Postmenopausal Hormone Therapy Increases Risk for Venous Thromboembolic Disease: The Heart and Estrogen/progestin Replacement Study Effect of Oral Postmenopausal Hormone Replacement on Progression of Atherosclerosis: A Randomized, Controlled Trial Effect of postmenopausal hormone therapy on coronary heart disease events after percutaneous transluminal coronary angioplasty. Arterial imaging outcomes and cardiovascular risk factors in recently menopausal women: a randomized trial. Randomized trial of hormone therapy in women after coronary bypass surgery. Evidence of differential effect of hormone therapy on angiographic progression of disease in saphenous vein grafts and native coronary arteries. Comparison of transdermal and oral estrogen-progestin replacement therapy: effects on cardiovascular risk factors Benefits and risks of postmenopausal hormone therapy when it is initiated soon after menopause. The estrogen replacement and atherosclerosis (ERA) study: study design and baseline characteristics of the cohort. The EWA (estrogen in women with atherosclerosis) study: a randomized study of the use of hormone replacement therapy in women with angiographically verified coronary artery disease. Characteristics of the study population. Effects on lipids and lipoproteins. Randomized trial of effects of continuous combined HRT on markers of lipids and coagulation in women with acute coronary syndromes: WHISP Pilot Study. A Prospective, Observational Study of Postmenopausal Hormone Therapy and Primary Prevention of Cardiovascular Disease The effects of hormone replacement therapy on hemostatic variables in women with angiographically verified coronary artery disease: results from the estrogen in women with atherosclerosis study. Oral conjugated equine estrogen increases plasma von Willebrand factor in postmenopausal women. Risk factors for venous thromboembolism in pre-and postmenopausal women. Effects of oral and transdermal estrogen/progesterone regimens on blood coagulation and fibrinolysis in postmenopausal women. A randomized controlled trial. Effect of Raloxifene on Stroke and Venous Thromboembolism According to Subgroups in Postmenopausal Women at Increased Risk of Coronary Heart Disease Commentary: hormone replacement therapy and coronary heart disease: four lessons.
Venous thromboembolism , including thrombosis of the deep veins of the legs and embolism to the pulmonary arteries , is a serious and potentially fatal event . Venous thromboembolism is uncommon in the general population , occurring in about 1 to 4 per 1000 adults annually ( 1 , 2 ) . However , the risk is increased in persons with previous venous thromboembolism ( 3 ) , recent surgical procedures ( 4 , 5 ) , immobilization , fracture of a lower extremity ( 4 , 6 , 7 ) , cancer ( 4 , 6 , 7 ) , and inherited coagulation disorders ( 8 , 9 ) . Use of oral contraceptive pills increases risk for venous thromboembolism ( 1 , 2 ) . This increased risk is thought to be due to estrogen and to be dose related ( 3 , 4 ) . The biological potency of the estrogens generally used in postmenopausal hormone therapy is about one-fourth to one-fifth that of the estrogens in modern oral contraceptives . Until recently , there has been little evidence that low-dose estrogen therapy is associated with increased risk for venous thromboembolism ( 5 - 8 ) . Recent observational studies have suggested that postmenopausal hormone therapy causes a twofold to fourfold increase in risk for idiopathic deep venous thrombosis and pulmonary embolism ( 9 - 13 ) . However , these findings may be biased if women taking estrogen are more likely to be evaluated for nonspecific symptoms suggestive of venous thromboembolism . The Heart and Estrogen/progestin Replacement Study ( HERS ) was a r and omized , blinded , placebo-controlled trial of the effect of daily conjugated equine estrogen , 0.625 mg , plus medroxyprogesterone acetate , 2.5 mg , on the rate of new coronary events in 2763 postmenopausal women with established coronary heart disease ( 14 ) . One of the specified secondary outcomes of this trial was venous thromboembolism . An increased risk for venous thromboembolism among women assigned to hormone therapy was noted by the HERS Data and Safety Monitoring Board . The Board instructed the HERS investigators to inform participants and the scientific community of this risk and to institute measures to reduce risk . At a mean follow-up of 3.3 years , the HERS investigators notified participants to discontinue study medication in situations associated with increased risk for venous thromboembolism , such as surgery , hospitalization , fracture , and cancer , and published a letter noting the increased risk ( 15 ) . This report presents the full analysis of the findings . Methods Participants in HERS were postmenopausal women younger than 80 years of age who had coronary disease ( myocardial infa rct ion , coronary artery bypass surgery , percutaneous coronary revascularization , or angiographic evidence of at least 50 % narrowing of one or more major coronary arteries ) and had not had a hysterectomy . Women were excluded if their coronary event occurred within 6 months of r and omization ; they had used hormone therapy within 3 months of r and omization ; they had a history or baseline findings suggestive of venous thromboembolism , breast cancer , or endometrial cancer ; or they had uncontrolled hypertension , diabetes , or other life-threatening diseases ( 16 ) . The protocol was approved by the institutional review board at each of the 20 HERS clinical centers , and all participants provided written informed consent . Participants were r and omly assigned to take one tablet daily of conjugated equine estrogen , 0.625 mg , plus medroxyprogesterone acetate , 2.5 mg , or placebo that was identical in appearance . R and omization was stratified by clinical center and performed in blocks of 4 . To prevent unblinding of clinical center staff , HERS participants reported breast discomfort and vaginal bleeding directly to gynecology staff , who were located separately from the clinical center staff , did not communicate with clinical center personnel about breast or gynecologic problems , and did not participate in ascertainment of outcomes . Follow-up visits to the clinical centers occurred at 4-month intervals . Coronary events ( nonfatal myocardial infa rct ion and coronary death ) were the primary outcome of the trial ( 14 ) . At each visit , clinic staff asked participants if they had been told by a physician that they had a blood clot in the legs or lungs . Women were also asked whether they had been hospitalized , and records were review ed to determine whether venous thromboembolism had occurred . Women were not routinely asked about symptoms of venous thrombosis , such as lower-extremity edema . Diagnosis of deep venous thrombosis required documentation of thrombosis of the popliteal or more proximal veins of the legs by venography , impedance plethysmography , or sonography . Pulmonary embolism required documentation by a nuclear lung scan that suggested a high probability of pulmonary embolism ( segmental or larger perfusion defect with ventilation mismatch ) or by pulmonary angiography that revealed a constant intraluminal filling defect on multiple films . Suspected venous thromboembolism was adjudicated independently and without knowledge of treatment assignment by two physicians at the HERS Coordinating Center , located at the University of California , San Francisco ; disagreements were resolved by consensus . Persons who analyzed data were also blinded to participants ' treatment status . Data were collected on events that occurred during the trial that might be predictors of venous thromboembolism , including fractures , nonfatal myocardial infa rct ion , congestive heart failure , stroke , and transient ischemic attack ( 16 ) . Venous thromboembolism was classified as idiopathic in women who did not have concomitant cancer , nonfatal myocardial infa rct ion , congestive heart failure , or stroke and did not have a fracture , inpatient surgery , or hospitalization in the 3 months before the venous thromboembolic event . In the primary analysis , an unadjusted Cox proportional-hazards model for time to first event was used to compare the rate of venous thromboembolism among women assigned to  hormone therapy with the rate among women assigned to placebo . The primary analysis was intention-to-treat ; participants were categorized according to treatment assignment regardless of compliance . Participants who were lost to follow-up ( 33 women in the hormone therapy group and 36 in the placebo group ) were censored at the last date at which they were known to be alive without venous thromboembolism ; vital status was known for all women at the end of the trial . We also performed an as-treated analysis , in which inclusion in the risk sets was limited to women in both treatment groups whose average compliance with therapy during the trial ( measured by pill count ) was at least 80 % . Relative hazards were also estimated by year since r and omization ( women with events in earlier years were censored ) , and continuous trend in the log relative hazard was examined in a companion model . We repeated the main analyses separately for idiopathic and nonidiopathic venous thromboembolism . Potential risk factors for venous thromboembolism were first examined by using univariate proportional hazards models adjusted for treatment assignment . In these models , postr and omization events and medication use were represented by time-dependent indicators , which reverted to zero 90 days after fracture , surgery , or hospitalization or when therapy was discontinued . Variables associated with venous thromboembolism for which the associated P value was less than 0.2 in univariate analyses were considered for inclusion in multivariate models and retained in the model if the P value remained less than 0.2 . Statistical analyses were performed by using SAS software , version 6.12 ( SAS Institute , Inc. , Cary , North Carolina ) . Results The 20 HERS centers enrolled 2763 women between February 1993 and September 1994 ; of these , 1380 were assigned to the hormone therapy group and 1383 to the placebo group . Participants ranged in age from 44 to 79 years ( mean age [ SD ] , 67 7 years ) . At baseline , the treatment groups did not differ significantly ( Table 1 ) . Table 1 . Baseline Characteristics of HERS Participants At the end of the first year , 82 % of women in the hormone therapy group and 91 % in the placebo group reported taking study medication ; by the end of the third year , these proportions had decreased to 75 % and 81 % , respectively . Cumulative incidence curves for all venous thromboembolic events ( deep venous thrombosis and pulmonary embolism ) are shown in the Figure . During 10 985 woman-years of follow-up , 47 women experienced a  venous thromboembolic event : 34 in the hormone-treated group ( 6.2 per 1000 woman-years ) and 13 in the placebo group ( 2.3 per 1000 woman-years ) ( relative hazard , 2.7 [ 95 % CI , 1.4 to 5.0 ] [ P = 0.003 ] ; excess risk , 3.9 per 1000 woman-years [ CI , 1.4 to 6.4 per 1000 woman-years ] ; number needed to treat for harm , 256 [ CI , 157 to 692 ] ) . The relative hazard of venous thromboembolism did not differ significantly among the 20 clinical centers . Figure . Kaplan-Meier estimates of the cumulative incidence of venous thromboembolic events ( top ) , deep venous thrombosis ( middle ) , and pulmonary embolism ( bottom ) . More women in the hormone therapy group than in the placebo group experienced deep venous thrombosis ( 25 compared with 9 ; relative hazard , 2.8 [ CI , 1.3 to 6.0 ] ; P = 0.008 ) and pulmonary embolism ( 11 compared with 4 ; relative hazard , 2.8 [ CI , 0.9 to 8.7 ] ; P = 0.08 ) ( Table 2 ) . Two women , both in the hormone therapy group , died of pulmonary embolism . The relative hazard was increased for idiopathic ( relative hazard , 3.1 [ CI , 0.8 to 11.3 ] ) and nonidiopathic venous thromboembolic events ( relative hazard , 2.5 [ CI , 1.2 to 5.3 ] ) . The overall results were unchanged in an as-treated analysis that was limited to women who reported taking more than 80 % of their assigned study medication ( relative hazard , 3.2 [ CI , 1.5 to 6.9 ] ; P = 0.003 ) . Table 2 . Venous Thrombolic Events by Treatment Group and Year of R and omization Table 2 shows relative hazards for venous thromboembolism by year since r and omization . The number of episodes of pulmonary Abstract —Postmenopausal hormone replacement therapy ( HRT ) is associated with low cardiovascular morbidity and mortality in epidemiological studies . Yet , no r and omized trial has examined whether HRT is effective for prevention of coronary heart disease ( CHD ) in women with increased risk . The objective of this study was to determine whether HRT can slow progression of atherosclerosis , measured as intima-media thickness ( IMT ) in carotid arteries . Carotid IMT is an appropriate intermediate end point to investigate clinical ly relevant effects on atherogenesis . This r and omized , controlled , observer-blind , clinical , single-center trial enrolled 321 healthy postmenopausal women with increased IMT in ≥1 segment of the carotid arteries . For a period of 48 weeks , subjects received either 1 mg/d 17&bgr;-estradiol continuously plus 0.025 mg gestodene for 12 days every month ( st and ard-progestin group ) , or 1 mg 17&bgr;-estradiol plus 0.025 mg gestodene for 12 days every third month ( low-progestin group ) , or no HRT . Maximum IMT in 6 carotid artery segments ( common , bifurcation , and internal , both sides ) was measured by B-mode ultrasound before and after intervention . HRT  did not slow IMT progression in carotid arteries . Mean maximum IMT in the carotid arteries increased by 0.02±0.05 mm in the no HRT group and by 0.03±0.05 and 0.03±0.05 mm , respectively , in the HRT groups ( P > 0.2 ) . HRT  significantly decreased LDL cholesterol , fibrinogen , and follicle-stimulating hormone . In conclusion , 1 year of HRT was not effective in slowing progression of sub clinical atherosclerosis in postmenopausal women at increased risk Despite several observational studies , 1–3 no clinical trial has evaluated the effect of hormone therapy on percutaneous transluminal coronary angioplasty ( PTCA ) outcomes in matched population s r and omized to hormones or placebo . We compared the incidence of  coronary heart disease ( CHD ) events after PTCA among women who previously had been r and omly assigned to hormone therapy and placebo in the Heart and Estrogen/progestin Replacement Study ( HERS ) .  The design , methods , and primary results of HERS have been previously published . 4,5 Briefl y , HERS participants were postmenopausal women aged 80 years with established CHD who had not had a hysterectomy . Inclusion criteria were prior myocardial infa rct ion , coronary artery bypass graft surgery ( CABG ) , PTCA , or angiographic evidence of a 50 % diameter narrowing of 1 major coronary artery . Exclusion criteria were a recent CHD event , New York Heart Association class IV or severe class III congestive heart failure , serum triglyceride levels 300 mg/ dl , recent use of any hormone therapy , uncontrolled hypertension or diabetes , a disease ( other than CHD ) judged likely to be fatal within 4 years , or prior intolerance to hormone therapy . At the initiation of the HERS , participants were r and omly assigned to receive a single identical tablet containing either conjugated equine estrogen 0.625 mg and medroxyprogesterone acetate 2.5 mg or placebo . During the HERS , 357 patients underwent PCTA and constituted the study population . These patients were followed subsequently to ascertain their rate for subsequent CHD events . Demographic characteristics , health history , CHD risk factors , medication use , educational level , and quality of life were assessed at baseline . Baseline levels of fasting total cholesterol , low-density lipoprotein cholesterol , high-density lipoprotein cholesterol , triglycerides , and lipoprotein ( a ) were determined by the Lipoprotein Analytical Laboratory at Johns Hopkins Hospital ( Baltimore , Maryl and ) . Follow-up time for this analysis began at the time of the initial PTCA and concluded at the closeout of the HERS . All suspected outcome events were classifi ed independently by 2 physician review ers who were unaware of treatment assignment . Discordant classifi cations were resolved in discussion s between the review ers BACKGROUND Whether menopausal hormone therapy ( MHT ) protects against cardiovascular disease ( CVD )  remains unclear . OBJECTIVE To assess atherosclerosis progression and CVD risk factors after MHT initiated in early menopause . DESIGN R and omized , controlled trial . ( Clinical Trials.gov : NCT00154180 ) . SETTING Nine U.S. academic centers . PARTICIPANTS Healthy menopausal women aged 42 to 58 years between 6 and 36 months from last menses without prior CVD events who had a coronary artery calcium ( CAC ) score less than 50 Agatston units and had not received estrogen or lipid-lowering therapy for at least 90 days . INTERVENTION Oral conjugated equine estrogens ( o-CEE ) , 0.45 mg/d , or transdermal 17β-estradiol ( t-E2 ) , 50 mcg/d , each with 200 mg of oral progesterone for 12 days per month , or placebo for 48 months . MEASUREMENTS Primary end point was annual change in carotid artery intima-media thickness ( CIMT ) . Secondary end points included changes in markers of CVD risk . RESULTS Of 727 r and omly assigned women , 89.3 % had at least 1 follow-up CIMT and 79.8 % had CIMT at 48 months . Mean CIMT increases of 0.007 mm/y were similar across groups . The percentages of participants in whom CAC score increased did not differ significantly across groups . No changes in blood pressure were observed with o-CEE or t-E2 . Low- and high-density lipoprotein cholesterol levels improved and levels of C-reactive protein and sex hormone-binding globulin but not interleukin-6 increased with o-CEE . Insulin resistance decreased with t-E2 . Serious adverse events did not differ by treatment . LIMITATION Power to compare clinical events was insufficient . CONCLUSION Four years of early MHT did not affect progression of atherosclerosis despite improving some markers of CVD risk . PRIMARY FUNDING SOURCE Aurora Foundation Clinical trials indicate that hormone therapy ( HT ) does not decrease cardiovascular disease events or angiographic coronary disease progression . The effects of HT on SVG vessels are unknown . To determine whether postmenopausal hormone therapy started after coronary bypass surgery ( CABG ) decreases saphenous vein graft ( SVG ) disease , we conducted a multicenter r and omized placebo-controlled angiographic study of estradiol+/-medroxyprogesterone started within 6 months of CABG in 83 postmenopausal women .  Angiographic and intravascular ultrasound ( IVUS ) assessment at 6 and 42 months was planned to assess SVG disease progression . The study was stopped early following publication of the Women 's Health Initiative Estrogen/Progestin study . Eighty-three subjects underwent a 6-month angiogram with 63 undergoing IVUS . Forty-five subjects completed the 42-month  angiogram  ( 20 underwent 42-month IVUS ) . In analysis of paired 6- and 42-month angiogram and IVUS studies , HT slowed angiographic progression of SVG disease assessed by mean percent stenosis ( p<0.001 ) , minimal lumen diameter ( p=0.029 ) , and total plaque volume ( p=0.006 ) . In contrast , HT accelerated disease progression in non-bypassed native coronary arteries ( minimum lumen diameter , p=0.01 ) . SVG disease and closure occurred in 38 % subjects within 1-year post-CABG . The groups had similar frequency of cardiovascular events expect for angioplasty that occurred in eight HT compared to one placebo subject ( p<0.05 ) . In HT subjects angioplasty was indicated for native coronary arterial stenoses while in the placebo subject angioplasty was indicated for SVG stenosis . This study suggests that hormone treatment may slow SVG disease progression while accelerating atherosclerosis in non-bypassed native coronary arteries Objective To determine the effects of oral and transdermal hormone replacement therapy on lipid profile and hemostatic factors in postmenopausal women . Design Twenty subjects were treated with oral E2 valerate ( 2 mg ) combined with cyproterone acetate ( 1 mg ) ( group I ) and 21 with transdermal E2 ( 1.5 mg ) plus oral medroxyprogesterone acetate ( 5 mg ) ( group II ) . The effects on lipid profile and hemostatic parameters were evaluated at baseline and after 3 , 6 , and 12 months of treatment . Results Group I showed a stronger increase of high-density lipoprotein ( HDL ) cholesterol levels ( 2–8 % ) and stronger reduction of atherogenic indices ( total cholesterol/HDL cholesterol and low-density lipoprotein/HDL cholesterol ) than group II . Group II showed a more pronounced reduction of triglyceride ( 21–31 % ) and factor VII ( 6–10 % ) levels than group I. Both groups showed reduced concentrations of total cholesterol , low-density lipoprotein cholesterol , tissue plasminogen activator , plasminogen activator inhibitor-1 , antithrombin III , and protein S , whereas protein C was increased after 12 months of treatment . Conclusions The cardioprotective effects of hormone replacement therapy are demonstrated by favorable effects on lipid profile and fibrinolytic activity . Oral hormone replacement therapy showed a more prominent effect on lipoprotein metabolism than did transdermal administration , but transdermal medication had a stronger effect on triglyceride and coagulation factors . However , it needs to be considered that there is an increased risk of venous thrombotic events in the first year of treatment The authors further analyzed results from the Women 's Health Initiative r and omized trials ( 1993 - 2004 ) of conjugated equine estrogens , with or without medroxyprogesterone acetate , focusing on health benefits versus risks among women who initiated hormone therapy soon after menopause . Data from the Women 's Health Initiative observational study ( 1993 - 2004 ) were included in some analyses for additional precision . Results are presented here for incident coronary heart disease , stroke , venous thromboembolism , breast cancer , colorectal cancer , endometrial cancer , or hip fracture ; death from other causes ; a summary global index ; total cancer ; and total mortality . Hazard ratios for breast cancer and total cancer were comparatively higher ( P < 0.05 ) among women who initiated hormone therapy soon after menopause , for both regimens . Among these women , use of conjugated equine estrogens appeared to produce elevations in venous thromboembolism and stroke and a reduction in hip fracture .  Estrogen plus progestin results among women who initiated use soon after menopause were similar for venous thromboembolism , stroke , and hip fracture but also included evidence of longer-term elevations in breast cancer , total cancer , and the global index . These analyses provide little support for the hypothesis of favorable effects among women who initiate postmenopausal estrogen use soon after menopause , either for coronary heart disease or for health benefits versus risk indices considered The Estrogen Replacement and Atherosclerosis ( ERA ) trial is a three-arm , r and omized , placebo-controlled , double-blind trial to evaluate the effects of estrogen replacement therapy ( 0.625 mg/day oral conjugated estrogen ) with or without continuous low-dose progestin ( 2.5 mg oral medroxyprogesterone acetate/day ) versus placebo on progression of atherosclerosis .  A total of 309 postmenopausal women at five sites underwent baseline coronary angiography and were r and omized . Participants will have repeat coronary angiography  after an average of 3.25 years of treatment . The primary outcome of interest will be change in minimum diameter of the major epicardial segments , as assessed by quantitative coronary angiography . The primary aim is to test the hypothesis that either form of hormone therapy will slow the progression or induce regression of coronary atherosclerosis compared to placebo . The secondary aims are to assess the effects of the two treatments versus placebo on endothelial function ( measured using flow-mediated vasodilator responses ) , on several presumed mediators of estrogen 's effect on atherosclerosis ( i.e. , plasma lipids and lipoproteins , blood pressure , glucose metabolism , hemostatic factors , and antioxidant activity ) , on other factors that influence the development of coronary heart disease ( i.e. , diet , smoking status , exercise , weight , and health-related quality of life issues ) , and on clinical cardiovascular events . The ERA trial is the first angiographic endpoint clinical trial to examine the effects of postmenopausal hormone replacement on  coronary atherosclerosis in women . It will provide an unparalleled opportunity to determine if either regimen of hormone therapy is effective in slowing the progress of angiographically defined coronary atherosclerosis . This study will complement other estrogen replacement trials , such as the PEPI , HERS , and Women 's Health Initiative studies , to provide a more comprehensive examination of the effects of estrogen replacement on cardiovascular risk factors , anatomic and functional manifestations of atherosclerosis , and risk for coronary heart disease in postmenopausal women . Control Clin Trials 2000;21:257 - OBJECTIVES To evaluate the effects of hormone replacement therapy ( HRT ) on lipids and lipoproteins in postmenopausal women with coronary artery disease . SETTING In this single-centre , controlled and r and omized study taking place in a tertiary referral clinic , patients were examined at baseline , and after 3 and 12 months . All analyses were performed examiner-blind . SUBJECTS Postmenopausal women ( n = 118 ) with angiographically verified coronary artery disease were recruited consecutively from patients referred for investigational procedures due to coronary artery disease . INTERVENTIONS The women were r and omized to HRT , i.e. transdermal application of continuous 17-beta oestradiol with cyclic medroxyprogesterone actetate tablets every 3rd month for 14 days , or to a control group . MAIN OUTCOMES Effects on lipids and lipoproteins . RESULTS After 3 months of unopposed oestradiol , triglycerides decreased significantly compared to the control group ( P = 0.006 ) . Sequential administration of medroxyprogesterone caused a decrease in HDL cholesterol ( P = 0.01 ) , concomitantly with a decrease in ApoA1 lipoproteins ( P = 0.007 ) . No other changes in lipids or lipoproteins were observed . After 12 months of therapy , no significant differences were observed between the two groups in lipid or lipoprotein levels . Concomitant statin treatment did not alter the main findings . CONCLUSIONS In postmenopausal women with established coronary artery disease in whom the majority is treated with statins , no additional effect of HRT on lipids or lipoproteins could be observed except for a transient decrease in triglycerides in the initial unopposed oestradiol phase . No deleterious effect could be observed during medroxyprogesterone administration except for a small transient decrease in HDL cholesterol and ApoA1 lipoproteins AIMS R and omized trials have not demonstrated coronary heart disease benefit from hormone replacement therapy ( HRT ) . We hypothesized that low-dose HRT may avoid harm . METHODS AND RESULTS We studied the effects of HRT on lipids and coagulation in women with acute coronary syndromes . A total of 100 post-menopausal women > 55 years were enrolled between 2 and 28 days after an acute coronary syndrome and r and omized to oral oestradiol-17beta 1 mg plus norethisterone acetate 0.5 mg daily , or matching placebo , and followed for up to 12 months . Levels of lipids , lipoproteins , and haemostasis markers were measured at baseline , 3 , and 6 months . There were no significant differences in lipid levels between the two groups , probably due to concomitant statin use . Antithrombin and factor VII levels were significantly lower in the HRT group , whereas fibrinogen was significantly decreased in the placebo group . No evidence of increased coagulation activation was observed , nor of adverse cardiovascular outcomes [ odds ratio ( OR ) 0.63 ( 95 % confidence intervals 0.31 - 1.31 ) ] . CONCLUSION Low-dose HRT may give cardiovascular benefit . These findings require confirmation in a full clinical trial with evaluation of cardiovascular outcomes as the primary objective Whether to take hormone therapy is one of the most difficult medical decisions that healthy postmenopausal women face . The apparent coronary benefits ( 1 ) of hormone use are an important part of that decision . Although the data appear consistent in suggesting long-term coronary benefits , the Heart and Estrogen/progestin Replacement Study ( 2 ) showed an increased risk for coronary events during the first year of therapy in women with existing heart disease ; we also found such an elevated risk in an examination of secondary prevention in the Nurses ' Health Study ( 3 ) . More recently , a report from the Women 's Health Initiative , an ongoing r and omized clinical trial of hormone therapy for primary prevention of cardiovascular disease , suggested similar findings in healthy women ( National Institutes of Health . Press release ) . However , additional data on short-term effects of hormone use in women without previous cardiovascular disease are sparse . Many further questions also remain . Among them is the cardiovascular effect of daily doses lower than the st and ard 0.625 mg of oral conjugated estrogen . Recent studies suggest that lower doses of hormone therapy provide bone benefits ( 4 ) and , compared with higher doses , might decrease the risk for thromboembolism ( 5 ) and reduce endometrial hyperplasia ( 4 ) . However , few data are currently available on the relation between low-dose estrogen and primary prevention of heart disease and stroke . In an earlier report , we examined the relation between postmenopausal hormone therapy and primary prevention of cardiovascular disease based on 16 years of follow-up from the Nurses ' Health Study ( 6 ) . In the current analysis , we have almost 50 % more follow-up time among women taking daily doses less than 0.625 mg and more than 800 additional cases of cardiovascular disease , allowing more precise assessment of specific associations . Thus , we now report on the relation among  low-dose estrogen , short-term hormone use , and cardiovascular events in 70 533 postmenopausal women with no previous cardiovascular disease who were followed for up to 20 years . We also provide additional information on the effects of estrogen combined with progestin . Methods The Nurses ' Health Study Cohort The Nurses ' Health Study began in 1976 when 121 700 female nurses 30 to 55 years of age completed a mailed question naire about their postmenopausal hormone use and medical history , including cardiovascular disease and its risk factors . We up date information with biennial follow-up question naires . Dietary and physical activity question naires were added in 1980 . Cohort follow-up is greater than 90 % . Ascertainment of Hormone Use In 1976 , women were asked about use and duration of hormone therapy after menopause . Beginning in 1978 , we collected information on type of hormones taken , and starting in 1980 , we asked about the dose of oral conjugated estrogen . All information is up date d biennially . Identification of Cardiovascular Disease We identified first occurrences of nonfatal myocardial infa rct ion , fatal coronary disease , and fatal and nonfatal stroke between the return of the 1976 question naire and 1 June 1996 . Nurses who reported a nonfatal infa rct ion or stroke were asked for permission to review their medical records . Nonfatal myocardial infa rct ions were confirmed by hospital records if they met World Health Organization criteria ( 7 ) ( symptoms plus either elevated levels of cardiac enzymes or diagnostic electrocardiograms ) . Infa rct ions that required hospitalization and were corroborated by interview or letter but for which medical records were unobtainable were included as probable . Infa rct ions of indeterminate age discovered on routine examination were excluded . Nonfatal strokes were confirmed by review of medical records if they were characterized by a typical neurologic deficit , were rapid in onset , lasted at least 24 hours , and met the criteria of the National Survey of Stroke ( 8) . We classified strokes as ischemic ( thrombotic or embolic occlusion of a cerebral artery ) , subarachnoid hemorrhage , or intraparenchymal hemorrhage . We excluded subdural hematomas and strokes caused by infection or neoplasia . Strokes that required hospitalization and were corroborated by letter or interview but for which medical records were unavailable were included as probable . Most deaths were reported by the participants ' families . We search ed the National Death Index to identify deaths among nonrespondents to each 2-year question naire ; mortality follow-up was more than 98 % complete ( 9 ) . For all deaths possibly attributable to cardiovascular causes , we requested permission from relatives ( subject to state regulations ) to review the medical records . Deaths were considered to be due to coronary disease if medical records or autopsy findings confirmed a fatal myocardial infa rct ion . We also included coronary disease listed on the death certificate as the underlying cause without another , more plausible cause , if the nurse was known ( from hospital records , family , or other sources ) to have had coronary disease before death . In no case was the cause listed on the death certificate used as the sole criterion for coronary death . Sudden death within 1 hour of the onset of symptoms in participants with no other plausible cause of death besides coronary disease was also included . Fatal strokes were documented by autopsy or hospital records or if stroke was listed as the underlying cause on the death certificate . The category of major coronary heart disease combines nonfatal myocardial infa rct ion and coronary death ; similarly , total stroke includes nonfatal and fatal cases . The category of combined cardiovascular disease includes major coronary heart disease and stroke . Confirmed and probable cases in each category were analyzed together ( 80 % of major coronary events and 73 % of strokes were confirmed ) . In this and previous analyses ( 6 ) , results for probable cases were similar to those for confirmed cases . The investigators conducted all interviews and record review s without knowledge of participants ' hormone use status . Population for Analysis Women who reported stroke , myocardial infa rct ion , angina , coronary revascularization , or cancer ( except nonmelanoma skin cancer ) on the 1976 question naire were excluded because their disease may have caused them to alter their hormone use . Similarly , women who reported such diagnoses on a subsequent question naire were excluded from further analysis . Thus , at the start of each 2-year interval , the base population included no women reporting these diagnoses . Our own studies ( 6 , 10 ) and other studies ( 11 ) have suggested that hormone therapy may differentially affect incident and fatal strokes ; thus , we separately examined deaths due to stroke . In these analyses , we excluded women with cancer and cardiovascular disease at baseline but did not up date the exclusions because the women who develop cardiovascular disease during follow-up are those most likely to die of stroke . We classified women as postmenopausal from the time of natural menopause or hysterectomy with bilateral oophorectomy .  Women who underwent hysterectomy without bilateral oophorectomy  were considered postmenopausal when they reached the age at which natural menopause had occurred in 90 % of the cohort ( 54 years for smokers and 56 years for nonsmokers ) . In this cohort , the women 's reports of age at menopause ( 12 ) and type of menopause ( 13 ) were highly accurate . In 1976 , 21 947 postmenopausal women entered the analysis , and 48 586 women were added during follow-up as they became postmenopausal , for a total of 70 533 participants ; 808 825 person-years of follow-up were accrued from 1976 to 1996 . Statistical Analysis For each participant , person-months were allocated to hormone categories according to the 1976 data and were up date d every 2 years ( for estrogen dose , follow-up began in 1980 ) . For analyses of type of hormone therapy , we assigned the regimen reported on the 1978 question naire to women who reported hormone use in 1976 . Analyses of type of hormone therapy were limited to users of oral conjugated estrogen with or without oral medroxyprogesterone acetate  , since these were the most common hormone regimens . If no data were available on hormones in a given time period , women were assigned to a missing category for that time period . To maintain the prospect i ve nature of the study , hormone use ( including duration ) during each 2-year period was established from women 's reports at the start of the period ; thus , we probably underestimate duration of use by an average of 1 year . Follow-up for a participant ended at the first diagnosis of cardiovascular disease , death , or 1 June 1996 , whichever came first . The primary analysis is based on incidence rates for which person-months of follow-up were used as the denominator . We used relative risk as the measure of association , defined as the incidence of cardiovascular events among women in various categories of hormone use divided by the incidence among women who never used hormones . We computed age-specific rates by using 5-year categories ( 14 ) and age-adjusted relative risks by using MantelHaenszel rate ratios ( 15 ) with 95 % CIs ( 16 ) . We used pooled logistic regression  across the ten 2-year time periods to adjust simultaneously for potential confounding factors ( 17 ) . In this approach , independent blocks of person-time are pooled for regression analysis , and time-varying covariates are readily accommo date d by assigning successive blocks of person-time to the covariate values at the start of each follow-up cycle . The dependence of the incidence rates on time is modeled nonparametrically with indicator variables . Simulation studies have established the asymptotic equivalence of pooled logistic regression to Cox regression with time-dependent covariates ( 18 ) . The necessary conditions for this equivalence include relatively short time intervals and small probability of the outcome during each interval , both Data on the effect of hormone replacement therapy on hemostasis are inconsistent , and there are few data in women with coronary artery disease . In a single-center , open , r and omized study , 118 postmenopausal women with angiographically verified coronary artery disease were r and omized to hormone replacement therapy , given as long-cycle transdermal 17-beta-estradiol ( 50 microg/24 hour ) for 3 months with sequential medroxy-progesterone acetate for 14 days , or to a control group receiving no therapy .  Hemostatic parameters were measured at baseline and after 3 and 12 months of therapy . The coagulation inhibitors antithrombin , protein C , and protein S , but not tissue factor pathway inhibitor , decreased significantly from baseline in the hormone replacement therapy group at both 3 and 12 months as compared with the control group . The absolute decreases within the hormone replacement therapy group were 3 to 10 % . No significant differences between the two treatment groups were observed for the coagulation products prothrombin fragment 1 + 2 or thrombin-antithrombin complex or for D-dimer , although there were significant decreases in the levels within the hormone replacement therapy group . Levels of fibrinogen , activated factor VII , and factor VII antigen were not significantly influenced by hormone replacement therapy treatment . Similarly , nonsignificant changes were detected for the fibrinolytic parameters tissue plasminogen activator activity , tissue plasminogen activator antigen , and global fibrinolytic activity , but plasminogen activator inhibitor type 1 was significantly lower in the hormone replacement therapy group due to a question able increase in the levels in the control group . In conclusion , treatment with transdermal estradiol combined with long-cycle progestins was associated with no net activation of coagulation despite reduced levels of coagulation inhibitors OBJECTIVES We sought to test whether one month of daily oral conjugated equine estrogen ( CEE ) or transdermal estradiol alters hemostatic factors in postmenopausal subjects . BACKGROUND Estrogen replacement therapy and hormonal replacement therapy ( HRT ) effect an early increase in cardiovascular events in postmenopausal women . Circulating plasma von Willebr and factor ( vWF ) antigen is a marker of generalized endothelial dysfunction and atherothrombosis . METHODS Thirty-eight healthy postmenopausal women ( average 59 + /- 7 years ) were r and omized to receive daily oral CEE , 0.625 mg ( n = 21 ) ; transdermal estradiol , 0.1 mg/day ( n = 7 ) ; or oral placebo ( n = 10 ) for one month . Blood sample s were collected at baseline and after two weeks and four weeks of therapy for measurement of circulating plasma hormones , lipid concentrations , and hemostatic factors . RESULTS Oral CEE decreased total cholesterol ( p < 0.01 ) and low-density lipoprotein cholesterol ( p < 0.01 ) , although it increased both triglycerides ( p < 0.05 ) and high-density lipoprotein cholesterol ( p < 0.01 ) . Transdermal estradiol had no significant effect on lipids . Plasminogen activator inhibitor-1 antigen declined in both oral CEE and transdermal estradiol users , but did not achieve statistical significance . Fibrin D-dimer antigen did not vary significantly in any group . However , oral CEE users had a significant increase in vWF from baseline to four weeks ( p < 0.03 ) and a decrease in tissue-type plasminogen activator antigen from baseline to four weeks ( p < 0.004 ) , which was significantly different from the change observed in the transdermal estradiol group ( p < 0.05 ) . CONCLUSIONS These data suggest that the oral CEE-mediated increase in plasma vWF may have clinical relevance given the early atherothrombotic effects of HRT in postmenopausal women INTRODUCTION Hemostasis in women is affected by changes of estrogen levels . The role of endogenous estrogens on risk of venous thromboembolism ( VTE ) remains unclear . The aim of this study was to investigate the importance of acquired and genetic risk factors for VTE in pre- and postmenopausal women . METHOD In a nationwide case-control study we included as cases 1470 women , 18 to 64years of age with a first time VTE . The 1590 controls were r and omly selected and matched by age to the cases . Information on risk factors was obtained by interviews and DNA-analyses . We used unconditional logistic regression to calculate odds ratios ( ORs ) with 95 % confidence intervals ( CIs ) . RESULTS The ORs were generally of similar magnitude in pre- and postmenopausal women . The highest risk was for the combination of surgery and cast ( adjusted OR 54.12 , 95 % CI 16.62 - 176.19 ) in postmenopausal women . The adjusted OR for use of menopausal hormone therapy was 3.73 ( 95 % CI 1.86 - 7.50 ) in premenopausal and 2.22 ( 95 % CI 1.54 - 3.19 ) in postmenopausal women . Overweight was linked to an increased risk and exercise to a decreased risk , regardless of menopausal status . CONCLUSION Menopausal status had only minor influence on the risk levels . Acquired transient risk factors conveyed the highest risks for VTE Postmenopausal hormone replacement therapy is associated with a reduction in the incidence of coronary heart disease . However , inconclusive results have been reported with respect to the risk of stroke , and recent studies consistently showed an increased risk of venous thromboembolism in postmenopausal women using oral estrogen .  There are surprisingly few interventional studies to assess the true effects of estrogen-progestin regimens on blood coagulation and fibrinolysis , and the impact of the route of estrogen administration on hemostasis has not been well documented . Therefore , we investigated the effects of oral and transdermal estradiol/progesterone replacement therapy on hemostatic variables . Forty-five healthy postmenopausal women , aged 45 to 64 years , were assigned r and omly to one of the three following groups : cyclic oral or transdermal estradiol , both combined with progesterone , or no hormonal treatment .  Hemostatic variables were assayed at baseline and after a 6-month period . Pairwise differences in the mean change between the three groups were compared using nonparametric tests . Oral but not transdermal estradiol regimen significantly increased the mean value of prothrombin activation peptide ( F1 + 2 ) and decreased mean antithrombin activity compared with no treatment . Differences in fragment F1 + 2 levels between active treatments were significant . The oral estrogen group was associated with a significant decrease in both mean tissue-type plasminogen ( t-PA ) concentration and plasminogen activator inhibitor ( PAI-1 ) activity and a significant rise in global fibrinolytic capacity ( GFC ) compared with the two other groups . A transdermal estrogen regimen had no significant effect on PAI-1 , t-PA , and GFC levels . There were no significant changes in mean values of fibrinogen , factor VII , von Willebr and factor , protein C , fibrin D-dimer , and plasminogen between and within the three groups . We conclude that oral estrogen/progesterone replacement therapy may result in coagulation activation and increased fibrinolytic potential , whereas opposed transdermal estrogen appears without any substantial effects on hemostasis . Whereas these results may account for an increased risk of venous thromboembolism in users of oral postmenopausal estrogen  , they emphasize the potential importance of the route of estrogen administration in prescribing hormone replacement therapy to postmenopausal women , especially to those at high risk of thrombotic disease Background and Purpose — Raloxifene , a selective estrogen receptor modulator , reduces risk of invasive breast cancer and osteoporosis , but the effect on risk for stroke and venous thromboembolism in different patient subgroups is not established . The purpose of this analysis was to evaluate the effect of raloxifene on the incidence of all strokes , stroke deaths , and venous thromboembolic events according to participant subgroups . Methods — This was a secondary end point analysis of an international , r and omized , placebo-controlled clinical trial of 10 101 postmenopausal women with or at increased risk of coronary heart disease followed a median of 5.6 years .  Strokes , venous thromboembolic events , and deaths were adjudicated by expert central ized committees . Strokes were categorized as ischemic , hemorrhagic , or undetermined and venous thromboembolic events were subclassified . Results — The incidences of all strokes did not differ between raloxifene ( incidence rate per 100 woman-years=0.95 ) and placebo ( incidence rate=0.86 ) treatment groups ( P=0.30 ) . In women assigned raloxifene versus placebo , there was a higher incidence of fatal strokes ( incidence rates=0.22 and 0.15 , respectively , P=0.0499 ) and venous thromboembolic events ( incidence rates=0.39 and 0.27 , respectively , P=0.02 ) . No significant subgroup interactions were found except that there was a higher incidence of stroke associated with raloxifene use among current smokers . Conclusions — In postmenopausal women at increased risk for coronary events , the incidences of venous thromboembolism and fatal stroke but not all strokes were higher in those assigned raloxifene versus placebo . Raloxifene ’s effect did not differ across subgroups , except that the risk of stroke differed by smoking status . Treatment decisions about raloxifene should be based on a balance of projected absolute risks and benefits In 1991 , Stampfer and Colditz , 1 review ing epidemiological studies of the effect of postmenopausal oestrogen on coronary heart disease concluded that : ‘ … the bulk of evidence strongly supports a protective effect of estrogens that is unlikely to be explained by confounding factors … ’ Their best estimate of the relative risk of coronary heart disease ( CHD ) in postmenopausal oestrogen users was calculated using meta-analytical techniques applied to the epidemiological studies they deemed to be of high quality based on their design s— prospect i ve studies with internal controls and angiographic studies . This estimate was 0.50 . The CI was narrow � 0.43 to 0.56
For non-oral HT , decreases in lipoprotein(a ) , cell adhesion molecules , and factor VII generally were significant , resistance to activated protein C ( APCr ) was slightly increased , and other markers including CRP and homocysteine did not change .
Compared with oral HT , changes in CRP and APCr were smaller , changes in cell adhesion molecules and some fibrinolytic parameters tended to be smaller , whereas changes in other factors including lipoprotein(a ) and homocysteine did not differ .
( S ) Potentially unfavorable changes seen with oral HT on two important markers , CRP and APCr , are substantially smaller with non-oral HT .
Non-oral HT has minor effects on the other cardiovascular risk markers studied .
Therefore , compared with oral HT , non-oral HT appears be safer with respect to atherosclerotic and venous thromboembolic disease risk
OBJECTIVE To review the effects of non-oral administration of postmenopausal hormone therapy ( HT ) on risk markers for atherosclerotic and venous thromboembolic disease .
Non-oral postmenopausal HT appears not to increase venous thromboembolic risk , whereas the effect on coronary heart disease risk is less clear .