Both hormone therapy and high dose antioxidant vitamins -either alone or in combination with hormones - do not reduce the risk of heart attacks, deaths, or progression of coronary disease, according to a new study by US researchers.
In fact, both treatments showed a potential for harm, researchers will report today at the American Heart Association's annual meeting in Chicago. Although the actual numbers of deathsin the study were small, participants taking both activehormones and vitamins had the highest death rate whileparticipants on placebo versions of both treatments had thelowest death rate.
Furthermore, participants taking hormones and vitamins hadeither more or equal progression of their coronary diseasecompared to participants taking placebo versions of thesetreatments.
The results of the Women's Angiographic Vitamin andEstrogen (WAVE) trial, sponsored by the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health, will be published in today's issue of the Journal of the American Medical Association.
"This study adds to the growing body of evidence thathormone therapy is not helpful in the treatment - or inthe prevention - of heart disease - and it provides newinformation on the absence of benefit from high-doseantioxidant vitamins," said NHLBI director Dr Claude Lenfant.
WAVE, which studied 423 postmenopausal women at 7 clinicalcenters in the US and Canada, is the largest trial to useangiography (a special x-ray technique which showsblockages in the blood vessels of the heart) to assess theeffects of hormone replacement therapy. It is also thefirst angiographic trial to look at antioxidants - highdose vitamins E and C - in conjunction with hormonetherapy. The vitamin doses in the WAVE study were muchhigher than those used in standard multi-vitaminpreparations.
"Although some other studies with lower doses of vitaminshave suggested that antioxidant vitamin supplements mightnot be helpful, the trend toward more deaths found in WAVEwas unexpected," said Dr David Waters, WAVE principalinvestigator, chief of cardiology at San Francisco GeneralHospital and professor of medicine at the University ofCalifornia, San Francisco (UCSF).
"The good news is that there are proven therapies to treatand prevent coronary heart disease, including weightcontrol and controlling high blood cholesterol and highblood pressure," added Waters.
Participants in the WAVE study were randomly assigned to oneof four treatment groups: (1) Hormone therapy and placebovitamin,(2) Placebo hormone and vitamins C and E,(3)Hormone therapy and vitamin C and E, (4) Placebo hormoneand placebo vitamin. Participants taking active hormonetook either 1 daily tablet of conjugated equine estrogen(Premarin, 0.625 mg) if they did not have a uterus or 1daily tablet of conjugated equine estrogen (Premarin, 0.625mg) plus medroxyprogesterone (2.5 mg, Prempro).Participants taking active vitamin were prescribed 400 IUof vitamin E and 500 mg of vitamin C, each to be taken twotimes a day.
The hormone preparation taken by women with a uterus wasthe same as that used in the much larger Women's HealthInitiative study, which was stopped in July 2002 due to anincreased risk of breast cancer and because, overall, risksfrom use of the hormones outweighed and outnumbered thebenefits. Unlike WAVE participants, most women in the WHIstudy did not have prior evidence of heart disease.
In the WAVE trial, angiograms were performed when womenentered the study and at study exit - approximately threeyears later. During the trial, participants visited theirclinics at 6 and 12 month intervals to undergo symptom andquality of life assessment and a comprehensive series ofdiagnostic tests, including blood pressure, pap smear, andmammography.
The WAVE investigators analyzed the results using a rankingsystem that incorporated both clinical events such as heartattack and death and angiographic change, a predictor offuture coronary events. By this measure, women receivingactive hormone therapy showed more progression of theircoronary disease than women receiving placebo. Womenreceiving active vitamins had a similar degree ofangiographic change as women receiving placebo but hadsignificantly more deaths.
In the active hormone group, researchers report 26 patients died, had a nonfatal heart attack, or suffered a stroke compared to 15 in the hormone placebo group while in the active vitamin group, 16 patients died from all causes compared to six 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.
Trade association the Council for Responsible Nutrition (CRN) however called the study conclusions "an exaggerated recommendation based on inconclusive data." CRN said that careful analysis of the study reveals no effects beyond random variations in response and that the researchers based their conclusions on statistically insignificant data.
"In fact, the actual data showed no difference in artery blockage between the antioxidant group and the control group, even after the researchers arbitrarily created 'worst-case' numerical values to fill missing data points," said Dr John Hathcock, vice president of nutritional and regulatory science at CRN.
"Even those statistics that would appear to be significant are, in actuality, the exact pattern that would randomly occur if no treatments had been administered, and as the authors have stated, this could be a 'chance finding.'"
The organisation added that the study groups were not stratified to assure that all the treatment groups were similar with respect to the degree of coronary artery blockage. In addition, the authors concede that their study was powered only to detect the degree of blockage of the arteries, not the differences in clinical outcomes, said CRN, yet much of their discussion focuses on comparisons of clinical outcomes.
Dr Hathcock added that there is broad scientific consensus that dietary supplements of vitamins E and C are safe in the general population. "It is the cumulative knowledge, or the weight of the overall evidence, that provides health care professionals and consumers with the best scientific guidance. Over the past 25 years, more than 20 studies involving more than 80,000 people have been conducted on vitamins E and C, and on balance these are overwhelmingly safe nutrients."
Another secondary prevention trial of antioxidant vitamins and cardiovascular disease (CVD) in women, the Women's Antioxidant and Cardiovascular Study (WACS), is currently being conducted by Harvard Medical School and funded by the National Heart, Lung and Blood Institute, and involves a larger, but similar, study population to WAVE. The randomized, double-blind, placebo-controlled trial is studying the balance of benefits and risks of vitamins E and C, and beta-carotene, among 8000 women with preexisting CVD.
According to statistics from a 2001 Gallup Study, over 100 million American adults annually take vitamins E and C in dietary supplement form, either in single nutrient supplements or in multivitamins.