Postmenopausal Hormone Therapy and Stroke. WEST: The Women’s Estrogen for Stroke Trial
Postmenopausal Hormone Therapy and Stroke. WEST: The Women’s Estrogen for Stroke Trial
Abstract & Commentary
Viscoli and colleagues conducted a randomized, double-blind, placebo-controlled trial of daily estrogen therapy in postmenopausal women after a recent (within 90 days) ischemic stroke or transient ischemic attack (25% of the women). The dose of estrogen was 1 mg estradiol orally per day. The women (a total of 664, 26% of the eligible women) were recruited from 21 hospitals in the United States and the age range was 46-91 years of age (mean, 71 years). After an average of 2.8 years of follow-up (range, 16-50 months), there was no difference in the risk of recurrent stroke or death comparing the treatment and placebo groups (relative risk [RR] = 1.1; confidence interval [CI], 0.8-1.4). There were no significant differences comparing the treatment and placebo groups in any of the assessed outcomes, including death or nonfatal stroke, fatal stroke, coronary death, nonfatal myocardial infarction, or transient ischemic attack. Viscoli et al emphasized that the women assigned to estrogen treatment had a higher risk of fatal stroke, but this did not achieve statistical significance (RR = 2.9; CI, 0.9-9.0) and the total number of cases was only 16. Adjustments for other risk factors such as heart disease, hypertension, diabetes, and smoking did not change the results. This study indicated that estrogen treatment was not effective for the secondary prevention of cerebrovascular events. (Viscoli CM, et al. N Engl J Med. 2001;
345:1243-1249).
Comment by Leon Speroff, MD
About 30 case-control and cohort studies of postmenopausal hormone therapy and the risk of stroke have produced no uniform results.1 Most of the evidence indicates no increase in the risk of stroke, and there is reason to believe, based on these epidemiologic studies, that postmenopausal estrogen therapy reduces the risk of fatal stroke. Primary prevention trials (treatment given to apparently healthy subjects) are lengthy and expensive. One reason to perform secondary prevention trials (treatment given to subjects already diagnosed with the disease in question) is to produce an answer faster and with fewer subjects. This was a major motivation behind the HERS trial, which addressed secondary prevention in women with coronary heart disease and the WEST trial, which studied secondary prevention of stroke in women with already diagnosed, symptomatic, clinically apparent disease.
Remember that the HERS trial reported an increase in cardiac events in the first year of treatment.2 Therefore, Viscoli et al of the WEST trial retrospectively analyzed the time course of cerebrovascular events and found a significantly increased risk of stroke at 6 months (RR = 2.3; CI, 1.1-5.0) based on 21 strokes in the estradiol group and 9 strokes in the placebo group. The severity of nonfatal strokes in the estradiol group was greater, but the difference was not statistically significant. In a post hoc analysis, the HERS trial found no difference in the risk of stroke comparing the treated group (with daily estrogen and progestin) and the placebo group.3 In contrast to the HERS trial, the WEST trial did not find an increase in venous thrombosis in the treated group; however, the patient numbers were too low to assess this infrequent event.
A major limitation of this study was the reduced compliance with treatment because of the problems associated with unopposed estrogen treatment. Over a 3-year period, 116 women in the estradiol group discontinued treatment (34%) compared with 79 in the placebo group (24%). Although Viscoli et al believe it unlikely that a benefit of treatment was missed because of noncompliance, it is still a possibility. The experience in the treated group is of interest, raising a real ethical question for future studies that include an arm with unopposed estrogen. Vaginal bleeding was experienced by 115 of the treated group and 33 of the placebo group; endometrial hyperplasia was diagnosed in 34 of the treated group and only 3 of the placebo group; 6 of the treated group were hysterectomized, only 1 of the placebo group; and there were 2 cases of endometrial cancer in the treated group.
The WEST trial, like the HERS trial, suggests that the risk of recurrent events is increased in the first year of estrogen exposure after a vascular event. Although these conclusions are based on relatively small numbers, they are derived from well-designed studies and warrant serious consideration. The clinical meaning is straightforward: patients should not be given estrogen treatment after a vascular event. Clinicians should not expect to prevent recurrent vascular events by the initiation of estrogen treatment. However, this recommendation is specifically targeted to women with existing vascular disease. In other words, there is a growing story that estrogen is ineffective—at least with short-term treatment in the secondary prevention of coronary and cerebrovascular events.
I believe it is not appropriate, however, to extend these results into the arena of primary prevention. There continues to be good reason (a large body of biologic and epidemiologic evidence) that postmenopausal hormone therapy reduces the risk of coronary disease in women who are apparently healthy and asymptomatic (primary prevention). The recent statement from the American Heart Association said that any recommendation regarding primary prevention must await the results of randomized clinical trials. My response is to point out that clinicians cannot and do not practice medicine in that fashion. If our practice were guided only by results from randomized clinical trials, we would never urge our patients to stop smoking. Everything we know about smoking and lung cancer comes from biologic studies and case-control and cohort epidemiologic data.
There is a theme emerging in the last 2 years based on the secondary prevention trials. Animal studies indicate that it takes a healthy endothelium to respond to estrogen, and therefore estrogen treatment of already diseased vasculature is too late. This can be applied to Alzheimer’s disease as well. Therefore, our emphasis should be directed to initiation of hormone treatment early in the postmenopausal years and maintenance for a period of time sufficient to achieve the benefits.
Another important thought is the consideration of the role of statin treatment. It is possible that the results in the first year of the HERS trial (and in the recent statements from the Women’s Health Initiative) reflected a decrease in events in the placebo group because of a greater rate of new statin use by the placebo group. There is no mention of statin use in the WEST report. A recent report documented that statin treatment reduced the risk of venous thrombosis even in postmenopausal women receiving estrogen therapy.4 Is it possible (and I think it is probable) that patients with vascular disease, once stabilized on statin therapy, are free of any risk associated with estrogen treatment. In other words, patients being treated with statins may be good candidates for hormone treatment.
References
1. Paganini-Hill A. Maturitas. 2001;38:243-261.
2. Hulley S, et al. JAMA. 1998;280:605-618.
3. Simon JA, et al. Circulation. 2001;103:638-642.
4. Ray JG, et al. Arch Intern Med. 2001;161:1405-1410.
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