Background Observational studies have suggested that estrogen-replacementtherapy may reduce a woman's risk of stroke and death.
Methods We conducted a randomized, double-blind, placebo-controlledtrial of estrogen therapy (1 mg of estradiol-17 per day) in664 postmenopausal women (mean age, 71 years) who had recentlyhad an ischemic stroke or transient ischemic attack. Women wererecruited from 21 hospitals in the United States and were followedfor the occurrence of stroke or death.
Results During a mean follow-up period of 2.8 years, there were99 strokes or deaths among the women in the estradiol group,and 93 among those in the placebo group (relative risk in theestradiol group, 1.1; 95 percent confidence interval, 0.8 to1.4). Estrogen therapy did not reduce the risk of death alone(relative risk, 1.2; 95 percent confidence interval, 0.8 to1.8) or the risk of nonfatal stroke (relative risk, 1.0; 95percent confidence interval, 0.7 to 1.4). The women who wererandomly assigned to receive estrogen therapy had a higher riskof fatal stroke (relative risk, 2.9; 95 percent confidence interval,0.9 to 9.0), and their nonfatal strokes were associated withslightly worse neurologic and functional deficits.
Conclusions Estradiol does not reduce mortality or the recurrenceof stroke in postmenopausal women with cerebrovascular disease.This therapy should not be prescribed for the secondary preventionof cerebrovascular disease.
Although many observational studies have linked postmenopausalestrogen therapy with a reduced risk of vascular disease, especiallymorbidity and mortality from cardiovascular causes,1 concernhas persisted that these findings may be attributable not toestrogen therapy but to other differences between users andnonusers of such therapy.2 Although estrogen therapy may havefavorable effects on lipid metabolism,3 coagulation,4,5 andvascular tone,6,7 it may also have adverse prothrombotic andproinflammatory effects.8,9
In 1998, the findings of the first placebo-controlled, randomizedclinical trial of hormone-replacement therapy for the secondaryprevention of cardiac disease in postmenopausal women, the Heartand Estrogen/Progestin Replacement Study (HERS), were reported.Surprisingly, daily therapy with conjugated estrogen and progestindid not reduce the incidence of coronary events or death fromany cause during four years of follow-up.10
When that study began, epidemiologic research also suggestedthat estrogen might protect against stroke,11,12,13,14 althoughthis evidence was less consistent than that for protection againstcoronary heart disease. Some studies reported no effect of estrogenuse on the risk of stroke,15,16,17,18,19,20,21,22 and two largecohort studies reported an increased risk.23,24 Our study, theWomen's Estrogen for Stroke Trial, was designed in 1993 as arandomized, placebo-controlled trial of estrogen replacementfor the secondary prevention of cerebrovascular disease. Theprimary end point was death from any cause or nonfatal stroke;secondary outcomes were transient ischemic attack and nonfatalmyocardial infarction. Other prespecified analyses includedthe effect of estrogen on the rate of death alone, the incidenceof stroke alone, the severity of recurrent strokes, and theincidence of cardiac events.
Methods
Study Participants
A description of the design and methods of our study has beenreported previously.25 We enrolled postmenopausal women olderthan 44 years of age within 90 days after a qualifying ischemicstroke or transient ischemic attack. Women were recruited betweenDecember 1993 and May 1998. Women were excluded if their indexevent was disabling (had a severity score greater than 5 onthe scale used in the North American Symptomatic Carotid EndarterectomyTrial26) or if it occurred while the woman was taking estrogen.Women were considered postmenopausal if they had had amenorrheafor at least 12 months or if they had undergone hysterectomyand were older than 55 years of age.
Women were not eligible if they had a history of breast or endometrialcancer, had had a venous thromboembolic event while receivingestrogen-replacement therapy, had a neurologic or psychiatricdisease that could complicate the evaluation of end points,or had a coexisting condition that limited their life expectancy.Screening tests to confirm eligibility were required beforeentry; these included computed tomography to rule out nonischemiccauses of the stroke syndrome, clinical breast examination,mammography, and (in women who had not undergone hysterectomy)a Papanicolaou smear. All women provided written informed consentfor their participation and were specifically informed aboutthe potential risk of uterine cancer associated with estrogentherapy. Approval was obtained from the institutional reviewboard at each participating hospital.
Neurologic deficits were assessed by a nurse during an initialhome visit with the use of the National Institutes of HealthStroke Scale (NIHSS),27 a measure of 11 categories of neurologicsigns. Index events were verified by a neurologist associatedwith the study who reviewed the nurse's assessment and pertinentmedical records. When women entered the study, their self-reportedfunctional ability in activities of daily living was recordedwith the use of the Barthel index.28
Randomization
At the start of the trial, a master list of computer-generatedrandom treatment assignments was stored at the investigationalpharmacy at Yale–New Haven Hospital. Randomization wasstratified according to clinical center (21 hospitals) and base-linerisk group as defined according to a previously validated clinicalindex (three groups)29 and was performed so as to equalize treatmentassignments in blocks of four subjects. Participants were randomlyassigned to receive either estradiol-17 (Estrace, Mead Johnson,Evansville, Ind.) at the standard replacement dose of 1 mg dailyor matching placebo. The use of a regimen of estrogen alonewas chosen to avoid any possible antagonizing effects of progestinson the hemodynamic benefits of estrogen.6
The women and the investigators were unaware of the treatmentassignment. The study internist could be unblinded when therewas an overriding concern about a woman's clinical care; thisoccurred in the case of six women in the estradiol group andseven women in the placebo group. The investigators who wereinvolved in the assessment of outcomes were not informed ofthe occurrence of vaginal bleeding or other effects of activetherapy.
Follow-up Procedures
Every three months after entry, a nurse contacted each womanby telephone to promote compliance with the study-drug regimen,assess side effects, and screen for outcomes with the use ofa standardized questionnaire.30 The women were also asked whetherany of the following events had occurred: stroke, transientischemic attack, myocardial infarction, blood clot in the legor lung, hospital admission or emergency room visit, and vaginalbleeding. We reviewed the medical records for all reported events.
To screen for endometrial hyperplasia, women with a uterus underwenttransvaginal ultrasonography annually or received an annual12-day course of medroxyprogesterone acetate (5 mg daily). Womenwith abnormal findings on ultrasonography (an endometrial thicknessof more than 5 mm or evidence of an irregular endometrial surface)or who had vaginal bleeding before day 11 of the course of progestinwere referred for endometrial biopsy.31 Adherence to the studyregimen was monitored by means of pill counts.
Monitoring for Adverse Events
We monitored the women for the occurrence of endometrial hyperplasiaor cancer by referring them for endometrial biopsy or transvaginalultrasonography whenever unexpected vaginal bleeding occurredand at the end of their participation in the study. Mammographywas performed annually to monitor for breast cancer. We alsomonitored the women for venous thromboembolic events; a diagnosisof deep venous thrombosis required a positive duplex ultrasonogramor venogram, and a diagnosis of pulmonary embolus required aventilation–perfusion scan indicating a high probabilityof pulmonary embolus, a positive pulmonary angiogram, or a diagnosticcomputed tomographic scan of the chest. When a diagnosis ofendometrial cancer, breast cancer, or venous thrombosis wasconfirmed, the study drug was discontinued, but follow-up forthe occurrence of the trial outcomes continued.
Ascertainment of Outcomes
Stroke was defined as an acute neurologic event of at least24 hours' duration, with focal signs and symptoms and withoutevidence supporting any alternative explanation; strokes wereclassified as ischemic or hemorrhagic on the basis of brainimaging.26 Transient ischemic attack, a secondary outcome, wasdefined by the presence of focal neurologic or retinal symptomslasting more than 30 seconds and resolving in less than 24 hours.Each suspected neurologic event was initially evaluated by theprincipal neurologist through the review of records and in consultationwith the treating physician, the woman, or both. When a nonfatalstroke occurred, the study drug was stopped and follow-up ended.The severity of strokes was quantified with the use of the NIHSSand the Barthel index during a final visit that was conducted,whenever possible, one month after the stroke occurred. Allsuspected neurologic events were adjudicated at the conclusionof the trial by the principal neurologist and two independentneurologists specializing in stroke.
Hospital records, nurses' notes, and death certificates wereobtained for all deaths. Any confirmed stroke that was followedby death within 30 days was classified as a fatal stroke. Deathsfrom cardiovascular causes included deaths that followed definiteor possible acute myocardial infarction as well as deaths fromcoronary events as defined according to the criteria of theWorld Health Organization's Monitoring Trends and Determinantsin Cardiovascular Disease project.32 Suspected nonfatal myocardialinfarctions were evaluated by a clinical investigator accordingto prespecified criteria based on the measurement of cardiacenzymes and electrocardiographic tracings.33
Statistical Analysis
Under the assumptions that the 3-year rate of the primary outcome(death or nonfatal stroke) would be reduced from 25 percent(in the placebo group) to 15 percent (in the estradiol group),that the average duration of follow-up would be 3.5 years, andthat the dropout rate would be 10 percent (including women inwhom treatment was discontinued and those who were lost to follow-up),we required a sample of 652 women to achieve 80 percent powerat a two-tailed alpha level of 0.05.34 The P values for stoppingthe trial after the five prespecified interim analyses wereset at 0.001, 0.001, 0.004, 0.012, and 0.024 with the use ofthe O'Brien–Fleming guidelines for early termination.35An independent external performance and safety monitoring boardreviewed the study protocol and monitored adverse events andinterim results during the trial.
All analyses were conducted according to the intention-to-treatprinciple. Time-to-event curves for each treatment group werecalculated by the Kaplan–Meier method36 and compared bymeans of the log-rank test.37 The estimates of relative risk,with 95 percent confidence intervals, were derived from Coxproportional-hazards models.38 We used another Cox proportional-hazardsmodel to estimate relative risks for the women in both treatmentgroups whose average compliance with the study regimen was atleast 80 percent (as-treated analysis).
Results
Of the 5296 women who were identified as having had cerebrovascularevents that met the criteria for eligibility, 2772 were foundto be ineligible for enrollment (652 were not capable of providinginformed consent, 632 had severe coexisting conditions, 512were already taking estrogen, 326 had a history of breast cancer,191 did not speak English, 171 lived out of state, 133 werepremenopausal, 108 had a history of endometrial cancer, 38 hadother contraindications to estrogen therapy, and 9 were enrolledin another trial). Among the 2524 eligible women, 1843 declinedto participate and 17 could not be randomly assigned to a treatmentgroup within 90 days after their qualifying event. The finalcohort comprised 664 women (26 percent of the eligible women);337 were assigned to the estradiol group and 327 to the placebogroup.
The mean age of the enrolled women was 71 years (range, 46 to91). Eighty-four percent reported their race as non-Hispanicwhite, 40 percent were currently married, and the median levelof education was completion of the 12th grade. The qualifyingevent was stroke for 75 percent of the women. There were nosignificant differences in demographic or clinical characteristicsaccording to treatment group (Table 1).
All women who were alive and had not had a stroke during thestudy period were withdrawn from the study during the close-outperiod (May 1999 through November 1999). The mean (±SD)duration of follow-up was 33±17 months. At the end ofthe study, the women who had not reached an end point had beenfollowed for at least 12 months (mean, 38±15). Vitalstatus was confirmed for all women at the conclusion of thetrial. Nine women (six in the estradiol group and three in theplacebo group) declined an exit visit. During the trial, thestudy drug was discontinued in 116 women in the estradiol group(34 percent) and 79 women in the placebo group (24 percent).Among the women who discontinued the study drug, four in theestradiol group (1 percent) and seven in the placebo group (2percent) reported using open-label estrogen. Overall, the meancompliance with study medication (including compliance by thewomen who discontinued treatment) was 70 percent (66 percentin the estradiol group and 74 percent in the placebo group);compliance among women who did not discontinue the study drugwas 90 percent in both treatment groups.
Trial Outcomes
Primary Outcomes
A total of 89 deaths and 103 nonfatal strokes occurred duringthe trial (Table 2). Primary outcomes were confirmed for 99women in the estradiol group and 93 women in the placebo group.As shown in Figure 1, there was no significant difference betweenthe treatment groups in the incidence of death or nonfatal stroke.Slightly more women in the estradiol group than in the placebogroup died during follow-up (48 vs. 41), but the differencewas not significant (Table 2). However, death due to strokewas more common in the estradiol group (Figure 2) (relativerisk, 2.9; 95 percent confidence interval, 0.9 to 9.0). Thisincrease primarily reflected a difference in the incidence ofischemic stroke (Table 2). The rates of death from cardiovascularcauses and death from other causes were similar in the two treatmentgroups (Table 2).
Figure 2. Kaplan–Meier Curves for the Time to Fatal Stroke (Panel A) and the Time to Any Stroke (Nonfatal or Fatal) (Panel B).
P=0.05 by the log-rank test for the analysis of time to fatal stroke; P=0.57 by the log-rank test for the analysis of time to any stroke.
The incidence of nonfatal stroke and nonfatal ischemic strokewas similar in the two treatment groups (Table 2). When nonfatalevents were included in the analysis, the risk of stroke wasnot significantly different between the two treatment groups(Figure 2). Adjustment for base-line risk factors (older age,history or electrocardiographic evidence of myocardial infarction,congestive heart failure, hypertension, diabetes, and currentsmoking) did not materially affect these results.
Because an increase in vascular events with hormone-replacementtherapy was observed in the first year of follow-up in HERS,10we conducted a post hoc analysis of early cerebrovascular events.During the first six months, 3 fatal strokes and 18 nonfatalstrokes occurred in women in the estradiol group, as comparedwith 1 fatal stroke and 8 nonfatal strokes in women in the placebogroup (P=0.03 by the log-rank test; relative risk of any strokeat six months, 2.3; 95 percent confidence interval, 1.1 to 5.0).
We also compared the two treatment groups in terms of the severityof nonfatal strokes (Table 3). The median interval between anonfatal stroke and the evaluation of its severity was 35 daysfor women in the estradiol group and 39 days for women in theplacebo group. Women assigned to the estradiol group were lesslikely than women in the placebo group to have no neurologicdeficits or only mild impairment of neurologic function (a NIHSSscore of 0 or 1) after stroke and less likely to have functionalindependence (a Barthel index of 90 or higher), although neitherof these differences was statistically significant. When fatalstrokes were included in the analysis, the differences in severitywere more extreme.
No significant difference was observed between the treatmentgroups in the incidence of transient ischemic attack or nonfatalmyocardial infarction (Table 2). The risk of any cardiac event(fatal or nonfatal) did not differ significantly between thetwo groups (relative risk in the estradiol group, 1.1; 95 percentconfidence interval, 0.6 to 1.9).
Outcomes According to Treatment Received
When the analysis was restricted to the 397 women who took atleast 80 percent of the assigned study medication, the adjustedrelative risk for women in the estradiol group as compared withthose in the placebo group was nonsignificantly elevated fordeath or nonfatal stroke (relative risk, 1.2; 95 percent confidenceinterval, 0.8 to 1.8), for any stroke (relative risk, 1.3; 95percent confidence interval, 0.8 to 2.1), and for death fromany cause (relative risk, 1.2; 95 percent confidence interval,0.7 to 2.3).
Vital Status at the End of the Trial
An additional 28 deaths occurred in women who had a nonfatalstroke as their study end point (15 in the estradiol group and13 in the placebo group). Including these deaths, overall mortalitywas 18.4 percent in the estradiol group and 16.3 percent inthe placebo group.
Other Events during Follow-up
The women in the estradiol group did not have higher rates ofvenous thromboembolic events, breast cancer, or hospitalizationfor fractures than those in the placebo group. However, womenin the estradiol group were more likely to have vaginal bleeding,to have endometrial hyperplasia, and to require a hysterectomy(Table 4). Two women in the estradiol group were found to haveendometrial adenocarcinoma after having vaginal bleeding (onethree months after randomization and the other six months afterrandomization).
Table 4. Other Events during Follow-up, According to Treatment Group.
Discussion
In this high-risk population of postmenopausal women with arecent cerebrovascular event, treatment with estradiol-17 forthree years was ineffective in reducing the overall risk ofstroke or death or the incidence of the individual end pointsof death, fatal or nonfatal stroke, transient ischemic attack,or cardiac events during follow-up. Moreover, this therapy wasassociated with adverse effects on the endometrium, includingelevated rates of vaginal bleeding and endometrial hyperplasiaand a more frequent need for hysterectomy.
Although we cannot rule out the possibility that estrogen therapyhas minimal cerebrovascular benefits, our study had sufficientpower to rule out reductions in the risk of death or strokeof more than 20 percent. The challenges involved in gettingwomen to continue taking estrogen are well documented,39 andnoncompliance may have limited our ability to detect an effectof treatment. However, the compliance rates achieved in thistrial (mean, 66 percent over a three-year period) are considerablyhigher than those found among estrogen users in the community.40Furthermore, the point estimates for increased risk among womenwho adhered well to the study regimen indicate that it is unlikelythat we missed a benefit of treatment because of noncompliance.
The incidence of venous thromboembolic events in the estradiolgroup in our study was low, and it did not differ significantlyfrom that in the placebo group. As in other studies, the incidenceof breast cancer was not affected by estrogen therapy duringthe relatively short period of follow-up. The risk of bone fracturewas also not significantly altered by treatment with estrogen.
Although our findings differ from those of observational studiesthat have reported a reduction in the risk of stroke associatedwith estrogen use,11,12,13,14 they are consistent with otherlarge population studies that have reported increases in therisk of stroke among generally healthy, relatively young postmenopausalwomen who were receiving estrogen therapy.23,41 HERS, anotherrandomized trial of estrogen for the secondary prevention ofvascular disease in women, tested a different regimen from theone we used (0.625 mg of conjugated equine estrogens plus 2.5mg of medroxyprogesterone acetate per day) and enrolled slightlyyounger women (mean age, 67 years) with established coronarydisease. That trial found no overall reduction in the risk ofcardiovascular events and, in a recent secondary analysis, noreduction in the risk of stroke in the study population (relativehazard, 1.23; 95 percent confidence interval, 0.89 to 1.70).42Although fatal stroke occurred more commonly in the participantsin HERS who were assigned to estrogen–progestin therapy,the increase in risk was not statistically significant.
Estrogen therapy may worsen the injury caused by recurrent cerebralischemia. In our study, women in the estradiol group were morelikely than those in the placebo group to die from a stroke,and nonfatal events in the estradiol group were associated withgreater neurologic and functional deficits, although these findingswere not statistically significant. These data also suggestthe possibility of an increase in the risk of stroke early afterthe initiation of therapy among women randomly assigned to receiveestrogen. The mechanism by which exogenous estrogen may exacerbatethe injury caused by stroke or may precipitate stroke is unclear.Although estrogen has been shown to reduce some vascular riskfactors, it is also associated with potentially deleteriouseffects. Estrogen has direct effects on neurons and might increasesensitivity to ischemia, either by modulating the excitatoryeffects of glutamate or by modifying the inhibitory effectsof -aminobutyric acid.43 Another possible mechanism for an adverseeffect of treatment may involve proinflammatory effects of estrogen.9,44
The ongoing Women's Health Initiative, a randomized trial, shouldhelp clarify the role of estrogen in the primary preventionof cardiovascular disease, including stroke. Our results indicatethat estrogen therapy should not be initiated for the purposeof secondary prevention of cerebrovascular disease and add tothe evolving body of evidence from clinical trials that do notshow a benefit of estrogen for women with established vasculardisease.
Supported by a grant (1-RO1-N531251) from the National Instituteof Neurological Disorders and Stroke and by Mead Johnson Laboratories,which also provided the study drug. Dr. Suissa was supportedby a Senior Scientist Award from the Medical Research Councilof Canada.
Drs. Viscoli, Brass, Kernan, Suissa, and Horwitz have receivedresearch support from Novartis. Dr. Suissa has also receivedresearch funding from Schering and Organon.
Source Information
From the Departments of Internal Medicine (C.M.V., W.N.K., R.I.H.), Neurology (L.M.B., P.M.S.), Epidemiology and Public Health (L.M.B., P.M.S., R.I.H.), and Gynecology and Obstetrics (P.M.S.), Yale University School of Medicine, New Haven, Conn.; the Veterans Affairs Connecticut Healthcare System, West Haven, Conn. (L.M.B.); and the Department of Epidemiology and Biostatistics and the Department of Medicine, McGill University, Montreal (S.S.).
Address reprint requests to Dr. Viscoli at the Department of Medicine, 333 Cedar St., Rm. 1072 LMP, P.O. Box 208056, Yale University School of Medicine, New Haven, CT 06520-8056.
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Appendix
The members of the Women's Estrogen for Stroke Trial performanceand safety monitoring board were as follows: Barbara C. Tilley,Ph.D. (chair), Department of Biometry and Epidemiology, MedicalUniversity of South Carolina; Joseph P. Broderick, M.D., Departmentof Neurology, University of Cincinnati Medical Center; PatriciaH. Davis, M.D., Department of Neurology, University of Iowa,Iowa City; Patrick D. Lyden, M.D., Neuroscience Department,University of California, San Diego; Veronica A. Ravnikar, M.D.,Department of Obstetrics and Gynecology, University of MassachusettsSchool of Medicine, Worcester; and John R. Marler, M.D., Divisionof Stroke, Trauma, and Neurogenerative Disorders, National Instituteof Neurological Disorders and Stroke, Bethesda, Md.
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(2009). Sex Differences in Incidence, Mortality, and Survival in Individuals With Stroke in Scotland, 1986 to 2005. Stroke
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WRITING GROUP MEMBERS, , Lloyd-Jones, D., Adams, R., Carnethon, M., De Simone, G., Ferguson, T. B., Flegal, K., Ford, E., Furie, K., Go, A., Greenlund, K., Haase, N., Hailpern, S., Ho, M., Howard, V., Kissela, B., Kittner, S., Lackland, D., Lisabeth, L., Marelli, A., McDermott, M., Meigs, J., Mozaffarian, D., Nichol, G., O'Donnell, C., Roger, V., Rosamond, W., Sacco, R., Sorlie, P., Stafford, R., Steinberger, J., Thom, T., Wasserthiel-Smoller, S., Wong, N., Wylie-Rosett, J., Hong, Y., for the American Heart Association Statistics Comm,
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(2007). NINDS Clinical Trials in Stroke: Lessons Learned and Future Directions. Stroke
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Schumacher, M., Guennoun, R., Ghoumari, A., Massaad, C., Robert, F., El-Etr, M., Akwa, Y., Rajkowski, K., Baulieu, E.-E.
(2007). Novel Perspectives for Progesterone in Hormone Replacement Therapy, with Special Reference to the Nervous System. Endocr. Rev.
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Bray, P. F., Howard, T. D., Vittinghoff, E., Sane, D. C., Herrington, D. M.
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de Lecinana, M. A., Egido, J. A., Fernandez, C., Martinez-Vila, E., Santos, S., Morales, A., Martinez, E., Pareja, A., Alvarez-Sabin, J., Casado, I., on behalf of the PIVE Study Investigators of the S,
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Goldstein, L. B., Adams, R., Alberts, M. J., Appel, L. J., Brass, L. M., Bushnell, C. D., Culebras, A., DeGraba, T. J., Gorelick, P. B., Guyton, J. R., Hart, R. G., Howard, G., Kelly-Hayes, M., Nixon, J.V., Sacco, R. L.
(2006). Primary Prevention of Ischemic Stroke: A Guideline From the American Heart Association/American Stroke Association Stroke Council: Cosponsored by the Atherosclerotic Peripheral Vascular Disease Interdisciplinary Working Group; Cardiovascular Nursing Council; Clinical Cardiology Council; Nutrition, Physical Activity, and Metabolism Council; and the Quality of Care and Outcomes Research Interdisciplinary Working Group: The American Academy of Neurology affirms the value of this guideline.. Circulation
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Goldstein, L. B., Adams, R., Alberts, M. J., Appel, L. J., Brass, L. M., Bushnell, C. D., Culebras, A., DeGraba, T. J., Gorelick, P. B., Guyton, J. R., Hart, R. G., Howard, G., Kelly-Hayes, M., Nixon, J.V., Sacco, R. L.
(2006). Primary Prevention of Ischemic Stroke: A Guideline From the American Heart Association/American Stroke Association Stroke Council: Cosponsored by the Atherosclerotic Peripheral Vascular Disease Interdisciplinary Working Group; Cardiovascular Nursing Council; Clinical Cardiology Council; Nutrition, Physical Activity, and Metabolism Council; and the Quality of Care and Outcomes Research Interdisciplinary Working Group: The American Academy of Neurology affirms the value of this guideline.. Stroke
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Hendrix, S. L., Wassertheil-Smoller, S., Johnson, K. C., Howard, B. V., Kooperberg, C., Rossouw, J. E., Trevisan, M., Aragaki, A., Baird, A. E., Bray, P. F., Buring, J. E., Criqui, M. H., Herrington, D., Lynch, J. K., Rapp, S. R., Torner, J., for the WHI Investigators,
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Dhamoon, M. S., Sciacca, R. R., Rundek, T., Sacco, R. L., Elkind, M.S.V.
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Sacco, R. L., Adams, R., Albers, G., Alberts, M. J., Benavente, O., Furie, K., Goldstein, L. B., Gorelick, P., Halperin, J., Harbaugh, R., Johnston, S. C., Katzan, I., Kelly-Hayes, M., Kenton, E. J., Marks, M., Schwamm, L. H., Tomsick, T.
(2006). Guidelines for Prevention of Stroke in Patients With Ischemic Stroke or Transient Ischemic Attack: A Statement for Healthcare Professionals From the American Heart Association/American Stroke Association Council on Stroke: Co-Sponsored by the Council on Cardiovascular Radiology and Intervention: The American Academy of Neurology affirms the value of this guideline.. Circulation
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Thom, T., Haase, N., Rosamond, W., Howard, V. J., Rumsfeld, J., Manolio, T., Zheng, Z.-J., Flegal, K., O'Donnell, C., Kittner, S., Lloyd-Jones, D., Goff, D. C. Jr, Hong, Y., Members of the Statistics Committee and Stroke Sta, , Adams, R., Friday, G., Furie, K., Gorelick, P., Kissela, B., Marler, J., Meigs, J., Roger, V., Sidney, S., Sorlie, P., Steinberger, J., Wasserthiel-Smoller, S., Wilson, M., Wolf, P.
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Sacco, R. L., Adams, R., Albers, G., Alberts, M. J., Benavente, O., Furie, K., Goldstein, L. B., Gorelick, P., Halperin, J., Harbaugh, R., Johnston, S. C., Katzan, I., Kelly-Hayes, M., Kenton, E. J., Marks, M., Schwamm, L. H., Tomsick, T.
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(2005). Effects of Exemestane Administered for 2 Years Versus Placebo on Bone Mineral Density, Bone Biomarkers, and Plasma Lipids in Patients With Surgically Resected Early Breast Cancer. JCO
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Nakamura, Y., Igarashi, K., Suzuki, T., Kanno, J., Inoue, T., Tazawa, C., Saruta, M., Ando, T., Moriyama, N., Furukawa, T., Ono, M., Moriya, T., Ito, K., Saito, H., Ishibashi, T., Takahashi, S., Yamada, S., Sasano, H.
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Hodis, H. N., Mack, W. J., Azen, S. P., Lobo, R. A., Shoupe, D., Mahrer, P. R., Faxon, D. P., Cashin-Hemphill, L., Sanmarco, M. E., French, W. J., Shook, T. L., Gaarder, T. D., Mehra, A. O., Rabbani, R., Sevanian, A., Shil, A. B., Torres, M., Vogelbach, K. H., Selzer, R. H., the Women's Estrogen-Progestin Lipid-Lowering Horm,
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Wassertheil-Smoller, S., Hendrix, S., Limacher, M., Heiss, G., Kooperberg, C., Baird, A., Kotchen, T., Curb, J. D., Black, H., Rossouw, J. E., Aragaki, A., Safford, M., Stein, E., Laowattana, S., Mysiw, W. J.
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Gibbons, R. J., Abrams, J., Chatterjee, K., Daley, J., Deedwania, P. C., Douglas, J. S., Ferguson, T. B. Jr, Fihn, S. D., Fraker, T. D. Jr, Gardin, J. M., O'Rourke, R. A., Pasternak, R. C., Williams, S. V., Gibbons, R. J., Alpert, J. S., Antman, E. M., Hiratzka, L. F., Fuster, V., Faxon, D. P., Gregoratos, G., Jacobs, A. K., Smith, S. C. Jr, Committee Members, , Task Force Members,
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(2002). Neuroprotective Effects of a Novel Non-Receptor-Binding Estrogen Analogue: In Vitro and In Vivo Analysis. Stroke
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[Abstract][Full Text]
Wakatsuki, A., Okatani, Y., Ikenoue, N., Fukaya, T.
(2002). Different Effects of Oral Conjugated Equine Estrogen and Transdermal Estrogen Replacement Therapy on Size and Oxidative Susceptibility of Low-Density Lipoprotein Particles in Postmenopausal Women. Circulation
106: 1771-1776
[Abstract][Full Text]
Lemaitre, R. N., Heckbert, S. R., Psaty, B. M., Smith, N. L., Kaplan, R. C., Longstreth, W. T. Jr
(2002). Hormone Replacement Therapy and Associated Risk of Stroke in Postmenopausal Women. Arch Intern Med
162: 1954-1960
[Abstract][Full Text]
Lucey, C. R., Cole, C. A.
(2002). Update in General Internal Medicine. ANN INTERN MED
137: 334-340
[Full Text]
Mershon, J. L., Baker, R. S., Clark, K. E.
(2002). Estrogen increases iNOS expression in the ovine coronary artery. Am. J. Physiol. Heart Circ. Physiol.
283: H1169-H1180
[Abstract][Full Text]
Humphrey, L. L., Chan, B. K.S., Sox, H. C.
(2002). Postmenopausal Hormone Replacement Therapy and the Primary Prevention of Cardiovascular Disease. ANN INTERN MED
137: 273-284
[Abstract][Full Text]
Levine, S. R., Coull, B. M.
(2002). Potassium depletion as a risk factor for stroke: Will a banana a day keep your stroke away?. Neurology
59: 302-303
[Full Text]
Wells, G., Tugwell, P., Shea, B., Guyatt, G., Peterson, J., Zytaruk, N., Robinson, V., Henry, D., O'Connell, D., Cranney, A.
(2002). V. Meta-Analysis of the Efficacy of Hormone Replacement Therapy in Treating and Preventing Osteoporosis in Postmenopausal Women. Endocr. Rev.
23: 529-539
[Full Text]
Yusuf, S., Anand, S.
(2002). Hormone replacement therapy: a time for pause. CMAJ
167: 357-359
[Full Text]
Chlebowski, R. T., Col, N., Winer, E. P., Collyar, D. E., Cummings, S. R., Vogel, V. G. III, Burstein, H. J., Eisen, A., Lipkus, I., Pfister, D. G.
(2002). American Society of Clinical Oncology Technology Assessment of Pharmacologic Interventions for Breast Cancer Risk Reduction Including Tamoxifen, Raloxifene, and Aromatase Inhibition. JCO
20: 3328-3343
[Abstract][Full Text]
Writing Group for the Women's Health Initiative In,
(2002). Risks and Benefits of Estrogen Plus Progestin in Healthy Postmenopausal Women: Principal Results From the Women's Health Initiative Randomized Controlled Trial. JAMA
288: 321-333
[Abstract][Full Text]
per day) in 664 postmenopausal women (mean age, 71 years) who had recently had an ischemic stroke or transient ischemic attack. Women were recruited from 21 hospitals in the United States and were followed for the occurrence of stroke or death. 
-aminobutyric acid.43 Another possible mechanism for an adverse effect of treatment may involve proinflammatory effects of estrogen.9,44 
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