Postmenopausal Hormone Therapy and Coronary Heart Disease
abstract & commentary
A secondary prevention trial did not detect any adverse or beneficial cardiovascular effects of postmenopausal hormone therapy in older women with existing heart disease. The Women’s Health Initiative is revealing an increase in heart attacks in the first two years of hormone treatment, followed by a reduction.
Herrington and colleagues have reported the results of a multicenter trial examining the effect of postmenopausal hormone therapy on the progression of coronary atherosclerosis as assessed by angiography. The results of this study, entitled Estrogen Replacement and Atherosclerosis (ERA), were presented on March 13, 2000, at the 49th Annual Meeting of the American College of Cardiology. A total of 309 women were randomly assigned to receive either unopposed estrogen, 0.625 mg Premarin (Wyeth-Ayerst Laboratories) per day; a daily combination of estrogen and progestin, 0.625 mg Premarin and 2.5 mg medroxyprogesterone acetate (PremPro; Wyeth-Ayerst Laboratories); or placebo. More than 3.5 years of treatment angiography did not detect any differences in disease progression between any of the groups. The women in this study had documented heart disease on entry and were a relatively older group of women (mean age, 65.8 years). Half had had a previous myocardial infarction (MI). There were no reported increases in cardiac events in any of the three treatment groups.
The large American randomized clinical trial examining the effects of postmenopausal hormone therapy, the Women’s Health Initiative (WHI), is informing the women in the study that a "small increase" in heart attacks, strokes, and venous thrombosis has been observed in the first two years of the study comparing hormone treatment with placebo. This increase is reported to be present in all treatment arms, including the group treated with estrogen alone. This information was made available by the Data and Safety Monitoring Board (DSMB); therefore, the actual data will probably not be revealed until the completion of the study. The DSMB has recommended that the study continue; it is scheduled for completion in 2005; another year should be required for data analysis.
COMMENT BY LEON SPEROFF, MD
It is unusual for us to review unpublished reports; however, I believe an acute response is important because of the anticipated reactions and widespread publicity. The ERA trial joins the HERS trial in demonstrating no secondary preventive effect of postmenopausal hormone therapy in older women with significant coronary heart disease. Comparing the two trials, however, there are several important observations.
Some have argued (most notably, Tom Clarkson and colleagues1-3) that the lack of a beneficial effect of estrogen in the HERS trial was because of the attenuating action that resulted from the daily presence of medroxyprogesterone acetate (PremPro). The ERA trial contained an estrogen-only arm, and the absence of a difference between the estrogen-only arm and the PremPro arm argues against a negative effect due to the daily administration of medroxyprogesterone acetate.
The HERS trial was not a totally null result. In the first year of the trial, there was a 52% increase in clinical events in the women treated with PremPro, and in years three and four there was evidence of emerging protection against cardiac events in the treated group. Like the HERS trial, the WHI is reporting evidence of protection in the last months of the first two years of the study. Why were similar observations not present in the ERA trial? Most likely, the answer lies in the numbers of patients combined with duration of treatment, 2763 women studied four years or more in the HERS trial compared with 309 women studied for 3.5 years in the ERA trial (ultimately a relatively small number of women finished the study in each treatment arm). The ERA results are not sufficiently robust to eliminate the concern arising from the HERS trial that there exists a group of women with heart disease in whom exposure to hormone therapy increases the risk of adverse events in the first months of treatment.
Further analysis of the HERS data has indicated that the increase in adverse events in the first year occurred in the first eight months of treatment, most likely, in my view, due to a prothrombotic effect of oral estrogen. Are these events occurring in a susceptible, vulnerable group of women, perhaps sicker women with unstable atherosclerotic plaques? We will have to await the full publication of the ERA data to see if there is a time and age distribution of importance, but this is unlikely because of the relatively small numbers.
The report from the WHI also provides a strong argument that medroxyprogesterone acetate is not preventing beneficial estrogen actions on the cardiovascular system (because, like the HERS trial, the adverse effects were present in the estrogen-only arm as well as with estrogen-progestin treatment).
The actual number of events upon which the WHI report is based totals less than 1% of WHI women (less frequent than in the HERS trial, probably less than several hundred events, including all three diagnoses—heart attacks, strokes, and venous thrombosis). The absence of an increase in cardiac events in the ERA trial also indicates that the risk is not a large one. I can’t help but believe that any increase must be small in terms of actual incidence, otherwise our clinical consciousness would have been imprinted with these experiences.
There are several important questions that hopefully can be answered by analysis of the WHI data:
• Is the increase in heart attacks confined to a susceptible group of women and, if so, what are their characteristics?
• What is the age distribution of the clinical events; are the heart attacks concentrated in older women? It is of importance to be aware that many of the subjects in the WHI are relatively older women who began treatment years after menopause. Thus, some of the participants had evidence of preexisting cardiovascular disease (including heart attacks, bypass surgery, angina, and angiographic procedures). Is the increase in events concentrated in this segment?
• Will a beneficial effect become significant with longer duration of treatment (as suggested in the HERS trial)?
The secondary prevention trials have led to the recommendation that older women with significant coronary heart disease should avoid initiating postmenopausal hormone therapy. Until the report from the WHI, there was reason to believe that the results from the secondary prevention trials did not imply that primary prevention, hormone therapy administered to younger postmenopausal women without evidence of coronary heart disease, would not be effective, as predicted by the many case-control and cohort studies. Furthermore, these reports are contrary to a huge number of biological studies documenting favorable actions of estrogen on the cardiovascular system.
Other studies presented in 2000 at the American College of Cardiology were uniformly consistent with a beneficial effect of estrogen on the cardiovascular system, even in women with existing atherosclerotic disease. An Italian double-blinded study indicated that estrogen treatment improved brachial artery resistance and increased forearm blood flow in women with risk factors for coronary artery disease (CAD). A short-term (3 months) study at Mt. Sinai in New York revealed that estrogen reduced thrombus formation in elderly women with evidence of cardiovascular disease. A study on serum lipids concluded that combined estrogen-progestin therapy together with a statin produced a greater favorable response than either treatment alone. In both a post-mortem histopathological study and a CT scan study of coronary arteries, coronary artery calcium content and atherosclerotic plaque area were lower in hormone users compared with nonusers. Premenopausal women with CAD in the Women’s Ischemia Syndrome Evaluation (WISE) study were reported to have lower estrogen levels compared with women without disease. These studies add to a large body of biological evidence that estrogen and estrogen combined with a progestin have effects that should provide protection against cardiovascular disease. Why such favorable effects were not apparent in the ERA trial remains a mystery. Is a three-year study too short to demonstrate beneficial effects on clinical events, especially with relatively small numbers? Is angiography as a method of assessment too limited, unable to detect important effects that are not expressed in anatomical changes? Will the WHI yield more favorable data as time passes?
Is it possible that the results of these trials are not real? There is one concern in my mind that makes this question reasonable. These studies cover a period when the efficacy of statins was established. The increasing use of statins, especially in older women who are not hormone users, makes it difficult to have a true placebo group in studies of coronary heart disease. We will need to carefully assess the degree and effect of statin use by the women in these trials. Specifically, is the early increase in events in the HERS and WHI trials due to a statin-induced decrease in events in the placebo groups?
I fully expect that these surprising results will reinforce those who have argued that the case-control and cohort studies of postmenopausal hormone therapy and coronary heart disease have been biased by the healthy user effect (hormone users are healthier than nonusers and therefore observational studies find less coronary heart disease in hormone users). But it seems to me that we should not discount the enormous literature that over and over documents favorable biological effects of estrogen on the cardiovascular system—effects that should produce protection against coronary heart disease. All the pieces are not fitting in this puzzle. It seems logical to me that the WHI results reflect a prothrombotic effect of estrogen in a susceptible group of women. With some urgency, we need to determine if such a group exists, and, if it does, what are the characteristics of these women?
Conclusions
1. These trial results are reasons to be conservative regarding hormone therapy for older women with evidence of coronary heart disease. Certainly we should not promote estrogen as a first-line drug to prevent further clinical events in women with CAD, especially in women who have had a recent MI. Multiple clinical trials have established that treatment with statins is effective in preventing clinical cardiac events.
2. The ERA and WHI results indicate that there is no need to avoid the use of medroxyprogesterone acetate.
3. The results of the WHI make an argument that the optimal approach to postmenopausal hormone therapy is to start treatment close to the menopause, avoiding a significant period of exposure to low estrogen levels prior to beginning therapy.
4. With evidence accumulating that a beneficial effect emerges with increasing duration of treatment, we need to intensify our efforts to improve and maintain compliance.
5. There continues to be good reason to believe that long-term therapy has preventive benefits.
6. These results indicate the need and importance of studying the question of whether older women should be started at lower doses of estrogen. Doses may need to be titrated according to patient characteristics. Another question that emerges from these studies is whether women with coronary heart disease would benefit from hormone therapy if treatment were to begin after stabilization is achieved with a period of exposure to statins.
7. We should continue to advise current users of postmenopausal hormone therapy that it is unwise to discontinue treatment.
8. We need to determine whether the transdermal route of delivery yields different effects on the cardiovascular system.
9. Because the events in the WHI occurred early, followed by a reduction, clinicians should encourage participants in the study to remain enrolled, impressing upon them the importance of this large clinical trial.
References
1. Adams MR, et al. Inhibition of coronary artery atherosclerosis by 17-beta estradiol in ovariectomized monkeys. Lack of an effect of added progesterone. Arteriosclerosis 1990;10:1051-1057.
2. Adams MR, et al. Medroxyprogesterone acetate antagonizes inhibitory effects of conjugated equine estrogens on coronary artery atherosclerosis. Arterioscler Thromb Vasc Biol 1997;17:217-221.
3. Williams JK, et al. Effects of hormone replacement therapy on reactivity of atherosclerotic coronary arteries in cynomolgus monkeys. J Am Coll Cardiol 1994;24:1757-1761.
The following statements are true regarding postmenopausal hormone therapy and coronary artery disease except:
a. The only primary prevention randomized clinical trial data are thus far limited to two years of treatment.
b. Randomized clinical trial data indicate that short-term (< 3 years) hormone treatment had no beneficial effects on already present coronary artery disease.
c. Postmenopausal women who have had a heart attack should be offered hormone therapy as part of an effort to prevent a subsequent cardiac event.
d. Almost all of the biological studies examining the effects of estrogen on the cardiovascular system are consistent with responses that should protect against coronary artery disease.
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