Healthy Skepticism Library item: 9292

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Publication type: news

Parker-pope T.
New Study Reassures Most Users of Hormones
Wall Street Journal 2007 Apr 4A1
http://online.wsj.com/google_login.html?url=http%3A%2F%2Fonline.wsj.com%2Farticle%2FSB117564478980559031.html%3Fmod%3Dgooglenews_wsj

Full text:

For Newly Menopausal, There’s No Heart Risk; A Reversal of Findings

In a flip-flop, a major government study that once warned that menopause hormones raised heart risk has now concluded that they don’t, for most women who use them.

The reversal comes from the fullest analysis yet of data generated by the Women’s Health Initiative, a big study funded by the National Institutes of Health. Nearly five years ago, the NIH halted the first part of the study early because it appeared to show that hormones raised heart risk. It was a surprising result that led millions of women to give up hormones overnight.

But in the new analysis, WHI researchers said the timing of hormone use is key. They found that women who use hormones in the first years after the arrival of menopause are not at increased heart risk.

The data also showed hormone users aged 50 to 59 had a 30% lower risk of dying of any cause during the five-to-seven-year WHI study than those given a placebo. The new analysis is especially important because it most closely measures effects on the typical hormone user: a recently menopausal woman, in her mid-40s or early 50s, who seeks relief from hot flashes and other symptoms.

The bottom line for these women: The new analysis offers the best reassurance yet that using hormones to relieve menopause symptoms won’t increase heart risk.

The Journal of the American Medical Association and the WHI investigators played down the finding, saying that the age-of-use difference wasn’t statistically significant and could be due to chance. In fact, the data do meet the most commonly used test of statistical significance. But the JAMA and WHI reviewers decided — after the study had been submitted — to impose a far more stringent significance standard on the results. Statistics experts described that as unusual. A top JAMA editor said it was “perfectly appropriate” as part of a rigorous review process.

WHI researchers said the focus shouldn’t be on the statistical issue but on the actual results of the new analysis. “To me there is good news in this paper, and that’s what should be transmitted, rather than arguing about statistics,” said Jacques Rossouw, an NIH official who was the architect of the WHI study.

“It probably represents the best data we have on the important question of whether there are some groups of women for whom hormone therapy remains a reasonable option,” Dr. Rossouw said. “It goes some way toward settling the issue for an important group of women and their physicians — that is, women who have menopausal symptoms around the age of menopause who have been avoiding hormone therapy when it may not have been necessary for them to do so.”

Dr. Rossouw disagreed that the findings represented a reversal, because, he said, the data still show that hormones shouldn’t be taken for the purpose of preventing heart disease, nor used by older women long past menopause. But he acknowledged that many women were confused by the first WHI reports. “I understand some people are going to say we’ve reversed course,” said Dr. Rossouw. “The data are the data. We’re saying the same things. We just have more detail.”

Dr. Rossouw said the data should be interpreted with caution, and that the lower mortality seen among women in their 50s who use hormones needs further analysis to be fully understood. The new analysis also showed that hormone use carries a slightly elevated risk of stroke. The analysis didn’t address hormones’ other benefits or risks, such as osteoporosis protection or breast-cancer risk.

JoAnn Manson, a WHI investigator, Harvard professor of epidemiology and co-author of the new analysis, said it gives “the most reassuring evidence to date” that women who use hormones to treat menopausal symptoms are not putting their hearts at risk.

The combined analysis showed that for every 10,000 women aged 50 to 59 who use hormones there would be 10 fewer deaths among hormone users, compared with nonusers. By comparison, among women aged 70 to 79 who use hormones, there would be 16 additional deaths per 10,000 women.

“These [latest] results support the theory that timing does matter when it comes to health outcomes on hormone therapy,” said Dr. Manson. “The findings support a more favorable benefit-to-risk profile of hormone therapy in younger than in older women.”

The latest report adds a striking twist to the 30-year debate about the effects of menopause hormones on women’s heart health. In the 1980s, data from Harvard’s Nurses Health Study showed that women who used menopause hormones had as much as 50% fewer heart attacks than nonusers of hormones. There were calls at the time for all women over 50 to start using hormones to protect their hearts.

In 1991, new NIH director Bernadine Healy sought to get a better understanding of hormone effects on the heart by creating the Women’s Health Initiative. The $725 million project involved two studies, totaling 27,000 women, given either hormones or a placebo. Designers of the study expected it to show that hormones reduced heart-attack risk. Instead, in July 2002, came the announcement that the NIH had stopped the study because hormone takers were having more heart attacks.

The result was near-panic among some menopausal women. Many immediately quit taking hormones, suffering through hot flashes and intense withdrawal symptoms because they were afraid to keep taking the pills. Hormone sales plummeted at hormone makers such as Wyeth, whose Prempro and Premarin were used in the study. Today about four million U.S. women use menopause hormones, down from about six million before 2002. To cope with menopausal symptoms, many women switched to more expensive — and less-studied — drugs such as antidepressants. Many switched to bone-building drugs to lower osteoporosis risk.

Investigators said then that the finding applied to all. “The results have broad applicability,” Dr. Rossouw said at a July 2002 news conference. “The study found no difference in risk by prior health status, age or ethnicity.”

While his pronouncement was accurate based on information he had at the time, a continuing analysis of the data began to show the hormone effect might be far more complex.

The WHI was a study of mostly older women, long past menopause. The average age of study subjects was 63, which is 10 to 15 years older than most women seeking advice about menopause hormones. Most of those given hormones in the WHI study were 10 years or more past menopause. Some were even 20 years past it.

The WHI had recruited women that old because this was supposed to be a heart-disease study, and investigators needed to study women who were old enough to be at risk for heart problems. As a result, of the 27,347 women in the WHI studies, only 3,425 were under age 55.

After results of the halted studies were reported, researchers began to realize there might be a difference in how hormones affected a woman’s health, depending on where she was along the menopausal timeline. They realized that her age wasn’t as important as the number of years since she entered menopause. A woman is officially menopausal once she has stopped having periods for 12 months. The age of the menopausal transition is highly variable, typically occurring between 45 and 55.

A reanalysis of the WHI heart data attempted to look at the effects of hormones based on the timing of hormone therapy relative to when a woman entered menopause. Overall, women in the WHI who used Prempro — a combination of estrogen and progestin — had a 24% higher risk of heart attack during the five-year study. The breakdown: Women who started taking hormones 20 years or more after they reached menopause had a 71% increased risk; women who started 10 to 19 years after menopause had a 22% higher risk; but women who started hormone use within 10 years after reaching menopause actually had an 11% lower risk of heart problems.

The problem was that because there were so few recently menopausal women in the study, the data failed to reach statistical significance.

A second part of the WHI study looked at estrogen alone, instead of estrogen plus progestin. It didn’t show any overall increased heart risk.

Here too, when women were studied by age, there was a difference in risk. Estrogen-only users who started the hormones between ages 70 and 79 — long after reaching menopause — had an 11% higher risk of heart problems. But women below 60 in the estrogen-only study had a 37% lower heart risk.

These findings failed to reach statistical significance. But they were provocative enough that WHI researchers decided to combine the data from both hormone studies in hopes of generating enough statistical power that the results could be more conclusive. While the idea of combining data from two separate studies is sometimes frowned on, it was a relatively easy step for the WHI, because the two hormone studies were of similar design and used women recruited at the same time, the only difference being the type of hormones they were given.

The combined analysis produced a powerful trend, showing that there were stark differences in heart risk based on the number of years since a woman entered menopause. Women close to menopause were at a 24% lower risk for heart problems, while women 20 years or more past menopause faced a 28% higher heart-attack risk.

The trend met a conventional test of statistical significance — meaning that it was unlikely to be due to chance. And this is how the NIH submitted it to JAMA. But something unusual happened once the results were calculated. During the standard review process that papers undergo before being published in a medical journal, the study authors and JAMA reviewers decided a more conservative approach was warranted, says Dr. Rossouw.

At issue is something called the P value, an index that measures how strong the evidence really is. Traditionally a P value of 0.05 is acceptable, showing that there is only a 1-in-20 chance that the result isn’t real. That is the standard used in most WHI analyses. The analysis easily met this test of significance, coming in with a P value of 0.02.

But once the paper started being reviewed, a decision was made to further lower the standard for statistical significance — to 0.01. “Both the internal reviews and the journal reviews drew attention to the need to be cautious and recommended this,” Dr. Rossouw said. A more conservative approach was needed, he says, because the data had already been subjected to a number of statistical analyses, a process that statisticians agree increases the likelihood of a false positive.

Statistics experts said they were surprised by the timing of the switch — which happened after the paper had been submitted and the results were already calculated. “You have to set the P value in advance,” said Martin Bland, professor of health statistics at the University of York in Britain and co-author of a British Medical Journal series on statistics. “To do a test of significance and say retrospectively, ‘I’m going to change the P value’ — it’s a rather unusual thing to do. I certainly would have been reluctant to change my decision rules after the fact.”

Phil Fontanarosa, executive deputy editor for JAMA, said the decision to use a lower P value was justifiable because the study involved multiple analyses and combining two studies. “When you’re testing multiple hypotheses and looking at multiple end points, you want to try to reduce the likelihood of finding something by chance,” he said.

Dr. Fontanarosa said there was nothing particularly unusual about the review process of the WHI data, including the fact that the authors opted for a more conservative interpretation of the data. “This is a standard part of the peer review system,” he said. “The normal process is rigorous review by experts, thorough revision by authors and, of course, some negotiation along the way.”

Wulf Utian, executive director of the North American Menopause Society, a medical group, said that the claim that the new analysis isn’t statistically meaningful amounts to a “statistical game.” Dr. Utian, who has long challenged the original interpretation of the WHI data, said the data clearly show that the timing of hormone use is important and hormones don’t pose a heart risk to younger menopausal women.

“It’s like a halfhearted apology,’‘ he said. “They did the analysis, but then they say it isn’t really statistically valid. Before, they were happy with 0.05 with every other study they wrote, but now they say it should be 0.01.’‘

Dr. Rossouw said the overall tone of the paper matters more than the statistical debate. What’s important about the analysis, he said, is that it shows there may be some credence to the notion that there’s a “window of opportunity” when hormone use is reasonably safe for younger women.

“We’re publishing this in an effort to help understanding of the whole hormone issue, which is terribly complicated,” Dr. Rossouw said. “It makes a contribution in reassuring younger women. You have to make your own decision about whether you believe the data or not. I do.”

Write to Tara Parker-Pope at tara.parker-pope@wsj.