Study of Menopausal Women with Heart Disease Finds Potential for Harm from Hormone Therapy

A study sponsored by the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health found that postmenopausal women with heart disease who took hormone therapy and high dose antioxidant vitamins - either alone or in combination with hormones - did not have fewer heart attacks, deaths, or progression of coronary disease. In fact, both treatments showed a potential for harm. Although the actual numbers of deaths in the study were small, participants taking both active hormones and vitamins had the highest death rate while participants on placebo versions of both treatments had the lowest death rate.

Furthermore, participants taking hormones and vitamins had either more or equal progression of their coronary disease compared to participants taking placebo versions of these treatments.

The results of the Women's Angiographic Vitamin and Estrogen (WAVE) trial will be published in the November 20 issue of the Journal of the American Medical Association and presented November 20 at the American Heart Association's annual meeting in Chicago.

"This study adds to the growing body of evidence that hormone therapy is not helpful in the treatment - or in the prevention -- of heart disease - and it provides new information on the absence of benefit from high-dose antioxidant vitamins," said NHLBI Director Claude Lenfant, M.D.

WAVE, which studied 423 postmenopausal women at 7 clinical centers in the U.S. and Canada, is the largest trial to use angiography (a special x-ray technique which shows blockages in the blood vessels of the heart) to assess the effects of hormone replacement therapy. It is also the first angiographic trial to look at antioxidants - high dose vitamins E and C - in conjunction with hormone therapy. The vitamin doses in the WAVE study were much higher than what is used in standard multi-vitamin preparations.

"Although some other studies with lower doses of vitamins have suggested that antioxidant vitamin supplements might not be helpful, the trend toward more deaths found in WAVE was unexpected.," said David Waters, M.D., WAVE principal investigator, chief of cardiology at San Francisco General Hospital and professor of medicine at the University of California, San Francisco (UCSF).

"The good news is that there are proven therapies to treat and prevent coronary heart disease, including weight control and controlling high blood cholesterol and high blood pressure," added Waters.

Participants in the WAVE study were randomly assigned to 1 of 4 treatment groups: (1) Hormone therapy and placebo vitamin,(2) Placebo hormone and vitamins C and E, (3)Hormone therapy and vitamin C and E, (4) Placebo hormone and placebo vitamin. Participants taking active hormone took either 1 daily tablet of conjugated equine estrogen (Premarin, 0.625 mg) if they did not have a uterus or 1 daily tablet of conjugated equine estrogen (Premarin, 0.625 mg) plus medroxyprogesterone (2.5 mg, Prempro). Participants taking active vitamin were prescribed 400 IU of vitamin E and 500 mg of vitamin C, each to be taken two times a day.

The hormone preparation taken by women with a uterus was the same as that used in the much larger Women's Health Initiative study, which was stopped in July 2002 due to an increased risk of breast cancer and because, overall, risks from use of the hormones outweighed and outnumbered the benefits. Unlike WAVE participants, most women in the WHI study did not have prior evidence of heart disease.

In the WAVE trial, angiograms were performed when women entered the study and at study exit - approximately 3 years later. During the trial, participants visited their clinics at 6 and 12 month intervals to undergo symptom and quality of life assessment and a comprehensive series of diagnostic tests, including blood pressure, pap smear, and mammography.

The WAVE investigators analyzed the results using a ranking system that incorporated both clinical events such as heart attack and death and angiographic change, a predictor of future coronary events. By this measure, women receiving active hormone therapy showed more progression of their coronary disease than women receiving placebo. Women receiving active vitamins had a similar degree of angiographic change as women receiving placebo but had significantly more deaths.

Specific findings were:

• In the active hormone group, 26 patients died, had a nonfatal heart attack, or suffered a stroke compared to 15 in the hormone placebo group.
• In the active vitamin group, 16 patients died from all causes compared to 6 in the vitamin placebo group.
• In the active vitamin group, 20 patients experienced either death or a nonfatal heart attack compared to 10 in the placebo group.
• There were few cases of breast cancer or other cancers - and no differences in the occurrence of cancer between the groups.

References:

To interview an NHLBI scientist about this study, contact the NHLBI Communications Office at (301) 496 - 4236. To interview Dr. Waters, contact Maureen McInaney at the UCSF Public Affairs office at (415) 476- 2557.

Information about postmenopausal hormone therapy is available at http://www.nhlbi.nih.gov