a heart attack, eight more will have a stroke, and 18 more will have blood clots, including eight with blood clots in the lungs, than will a similar group of 10,000 like women who are not taking these hormones.
