The results of the first large randomized clinical trial to examine the effect of hormone replacement therapy (HRT) on women with heart disease appear in the August 19 issue of the Journal of the American Medical Association (JAMA).
The Heart and Estrogen/Progestin Replacement Study (HERS) found that the use of estrogen plus progestin in postmenopausal women with heart disease did not prevent further heart attacks or death from coronary heart disease (CHD). This occurred despite the positive effect of treatment on lipoproteins: LDL (bad) cholesterol was reduced by 11 percent and HDL (good) cholesterol was increased by 10 percent.
The hormone replacement regimen also increased the risk of clots in the veins (deep vein thrombosis) and lungs (pulmonary embolism). HERS involved 2,763 postmenopausal women, average age 67, who were treated for approximately 4 years. Women were randomly assigned to an estrogen/progestin combination or to a placebo. The study was funded by Wyeth-Ayerst Laboratories.
The results of HERS are surprising in light of previous observational studies, which found lower rates of CHD in women who take postmenopausal estrogen. Although observational studies cannot provide conclusive answers about a particular treatment since the groups studied can differ in significant ways, they provide important clues and the unexpected null finding in HERS is worthy of analysis. The authors speculate that the HERS results may be explained by differences in the effect of therapy over time. When they examined the results by year, they found that there was a trend towards a higher risk for CHD "events" such as heart attack during the first year of therapy but that this trend was reversed during the final two years. By the end of the study, there was no significant difference in CHD risk between the two groups.
One possible explanation for the early increase in CHD events could be due to negative effects of treatment on clot formation. The authors suggest that over time these negative effects were gradually outweighed by a longer term positive effect on the progression of atherosclerosis that was caused by the favorable cholesterol changes. In previous studies in which cholesterol-lowering drugs have produced a favorable effect on lipoproteins, there is usually a 1- to 2- year delay before CHD risk is reduced. Many of the women in the HERS study may not have been on treatment long enough for the positive cholesterol-lowering effects of HRT to reduce the risk of CHD.
Despite this explanation, the HERS investigators conclude that until results from other ongoing randomized trials of HRT are available, estrogen plus progestin should not be started in women with CHD to prevent heart attacks.
The National Heart, Lung, and Blood Institute (NHLBI) continues to advise postmenopausal women considering hormone replacement therapy--both those with and without CHD--to discuss this issue with their physician. The decision to continue or to stop HRT is complicated, and the benefits and risks of treatment should be decided on an individual basis. A woman's health profile and her family history of heart disease; uterine, breast, and ovarian cancers; and osteoporosis should be evaluated when considering HRT. Postmenopausal women should also discuss with their physicians the many other options available for the prevention and treatment of CHD.
The HERS study is important since it is the first of several ongoing randomized trials looking at the effects of HRT on heart disease. The NHLBI is supporting several of these trials, including the Women's Health Initiative (WHI), the Women's Angiographic Vitamin and Estrogen (WAVE) Trial, the Women's Estrogen/Progestin and Lipid Lowering Hormone Atherosclerosis Regression Trial (WELL-HART), and the Estrogen Replacement and Atherosclerosis (ERA) Trial.
The WHI differs from HERS in several key ways, including its size, length of study, and objectives. The HRT "arm" or component of WHI involves 27,500 women who do not have a prior history of CHD. The hormones being tested are estrogen alone as well as estrogen combined with progestin, and the trial is scheduled to run for an average of nine years. The WHI will examine the long term effects of HRT on heart attacks, strokes, blood clots, fractures, and cancers. Recruitment for the study will be completed this month, according to schedule, and results will be available after 2005.
The other trials mentioned above--WAVE, WELL-HART, and ERA--involve the use of coronary angiography, a test used to detect the blockages caused by atherosclerosis. They will help to prove whether the theory is correct that HRT produces a long term positive effect on the progression of atherosclerosis. The WAVE trial is looking at the effect of postmenopausal HRT and/or antioxidant vitamins (C and E) on the progression of coronary artery disease. This is a multicenter trial involving 400 to 450 women. The WELL-HART study is comparing estrogen, estrogen plus progestin (premarin), and placebo in 226 post-menopausal women with coronary artery disease and moderately elevated LDL cholesterol. Participants also receive the cholesterol-lowering drug lovastatin. ERA, another angiographic study, is a three-armed trial comparing estrogen, estrogen plus progestin, and placebo in 309 post-menopausal women with CHD.
When completed, these studies, together with the results of HERS, should provide the first comprehensive evaluation of the benefits and risks of long-term hormone replacement therapy.
Dr. Jacques Rossouw, NHLBI's lead project officer for the Women's Health Initiative, is available to comment on the HERS study and the WHI. To arrange an interview, contact the NHLBI Communications Office at (301) 496-4236.