The WAVE Trial—More of the Same 

Abstract & Commentary

The Women’s Angiographic Vitamin and Estrogen (WAVE) Trial was a randomized, controlled secondary prevention study. This study enrolled 423 postmenopausal women with coronary atherosclerosis already established at baseline by angiography. The design was complicated, assessing progression of coronary artery disease by serial angiography in 4 groups of women:

  1. hormone therapy;
  2. super doses of vitamin C (500 mg b.i.d.) and vitamin E (400 IU b.i.d.);
  3. hormone therapy and vitamins C and E; and
  4. placebo.

The hormone therapy consisted of daily 0.625 mg conjugated equine estrogens, and when a uterus was present, the estrogen was combined with 2.5 mg medroxyprogesterone daily. The mean age of the women was 65 years and the mean length of follow-up was 2.8 years. The main conclusion was that neither hormone therapy nor large doses of antioxidant vitamin supplements provided any cardiovascular benefit. Indeed, Waters and colleagues further state, "a potential for harm was suggested with each treatment" (Waters DD, et al. JAMA. 2002;288:2432-2440).

Comment by Leon Speroff, MD

The conclusions are based upon the angiographic outcomes in the 320 women who completed follow-up studies. The lumen diameters of the coronary arteries diminished in all groups and there were no statistically significant differences comparing the groups. There were also no significant differences in clinical events. Waters et al point out that potential harm was observed with both treatments. This was based upon an analysis that included both angiographic change and clinical events, indicating a statistically significant risk associated with hormone therapy (P = 0.45) and an increased risk with vitamins that was of "borderline significance" (P = 0.09).

Let’s look at these conclusions a little closer. You have to examine the publication carefully, but there are 2 observations of note:

1. The women receiving hormone therapy had a statistically significant greater prevalence of diabetes (associated with both greater glucose and insulin levels);

2. The prevalence of statin use at baseline was nearly 60% and aspirin use at baseline was 85%. There is no information regarding initiation of new statin or aspirin treatment during the study.

Under the results, there exists a very important sentence referring to the significant increase in risk reported in the hormone users: "After adjusting for diabetes and diabetes-related variables, the risk was no longer significant." And yet in the discussion, and in the abstract conclusion, Waters et al fail to repeat this sentence, unfairly leaving the reader with the incorrect conclusion, that hormone therapy increased cardiovascular risk. This is another publication from the National Heart, Lung, and Blood Institute (like the Women’s Health Initiative [WHI] report) that chooses to emphasize a negative effect of estrogen by providing a presentation that is less than fair.

And that’s not all. About 20% of the study patients failed to have follow-up angiography or clinical events, and, even more importantly, 33% of the hormone users didn’t take the prescribed medication (leaving only 114 women divided among 2 groups for analysis). The power-to-detect effects was severely limited.

Notice the high percentage of statin and aspirin use at baseline. Remember that there is good evidence that in the presence of statins, the beneficial effect of estrogen can no longer be detected. And, finally, are the numbers influenced by new statin and aspirin treatment during the duration of the study?—a very important issue that must be addressed in the WHI data as well.

This study is limited in power by an inability to keep patients in the study, its failure to balance the prevalence of diabetes in its randomization of patients, and its influence by statin and aspirin treatment. It is reasonable to add the WAVE trial to the evidence indicating that hormone therapy is not indicted for the secondary prevention of coronary artery disease (not a new lesson), but the implication that hormone therapy was harmful is not supported by the WAVE data.

Dr. Speroff is Professor of Obstetrics and Gynecology Oregon Health Sciences University, Portland.