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PREgnant MARes urINe

December 2002


The biggest snow job in American history has come to a grinding halt with a study that puts to rest once and for all the notion that a drug made from the urine of pregnant horses will keep women healthy and youthful. It may kill them instead says an NIH study of 8,000 women who took "Prempro", a combination of the drug, Premarin, and synthetic progestin (medroxyprogesterone acetate). Prempro was supposed to enhance health, not endanger it, but five years into the eight-year study, the monitoring committee put a stop to it, and announced that the side effects weren't worth the risk. Blood clots increased 100%, stroke increased 41%, heart attacks increased 29%, heart disease increased 22%, and most ominously, the risk of invasive breast cancer increased 26%. Prempro now has the dubious distinction of increasing the risk of all of the leading causes of death in older American women. It did reduce colorectal cancer 37%, hip fractures 33%, and other fractures 24%, though.

The NIH study that was halted is part of a huge, government-sponsored trial known as the Women's Health Initiative (WHI). Over 160,000 women are involved in the WHI, which is designed to find ways to prevent heart disease, cancer and broken bones in older women. Although the Prempro portion of the study was stopped, a study on Premarin ("conjugated equine estrogens") is ongoing. Researchers are still hoping the drug will prevent heart attacks-a hope that may be founded more in hype than science. No study has ever convincingly shown that Premarin can prevent heart attacks or heart disease. Small studies have shown that it can create a better lipid profile, but that has never translated into preventing heart attacks in any meaningful way. The lipid changes Premarin causes are not comprehensive to begin with. Adding synthetic progestins (to protect the uterus from cancer) reverses some of those benefits, leaving a less-than-stellar overall effect.

Heart hype

The notion that Premarin's lipid-lowering effects would prevent heart attacks was tested and rejected decades ago. The WHI Prempro study that was recently halted is not the first Premarin heart study that has been halted. In 1973, a huge, government-sponsored study of 8,000 men was also halted at 5 years so as to "minimize possibilities of subjecting study patients to potential harm." Lung cancer rates in the men taking Premarin were four times higher even though their smoking habits were the same as those getting placebo. Cancer mortality was higher, and the incidence of serious blood clots was much higher. (On the bright side, breast cancer rates didn't go up, and prostate problems decreased).

It may seem odd for men to take estrogen, yet men naturally make this "female" hormone in their bodies just as women make the "male" hormone, testosterone. The study was done because researchers thought at the time that cholesterol was the cause of heart attacks. Since Premarin could lower cholesterol, they assumed it would prevent heart attacks.

Given this study and others showing a big increase in the risk of blood clots and other problems, why would researchers keep pursuing the notion that Premarin would prevent heart attacks? One reason is that observational studies looked promising. The Nurses' Health Study, in particular, gives strong evidence that women who take Premarin and other synthetic estrogens will be protected from heart disease-at least by one group's analysis of the data. Researchers from Harvard took data from the large, ongoing nurses' study, analyzed it and came to the conclusion that synthetic estrogen (with or without progestin) protects the heart.

Although the analysis was published in The New England Journal of Medicine, it was highly criticized by researchers in the field. Dr. Jacques Rossouw, chairman of the Women's Health Initiative, pointed out that the nurses taking the estrogen-progestin drugs were of a higher (and equal) socioeconomic class, better educated, had better access to doctors, had higher incomes and took better care of themselves. In other words, they were healthier to begin with. This is not disputed in the report itself which acknowledges that the women who appeared to get heart benefits from Premarin also took multivitamins (including folate), vitamin E, didn't smoke, didn't have a history of diabetes or heart attacks in the family, were younger, leaner, and took aspirin. But because the report was published in the NEJM, it was widely accepted.

But there is another reason to believe that Premarin might prevent heart attacks. Estrogen is beneficial for blood vessels. Studies show that estrogen drugs like Premarin do help prevent the hardening and lesions characteristic of cardiovascular disease. The problem is-at what price? Natural estrogens without side effects do the same thing without risk. Vitamin K has excellent benefits for blood vessels, and it not only has no side effects, it has other benefits as well. Statin drugs, changes in diet, and supplements like policosanol are much safer choices for lowering lipids.

Although the NEJM report was the most persuasive evidence, it would not be the last. Soon after it was published, serious cracks began appearing in the concept that synthetic estrogen would protect women from heart disease. Researchers in Finland, looked at a chart of side effects from a study called the "PEPI" trial, and saw that women taking estrogen drugs were more likely to have a cardiac "event" than women not taking them. This directly contradicted widespread beliefs about synthetic estrogen. Looking into it further, they reviewed 22 studies of women taking synthetic estrogen, mostly Premarin. In 1997, they published their findings in The British Medical Journal. Their analysis confirmed what PEPI had found: heart problems are more likely to occur in women taking estrogen drugs. Despite its serious implications, their report went virtually unnoticed.

New Labeling for Premarin

• Within weeks of the announcement that the WHI studies on Prempro/Premphase had been halted, Wyeth-Ayerst announced that it was changing the package inserts for Premarin and related drugs. The modifications are extensive, and reverse popular misconceptions about Premarin - misconceptions that federal authorities repeatedly warned the company to quit fostering. The new warnings make clear, for the first time, that the benefits of these drugs may not outweigh the risks. Doctors who have prescribed the drugs for decades may be shocked by what they read.

• The new labeling makes everyone aware of the findings of the Women's Health Initiative study which was halted after 5 years. "Because of the potential increased risk of heart attack, stroke, breast cancer, and blood clots, use of Premarin, Prempro, or Premphase should be limited to the shortest duration consistent with treatment goals and risks for the individual woman and should be discussed with her physician regularly." In other words, the old days of putting a woman on Premarin for life are over.

• The second new warning advises women to consider other treatments for osteoporosis even though Premarin is approved for this use. In other words, the risks may outweigh the benefits. There are safer alternatives.

• In addition, the new labeling will reiterate the approved uses of Premarin. Because of Wyeth-Ayerst's massive advertising campaign, many doctors and patients alike, have come to believe that Premarin is good for all sorts of things that haven't been proven. The new warnings make it clear that the approved uses of Premarin drugs are limited to: moderate to severe hot flashes, night sweats, vaginal dryness and the prevention of osteoporosis.

• The label will also contain a reminder that Premarin may cause endometrial carcinoma, and that Prempro or Premphase (Premarin combined with progestin) should be used in women who have a uterus. Women are also reminded that they should not take Premarin if they have ever had a stroke, blood clot, heart attack, and liver disease, or a known or suspected estrogen-sensitive cancer, including breast cancer, or pregnancy.

• The most common side effects of Premarin drugs are hair loss, weight gain, headache, bleeding and breast pain.

Carefully coiffed pop stars singing the praises of Premarin, are conspicuously absent from this new information campaign.

Snake oil salesmen with millions

The WHI Premarin/Prempro trial has cost taxpayers millions of dollars. With all the adverse findings on the Premarin drugs-the strokes, the cancer, the gallstones, and all the side effects that cause most women to stop taking them-why are we spending millions to do more tests? And how has a drug that is supposed to cure hot flashes become the panacea for every ailment an adult woman can get? The answer to both questions is advertising. More than thirty-seven million dollars were spent pushing Premarin in the year 2000 alone. That's $100,000 a day and it's been going on for decades. Contributions and "inducements" to physicians and big physician organizations; "incentives" to insurers and pharmacists to only reimburse for Premarin, "direct-to-consumer" ads designed to target empathy, personalize the message and improve patients' motivation have made Premarin the white noise of women's health. The truth hasn't been able to penetrate the million dollar babble.

Wyeth-Ayerst has been cited repeatedly by the FDA for falsely advertising its products. In one ad, the company reduced by two-and-a-half times the bone density achieved by a competing drug (Evista). In another, it omitted the information that Premarin could harm a fetus. In another, important side effects like blood clots, nausea and vomiting were omitted. But the most enduring lie, and the one that is taking millions of taxpayer dollars to dispel, is the notion that Premarin is the panacea for everything that can plague an older woman. The FDA warned the company in 1998 that Premarin's advertising "is misleading because it implies that Premarin can be used for a broader indication than that supported by substantial evidence." That's a delicate way of telling a snake oil salesman that his cure-all elixir doesn't. The company was told to "immediately withdraw" this direct-to-consumer advertisement in question. Wyeth-Ayerst has been reminded repeatedly that the only approved uses for Premarin in most women are hot flashes and osteoporosis. The company has also been given notice of violation for its osteoporosis ads. The Food and Drug official pointed out that contrary to the ads, it's not necessary for a woman to gain bone density to avoid osteoporosis, only to maintain it.

In 1999, the company was again cited for violating federal law with regard to its advertising, the FDA official noting that the Premarin ads contained "false or misleading" statements. Again the company was told to quit advertising Premarin for everything under the sun. "These advertisements," the official wrote, "promote Premarin for unapproved uses by implying or stating that Premarin is useful in a broad range of undefined health problems."*