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    Raymond Frazier
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    Stroke

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    Stroke

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    9 Ansichten12 Seiten

    Estrogen and Stroke

    Hochgeladen von

    Raymond Frazier
    Stroke

    Copyright:

    © All Rights Reserved
    Als PDF herunterladen oder online auf Scribd lesen
    Markieren Sie unangemessene Inhalte
    von 12
    Him ORIGINAL CONTRIBUTION Effect of Estrogen Plus Progestin on Stroke in Postmenopausal Women The Women's Health Initiative: A Randomized Trial Marian Limacher, MD. Gerardo Heiss, MD ‘Gharles Kooperberg, PhD MPH J David € Henry Black, MD. Jacques F. Rosouw, MD. Tor the WHI Investigators TROKE IS A MAJOR HEALTH issue for women." Cerebro- vascular diseases are the third leading cause of death in the United States? and are the leading ccause of adult disability. The Wom- en's Health Initiative (WHD, beg ning in the early 1000s was designed lo examine a number of factors alfecting the health of postmeno- pausal women.’ Recently 1 arm of the WHI, the elinical trial of estrogen, plus progestin, was terminated 3 years before its planned completion date because its harmful effects out- weighed its benelits, See also pp 2651, 2663, and 2717. (©2003 American Medical Association, All rights reserved, Context The Women’s Health native (WHD tal of estrogen plus progestin was stopped eal because of adverse elect, including an increased kof stoke inthe esttogen pls progestin group Objective To assess the eect of estrogen plus progestin on ischemic and hemor- thagi stoke and in subgroups, and to determine whether the efecto extogen pls progestin was modified by Baseline levels of blood biomarkers Design Multicenter double-bind placebo-contoled randomized cincal al invoh- ing 16608 women aged 50 through 79 years wih an average fallow up of 56 year. Baseline levels of blood-based markers of nfammation,tromboss, and pid eves were eased inthe fst 140 cently confimed stroke cases and 513 contol Interventions Participant received 0.625 mg/d of conjugated equine estrogen plus 215 mg/d of medroxyprogesterane acetate (n=8506) or placebo (1=8 102). Main Outcome Measures Overall stokes and stoke sublype and sevety were cently adudiested by stroke neurologists Results One hundred fity-one patients (1.8%) inthe estrogen plus progestin and 107 (1.3%) nthe placebo groups had strokes. Overall 79.8% of rakes were fche~ mc. For combined Ischemic and hemorrhage strokes, the Intenion-t-teat hazard Taio (HR) fr estrogen plus progestin vs placebo was 1.31 (95% confidence interval (Cl, .02-1.68); with adustment for adherence the HR was 1.50 (95% Cl, 1.08-2.08). ‘The HR or chem stroke was 1.44 (95% C,1.09-1.90) and for hemorhagi stroke, (0.82 (95% Cl, 043-1156). Pont estimates of the Hs indeate that excess kof al stoke was apparent i all age groups, in al categories of baseline stoke risk, and in ‘women with and without hypertension, rior history of cardiovascular disease, use of Formanes, ttn, of asin: Other rak factors for take, including smoking, blood pressure, diabetes, loner use of vitamin supplements, blood-based biomarkers of fvlammaton, higher whteblood cell coun, and higherhematoctlevels i not ody the effect of estogen plus progestin on stroke rk Conclusions. Estrogen pus progestin increases the risk of fchemie stroke in gener- aly healthy postmenopatsal women Exess ik fo al stokes ttabuted to estogen pls progestn appeared to be present nal ubgroups of women examined sau. 2003269-2672-2684 wi amacom The overall results in this random- of stroke, based on central adjudica- zed double-blind clinical trial indi- cated that women in the estrogen plus progestin group had a 41% increase in locally adjudicated strokes over 5.2 cars compared with women in the pla- cbo group. Our report provides re- sults over an additional 4 months (av- erage follow-up 5.6 years) on subtypes ‘Downloaded From: http:/fjama,jamanetwork.com’ by Venty Yogyantari on 03/08/2016 (Repsned) JAMA tay 2 tion of stroke events by neurologists, additional data on the effects of estro- ‘Author Afilation, Financial Disclosures and WH Investigators ae ted athe endof sate {Comesponding Author and Reprint: ya Waser {hel-Smoler Ab, Department of denlogy and ‘Socal Medicine Abert Ensen Coleg of Meine, 1300 Mors Pak ve, Room 1312 Beer, Bons NY 4046! female smoterBaecom yu) 1.0.20 2673 EFFECT OF ESTROGEN PLUS PROGESTIN ON STROKE igen plus progestin in various sub- ‘groups of women, and data on the elfect ff lipid levels and biomarkers of in- ammation and thrombosis A relationship between stroke and hormone use was suggested in early studies showing that oral contracep- live users had higher stroke rates than, those not taking oral contraceptives.* However, results of subsequent epidi iologic studies have been inconsis- tent and had small numbers of stroke ceases. The WHI is the first random- ized trial to show that estrogen plus pro- jgestin increases risk of stroke in gen- erally healthy women.” Stroke is a heterogeneous condition, with dilfer- ing types, mechanisms, and out- ‘comes. Most prior observational stud- ies and randomized clinical tials reported that stroke risk generally en- compassed both hemorrhagic and is- cchemie strokes without consideration ‘of subtype and mechanism although in more recent studies hemorrhagic and. ischemic strokes have been reported. separately.” By refined classification of stroke type, it may be possible to elu- cidate better the mechanism of the in- creased incidence of stroke in the WHI ized clinical tial of estrogen plus progestin vs placebo. The mechanism through which thes hhormones act has not yet been estab- lished, but it has been hypothesized to be through inflammatory or throm- botic effects. The interactions of other risk factors with estrogen and proge ln use may enhance or diminish these effects. Although a well-studied set of risk factors (including age, blood pre sure, diabetes mellitus, and cigarette smoking)'*** may permit reasonably ac- ‘curate predictions of an individual's fu- lure risk of ischemic stroke, 40% or more of strokes may remain unexplained al- ter these known risk factors are taken into account.'*" Even among patients ‘with severe stenosis of the large cere- bral arteries, approximately half ofall strokes do nol originate [rom lesions in the large arteries." Exposures that may affect risk of ischemic stroke, which may act through the pathways of inflamma- tion and thrombosis, are smoking, random) 2674 JAMA sty 003 Vol 209, No. 20 Reprinted) hypertension,” overweight, insulin re- sistance," and physical exertion.” Therapies known oF hypothesized to modify risk of stroke such as aspirin,” anthhypertensive medications,” antioni- dants,” oral anticoagulants,” and comegi-3 faty acid” are also assoc ated with changes in biomarkers of in- flammation oF thrombosis. Our report examines in more detail the elects of trogen pls progestin on ischemic and hhemorthagie stroke, including « con- sideration of risk factors and medical therapies that may modify the effect of estrogen plus progestin on stroke METHODS: Study Population Details of the WHI design are re- ported elsewhere.* Postmenopausal women aged 50 through 79 years who gave writen informed consent were e rolled in the WHI at 40 clinical cen- ters in the United States, Women were considered postmenopausal ifthey were between the ages 50 and 54 years and hhad no vaginal bleeding for at least 12 months of were aged 35 through 79 years and had no bleeding in the prior fo months. To be eligible forthe trial of estrogen plus progestin, women had to hhavean intact uterus. Exclusions were participation in other randomized tals predicted survival of less than 3 years, alcoholism, drug dependency, diag- nosed mental illness, dementia, or other conditions suggesting that woman would not be adherent to study medi cines or other procedures, Exclusions for safei cluded prior diagnosts of breast can- cer of other cancers within the past 10 years (except nonmelanoma skin can- cer). Women with systolic blood pres- sure (SBP) of 200 mm Hg or higher or diastolic blood pressure (DBP) of 105 mim Hg o higher were advised to see their physician within a specified pe- riod depending on blood pressure level and were temporarily excluded from the clinical trials until their blood pre: sure was determined to be under con- twol. Most women had never taken hor- mone therapy prior to enrollment, Those who were taking hormones were ‘Downloaded From: http:/fjama,jamanetwork.com’ by Venty Yogyantari on 03/08/2016 required to have a 3-month washout pe- riod before their baseline visit, ‘Study Pills Treatment consisted of combined ¢ trogen and progestin, provided as I tab- lettaken daily, containing 0.625 mg of conjugated equine estrogen and 2.5 mg of medroxyprogesterone acetate (Prem- pro, Wyeth Ayerst, Philadelphia, Pa), for matching placebo, Details of ran- ddomization have been published ° The trial reported herein consists of 8506 participants randomized to take the es- trogen plus progestin and 102 ran- domized to be in the placebo group. Participants were followed up for an av erage of 5.6 years, Study medication was discontinued permanently by protocal for women ‘who developed breast cancer; endome- trial hyperplasia not responsive to treat- ment; atypia or cancer, deep-vein throm- bosis or pulmonary embolism; malignant melanoma; meningioma; ri- alyceride level greater than 1000 mg/dl. (21.3 mmol); or prescription ofestro- gen, testosterone, or selective estroge! receptor modulators by their personal physicians. Medications were tempo- rarily discontinued for participants who ‘had acute myocardial infarction, str} fracture, or major injury requiring hos- pitalization, surgery involving use ofan- cesthesia, of any illness resulting in im- mobilization for mote than 1 week Follow-up and End Point Determination Women were required to come to the clinic annually and have semiannual contacts in the elinie or by telephone. Ateach semiannual contact, standard- ized interview asked them about symp- toms, safety, adherence to study pills, ‘and potential outcome events. When a potential outcome was identified, medi- cal records and death certificates we obtained as necessary. Physician adju- dicatorsat clinical sites reviewed the i formation to determine the cause of the event. Third-party reports directly given to clinic stall were also followed up by obtaining the requisite records. Tran- sient ischemic attacks requiring hospi- (©2003 American Medical Association, All rights reserved. lalization were ascertained and records obtained. One of 3 stroke neurologists centrally adjudicated locally deter- mined strokes, transient ischemic at- tacks, and women’s seleports of stroke that had been not confirmed by local ad judicators after careful review of the medical records. Of locally adjudicated, strokes, 94.5% were confirmed by the central adjudicators. Of centrally adju- dicated strokes, 93.8% had been classi- lied as strokes by the local adjudiea- tors. This article presents stroke data centrally confirmed by neurologists. Lo- caland central adjudicators were blinded to treatment assignment. stroke diagnosis requiring and/or oc- curring during hospitalization was based on rapid onset of a neurological deficit attributable to an obstruction or rupture ofan arterial vessel system. The deficit was not known to be secondary to brain trauma, tumor, infection, or other cause and must have lasted more than 24 hours unless death supe: vened or lesion compatible with acute stroke was evident on computed to- mography or magnetic resonance im- aging scan. Strokes were classified as chemie or hemorrhagic based on review fof reports of brain imaging studies. stroke was defined as procedure re- lated if t occurred within 24 hours after any procedure or within 30 days after a cardioversion or invasive car- diovascular procedure. The 6 categories of stroke were (1) subarachnoid hemorthage not result- ing from a procedure; (2) intracerebral hemorrhage not resulting from a pro- cedure; (3) other or unspecified intra- cranial hemorrhage not resulting from a procedure (nontraumatic epidural hhemorthage or subdural hemorshage); (#) occlusion of cerebral or pericere- bbral arteries with infarction not result ing from a procedure (cerebral throm- bosis, cerebral embolism, lacunar infarction); (5) acute, but ill defined, cerebrovascular disease not resulting from a procedure (this option is used. only if the adjudicator was unable to code it as hemorshagic or ischemic); (6) and central nervous system complica- lions during oF resulting from a proce- (©2003 American Medical Association, All rights reserved, EFFECT OF ESTROGEN PLUS PROGESTIN ON STROKE dure. For analysis purposes, categories 1, 2, and 3 were combined as hemor- rhagie strokes; category 4 was class fied as ischemic stroke; and categories S and 6 were combined as other stroke. Ischemic strokes were further class fied by the central neurologist adjudh catorsaccording o the Oxfordshire” and Trial of Org 10172 Acute Stroke Trial (TOAST)® criteria to examine stroke subtypes. The TOAST classification fo- ceuseson the presumed underlying stroke ‘mechanism; requires detailed invest gations (suchas brain computed tomog- raphy, magnetic resonance imaging, an- giography, carotid ultrasound, and echocardiography); and distinguishes 5 categories of stroke, which include large- artery atherothrombosis, cardioem- bolic, lacunar (small vessel), other, and undetermined mechanism, However, even with the extensive work-up, 30% ofstrokes were of undetermined mecha- nism, including cryptogenic stroke (no cause found on work-up), incomplete evaluation to make a determination, and 2 oF more causes identified. This clas- sification, the best currently availabe, shows moderate to good interobserver reliability with training For the purpose of analyses, stroke subtypes judged probable or possible are combined, The Oxfordshire clas fication’ is based on clinical assess- ‘ment of the patient in whom a com- puted tomographic brain sean has excluded cerebral hemorthage and clas- sifies patients into total anterior eireu- lation infarct, partial anterior eircula- tion infarct, lacunar infarct, and posterior circulation infarct. This scale hhas the advantage that virwally all pa- tients can be classified; it shows a cor- relation with outcome and severity and hhas a moderate-to-good interobserver reliability for the elassification in prac lice. The Glasgow Outcome Seale score was ascertained by clinical infor- ‘mation available at the time of hospi- tal discharge to provide an assessment of stroke outcome.” Definition of Va Hypertension was defined as either el evated clinic blood pressure (SBP =140 ‘Downloaded From: http:/fjama,jamanetwork.com’ by Venty Yogyantari on 03/08/2016 mm Hg and/or DBP =90 mmbig),asell- report of taking medications for hyper tension, or both. Baseline blood pre: sure was measured at the first clini vist by certified stall using standardized pro- cedures and instruments using a con- ventional mercury sphygmomanom- ter, after the participant was seated and resting for 5 minutes. The average of 2 sitting readings, obtained at least 30 sec- fonds apart, was used for analyses. Physical activity was assessed by ask- ing about the frequency and duration ‘of walking at various intensities and 3 other types of recreational activity clas- sified by intensity (strenuous, mode ate, or light). Data were summarized into episodes per week of moderate or strenuous activity (as defined by a metabolic equivalent score of atleast 4.0 as indicated by Ainsworth and col: leagues” of at least 20 minute duration). One metabolic equivalent is the amount of energy expended st ting quietly at rest adjusted to body weight, equal to 1 kea/kg per hour. Women reporting some recreational ac- Livity but of shorter duration and/or lesser intensity were classified as en- gaging in some activity. Vasomotor symptoms were assessed [rom re sponses to questions on the presence fof hot flashes oF night sweats. A 12- lead electrocardiogram was per- formed at baseline and every 3 years Statistical Analyses Baseline characteristics between pla- ccebo and estrogen plus progestin groups ‘were compared using the x? test. The Fisher exact test was used for compari sons between randomization assign- ment and stroke-severity classifica lion, The Cochran-Armitage test was used to determine whether treatment assignment was associated with a lin- cear end in stroke severity ‘Outcome comparisons were made Irom Cox proportional hazards anal ses and Kaplan-Meier cutves forthe e tire population. Additional analyses ex- amined effects of estrogen plus progestin in 11 subgroups of special clinical interest: by age group, race oF ethnicity, years since menopause, prior (Reprints) JAMA, My 28, 2003Vol 209, No. 20. 2675 EFFECT OF ESTROGEN PLUS PROGESTIN ON STROKE tT le 1, Baeeline Characterster ofthe Women’s Heath Ineatve Estrogen Pur Progestin, “ial Pattiipants by Randomization Assignment” Characteristics Feagicup a serena. y ca ae ic Faceoretiaty 8 Black Fispane Zmercan Fea ‘eanPactio laand Teno Smoky sats ‘New ‘Salted me eaTen ae ‘Stain Repen NAD Treated Fistor ot OO Fipertensont yocardal nixeion eer Stoke aver Fistor of wanaiont cham aack 0G etal feraton VR. Minnesota coo ‘Gabe endarterectomy argon Frampgham store isc ok est et ‘cum isk, cond Tae igh rik thd ttle yar Boy macs index Flood pressure, ren ‘Systaie Dastore Pile 2676 JAMA sty 003 Vol 209, No. 20 Reprinted) Tet Enrogen «Progestin Placebo 08) (r=810 _ pVatuot 0 23 Teo rors 3 ] es 52510 6020 74. ‘sata | oe e020 (42 i 36 | # 255 82) aoveda) 52 38 0 7631 20.1 T2BS1TS5) 360) 706 eT TSF) (19) 1 (02) HZ63) 79,02 2eta,a4.n, a 16 6 51 Te 31 tary a7 ‘Downloaded From: http:/fjama,jamanetwork.com’ by Venty Yogyantari on 03/08/2016 history of cardiovascular disease, by pertensive status, duration of prior hor- mone use, statin and aspirin use, vaso- motor symptoms at baseline, vasomotor symptoms within the youngest group, and by terule of Framingham scores for stroke risk. Framingham risk scores lect the probability ofstroke within 10, years for women aged 55 to 84 years, based on use of antihypertensive medi- cations, as well as SBP, age, diabetes mellitus, cigarette smoking, prior ear diovascular disease, atrial ibrillat and left ventricular hypertrophy by clec- trocardiogram.” In addition, 16 bio markers were examined, resulting ina total of 27 subgroups. At the 05 level of significance, 1 of 20 comparisons may be statistically significant by chance. Nominal confidence intervals (Cls) are presented throughout, ex cept for stroke outcome, which was 1 of 7 outcomes monitored by the data and safety monitoring board, so we also present the adjusted Cls in this in- first ‘All primary analyses of tn stroke were based on the intention-to- leat principle, The effect modifica lion of stroke risk with estrogen plus progestin by potential risk factors was assessed by first-filting univariate Cox proportional hazards models. Vari- ables showing a marginal relationship with stroke (P<.25) were all included in a multivariate Cox model with e trogen plus progestin. Statistical sig- nificance of the interaction between es- trogen plus progestin and these variables was explored 1 at a time us- ing the score test. All Cox models wer stratified on age, prior stroke, and ran- domization assignment in the dietary modification trial and were adjusted for race or ethnicity. The proportional haz- ards assumption was verified by te ing the interaction of time and estro- {gen plus progestin and through visual inspection of the survival function. Secondary analyses were performed to account for participant adherence, todetermine if any risk conferred by es trogen plus progestin could not be ex plained by increases in SBP and if risk differed by stroke type. In the adhe (©2003 American Medical Association, All rights reserved. cence-adjusted analyses, participants ‘event histories were censored 6 months after they became nonadherent (stopped taking study drugs, were us- ing <80% of study drugs, or, ifin the placebo group, started hormone therapy). A Cox model that included. follow-p SBP asa time-dependent co- variate was used 10 estimate the addi- ional risk of estrogen plus progestin unrelated to ils effect on SBP. Differ ences in risk between ischemic and hhemorthagie strokes were assessed by competing-risks analysis using Cox models. Significance was based on a Wald y* test of sealed coefficient dif- ferences, Analysis were performed by SAS statistical software version 8.02 (SAS Ine, Cary, NC). The protocol included a blood draw at baseline after a minimum 10-hour fast, Serutn and plasma specimens wes maintained at 4°C until separated, ali- quoted, and frozen at -70°C, until they were shipped on dry ice to the labora- tory (Medical Research Laboratories, Highland Heights, Ky), for analysis. All lipid and lipoprotein fractions were ans- lyzed on EDTA-treated plasma, using methods described elsewhere.” Fic brinogen and factor VIII were mea- sured in frozen citrated plasma using 4 clot-based turbidometrie detection system (MLA Electra 1400e, Pleasant ville, NY). Human interleukin 6 (IL-6) was quantitated using a high- sensitivity sandwich enzyme-linked im- munoassay (REeD Systems, Minneapo- lis, Minn). Soluble endothelial leukocyte adhesion molecules (E- selectin) was measured by enzyme- linked immunosorbent assay (R&D Systems). High-sensitivity C-reactive protein was measured using an ultra sensitive rate immunonephelemetric method (Dade-Behring, Marburg, Germany). Matrix metalloproteinase 9 (MMP-9) was quantitated using an en- zyme linked immunosorbent assay pro- cedure (Quantikine human MMP-9, R&D Systems) "Associations of biomarkers with stroke by randomization group were assessed using logistic regression models on avail- able case-control data, Cases were the (©2003 American Medical Association, All rights reserved, EFFECT OF ESTROGEN PLUS PROGESTIN ON STROKE first 140 strokes that were locally adju- dicated as stroke before February 2001 and later confirmed centrally. There were 513 controls: control with an in- tact uterus was selected for each case, matched on age, randomization year, and presence of baseline stroke. Add tional controls that had been selected for ‘women who developed coronary heart disease and venous thrombosts we cluded in these analyses. RESULTS Baseline Characteristics Baseline characteristics of the estro- ‘gen plus progestin and placebo groups ‘Table 2. Diagnosis, Classfieation, ana Severity of Centraly Adjudicated Suoke inthe ‘Women’s Heath Initiative Estrogen Pus Progestin Tral Participants by Randomization Assignment” Variables value ‘Siroke Diagnosis Hemonthagic stoke Saeracrod Taran Report ofcerbrowascdardeaheny ors a J TOAST Gassteaton atheroecerosis Shal-veeel ocean Shaka of cher dtemmad og 18 (119 EE] THES) Tata) 0 Tog 2527 EE 213) Tog) 689 5 (a7 Tor of echemie Svoke BEER) ZEA Shake of undetermined engin Causes ented TT egatve eatin BITE) Tea) _ieonpetesmuaton oo | Ta TOO ‘Oxtordchire Cassiication| Total anti cation infarct Parialanleror creation “sie saa 8 Ta | Bas) ar Taeanar hart 3a a Posterarereuaton Fara 75 785) To TOTO Glasgow Outcome Seal) sing 107) ° ood recovery 22078) 38 95.5) Modesty assed 75 8) 3508) Ser assbied Ta Te) 52 Vegetative saved Zieh Death To Te caeger THES) EN ‘Downloaded From: http:/fjama,jamanetwork.com’ by Venty Yogyantari on 03/08/2016 154 100) TO7 Toop (Reprints) JAMA, My 28, 2003Vol 209, No. 20. 2677 EFFECT OF ESTROGEN PLUS PROGESTIN ON STROKE are shown in TABLE 1. Both groupswere with no significant differences he- chemicattack, which was higher in the similar with respect to baseline demo- (ween the 2 groups on any of the vari- placebo group (P=.03) than in the treat. araphic and risk factor characteristics ables except for history of transient is- ment group. The average participant age was 63.3 years; 33% of women were 3. Annualized Percentage of Stroke Events and Hazard Ratios of the Women's Health int the 30 through 59 year age group. Intatve Estrogen Pls Progestin Thal Parpants by Randomization Assignment and in Before WHI enrollment, 74.3% of pat Selected Subgroups" Uicipants never used hormones. Ninety- No five percent had no history of cardio- Hazard Ratiot scar disease Variables ae Falowp ire. ean SOL Bara) Stroke and Stroke Subtype Events reece TEIOR TWO TSTTBETEH here were 151 strokes in the estro- inca 125 028 SE 3 gen plus progestin group (1.8%) and moran TeroauT 2010040820425 107 in the placebo group (1.3%) as oe cn ‘010 taoprrazy, oFSulY 7, 2002, after an average of RE 5.0 years of follow-up; all women Bp TRA TERT TST had becn enrolled for a minimum of Tato ET BOA) 125 055-159 <= 3.7 years and a maximum of 8.6 “mera Pan er Asan Nate 00.09 0000 yes. Ischemic strokes accounted for Fanos Pate in 508) TEPAAWR 79.8% ofall strokes (82.8% estrogen Sack T7955) TEE[LIEHOH plus progestin; 75.7% placebo), and span 710.08) hemorthagte strokes accounted for Tino ‘Tera snca manopaizat <5 i) 73) 14.8% of strokes (11.9% estrogen plus progestin; 18.6% placebo, TABLE 2). Three strokes were not classified as ischemic or hemor- thagic, 1 of which resulted from a surgical procedure. Of 38 hemor- rhagie strokes, 10 (26.3%) were due 8 0.10) Seaio 7607, Zh 5) 1.45 048-445) Tar OBE S63) tae 1370.39 4at(io1-179 tw subarachnoid hemorrhage % TH TEOAEZET OF 206 ischemic strokes in both Piper ar groups, 24 (11.7%) were cardioem- Ne supo2t) 41019 _120/086-190 folic 28 (13.0%) large artery. and 58 es BOAT) 6110.88) 1-22 (087-171) (28.2%), small vessel. There were 23 Dugior oT ar aTTaTe EY a copay varjooiay *0Ke deaths, 12 inthe estrogen pls progestin and 11 in the placebo groups; 11 of these were reports of cerebro- vacular deaths only (6 estrogen plus progestin; 5 placebo) without classifi- a0 70,0}, 708 040-273 Tag) O22) 217 SERA ota 031 96(020) 122(102-17)__callon of type. Distributions of tsche- % FE] DO] TA SELAH —miestroke subtypesby Oxfordshire and Reoens TOAST classifications did not dlr sig- a 1151029 81022) 131(0994.78 pificantly between the 2 treatment % ol 2502911 O72 TB) ‘groups nor did severity of stroke dif- Fer on the Glasgow Outcome Seale The hazard ratio (HR) for all stroke subtypes combined was 1.31 (nominal iia, madarate, sree vasamotor ympiors| No 108, = a 3m Zi ey 95% C1 1.02-1.8) Because nd pois toe Satie 100.09) 140'0.843.0% were monitored by the data and safety ei i sor ELE TZOGTO-TET ‘Nonoring board and examined 1 as- ara Ta 7 TET sess the global risk vs bent of estro- ‘Sore ete cago ay notch oto ota hrc’ ot sore er esiment rows becauseotmeaingasia. gen pls progestin,? the conservs Bonferroni adjusted 95% Cl was (0.93-1.84). The HR for ischemic stroke was 1.44 (05% Cl, 1.09-1.90), and for {Simons werent sees not taro cro 22678 JAMA sy 28, 2003Vol 209, No. 20 Reprinted) (©2003 American Medical Association. AI rights reserved ‘Downloaded From: http:/fjama,jamanetwork.com’ by Venty Yogyantari on 03/08/2016 hemorrhagic stroke, it was 0.82 (05% Cl, (0.43-1.56, TABLE 3) ‘Subgroup Analyses Hazard ratios for all stroke subtypes ‘combined were similar across age groups (Table 3). Women who ne ones before randomization had a 37% excess risk of stroke with estrogen plus progestin (HR, 1.37;05% Cl, 1.03-1.82). Use of statins or aspirin at baseline dic not modify the effect of estrogen plus progestin, and the findings remained similar when participants with prior ext= diovascular disease were excluded (n=24) from the analysis (data not shown). The effect of estrogen plus pro- gestin on stroke risk was similarly in- creased in women with and without va- somotor symptoms at baseline. Thirteen ‘women taking estrogen plus progestin and 5 women taking placebo who were ‘aged 50 through 59 years and who had vasomotor symptoms had experienced a stroke, Point estimates of HRs wer higher for estrogen plus progestin in vi- twally all subgroups examined and did not differ from the overall HR of 1.31 for total strokes srused hor- ime Trends Kaplan-Meier cumulative hazard of stroke (all types of stroke combined) be- gins to diverge between 1 and 2 years alter randomization (FIGURE 1). Curmu- lative hazards within each of the 3 age ‘groups (50-59, 60-69, 70-79 years), for normotensive and hypertenst and within low, medium, and high stroke-isk teriles as detertnined from the Framingham equations, indicate that ‘within each of these groups there was aan adverse effect of estrogen plus pro- jgestin compared with placebo, but the adverse elect of estrogen plus proge tun was delayed in the low-risk tertile ‘compared with the middle or highest te tle of Framingham stroke risk and in normotensive compared with hyperten- sive women (data not shown). Other Stroke Risk Factors Black women were 75% more likely 10 have a stroke than white women (HR, 1.75; 95% Cl, 1.14-2.68). Risk of stroke, (©2003 American Medical Association, All rights reserved, EFFECT OF ESTROGEN PLUS PROGESTIN ON STROKE Figure 1. Fsumstes of Cumulative Hazaras for Stokes adjusted for race or ethnicity, was sig- nificantly associated with current smok- ing (HR, 231; 95% C1, 161-331), hy- pertension (HR, 1.85; 95% Cl. 1.42-2.42), higher baseline SBP (HR, 1.22; 05% Cl, 1-14-1.30 per 10 mm Hg, Increase), or DBP (HR, 1.21; 95% Cl, 1.06-1.38 per 10 mm Hg increase), hav- ing let ventricular hypertrophy at base- line (HR, 1.73;95% Cl, 1.13-2.66), hav- ing diabetes (HR, 2.23; 95% Cl. 1.47-3.38),and with Framingham stroke risk score (HR, 6.36; 95% Cl, 3.76- 10.76 for highest tertile compared with lowest tere of Framingham stroke risk). Increased white blood cell count (P<001) and higher hematocrit levels (P<.001) were also significantly re- lated to stroke risk. Reduced risk was as- sociated with taking vitamin C supple ments (HR, 0.74; 05% C1,0.58-0.95) and physical activity (HR, 0.65;05% Cl, 0.44 0.97 for participants who reported 4 oF more episodes a week of moderate or strenuous activity). Prior oral contra ceplive use was not related to stroke risk. ‘Multivariate Analyses We ran Cox regression models includ- ingas independent variables those uni- variately related to stroke with P<.05 as noted above, plus additional vari- ables with P>.05 and P<.25 (data not shown). To examine potential interac- tions of variables from this core set with ‘Downloaded From: http:/fjama,jamanetwork.com’ by Venty Yogyantari on 03/08/2016 estrogen plus progestin, we included ‘each interaction term 1 ata time, Ther ‘were no significant interactions (P>.05) of estrogen plus progestin with any of these variables or with the Framing- hham risk score, which is a composite ‘ofsome of these variables, Other analy- ses indicated no significant interac- Lions of estrogen plus progestin with age for use of aspirin, nonsteroidal anti- inflammatory drugs, statins, or prior coral contraceptives. Use of estrogen plus progestin was not associated with an increase in DBP, >but it was associated with an increase in SBP (average <2 mim Hg).” For women laking estrogen plus pro- gestin, the unadjusted HR was 1.31 (05% Cl, 1.02-1.68, TABLE 4). Adjust- ment for race or ethnicity and base- line SBP did not affect the risk of stroke for those taking estrogen plus proge: tin, nor did further adjustments for mul- tiple covariates affect stroke risk. Ad- justment for SBP as a time-dependent variable did not appreciably change the HR. Thus, the effect of estrogen plus progestin on SBP did not explain the e cess risk of stroke associated with e trogen plus progestin. In an analysis that adjusted for adherence, the HR was hhigher than in the intention-to-treat analysis (HR, 1.50;5% Cl, 1.08-2.08), and higher HRs were found in all mod- cls tested (Reprints) JAMA, My 28, 2003Vol 209, Nv. 20. 2679 EFFECT OF ESTROGEN PLUS PROGESTIN ON STROKE Blood Biomarkers re Blood Biomater cts Hazard Ratio of Estrogen + examine the effects of lipid levels, in- ait IPRS ty

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