Clinical Abstracts: HRT, Antioxidants, and Atherosclerosis

With Comments by Mary Hardy, MD

Source: Waters DD, et al. Effects of hormone replacement therapy and antioxidant vitamin supplements on coronary atherosclerosis in postmenopausal women. JAMA 2002;288:2432-2440.

The aim of this study was to determine whether hormone replacement therapy (HRT) or antioxidant (AO) vitamin supplements, alone or in combination, influence the progression of coronary artery disease (CAD) in postmeno-pausal women, as measured by serial quantitative coronary angiography.

A total of 423 postmenopausal women with at least one 15-75% coronary stenosis at baseline coronary angiography were studied from July 1997 to January 2002 in seven clinical centers in the United States and Canada.

Patients were randomly assigned in a 2 x 2 factorial design to receive either 0.625 mg/d of conjugated equine estrogen (plus 2.5 mg/d of medroxyprogesterone acetate for women who had not had a hysterectomy), or matching placebo, and 400 IU of vitamin E bid plus 500 mg of vitamin C bid, or placebo.

Annualized mean (SD) change in minimum lumen diameter from baseline to concluding angiogram of all qualifying coronary lesions was averaged for each patient. Patients with intercurrent death or myocardial infarction (MI) were imputed the worst rank of angiographic outcome.

The mean (SD) interval between angiograms was 2.8 (0.9) years. Coronary progression, measured in mean (SD) change, worsened with HRT by 0.047 (0.15) mm/y and by 0.024 (0.15) mm/y with HRT placebo (P = 0.17); and for AO vitamins by 0.044 (0.15) mm/y and with vitamin placebo by 0.028 (0.15) mm/y (P = 0.32). When patients with intercurrent death or MI were included, the primary outcome showed an increased risk for women in the active HRT group (P = 0.045), and suggested an increased risk in the active vitamin group (P = 0.09). Fourteen patients died in the HRT group and eight in the HRT placebo group (hazard ratio [HR], 1.8; 95% confidence interval [CI], 0.75-4.3), and 16 in the vitamin group and six in the vitamin placebo group (HR, 2.8; 95% CI, 1.1-7.2). Death, nonfatal MI, or stroke occurred in 26 HRT patients vs. 15 HRT controls (HR, 1.9; 95% CI, 0.97-3.6) and in 26 vitamin patients and 18 vitamin controls (HR, 1.5; 95% CI, 0.80-2.9). There was no interaction between the two treatment interventions.

In postmenopausal women with CAD, neither HRT nor AO vitamin supplements provides cardiovascular benefit. Instead, a potential for harm was suggested with each treatment.


Epidemiological evidence suggests a protective benefit for heart disease by consuming a diet high in AO-rich foods, such as fruits and vegetables. However, for AOs given as supplements, the evidence for the same benefit is less strong. Studies generally have not shown a possible effect of AO vitamins given independent of diet, although the majority of the subjects have been male.

The patients in this trial averaged 69 years of age and were obese (body mass index > 30); 66% of the patients were white. The groups were largely equivalent at the time of diagnosis with equal numbers of patients with prior history of MI, smoking, hysterectomy, aspirin, and lipid-lowering drug and beta-blocker use. Significant differences included more diabetics in the active HRT group and fewer users of angiotensin converting enzyme inhibitors in the active AO group. Compliance with HRT was only fair (67% patients took medication as directed); the AO users were more compliant (87%). The dropout rate in the trial was high.

Although the results from this trial showed no benefit from HRT or AOs on the progression of occlusion of the coronary lumen in these subjects, approximately 20% of the subjects in all treatment groups showed regression of lesions over the course of the trial. The authors did not comment on this finding.

The significance of this study lies in confirming previous poor results with HRT on coronary endpoints, as well as adding to our information about AOs, in postmenopausal women with pre-existing CAD. In other clinical trials, AOs have been reported to interfere with the ability of statin drugs to raise HDL. Patients taking lipid-lowering drugs, presumably statins, in this study were not analyzed separately, so it is not possible to determine if AOs interfered with the clinical efficacy of these drugs. If the impact of AOs is small, their effects would be eclipsed by the much larger effects of pharmacological treatment.

Finally, it is likely that any effect seen in the epidemiological trials is not related to AOs only, but to other concomitant healthy habits, such as weight loss or increased exercise, or to other biologically active constituents in food. Experts have suggested that AO treatment may need to last a decade or more to see benefit. In addition, I would encourage authors using AO interventions to be more specific in describing the formulations used.

Neither HRT nor AO in these doses for this population seems to be of benefit in secondary prevention. HRT usage, in fact, seems to be associated with a slight increase in risk of adverse cardiac events, especially in diabetics. This leaves us all waiting for results from the ongoing portion of the Women’s Health Initiative, a primary prevention trial studying a general population without prior evidence of CAD, to see the effects of long-term AO use on CAD prevention.

Dr. Mary Hardy is Medical Director at Cedars-Sinai Integrative Group in Los Angeles, CA.