June 21, 2007 — A new analysis of the Women's Health Initiative (WHI) trial has found that younger postmenopausal women treated with estrogen-only hormone replacement therapy (HRT) had significantly less coronary artery calcification than their counterparts taking placebo. Dr JoAnn E Manson (Harvard Medical School, Boston, MA) and colleagues report the findings of the WHI-Coronary Artery Calcium Study (WHI-CACS) in the June 21, 2007, issue of the New England Journal of Medicine.
While the results provide further reassurance to younger women that estrogen is unlikely to have an adverse effect on their risk of coronary events, "there is also a suggestion from the data that estrogen may slow the early stages of atherosclerosis," Manson told heartwire. These possible protective effects have been leaped on by at least one body as a vindication of HRT, with the International Menopause Society (IMS) issuing a press release calling the results of WHI-CACS "encouraging," adding that "women can be reassured that estrogen therapy is cardioprotective until at least 65."
But others caution against such extrapolation. Chief of the National Heart, Lung, and Blood Institute WHI branch and second author on the new study, Dr Jacques E Roussouw, told heartwire: "There are two issues that need to be addressed. One is the use of short-term use of HRT around the time of menopause, and I think we can conservatively state that there is no increased risk from this, and there may even be a trend toward benefit in terms of heart disease."
"The second issue is the long-term use of HRT for the prevention of chronic disease. We cannot assume that any possible short-term, cardiovascular benefit from hormone therapy to postmenopausal women in their 50s would extend into older ages if they were to continue using hormones. We already know that starting hormone therapy in older women increases their risk of heart disease. And long-term hormone therapy has other risks, such as strokes and venous thromboembolism, and, with the use of combination therapy, breast cancer."
Unfortunately, there will never be an answer as to whether long-term use of HRT is cardioprotective or not, he says, explaining that any trial examining this would likely be unethical and certainly unfeasible. "We no longer believe that estrogen is the elixir of life," he noted, pointing out that there are many other options for the prevention of chronic disease. He is therefore critical of the stance taken by the IMS: "They are quite explicit, stating that there is no reason to be against long-term use of HRT. I totally disagree."
"Clear and Striking" Cardioprotective Effect of Estrogen in Young Women Requires Confirmation
In this latest ancillary study, coronary artery calcium was measured by cardiac computed tomography (CT) scans in 1064 women aged 50 to 59 years from 28 of the original 40 WHI centers across the US, who were randomly assigned to estrogen or placebo at the start of the WHI estrogen-alone trial.
The CT scans were completed an average of 1.3 years after the study was halted prematurely in 2004. No CT scans were performed at baseline.
The findings reveal that those women receiving estrogen (for an average of 7.4 years) were 42% less likely to have severe coronary artery calcium (a score of > 300) than women receiving placebo. And among those who were particularly compliant, women receiving estrogen had a 61% lower risk of severe coronary calcium.
"These findings suggest that estrogen leads to less calcified plaque in the coronary arteries, and this is a marker for the extent of atherosclerosis and a predictor of future risk," Manson told heartwire.
The results thus provide support for the hypothesis that estrogen therapy may have cardioprotective effects in younger women, the researchers say, although they emphasize that this requires confirmation in future studies.
For example, there is no way to know whether the reduced plaque levels seen in WHI-CACS will continue to be a reliable indicator of the progression of coronary artery disease in these women as they age.
And "it is also possible that estrogen could reduce the CAC scores but still increase the risk of clinical CHD events, owing to adverse effects on thrombosis and plaque rupture, which are more likely in older women with advanced stages of atherosclerosis. Such a duality of effects would not necessarily apply to younger women with lower burdens of atherosclerosis," they state.
In an accompanying editorial, Drs Michael E Mendelsohn and Richard H Karas (Tufts University School of Medicine, Boston, MA) say the results of WHI-CACS "are clear and striking ... [and are] supportive of estrogen's having a cardioprotective effect in younger menopausal women."
"However, it remains important to continue to emphasize that HRT should not be considered as a strategy to prevent cardiovascular disease in women," the editorialists state. "There are proven therapies for cardiovascular disease that remain underused in women."
WHI-CACS Results Do Not Necessarily Support the Timing Hypothesis
The new data add to results reported from WHI in April showing that coronary heart disease risk associated with combined as well as estrogen-only HRT was not significantly increased in women taking it within 10 years of menopause. "I think there is mounting evidence that a woman's age and time since the menopause influence her health outcomes on estrogen, particularly her risk of heart disease," Manson commented to heartwire.
Manson believes that younger women appear to get coronary benefit from estrogen because their endothelia are still healthy, elastic, and able to dilate. "The endothelium needs to be responsive to estrogen and estrogen-receptor function needs to be normal. Once it's already a hardened pipe, you're not going to get the same benefits, and you are more likely to get the risks," she noted.
This explanation is the basis for the so-called "timing hypothesis" for HRT, which states that any benefits of HRT in preventing atherosclerosis occur only when the therapy is started during a "window of opportunity" before advanced atherosclerosis develops.
In their editorial, Mendelsohn and Karas say WHI-CACS and the other recent WHI studies support the "timing hypothesis," which "provides a scientific framework within which to understand much of the clinical data from the past two decades, including data from observational studies of HRT, the original HRT reports and now, WHI-CACS."
But not all of the WHI-CACS investigators are comfortable with this concept. Senior author of WHI-CACS Dr Marcia Stefanick (Stanford University, Palo Alto, CA) told heartwire: "I don't think we have evidence that there is a critical time window in which estrogen must be initiated to get benefit, after which there is an adverse response. I agree that older women are worse off if they initiate estrogen than young women are, but I don't think we have evidence that young women are better off by initiating estrogen than by not initiating it, as far as actual heart disease is concerned — rather, we have bits and pieces that relate to risk factors which may or may not provide useful information about long-term risk."
"It might sound like a nuance, but I think it's important not to resurrect the idea that estrogen is cardioprotective for younger women, as we do not have data to support that — certainly not from the data being presented in NEJM this week — though it does provide some reassurance that estrogen is not harmful for younger women, who are the group that may benefit from estrogen's effects on menopausal symptoms," she continues.
In addition, Stefanick says the WHI-CACS results, "do not address the timing hypotheses because we only studied women aged 50 to 59 and we have only one (cross-sectional) time point, so there are no longitudinal data — I don't think the whole author group believes in the concept; however, this is different from agreeing that the data may support the hypothesis — they clearly do not provide evidence against it — but a very different kind of study would be needed to test the hypothesis.
A New Safety Margin of 65?
Despite all of these caveats, the IMS has issued an incredibly upbeat press release: "This study reaffirms what was actually known for many years ... estrogen has a wide range of well-documented beneficial metabolic and vascular effects: it reduces the pace of accumulation of atherosclerosis, and decreases the risk of coronary events, provided the treatment is started early in the menopause."
And because the CT scans in WHI-CACS were performed at a mean age of 64.8 years, the results suggest a "new safety margin" for age and duration of estrogen therapy, it states. "Women can be reassured that estrogen therapy is cardioprotective until at least 65."
IMS does point out, however, that: "since most, if not all, women do not start HRT at an old age, safety concerns on its possible adverse cardiac effects are actually invalid for the vast majority of users."
Roussouw says he has no problem with the use of HRT for moderate to severe menopausal symptoms, at the lowest effective dose for the shortest duration, but the menopause societies, "speak out of both sides of their mouths."
He is most critical of the IMS, pointing out that the British and North American menopause societies encourage prescribing on an individual basis, and only for a maximum of 10 years. Nevertheless, he feels that 5 years would be a better option, and points out that most women discontinue HRT after a year or two anyway.
But in terms of the prevention of chronic disease, he believes doctors should steer clear of HRT. "Hormones are so unusual, they have so many adverse effects and don't have a good profile. Cardiologists have many options for the prevention of heart disease, and they have never been that comfortable with HRT anyway," he says.
And even the Osteoporosis Foundation in the US no longer recommends HRT as first-line use for the prevention of osteoporosis in those at risk, he notes.
[IMS did not respond to heartwire's request for an interview.]
New Engl J Med. 2007;356:2591-2602, 2639-2641
