HRT and antioxidant vitamins provide no benefit for menopausal women with heart disease and may cause harm

By Maureen McInaney on November 19, 2002

In postmenopausal women with coronary disease, neither hormone replacement therapy (HRT) nor antioxidant vitamin supplements provide cardiovascular benefit. In fact, a potential for harm was suggested with each treatment, according to a UCSF-led study.

Results from the study, also called the Women’s Angiographic Vitamin and Estrogen (WAVE) trial, appear in the November 20, 2002 issue of the Journal of the American Medical Association (JAMA) and will be presented on November 20, 2002 at the American Heart Association annual meeting in Chicago.

Although the actual numbers of deaths in the study were small, participants taking both hormones and vitamins C and E had the highest death rate, while patients taking the placebo had the lowest death rate, said David D. Waters, MD, UCSF professor of cardiology at San Francisco General Hospital Medical Center (SFGHMC) and lead author of the study.  In addition, patients taking hormones and vitamins had more or equal progression of their coronary disease as compared to patients taking the placebo treatment. 

“This study reinforces the concept that hormone replacement therapy is not helpful in the treatment or prevention of heart disease,” said Waters.  “In addition, although some other studies with lower doses of antioxidant vitamins have suggested that vitamins had no overall effect, this study indicates a trend toward more deaths in patients who took vitamins, either alone or in combination with hormones.

“The good news is that there are proven therapies to treat and prevent coronary heart disease, including diet, exercise, reducing blood cholesterol, and treating high blood pressure,” he added.

The WAVE Trial is the largest study to use changes in coronary artery dimensions as assessed by angiography to evaluate the effects of HRT and antioxidant vitamins E and C. Researchers enrolled 423 postmenopausal women at seven clinical centers in the United States and Canada. Patients were randomly assigned to one of four treatment groups:

* 1) Hormone therapy and placebo vitamin;
* 2) Placebo hormone and vitamins C and E;
* 3) Hormone therapy and vitamin C and E; and
* 4) Placebo hormone and placebo vitamin.

Hormones included one daily tablet of conjugated equine estrogen (Premarin, 0.625 mg) and medroxyprogesterone (Prempro, 2.5 mg).  Prescribed vitamins included 400 IU of vitamin E and 500 mg of vitamin C - two times a day.  In the WAVE trial, angiograms were done upon entrance to the study and at the end of the study, approximately three years later. 

During the study, women visited clinics at 6 and 12 month intervals to have a series of tests, including blood pressure, pap smear, and mammography.

The first randomized trial of HRT evaluated women with coronary disease. This UCSF-led study, the Heart Estrogen/Progestin Research Study (HERS), showed an increase in early cardiac events in women randomized to HRT, and no overall benefit. Advocates of HRT questioned the HERS results because it flew in the face of all of the previous non-randomized studies, said Waters.  Advocates also suggested that perhaps HRT would work if given before coronary disease developed, he added. The Women’s Health Initiative, published last summer, showed that HRT caused harm in women who had not yet developed heart disease. The WAVE trial studied women with heart disease and reaffirmed the findings of HERS, he said.

## Additional researchers on the WAVE trial included:

* Edwin L. Alderman, MD, cardiovascular medicine division, Stanford University;
* Judith Hsia, MD, department of medicine, George Washington University; 
* Barbara V. Howard, PhD, department of cardiology, Medstar Research Institute;
* Frederick R. Cobb, MD, Duke Center for Living, Duke University; 
* William J. Rogers, MD, University of Alabama at Birmingham;
* Pamela Ouyang, MD, John Hopkins Bayview Medical Center;
* Paul Thompson, MD, division of cardiology, Hartford Hospital;
* Jean Claude Tardif, MD, Montreal Heart Institute;
* Lyall Higginson, MD, University of Ottawa Heart Institute;
* Vera Bittner, MD, University of Alabama at Birmingham;
* Michael Steffes, MD, PhD, University of Minnesota;
* David J Gordon, MD, PhD, National Heart, Lung and Blood Institute, National Institutes of Health;
* Michael Proschan, PhD, National Heart, Lung Blood Institute, National Institutes of Health;
* Naji Younes, PhD, department of statistics, George Washington University; and
* Joel I. Verter, PhD, department of statistics, George Washington University.

The WAVE trial was sponsored by the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health.