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Hormone Replacement Gets New Scrutiny

Finding of Increased Risks Prompts Federal Effort



By Marc Kaufman

Washington Post Staff Writer

Wednesday, August 14, 2002; Page A01



Federal officials announced yesterday that they have begun a major reassessment of the risks and benefits of all combination hormone products containing estrogen used by post-menopausal women, one month after a large government study found potentially serious side effects from hormone replacement therapy.


The federal effort could change how popular drugs such as Prempro are advertised, prescribed and used, with new recommendations about who should take them, at what dosages and for how long.


The initiative, which will include several public forums this fall sponsored by the National Institutes of Health, the Food and Drug Administration and the Agency for Healthcare Research and Quality, will also try to guide future research on the suddenly more complex and controversial subject.


The move marks the first significant action by the federal government in response to the latest findings about hormone therapy. It is designed to address the widespread confusion that has caused anxious women to inundate doctors with questions about whether they should continue taking the powerful hormones.


"Somebody needed to take a leadership role, because there is chaos in the medical societies," said Wulf H. Utian, executive director of the North American Menopause Society, who has been invited to participate in the meetings. "It's time to clear the air and address the issues."


The brief announcement of the initiative came as the FDA separately pushed for immediate changes in the label and the package insert for the hormone combination sold as Prempro to reflect the risks confirmed by the Women's Health Initiative (WHI).


Part of that federally funded study was stopped three years early because of small but statistically significant increases in heart disease, breast cancer, stroke and blood clots among women taking Prempro, a combined estrogen-progestin drug. While the study used only Prempro, agency officials said they have new questions about other estrogen-progestin products on the market, as well.


In response to the immediate FDA concerns, officials at Wyeth Pharmaceuticals, maker of Prempro, said the company expects to submit new safety precaution information as early as this week that will take into account the WHI findings. The WHI study was testing the widely held hypothesis that hormone therapy reduced the risk for heart disease in particular and, so, was especially surprising.


"The FDA says it is our responsibility to get new information out there, and we agree," said Bruce Burlington, Wyeth's vice president for regulatory compliance. He said that many of the WHI findings on increased risks to women were already known and incorporated into the Prempro label but that "the risks were better quantified in WHI."


These initial steps can be taken without formal FDA approval. But officials said that they are aggressively reviewing hormone replacement therapy generally -- now used by 14 million menopausal and post-menopausal American women -- and that more wide-ranging changes can be expected.


As part of the effort, federal officials want to explore whether hormone therapies and their producers have encouraged women to believe menopause is a condition to be treated, rather than an inevitable and natural set of changes to be managed. The hormone therapy issue is being actively debated within medical societies, too, with the American College of Obstetricians and Gynecologists, the North American Menopause Society and others forming task forces on hormone replacement in response to the WHI findings.


Reflecting the FDA's discomfort with the way that hormone treatments have been widely presented as an antidote to menopause, the agency has told Wyeth to remove all references to "hormone replacement therapy" from its Prempro label. The "replacement" model, officials said, has never been accepted by the agency, which approved Prempro for specific symptoms of menopause and to prevent osteoporosis, a reduction in bone mass.


"The impact of the WHI findings [is] very far-reaching, and that fact is not lost on the FDA," said Florence Houn, a director at the FDA's Center for Drug Evaluation and Research. "As a public health agency, we need to step to the plate and reassess the risk-benefit conditions for labeling and risk management for patients."


Estrogen products have been used for decades and have helped millions of women handle the sometimes-severe symptoms of menopause, including hot flashes, night sweats, sexual discomfort and the increased risk of bone fractures.


For years, studies on heart disease, Alzheimer's, colon cancer and bone fractures also showed potential benefits to women taking hormone replacement long-term, and those findings were widely embraced by doctors and advertised by the drugmakers. The earlier positive findings on estrogen and heart disease, for instance, were considered strong enough by the American Heart Association to be included in its literature for women as recently as 1997.


But studies in the past several years began to raise doubts about the benefits and risks from long-term hormone therapy, and the large WHI study concluded that hormone therapy actually increased the risk of heart disease. That finding has required a quick pivot by medical authorities, individual doctors and, now, federal officials.


Further complicating the picture, the WHI study found that hormone therapy did help protect women against colon cancer and hip fractures. In addition, another arm of the WHI study did not find cardiovascular and cancer dangers with estrogen treatment alone (as opposed to the estrogen-progestin combination) when it was used by women who have had hysterectomies. That part of the study was allowed to continue.


The FDA expects to hold an expert advisory meeting this fall or winter to make recommendations about how hormone therapies should be used. Among the issues to be addressed are whether hormone treatment should be limited to several years, whether all hormone combinations containing estrogen carry the same risks, and whether estrogen-combination products require the kind of more prominent black box warnings that are used for drugs with potentially fatal side effects.


Although the WHI study did not find an increase in deaths from breast cancer, heart disease or stroke before it was stopped, the study did conclude that Prempro was associated with a greater risk of those diseases.


"Ultimately, the label that does get full FDA approval may well look quite different from what the company feels is needed for immediate strengthening," Houn said.


The FDA-approved label for a drug is key to how it is advertised, prescribed and used by patients. While doctors can write prescriptions off-label, companies can advertise to consumers and doctors only the uses approved by the FDA, and they must convey the side effects deemed serious by the agency.


Wyeth officials said that since the WHI study was discontinued, they have stopped direct-to-consumer advertising about hormone replacement but increased visits to doctors to explain the results.



? 2002 The Washington Post Company

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  • Chief Cushie

Government Offers Hormone Caution


.c The Associated Press


WASHINGTON (AP) - Women should not use estrogen and progestin supplements in hopes of preventing bone loss or other chronic ailments, the government said Tuesday.


Federal scientists broke the news in July that long-term use of the combination hormone therapy significantly increased women's risk of breast cancer, heart attacks and strokes.


The news caused dismay and confusion for millions of American women. Many used the combination not just in hopes of long-term health but to relieve short-term menopausal symptoms such as hot flashes and night sweats, and wondered how long they could safely use hormones for that purpose.


Now the independent panel charged by the U.S. government to set the nation's disease-prevention guidelines has weighed in, with recommendations not likely to settle the confusion.


The clear risks of routine estrogen-and-progestin use outweigh the few long-term benefits, such as bone strength, the U.S. Preventive Services Task Force said Tuesday. But when it comes to menopause symptom relief, the panel urged women to discuss their personal disease risks with their health provider in choosing whether to try hormones.


For example, most discussion of hormone therapy's risks has centered on long-term use, yet the risk of heart attack actually rises in the first year women swallow the pills, said task force co-chairwoman Dr. Janet Allan. A woman with high cholesterol or high blood pressure might make a different decision on using hormones for hot flashes than a healthier woman would.


"This is tough for women," Allan acknowledged.


The task force last examined hormone therapy in 1996, calling the evidence too paltry to decide if women should use it. But doctors' and patients' enthusiasm for hormones overrode that cautionary note, and an estimated 6 million women were taking the estrogen-progestin combination when the National Institutes of Health announced the bad news in July.


Millions more are thought to be taking estrogen alone, something reserved for women who have had their uterus removed. The task force said there's not enough evidence to know yet if estrogen-only therapy is any safer than combination therapy; a study of that question is continuing.




10/15/02 18:20 EDT

Copyright 2002 The Associated Press.

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Doubts Grow About Post-Menopausal Hormone Use

At NIH Conference, Emerging Skepticism That Combination Therapy Should Be Used to Prevent Disease



By David Brown

Washington Post Staff Writer

Sunday, October 27, 2002; Page A12



Three months after the unexpected end of a huge study of postmenopausal hormone use, a consensus is emerging that there is essentially no use for the drugs in the prevention of chronic ailments that come with age.


Although the hormones have both good and bad effects -- raising the risk for heart attack, breast cancer and blood clots while lowering it for osteoporosis and colon cancer -- their net effect is harmful in terms of disease prevention. They still have a role in the treatment of symptoms of menopause. But how large a role is a matter of dispute.


Those were among the conclusions that emerged from a two-day meeting held this week at the National Institutes of Health. The gathering was called to assess the immediate consequences of the hormone study results and talk about what new research may be needed.


"For the community of practitioners, the clear message is: If you're using hormones, try to limit it to short-term treatment for symptoms. It's not a prescription for life -- and that's a big, big change," said Florence Comite, a physician and founder of the women's clinic at Yale University, and one of about 500 medical researchers, clinicians and regulatory officials who attended.


When the results from the Women's Health Initiative hormone trial were released in early July, Comite had more than 100 patients taking combinations of estrogen and progestin, the two hormones that were studied. About one-third have stopped. "I think the dust has settled to some degree," she said.


Ronald K. Ross, a preventive medicine physician at the University of Southern California said he believes there is less confusion in the scientific community about the study results than the public might think. "Combination treatment [for disease prevention] is certainly out of the question," he said, summing it up.


Agreement on the study's implications, however, is far from universal.


Some people at the NIH workshop argued that hormone preparations different from those used in the study might have given different results. Some believe that the long-imagined cardiovascular benefit would have been seen if younger women had been enrolled, and if they'd started taking hormones as soon as they entered menopause. Some people think lower doses of the medicines won't cause harm. There was much talk about "individualizing" therapy for each woman -- a concept that appears to leave much room for the liberal prescription of hormones for long-term use.


"Is there a role for hormone therapy in prevention? Absolutely," said Frederick Naftolin, an obstetrician-gynecologist who is also affiliated with Yale. "Preventing bone loss, preserving skin, possibly in dementia. And I'm still not convinced there is no role in [preventing] cardiovascular disease."


This view appeared to be a distinct minority. A number of experts -- and authority figures -- went out of their way to say it was also an incorrect interpretation of study's results.


"It is clear that this combination hormone therapy should not be generally used for prevention purposes of chronic diseases," NIH's director, Elias A. Zerhouni, said in a statement published at the end of the workshop. Asked if this means that prescribing estrogen and progestin to a woman without symptoms is bad practice, he said: "Yes, it is bad practice."


Marcia L. Stefanick, a physiologist at Stanford University and one of the chief architects of the study, said she believes there is a real hazard in trying to find exceptions to the main findings.


"To say that the risks don't exceed the benefits -- unless you are focusing on menopausal symptoms -- is simply wrong," she said.


In what is probably the closest to an official position on the issue, the United States Preventive Services Task Force -- which provides advice to the Department of Health and Human Services -- next month will publish a guideline that "recommends against" combination hormone use for the prevention of disease in women.


In the mid-1980s, about 40 percent of postmenopausal women in America took hormone replacements at least for a while. The fraction who do today is unknown, although it is in the millions.


The main reason estrogen and progestin combinations are prescribed is to relieve hot flashes and other symptoms of menopause. The Women's Health Initiative study didn't examine that use -- or the benefit gained from the medicines' near-certain ability to relieve those symptoms. Instead, it looked at the claims that hormones, taken for years or decades, prevent disease, heart disease in particular.


The study randomly assigned nearly 17,000 women to take either a placebo or an estrogen-and-progestin combination. The participants' average age was 63, meaning that most were more than a decade beyond menopause, which occurs on average at age 51 in the United States.


Although designed to last eight years, the study was stopped after a little more than five because it was clear that the major anticipated benefit -- fewer heart attacks in hormone takers -- wasn't occurring. In fact, there were more heart attacks in women assigned to the drugs.


(A study of about 11,000 women who have had a hysterectomy -- the surgical removal of the uterus -- is continuing. They are assigned to take estrogen alone or a placebo. None is taking progestin.)


In the entire group, the number of bad events was small, and the absolute risk for any individual woman very low.


For example, at the rates seen over the course of the study, hormone use will cause an extra heart attack each year in about 1 in every 1,100 women taking the medicines; an extra stroke in 1 in 1,200; an extra blood clot of a serious nature in 1 in 600; and an extra case of breast cancer in 1 in 1,300. At the same time, hormone use will protect 1 in about every 2,000 women from a hip fracture she would otherwise have suffered; and 1 in 1,700 from a case of colon cancer.


A calculation presented at the meeting by Deborah Grady, a physician and epidemiologist at the University of California in San Francisco, suggested that given those numbers, essentially nobody is likely to benefit from preventive use of hormones.


For example, if women with family histories of colon cancer (which doubles their own risk) take hormones, the net effect still tips toward harm, with 1 in 700 users suffering an additional one of the bad events. For women with osteoporosis, it's 1 in 650. Only in women with osteoporosis who have already suffered a fracture do the risks and benefits balance out, according to Grady's calculation. But for them, she argued, there are many lower-risk interventions, such as exercise, smoking cessation, calcium and vitamin D supplements, and the anti-osteoporosis drugs called bisphosphonates.


Further analysis of the data is underway. But the investigators said the main trends were seen in all age groups and races, and that no subpopulations appear to benefit.


For example, for cardiovascular events (heart attack, stroke, clots) the risk was increased 67 percent in the youngest group of hormone users, those age 50 to 59 at the start of the study. For women 60 to 69, it was up 26 percent, and for the oldest women, those 70 to 79, it was up 18 percent. Breast cancer risk was up 23 percent, 22 percent and 42 percent, respectively, in those three age groups.


The potential wild card in hormone use is dementia.


Studies have shown that women with Alzheimer's disease are less likely to have taken hormones than women without Alzheimer's. That observation, however, doesn't mean hormones protected them. Only a randomized, controlled trial could determine that.


A subgroup of elderly women in the Women's Health Initiative study is being observed for the development of dementia. There is also a trial of two estrogenlike compounds (tamoxifen and raloxifene) underway.


A recent trial of estrogen in women who already have Alzheimer's found the hormone didn't help. However, if it turned out there was a preventive effect, that benefit might swamp the harms.


For example, out of 10,000 women who are older than 65 and have a close relative with Alzheimer's, 500 every year will develop dementia. That's far, far more than the 20 additional bad events per 10,000 women per year seen in the hormone users in the Women's Health Initiative study.



? 2002 The Washington Post Company

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