Special Feature: Estrogen Treatment of Postmenopausal Women With Unstable Angina
By Leon Speroff, MD
Schulman and colleagues from baltimore, Pittsburgh, and Sao Paulo, Brazil, conducted a randomized, double-blind, placebo-controlled study of 293 women with unstable angina. Unstable angina was defined as 10 or more minutes of pain with reversible electrocardiogram ST-segment changes, or ischemic chest pain in patients with a prior diagnosis of coronary artery disease (CAD) (prior angiography or MI). After an episode of unstable angina, within 24 hours the women received either intravenous estrogen (1.25 mg conjugated estrogens over 30 minutes) followed by 1.25 mg conjugated estrogens orally and daily for 21 days or a combination of 1.25 mg conjugated estrogens and 2.5 mg medroxyprogesterone acetate orally and daily for 21 days, or both the intravenous treatment and the oral treatment were placebos. The women ranged in age from 48-93 with an average of about 70. They had a high prevalence of heart disease risk factors, such as hypertension and diabetes mellitus. The attending physicians treated the patients with the usual anti-ischemic methods, including heparin, aspirin, beta-blockers, and nitroglycerin. In the first 48 hours, there were no adverse effects of the intravenous estrogen, and the ischemic events in the 3 treatment groups were essentially the same. The clinical outcomes during the initial hospitalization (death, MI, coronary procedures) also did not differ among the 3 groups. Twenty percent of the patients discontinued the study drug before the end of the 21 days, and these were evenly distributed among the 3 groups. The number of ambulatory electrocardiographic ischemic episodes showed no differences, but only about 10% of the patients experienced ischemia. One patient on estrogen alone developed a pulmonary embolus on day 2, and 2 patients on hormone treatment had strokes after coronary artery bypass surgery. Six months later, there were no differences among the 3 groups. Schulman et al concluded that acute hormone therapy does not reduce ischemia in postmenopausal women with unstable angina (Schulman SP, et al. J Am Coll Cardiol. 2002;39:231-237).
Discussion
This is another secondary prevention trial of estrogen treatment in women with CAD, but this time the study focused on acute therapy. Women with CAD present more often with unstable angina compared with men. Up to 30% of women who present with unstable angina have no detectable CAD on angiography; in this group of women the pathophysiology of the ischemic chest pain is a puzzle. Presumably the ischemic pain is due to coronary vasoconstriction originating in endothelial dysfunction, even in those women with normal angiographic studies. In patients with atherosclerosis, the ischemic episode is believed to be due to some degree of rupture in an unstable plaque, activating platelets and the release of vasoconstricting agents. Previous studies have demonstrated that the acute administration of estrogen produces a rapid vasodilatory response in the coronary arteries; therefore, it was reasonable to determine if acute treatment would have an effect on recurrent ischemia as measured by electrocardiographic assessment.
There are 2 major problems with the above study. First of all, Schulman et al failed to achieve the number of ischemic events that their power calculations predicted beforehand. This relates to the second major problem. The reason for a decreasing number of ischemic events in the patients (in a proportion that increased as the study progressed) was the aggressive anti-ischemic therapy given these patients, although Schulman et al argued that a similar decrease in the placebo group made it unlikely that this treatment affected the results. So the study lacked the power to detect even a modest difference among the groups, and what if the beneficial effect of estrogen was overpowered by the anti-ischemic treatments, especially nitroglycerin (nitroglycerin is believed to act through the same mechanisms as estrogen, specifically involving nitric oxide and endothelin-1).
A retrospective study from Duke found an increased risk of unstable angina in women initiating estrogen treatment after a cardiac event.1 It is interesting to me that the cardiologists, when referring to this study, uniformly overlook the fact that there was a statistically significant reduced risk of dying of a myocardial infarction in the hormone users.
Accompanying this report is an editorial subtitled "Another Bump for the Bandwagon," written by David D. Waters from the Division of Cardiology at the University of California in San Francisco (Waters DD. J Am Coll Cardiol. 2002;39:238-240). Waters reviews the by now well-known previous secondary prevention trials (the HERS trial, the ERA trial, the PHASE trial) and endorses the current recommendation that postmenopausal hormone therapy should not be initiated for the prevention of coronary disease in women already diagnosed with CAD. He concludes that "the bandwagon is now bedraggled and the music has died." I would argue, however, that this conclusion applies to a small number of patients being treated with hormone therapy. Primary care physicians are well aware that other treatments, especially statins, are effective and the methods of choice in women with diagnosed CAD. To jump to the conclusion that hormone therapy has nothing to offer for the cardiovascular system of apparently healthy women denies an enormous body of epidemiologic (case-control and cohort studies) and biologic data supporting beneficial effects.
The American Heart Association, in their recent statement, said that any recommendation regarding primary prevention of heart disease by estrogen must await the results of randomized clinical trials. My response is that we can’t practice medicine that way. If we did we would never tell our patients to stop smoking (certainly no randomized trial data linking smoking and lung cancer!). Furthermore, there is good experimental evidence to support the conclusion that it takes a healthy endothelium to respond to estrogen. In Tom Clarkson’s monkey model, as the endothelial cells become involved with atherosclerosis, estrogen’s beneficial effects are progressively reduced.
The results of a primary prevention trial in Los Angeles have been recently published indicating a preventive effect of estrogen. Measuring carotid intima media thickness by ultrasonography, women treated with estrogen demonstrated a decrease in thickness after 2 years of treatment in contrast to an increase observed in the placebo group.2 A similar study in Germany found no effect of hormone treatment, but the patients already had increased thickness (and thus atherosclerosis) upon entry to the study and the treatment duration was only 1 year.3
Therefore, the current study is an extremely small bump on the bandwagon, because it is underpowered and the patients received potent anti-ischemic treatments that could have obscured any effects of estrogen. Furthermore, there continues to be good reason to believe that long-term hormone therapy in asymptomatic, apparently healthy women has a beneficial effect on the cardiovascular system and reduces the risk of CAD. This represents almost all of our patients; the cardiologists are making a big bump out of a mole hill!
References
1. Alexander KP, et al. J Am Coll Cardiol. 2001;38:1-7.
2. Hodis HN, et al. Ann Intern Med. 2001;135:939-953.
3. Angerer P, et al. Atheroscler Thromb Vasc Biol. 2001; 21:262-268.
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