Hormone Replacement Therapy Does Not Benefit and May Harm Stroke Patients
Abstracts & Commentary
Sources: Viscoli CM, et al. A clinical trial of estrogen-replacement therapy after ischemic stroke. N Engl J Med. 2001;345:1243-1249; Angeja BG, et al. Hormone therapy and the risk of stroke after acute myocardial infarction in post-menopausal women. J Am Coll Cardiol. 2001;38:1297-1301.
Hormone replacement therapy (HRT) is prescribed for postmenopausal women at risk for osteoporosis. Possible benefits may also include a reduced risk of vascular disease, such as coronary artery disease. Such benefits may also extend to the prevention of stroke. The reports summarized here, however, indicate that HRT does not seem to significantly affect the incidence of stroke among patients with a previous stroke or among women at high-stroke risk due to a recent myocardial infarction (MI).
It has been suggested through observational data, such as those of the Framingham Heart Study, that HRT is linked with a reduced risk of morbidity and mortality from cardiovascular causes. Randomized data, however, from the placebo-controlled Heart and Estrogen/Progestin Replacement Study (HERS), found no effect of HRT for secondary prevention of cardiac events. In the case of stroke, nonrandomized data have been conflicting with some studies, such as those of patients with atrial fibrillation, suggesting a higher stroke risk among estrogen users. While estrogen may have favorable effects on lipids and vascular tone, and induces fibrinolysis, it may be also be prothrombotic. This has been definitively shown for high estrogen-containing oral contraceptive preparations and likely applies to HRT as well.
Viscoli and colleagues report the results of the Women’s Estrogen for Stroke Trial (WEST) in which 664 postmenopausal women who had recently had an ischemic stroke or TIA were randomized to either estradiol-17B (1 mg/d) or placebo. There were 99 strokes or deaths in the estradiol group compared with 93 in the placebo group, a nonsignificant difference. Death due to stroke was significantly more common in the estradiol group, but there was no difference in nonfatal stroke. Although not statistically significant, drug-treated patients tended to have strokes earlier in their course of therapy and were less likely to have favorable outcomes or functional independence. Estradiol-treated patients did not have higher rates of venous thromboembolism or breast cancer, but did have increased rates of vaginal bleeding, endometrial hyperplasia, and 2 were found to have endometrial adenocarcinoma.
Angeja and colleagues report on data from the National Registry of Myocardial Infarction (NRMI), a cohort of 114,724 women treated at 1674 hospitals with the diagnosis of acute MI. More than 7300 of the patients were HRT users. A total of 2152 in-hospital strokes occurred, 442 hemorrhagic and 1017 ischemic. The incidence of both hemorrhagic and ischemic stroke was nearly equal among HRT users and nonusers. Prior evidence has suggested that women are at increased risk of hemorrhagic stroke as a complication of thrombolytic therapy for MI. This has been postulated to result from hormone-related factors. Among 13,328 women who received thrombolytic therapy, rates of hemorrhagic stroke were also not significantly different in HRT users compared to nonusers.
Commentary
These data provide compelling evidence that HRT should not be considered an important therapy in either the secondary prevention of stroke or as a means to decrease cerebrovascular complications in patients with coronary artery disease. Because the pathophysiology of stroke is varied—hemorrhagic vs. ischemic, embolic vs. thrombotic or lacunar—it would be unlikely that HRT would effect all of these in a uniform manner. Hormonal effects may furthermore be heterogenous, prothrombotic in some circumstances, fibrinolytic in others.
These data also indicate that not all HRT is the same. Unopposed estrogen may be used in patients who have had a hysterectomy, but, it otherwise may predispose to endometrial carcinoma, as the complications found by Viscoli et al suggest. The addition of progesterone protects the uterus, but it may counteract the favorable effects of estrogens on lipid profiles and, therefore, attenuate any possible cardiovascular benefits. Duration of therapy is also important. Since adverse events related to a prothrombotic tendency occur early in therapy, patients who have been on longstanding HRT may be past this risk and gain benefit from favorable sustained late effects such as decreased atherogenesis.
In conclusion, the data do not suggest that patients who have had a stroke should be treated with HRT. If patients have been on HRT prior to stroke, it should be continued only if the patient’s bone density suggests that she is at major risk of complications from osteoporosis. HRT should certainly be stopped in stroke patients recently initiated on hormones or in young stroke patients who have minimal risk factors and no other compelling reason to have had a CVA. —Alan Z. Segal
Segal, MD, Assistant Professor, Department of Neurology, Weill-Cornell Medical College, and Attending Neurologist, New York Presbyterian Hospital, is Assistant Editor of Neurology Alert.
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