U.S. Scientists Abruptly End Key Hormone-Therapy Study

By THOMAS M. BURTON, Staff Reporter of THE WALL STREET JOURNAL
July 10, 2002

In a dramatic move certain to inflame the long-running debate over hormone-replacement therapy, researchers halted a government-run study of a hormone pill taken by millions of older women. Long-term use of the pill increases the risk of coronary heart disease, invasive breast cancer, strokes and blood clots in the lungs, the researchers said.

The action, which involved Prempro, a popular combined estrogen/progestin pill produced by Wyeth, is likely to change how menopausal women and their doctors approach medical decisions related to aging.

The findings come less than two weeks after published research showed that estrogen alone -- often sold under Wyeth's brand name Premarin -- didn't help protect older women heart patients from further heart disease.

Women have used such drugs for half a century, assured that the medicines provided protection against heart disease and osteoporosis in addition to treating the symptoms of menopause.

"I think this is the end of the standard practice of prescribing hormones for long-term disease prevention," says Jennifer Hays, director of the Baylor College of Medicine's center for women's health in Houston, who participated in the study. The study did find that Prempro reduced the incidence of osteoporosis and colorectal cancer, but the dangers were found to outweigh these benefits.

The findings pose a dilemma for the many women who have depended on the pills to treat sometimes-severe menopausal symptoms such as hot flashes, night sweats and vaginal dryness. Should they still take these drugs, and for how long?

"There are some women who really are miserable -- who can't sleep because of hot flashes," says University of Chicago endocrinologist Murray J. Favus. "For them it's a tough call." And many doctors are so accustomed to prescribing estrogen that even this devastating study could simply lead them to modify their prescribing of estrogen, not stop it. Dr. Hays, for instance, says she has already heard of doctors "talking creatively" about simply monitoring patients more closely while giving them estrogen.

Leon Speroff of Oregon Health and Science University in Portland, an author and proponent of estrogen, doubts that the negative cardiac findings really apply to all postmenopausal women.

In my view, the results do not justify a definitive conclusion" that combined therapy doesn't benefit the heart, he says. He suggests that the age of the study participants -- and the probability that they already had atherosclerosis, in which blood vessels are blocked by fatty plaque -- would likely diminish hormone therapy's beneficial effects on the heart.

Norman A. Ginsberg, an obstetrician-gynecologist in Chicago, stresses that "people should keep in perspective that these findings represent a small incremental risk. And I am sure that there will be staunch supporters still. There are lots of conflicting data in this study. "

Lorraine Fitzpatrick, professor of medicine at the Mayo Clinic in Rochester, Minn., sees another potential benefit for estrogen: "I do think there are strong suggestions there may be some benefit in cognition from estrogen." She cites examples of Alzheimer's patients who seem better able to take care of themselves while taking the drug. Dr. Fitzpatrick notes there still need to be clinical studies of this premise, though.

As at many doctors' offices, her patients are frantic with the latest news. "Patients are getting so much information that it's hard for them to sort it out," she says. "Our phones have just been ringing off the hook."

There are, of course, alternatives to the pills, including estrogen/progestin patches, which researchers speculate may be safer. But there is a great void of knowledge about precisely how safe, and how useful, the alternatives are.

How individual women respond to the news may depend on why they were interested in taking estrogen, or estrogen/progestin, in the first place. If severe menopausal symptoms cause insomnia or great discomfort during sex, a woman may still want to take estrogen, but perhaps through a topical cream or vaginal ring that would be less likely to have a powerful systemic effect.

"You should start with the least risky intervention," says Dr. Hays. For instance, she says, some women can control hot flashes by avoiding alcohol, caffeine and spicy foods.

If osteoporosis and bone fractures are the main concern, other drugs such as Merck & Co.'s Fosamax and Eli Lilly & Co.'s Evista are options, and Evista has even been shown to lower the rate of breast cancer, though it isn't approved for that use. If heart disease is the main worry, there are a range of effective drugs, including statin medications, the class of cholesterol drugs that includes Pfizer Inc.'s Lipitor and Merck's Zocor.

Research on the combination-hormone drug had been scheduled to continue until 2005. But a safety monitoring board ended the study abruptly on May 31.
"Overall health risks exceeded benefits from the use of combined estrogen plus progestin," the researchers wrote in an article to be published in the Journal of the American Medical Association next week and now posted on JAMA's Web site. The researchers concluded, "The risk-benefit profile found in this trial is not consistent with the requirements for a viable intervention for primary prevention of chronic diseases."

The belief that the pills improved long-term health was based partly on huge epidemiological studies, including one involving Harvard nurses, that seemed to show, for example, cardiac benefits from estrogen.

But epidemiology -- looking at huge populations and asking retrospectively about their habits -- is an imprecise science. It's now believed that nurses on estrogen may have had better health because they were informed and motivated, adopting salutary diets and lifestyles. Once better studies were conducted, with patients randomly assigned to a drug or a placebo, the purported benefits vanished and dangers began to appear.

Prempro is used by about six million women and generates about $948 million in annual U.S. sales, says NDC Health, a medical data-gathering service. Victoria Kusiak, Wyeth's vice president of global medical affairs, says, "About 85% of women going through menopause have symptoms, and that is the No. 1 reason women take these drugs." But Wyeth adds that it isn't challenging the study's findings about the long-term risks of the drugs.

Women taking Prempro had a higher risk of some diseases, and a lower risk of others, than those taking a placebo.

The study followed 16,608 women for 5.2 years:

Disease Percentage change Total cases
Breast cancer 26% increase 290
Colorectal cancer 37% decrease 112
Heart attack & cardiac death 29% increase 286
Hip fracture 34% decrease 106
Pulmonary embolism 113% increase 101
Stroke 41% increase 212

Source: Women's Health Initiative, JAMA

The study, called the Women's Health Initiative and run by the National Institutes of Health, involved 16,608 women. Compared with a group of women taking a placebo, women on estrogen/progestin had 29% more coronary events such as heart attacks and cardiac deaths over the average 5.2 years of the study. Breast cancer was up 26% in the Prempro group, and pulmonary embolisms, or lung clots, more than doubled.

The estrogen/progestin study is part of a larger study of estrogen, and the evaluation of estrogen alone will continue, despite the recent findings that estrogen alone didn't lower the rate of coronary events over seven years among women with previously diagnosed heart disease. Most patients in the Prempro study didn't have known heart disease when the research started.