HRT vs. Heart Disease: Down But Not Out

A decade ago, health experts were convinced that estrogen would be a key player in reducing our risk for heart disease, the number-one killer of women. Throughout the 1990s, clinicians routinely offered it in hormone replacement therapy (HRT) as part of a prevention plan. This strategy made sense for several reasons:

Premenopausal women are less likely to have a heart attack than men the same age; after menopause, their risk is the same. Estrogen declines after menopause, so it's biologically plausible that it provides some protection.
Observational studies suggest that taking estrogen cuts postmenopausal cardiovascular risk by 35%-50%.
Estrogen raises HDL (good) cholesterol, lowers LDL (bad) cholesterol, reduces fibrinogen (a clotting factor), raises levels of some natural clot inhibitors, and improves arterial wall elasticity.

But we now have abundant evidence that HRT does not help women with heart disease and may even worsen their condition. We still aren't sure whether HRT prevents heart disease in healthy women, but we do know that some women have cardiovascular problems early in the course of therapy.

Consequently, many experts now believe that HRT should not be prescribed for preventing heart disease or further coronary events. Harvard Women's Health Watch advisory board member Dr. JoAnn Manson and co-author Dr. Kathryn Martin recommended in the July 5, 2001, New England Journal of Medicine that cardiovascular protection no longer be included among the benefits that women and their doctors weigh against HRT's risks. Moreover, the American Heart Association (AHA) now advises doctors not to prescribe HRT for women with heart disease, nor to prescribe it for healthy women solely to prevent cardiovascular problems.


How did we get here? Most significantly, several studies tested and refuted some earlier assumptions about HRT and heart disease.

In 1998 the Heart and Estrogen/Progestin Replacement Study (HERS) reported that HRT with Prempro (the estrogen preparation Premarin plus a progestin) ultimately showed no advantage over a placebo in preventing coronary events in women with heart disease. Women taking HRT had 50% more heart attacks than women on placebo during the first year of the four-year trial, although this was offset by a 40% decrease in the last two years of the study.
In March 2000, the Estrogen Replacement and Atherosclerosis (ERA) study reported no difference in the progression of coronary atherosclerosis among postmenopausal women with established heart disease, whether they received Premarin, Prempro, or a placebo.

In April 2000, participants in the Women's Health Initiative (WHI) -a randomized trial of Premarin or Prempro versus placebo in women without heart disease - were notified of a very small, early increase in heart attacks, strokes, and blood clots in the lungs of the women receiving HRT. The risk was not significant enough to halt the trial.
The Papworth HRT and Atherosclerosis Survival Enquiry (PHASE) - a British study of postmenopausal women with heart disease who received either transdermal estrogen (with or without a progestin) or a placebo -was stopped early because of no apparent benefit.

Recently, the Coumadin Aspirin Reinfarction Study (CARS) found that women with heart disease who started HRT after a heart attack were more likely than those who took it before a heart attack - or didn't take it at all - to experience further coronary events within two years.

In contrast, the only completed trial testing estrogen against a placebo for the prevention of cardiovascular disease in apparently healthy women - the Estrogen in the Prevention of Atherosclerosis Trial (EPAT) - found some benefit from estradiol (a form of estrogen) over a placebo in curbing the development of atherosclerosis of the carotid artery, which runs up the neck and supplies the brain with blood.


For now, there's no compelling reason to start HRT at menopause just to reduce cardiovascular risk. But the story is far from over. Before we decide that the biological data and observational findings are wrong, questions raised by the randomized trials must be explored.

Could genetic or biological factors predispose some women, in particular, to the cardiovascular effects - good or bad - of HRT? For example, the Nurses' Health Study recently reported (Annals of Internal Medicine, July 3, 2001) that second coronary events increased by 25% in women with heart disease who took short-term HRT, but decreased by 62% in women who took HRT for two years or more.

Does the type of estrogen or progesterone - or its dose, regimen, or delivery system - make a difference? No study to date has juggled all these variables.

Should women - with or without heart disease - who have been taking estrogen for a year or two discontinue taking it, even if they are doing well? Probably not. Research thus far points only to an early elevation in risk for cardiovascular events, with the possibility of later benefit.

Data are still to come from the largest randomized studies of HRT in healthy postmenopausal women - the WHI and the Women's International Study of Long-Duration Oestrogen after Menopause (WISDOM), a 34,000-person European trial. Meanwhile, our first line of defense should continue to be diet, exercise, and not smoking. And when lifestyle changes alone aren't enough, the preferred medications are still cholesterol-lowering drugs (such as statins) and blood pressure-lowering drugs.

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