Hormone Replacement Therapy and Heart Disease

by DrRich

For many years, it was believed by medical science that hormone replacement therapy (HRT - treatment with either estrogen or an estrogen-progesterone combination) in post-menopausal women would reduce the risk of coronary artery disease.

This belief was based on three lines of evidence. First, in the decade after menopause a woman's risk of developing heart disease rises dramatically. The large drop in hormone levels seen with menopause has always seemed the most likely explanation for this increase in cardiac disease. Second, over 30 observational studies (clinical studies in which treatment is not carefully controlled) seemed to show a clear cardiac benefit with HRT. And third, treatment with estrogen unquestionably increases HDL cholesterol levels (the "good" cholesterol), and lowers the LDL cholesterol levels (the "bad" cholesterol.)

The notion that HRT was good for womens' hearts was so strongly held that, for many, the best rationale for conducting large, expensive, randomized clinical trials was to "prove" the benefit of HRT to those remaining doctors who had always avoided prescribing it.

For this reason, it has been quite a surprise that the three large randomized trials designed to prove the cardiac benefits of HRT have, so far, failed to do so.

In the Heart and Estrogen/progestin Replacement Study (HERS), reported in 1998, post-menopausal women with proven, preexisting coronary artery disease were randomly assigned to take either estrogen/progestin HRT, or placebo (a dummy pill). When the data was analyzed, those receiving HRT pill actually had a higher risk of heart attacks and death, during the first year of the study, than women getting placebo. During the next few years of the study, the risk for patients in the HRT group dropped, however, and the overall result was no long-term difference between the HRT group and the placebo group.

In the spring of 2000, results from the Estrogen Replacement and Atherosclerosis (ERA) trial were reported. This study, a similar randomized trial comparing HRT to placebo in post-menopausal women with pre-existing coronary artery disease, also failed to show a cardiac benefit with HRT. This lack of benefit occurred despite the fact that women receiving HRT in this study had a significant increase in HDL cholesterol, and decrease in LDL cholesterol.

Finally, also in the spring of 2000, investigators conducting the huge Women's Health Initiative (WHI) trial stirred up even more controversy. The WPI trial, similar to HERS and the ERA trial, is a randomized trial comparing HRT with placebo in post-menopausal women. The major differences between WPI and the other two trials are WPI's huge size (over 26,000 women were enrolled), and the women enrolled in WPI had no preexisting coronary artery disease. WPI is scheduled to run until 2005. The controversy erupted when investigators felt compelled by preliminary data to send letters to women participating in the trial stating that those in the HRT group had experienced an increased risk of heart attacks, strokes, and blood clots during the early portion of the trial. At the same time, the investigators stated that the results were small (only 1% of study participants had experienced such bad events) and very preliminary. They pointed out that the early detriment seen with HRT in the HERS trial had reversed itself after the first year. They recommended that the study proceed as planned, which it is doing.

Where does this leave post-menopausal women, and the doctors caring for them?

The decision as to whether to use HRT after menopause was difficult enough before HERS, ERA and WPI threw more mud onto the picture. More may be known in 5 years, to be sure, but thousands of women need to make decisions on HRT today.

The best women and their doctors can do is to try to scrape away as much mud as possible - to sort out what we know and what we don't know - and take their best guess.

What we know - At the very least, HRT is not as dramatically effective as most people thought it would be in improving the risk of heart disease. While the jury is still out as to whether HRT will ultimately improve (somewhat) the risk of heart disease, or whether it will worsen that risk, we can say this for sure: Today, there is no compelling reason to use HRT for the purpose of reducing the risk of heart disease in post-menopausal women.

We also know that when HRT is used to lower LDL cholesterol and raise HDL cholesterol, the expected improvement in outcome has not been seen. This result stands in contrast to the result seen when the statin drugs are used to improve cholesterol values. Therefore, HRT should no longer be used as primary therapy for lowering cholesterol in post-menopausal women, especially women with coronary artery disease. Instead, the statin drugs (or other cholesterol-lowering agents) should be used.

Finally, there is no question that HRT significantly increases the risk of forming blood clots in arteries and veins in post-menopausal women. All three studies have shown an increase in venous thrombosis (clotting of the veins) and its attendant problems, phlebitis and pulmonary embolus (blood clots moving to the lungs) in patients taking HRT. Thus, HRT should be avoided in women who have had recent fractures, cancer, recent surgery, a history of blood clots, or any other factor making them more prone to developing clotting problems.

What we don't know: We don't know what the long-term cardiac effects of HRT might be, especially in women who do not have pre-existing coronary artery disease. It is still possible that the benefit of increasing HDL and reducing LDL cholesterol in these women might yield a significant long-term benefit. This is one prime rationale (aside from the monumental time and expense that have already been invested) for continuing the WPI trial.

What recommendations are doctors making? Most doctors continue to recommend HRT for preventing and treating osteoporosis, hot flashes, and problems seen with the genito-urinary system in some women after menopause. But they generally are no longer recommending HRT for treating cholesterol levels, or for preventing cardiac disease. For women who already have been taking HRT for a year or longer, there seems to be no good reason to recommend they discontinue therapy. Any detriment seen with HRT in these three trials, it appears, seemed to occur early in therapy; any potential cardiac benefit must occur (if it occurs at all) late.

One final aside: The saga of HRT nicely illustrates just how messy science can be. Despite years of effort and hundreds of millions of dollars spent in studying HRT, medical science still cannot prove whether or not it is a good idea. This is why there will always be a market for alternative medicine. After dealing with medical scientists for a while, with all their "inconclusive data," and "awaiting further study," and "statistically indistinguishable from placebo," patients who need to be treated today can be forgiven for being drawn to a branch of commerce where the practitioners always know with complete surety that their products work as advertised. Why, sometimes it even sounds attractive to DrRich, a dyed-in-the-wool allopath.

Links

The HERS trial - a report from the Mayo Clinic describing the results of the trial, and how those results are being interpreted.

HRT and the treatment of cholesterol - a report from Heart Watch on the recent recommendation by the AHA that doctors use statins rather than HRT to control womens' cholesterol levels.

What to do about WPI - another report from Heart Watch, with a perspective from a woman cardiologist on the status of HRT

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