Effects of oral and transdermal estrogen/progesterone regimens on blood coagulation and fibrinolysis in postmenopausal women. A randomized controlled trial. Postmenopausal Hormone Therapy Increases Risk for Venous Thromboembolic Disease: The Heart and Estrogen/progestin Replacement Study Benefits and risks of postmenopausal hormone therapy when it is initiated soon after menopause. Hot flushes and biochemical markers for cardiovascular disease: a randomized trial on hormone therapy Effect of Raloxifene on Stroke and Venous Thromboembolism According to Subgroups in Postmenopausal Women at Increased Risk of Coronary Heart Disease Effects of hormone therapy on soluble cell adhesion molecules in postmenopausal women with coronary artery disease Hormone therapy and coronary heart disease: the role of time since menopause and age at hormone initiation. Reproductive hormone exposure timing and ischemic heart disease: Complicated answers to a simple question. Hormone Therapy and Venous Thromboembolism Among Postmenopausal Women: Impact of the Route of Estrogen Administration and Progestogens: The ESTHER Study Prothrombotic Mutations, Hormone Therapy, and Venous Thromboembolism Among Postmenopausal Women: Impact of the Route of Estrogen Administration Changes in remnant and high-density lipoproteins associated with hormone therapy and progression of coronary artery disease in postmenopausal women. Risk factors and short-term mortality of venous thromboembolism diagnosed in the primary care setting in the United Kingdom. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/progestin Replacement Study (HERS) Research Group. Methods and baseline cardiovascular data from the Early versus Late Intervention Trial with Estradiol testing the menopausal hormone timing hypothesis 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. Main morbidities recorded in the women's international study of long duration oestrogen after menopause (WISDOM): a randomised controlled trial of hormone replacement therapy in postmenopausal women Venous thromboembolism and oral contraceptive use: a methodological study of diagnostic suspicion and referral bias The effect of postmenopausal hormone therapy with or without folic acid supplementation on serum homocysteine level Lifestyle intervention and coronary heart disease risk factor changes over 18 months in postmenopausal women: the Women On the Move through Activity and Nutrition (WOMAN study) clinical trial. Statin Therapy, Cardiovascular Events, and Total Mortality in the Heart and Estrogen/Progestin Replacement Study (HERS) Risk factors for venous thromboembolism in pre-and postmenopausal women. Development and validation of risk prediction algorithm (QThrombosis) to estimate future risk of venous thromboembolism: prospective cohort study Third generation oral contraceptives and risk of venous thromboembolic disorders: an international case-control study Safety and Adverse Effects Associated With Raloxifene: Multiple Outcomes of Raloxifene Evaluation Risk of venous thromboembolism in users of oral contraceptives containing drospirenone or levonorgestrel: nested case-control study based on UK General Practice Research Database Extended Oral Anticoagulant Therapy after a First Episode of Pulmonary Embolism
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 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 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 Introduction Menopausal hot flushes may affect the responses of various vascular risk factors to hormone therapy ( HT ) . We compared the responses of biochemical markers for cardiovascular diseases to HT in recently postmenopausal women with tolerable or intolerable hot flushes . Methods Healthy , non-smoking freshly postmenopausal women ( n = 150 ) with no previous HT use were studied . Seventy-two women reported intolerable hot flushes ( ≥7 moderate/severe episodes/day ) and 78 women tolerable hot flushes ( ≤3 mild episodes/day ) . The participants were treated in r and omized order with either transdermal estradiol gel ( 1 mg ) , oral estradiol valerate ( 2 mg ) with or without medroxyprogesterone acetate ( 5 mg ) , or placebo for 6 months . Treatment-induced changes in lipids , lipoproteins , apolipoproteins , sex hormone binding globulin ( SHBG ) and high-sensitivity C-reactive protein were compared . The trial is registered in the US National Institutes of Health Clinical Research Registry ( no. NCT00668603 ) . Results Pretreatment hot flush status was not related to the responses of these markers to different forms of HT . However , when all active regimens were evaluated together as a post-hoc analysis , 7/10 markers showed a tendency toward greater beneficial changes in women with intolerable hot flushes . Furthermore , in women with intolerable hot flushes and with HT use , the increases in SHBG ( Spearman 's rho = − 0.570 , p < 0.001 ) were related to the reductions in hot flushes during the use of HT . Conclusions Hot flushes appear to be no significant determinant for the responses of vascular  markers to HT use 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 Objective : Although observational studies showed an apparent lower ischemic coronary disease risk in postmenopausal women receiving hormone therapy ( HT )  , r and omized clinical trials in postmenopausal women showed an increase in ischemic cardiovascular events . Soluble cell adhesion molecules have been associated with cardiovascular risk factors and events . HT reduces circulating levels of soluble cell adhesion molecules in healthy postmenopausal women , but its effects in postmenopausal women with coronary artery disease are less clear . We assessed the effect of HT on soluble cell adhesion molecules in the Estrogen Replacement and Atherosclerosis trial . Design : The Estrogen Replacement and Atherosclerosis trial was a double-blind , placebo-controlled study that r and omized 309 postmenopausal women ( mean age , 65.8 y ) to daily unopposed estrogen ( conjugated estrogens 0.625 mg ) , estrogen plus 2.5 mg of medroxyprogesterone acetate , or placebo  , with a mean follow-up period of 3.2 years . Soluble intercellular adhesion molecule-1 , vascular cell adhesion molecule-1 , and E-selectin were measured in serum obtained from participants at baseline and after 12 months of follow-up . Results : Of the 265 women with complete data , 87 women were assigned to unopposed estrogen , 88 women to estrogen plus medroxyprogesterone acetate , and 90 women to placebo . Compared with placebo , 12 months of HT ( n = 175 ) was associated with reductions in soluble intercellular adhesion molecule-1 ( 25.6 ± 4.7 vs 10.6 ± 6.4ng/mL , P = 0.06 ) , soluble vascular cell adhesion molecule-1 ( 80.2± 10.6 vs 28.8 ± 14.7 ng/mL , P = 0.005 ) , and E-selectin ( 8.8 ± 0.9 vs −1.1 ± 1.2 ng/mL , P < 0.001 ) . Conclusions : Twelve months of HT in postmenopausal women with established coronary artery disease was associated with reductions in serum markers of endothelial cell activation/injury such as soluble intercellular adhesion molecule-1 , vascular cell adhesion molecule-1 , and E-selectin BACKGROUND Apparently discrepant findings have been reported by the Women 's Health Initiative ( WHI ) trial compared with observational studies of postmenopausal hormone therapy ( HT ) and coronary heart disease ( CHD ) . METHODS We prospect ively examined the relation of HT to CHD , according to timing of hormone initiation relative to age and time since menopause . Participants were postmenopausal women in the Nurses ' Health Study , with follow-up from 1976 to 2000 . Information on hormone use was ascertained in biennial , mailed question naires . We used proportional hazards models to calculate multivariable adjusted relative risks ( RR ) and 95 % confidence intervals ( CI ) . We also conducted sensitivity analyses to determine the possible influence of incomplete capture of coronary events occurring shortly after initiation of HT . RESULTS Women beginning HT near menopause had a significantly reduced risk of CHD ( RR = 0.66 , 95 % CI 0.54 - 0.80 for estrogen alone ; RR = 0.72 , 95 % CI 0.56 - 0.92 for estrogen with progestin ) . In the subgroup of women demographically similar to those in the WHI , we found no significant relation between HT and CHD among women who initiated therapy at least 10 years after menopause ( RR = 0.87 , 95 % CI 0.69 - 1.10 for estrogen alone ; RR = 0.90 , 95 % CI 0.62 - 1.29 for estrogen with progestin ) . Among women who began taking hormones at older ages , we also found no relation between current use of estrogen alone and CHD ( for women aged 60 + years , RR = 1.07 , 95 % CI 0.65 - 1.78 ) , although there was a suggestion of possible reduced risk for combined HT ( RR = 0.65 , 95 % CI 0.31 - 1.38 ) . In sensitivity analyses , we found that the incomplete capture of coronary events occurring shortly after initiation of HT could not explain our observation of a reduced risk of coronary disease for current users of HT . CONCLUSIONS These data support the possibility that timing of HT initiation in relation to menopause onset or to age might influence coronary risk Premenopausal women have a relatively lower risk of ischemic heart disease ( IHD )  compared to age matched men and this gender gap narrows after menopause . The observation that the onset of IHD occurs 10 years later in women than it does in men is said to suggest that endogenous reproductive hormones play a protective role . Indeed , animal models and human epidemiological studies suggest that oophorectomy is a risk factor for accelerated IHD . In animal models , hormone therapy ( HT ) has anti-atherosclerotic effects after oophorectomy , HT in the form of oral contraceptives ( OCs ) prevents atherosclerosis in anovulatory cycling women , and large numbers of premenopausal women taking OCs have relative safety from an IHD st and point ( 1 ) . Further , observational epidemiological studies in humans have consistently demonstrated protective effects for IHD among HT users . Such studies are typically performed on relatively younger women where  HT  is prescribed for  vasomotor symptoms during menopausal transition or shortly following menopause . In contrast , clinical trials in older , postmenopausal and often asymptomatic women have demonstrated no overall benefit and early adverse effects when r and omized to a variety of forms of HT ( 1 ) . These data discrepancies have called into question the validity of the reproductive hormone estrogen protection hypothesis , and raise the alternative possibility that  HT efficacy may differ according to the timing of exposure . Stated as a simple question , is the effect of HT on the risk of IHD in relatively young pre- or early menopausal women with vasomotor symptoms , different than it is in older , fully menopausal women ? Data from the Women ’s Ischemia Syndrome Evaluation ( WISE ) , a prospect i ve multi-center NHLBI-sponsored study design ed to explore female-specific pathophysiology in a large sample of women undergoing coronary angiography for suspected IHD ( 2 ) , may shed light on this controversy . These new data , prospect ively obtained using novel methods , including detailed reproductive health question naires , menopausal adjudication algorithms , and quantitative coronary angiography as a measure of atherosclerosis , allow a more precise inspection of this question . However , to answer this simple question we need to first answer others . Specifically , how can we integrate and underst and the findings from the available observational , animal and clinical trial data ? And to interpret these data other questions become relevant : 1 ) How accurately was menopause assessed in prior observational HT studies ? 2 ) Does HT in premenopausal women in the form of OC therapy confirm atherosclerosis benefit ? and 3 ) Does HT in early menopausal women confer reduced atherosclerosis and benefit on the risk of IHD Background — Oral estrogen therapy increases the risk of  venous thromboembolism ( VTE ) in postmenopausal women .  Transdermal estrogen may be safer . However , currently available data have limited the ability to investigate the wide variety of types of progestogen . Methods and Results — We performed a multicenter case – control study of VTE among postmenopausal women 45 to 70 years of age between 1999 and 2005 in France . We recruited 271 consecutive cases with a first documented episode of idiopathic VTE ( 208 hospital cases , 63 outpatient cases ) and 610 controls ( 426 hospital controls , 184 community controls ) matched for center , age , and admission date . After adjustment for potential confounding factors , odds ratios ( ORs ) for VTE in current users of oral and transdermal estrogen compared with nonusers were 4.2 ( 95 % CI , 1.5 to 11.6 ) and 0.9 ( 95 % CI , 0.4 to 2.1 ) , respectively . There was no significant association of VTE with micronized progesterone and pregnane derivatives ( OR , 0.7 ; 95 % CI , 0.3 to 1.9 and OR , 0.9 ; 95 % CI , 0.4 to 2.3 , respectively ) . In contrast , norpregnane derivatives were associated with a 4-fold-increased VTE risk ( OR , 3.9 ; 95 % CI , 1.5 to 10.0 ) . Conclusions — Oral but not transdermal estrogen is associated with an increased VTE risk . In addition , our data suggest that norpregnane derivatives may be thrombogenic , whereas micronized progesterone and pregnane derivatives appear safe with respect to thrombotic risk . If confirmed , these findings could benefit women in the management of their menopausal symptoms with respect to the VTE risk associated with oral estrogen and use of progestogens Background — Oral estrogen increases the risk of venous thromboembolism ( VTE ) in postmenopausal women , particularly in those with a prothrombotic mutation .  Transdermal estrogen may be safe with respect to VTE . We investigated the impact of the route of estrogen administration on the association between a prothrombotic mutation ( factor V Leiden or prothrombin G20210A mutation ) and VTE risk . Methods and Results — We performed a multicenter case-control study of VTE among postmenopausal women who were enrolled in 1999 through 2004 at 7 clinical centers in France . We recruited 235 consecutive patients with a first documented episode of idiopathic VTE and 554 controls . Factor V Leiden was associated with a 3.4-fold – increased risk of VTE ( 95 % confidence interval [ CI ] , 2.0 to 5.8 ) , and a prothrombin mutation was associated with a 4.8-fold – increased risk of VTE ( 95 % CI , 2.5 to 9.4 ) . Oral but not transdermal estrogen was associated with an increased risk of VTE ( odds ratio [ OR ] , 4.3 ; 95 % CI , 2.6 to 7.2 ; and OR , 1.2 ; 95 % CI , 0.8 to 1.7 , respectively ) . After adjustment for potential confounding factors , the combination of either factor V Leiden or prothrombin G20210A mutation and oral estrogen gave a 25-fold – increased risk of VTE compared with nonusers without mutation ( 95 % CI , 6.9 to 95.0 ) . However , the risk for women with prothrombotic mutation  using transdermal estrogen was similar to that of women with a mutation who were not using estrogen ( OR , 4.4 ; 95 % CI , 2.0 to 9.9 ; and OR , 4.1 ; 95 % CI , 2.3 to 7.4 , respectively ) . Conclusions — In contrast to oral estrogen , transdermal estrogen does not confer additional risk on women who carry a prothrombotic mutation . The safety of transdermal estrogen has to be confirmed in r and omized trials OBJECTIVE This study examined the effect of hormone therapy ( HT ) on the plasma concentration of remnant lipoprotein cholesterol ( RLP-C ) and high-density lipoprotein ( HDL ) sub population s and the contribution of HT-related changes in these lipoproteins to the progression of coronary heart disease ( CHD ) in postmenopausal women . METHODS Study participants were 256 women who completed the Estrogen Replacement and Atherosclerosis ( ERA ) trial , a placebo-controlled , r and omized trial that examined the effects of 3.2 years of conjugated equine estrogen ( CEE , 0.625 mg/day ) or CEE ( 0.625 mg/day ) plus medroxyprogesterone acetate ( MPA , 2.5mg/day ) on postmenopausal women with established coronary atherosclerosis . Quantitative coronary angiography and plasma RLP-C and HDL sub population s were assessed at baseline and at follow-up . RESULTS Relative to placebo , both CEE and CEE+MPA caused a significant reduction in plasma RLP-C concentrations and a significant increase in alpha1 and alpha2 HDL sub population s. However , in the HT-treated subjects , faster progression of coronary atherosclerosis was observed in women who experienced the greatest reductions in RLP-C and in prebeta1 HDL sub population s. CONCLUSIONS Our data suggest that individual variability in RLP-C and HDL sub population response to HT is a predictor of CHD progression . Lipoprotein response to HT may be an indirect marker of susceptibility to other harmful effect of HT in postmenopausal women with established CHD or an indication of formation of dysfunctional lipoproteins BACKGROUND Venous thromboembolism ( VTE ) manifesting as deep vein thrombosis ( DVT ) and pulmonary embolism ( PE ) remains a common vascular disease with high mortality and morbidity . Our aim was to study the clinical spectrum of VTE , assess its incidence in the general population , and evaluate potential risk factors . METHODS Prospect i ve cohort study with nested case-control analysis using the General Practice Research Data base ( 1994 - 2000 ) . Venous thromboembolism was newly diagnosed in 6550 patients . Cases were compared with a r and om sample of 10,000 controls and frequency-matched by age , sex , and year . RESULTS The incidence rate of VTE was 74.5 per 100,000 person-years . Overweight , varicose veins , inflammatory bowel disease , cancer , and oral corticosteroid use were associated with a greater risk of VTE . Ischemic heart disease , heart failure , and cerebrovascular diseases were associated with an increased risk of PE but not with DVT . Venous thromboembolism was strongly associated with fractures ( odds ratio [ OR ] , 21.3 ; 95 % confidence interval [ CI ] , 15.7 - 28.9 ) and surgery ( OR , 25.0 ; 95 % CI , 14.4 - 43.5 ) . In women , the risk of VTE was 1.9 ( 95 % CI , 1.5 - 2.3 ) among those receiving opposed hormone therapy ( in which the woman takes estrogen throughout the month and progesterone for 10 - 14 days later in the month ) and 1.9 ( 95 % CI , 1.4 - 2.5 ) among those taking oral contraceptives . Cancer and cerebrovascular diseases presented a greater relative risk of fatal PE compared with nonfatal PE . CONCLUSIONS Overweight , varicose veins , cancer , inflammatory bowel disease , fractures , surgery , and use of oral corticosteroids , oral contraceptives , and opposed hormone therapy were independent risk factors for both DVT and PE . The magnitude of the association with some risk factors varied between DVT and PE , as well as between fatal and nonfatal PE CONTEXT Observational studies have found lower rates of coronary heart disease ( CHD ) in postmenopausal women who take estrogen than in women who do not , but this potential benefit has not been confirmed in clinical trials . OBJECTIVE To determine if estrogen plus progestin therapy alters the risk for CHD events in postmenopausal women with established coronary disease . DESIGN R and omized , blinded , placebo-controlled secondary prevention trial . SETTING Outpatient and community setting s at 20 US clinical centers . PARTICIPANTS A total of 2763 women with coronary disease , younger than 80 years , and postmenopausal with an intact uterus . Mean age was 66.7 years . INTERVENTION Either 0.625 mg of conjugated equine estrogens plus 2.5 mg of medroxyprogesterone acetate in 1 tablet daily ( n = 1380 ) or a placebo of identical appearance ( n = 1383 ) . Follow-up averaged 4.1 years ; 82 % of those assigned to hormone treatment were taking it at the end of 1 year , and 75 % at the end of 3 years . MAIN OUTCOME MEASURES The primary outcome was the occurrence of nonfatal myocardial infa rct ion ( MI ) or CHD death . Secondary cardiovascular outcomes included coronary revascularization , unstable angina , congestive heart failure , resuscitated cardiac arrest , stroke or transient ischemic attack , and peripheral arterial disease . All-cause mortality was also considered . RESULTS Overall , there were no significant differences between groups in the primary outcome or in any of the secondary cardiovascular outcomes : 172 women in the hormone group and 176 women in the placebo group had MI or CHD death ( relative hazard [ RH ] , 0.99 ; 95 % confidence interval [ CI ] , 0.80 - 1.22 ) . The lack of an overall effect occurred despite a net 11 % lower low-density lipoprotein cholesterol level and 10 % higher high-density lipoprotein cholesterol level in the hormone group compared with the placebo group ( each P<.001 ) . Within the overall null effect , there was a statistically significant time trend , with more CHD events in the hormone group than in the placebo group in year 1 and fewer in years 4 and 5 . More women in the hormone group than in the placebo group experienced venous thromboembolic events ( 34 vs 12 ; RH , 2.89 ; 95 % CI , 1.50 - 5.58 ) and gallbladder disease ( 84 vs 62 ; RH , 1.38 ; 95 % CI , 1.00 - 1.92 ) . There were no significant differences in several other end points for which power was limited , including fracture , cancer , and total mortality ( 131 vs 123 deaths ; RH , 1.08 ; 95 % CI , 0.84 - 1.38 ) . CONCLUSIONS During an average follow-up of 4.1 years , treatment with oral conjugated equine estrogen plus medroxyprogesterone acetate did not reduce the overall rate of CHD events in postmenopausal women with established coronary disease . The treatment did increase the rate of thromboembolic events and gallbladder disease . Based on the finding of no overall cardiovascular benefit and a pattern of early increase in risk of CHD events , we do not recommend starting this treatment for the purpose of secondary prevention of CHD . However , given the favorable pattern of CHD events after several years of therapy , it could be appropriate for women already receiving this treatment to continue Objective This study aims to present methods and baseline data from the Early versus Late Intervention Trial with Estradiol ( ELITE ) , the only clinical trial design ed to specifically test the timing hypothesis of postmenopausal hormone therapy ( HT ) . The timing hypothesis posits that HT effects depend on the temporal initiation of HT relative to time since menopause . Methods ELITE is a r and omized , double-blind , placebo-controlled trial with a 2 × 2 factorial design . Six hundred forty-three healthy postmenopausal women without cardiovascular disease were r and omized to oral estradiol or placebo for up to 6 to 7 years according to time since menopause ( < 6 or ≥10 y ) . Carotid artery intima-media thickness ( CIMT ) and cardiac computed tomography  were conducted to determine HT effects on sub clinical atherosclerosis across menopause strata . Results Participants in the early and late postmenopausal strata were well-separated by mean age ( 55.4 vs 65.4 y ) and median time since menopause ( 3.5 vs 14.3 y ) . Expected risk factors ( age , blood pressure , and body mass index ) were associated with CIMT at baseline in both strata . In the early postmenopausal group , but not in the late postmenopausal group , we observed significant associations between CIMT and factors that may play a role in the responsiveness of atherosclerosis progression according to timing of HT initiation . These include low-density lipoprotein cholesterol , high-density lipoprotein cholesterol , sex hormone – binding globulin , and serum total estradiol . Conclusions The ELITE r and omized controlled trial is timely and unique . Baseline data indicate that ELITE is well-positioned to test the HT timing hypothesis in relation to atherosclerosis progression and coronary artery disease 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 assess the long term risks and benefits of hormone replacement therapy ( combined hormone therapy versus placebo , and oestrogen alone versus combined hormone therapy ) . Design Multicentre , r and omised , placebo controlled , double blind trial . Setting General practice s in UK ( 384 ) , Australia ( 91 ) , and New Zeal and ( 24 ) . Participants Postmenopausal women aged 50 - 69 years at r and omisation . At early closure of the trial , 56 583 had been screened , 8980 entered run-in , and 5692 ( 26 % of target of 22 300 ) started treatment . Interventions Oestrogen only therapy ( conjugated equine oestrogens 0.625 mg orally daily ) or combined hormone therapy ( conjugated equine oestrogens plus medroxyprogesterone acetate 2.5/5.0 mg orally daily ) . Ten years of treatment planned . Main outcome measures Primary outcomes : major cardiovascular disease , osteoporotic fractures , and breast cancer . Secondary outcomes : other cancers , death from all causes , venous thromboembolism , cerebrovascular disease , dementia , and quality of life . Results The trial was prematurely closed during recruitment , after a median follow-up of 11.9 months ( interquartile range 7.1 - 19.6 , total 6498 women years ) in those enrolled , after the publication of early results from the women 's health initiative study . The mean age of r and omised women was 62.8 ( SD 4.8 ) years . When combined hormone therapy ( n=2196 ) was compared with placebo ( n=2189 ) , there was a significant increase in the number of major cardiovascular events ( 7 v 0 , P=0.016 ) and venous thromboembolisms ( 22 v 3 , hazard ratio 7.36 ( 95 % CI 2.20 to 24.60 ) ) . There were no statistically significant differences in numbers of breast or other cancers ( 22 v 25 , hazard ratio 0.88 ( 0.49 to 1.56 ) ) , cerebrovascular events ( 14 v 19 , 0.73 ( 0.37 to 1.46 ) ) , fractures ( 40 v 58 , 0.69 ( 0.46 to 1.03 ) ) , and overall deaths ( 8 v 5 , 1.60 ( 0.52 to 4.89 ) ) . Comparison of combined hormone therapy ( n=815 ) versus oestrogen therapy ( n=826 ) outcomes revealed no significant differences . Conclusions Hormone replacement therapy increases cardiovascular and thromboembolic risk when started many years after the menopause . The results are consistent with the findings of the women 's health initiative study and secondary prevention studies . Research is needed to assess the long term risks and benefits of starting hormone replacement therapy near the menopause , when the effect may be different . Trial registration Current Controlled Trials IS RCT N Background In studies of oral contraceptive oral contraceptive  use and risk of venous thromboembolism , bias related to heightened diagnostic suspicion and preferential referral of oral contraceptive users has been an issue . The aim of our study was to determine the presence and potential impact of diagnostic suspicion and referral bias . Methods We conducted a case/non-case study in 21 regional study centers in Germany and , in parallel , a conventional case-control study using the same cases but r and omly selected population controls from the same areas . Women with symptoms compatible with venous thromboembolism were included in the study between 1994 and 1999 , and classified as cases or non-cases ( first reference group ) according to the diagnostic work-up ( case/non-case study ) . A second reference group consisted of  population controls  ( conventional case-control study as an internal comparison for the case/non-case study ): 606 cases , 462 non-cases and 2942 population controls aged 15–49 years . Adjusted unconditional regression analyses were performed . Results Adjusted odds ratios for venous thromboembolism in oral contraceptive users were systematic ally higher in the classical case-control study compared to the case/non-case approach ( using the same cases ) across all subgroup analyses ( e.g. for idiopathic cases , the odds ratio was 67 % higher in the case-control study : 4.33 ( 95 % confidence interval ( CI ) 3.27–5.74 ) versus 2.60 ( 95 % CI 1.75–3.88 ) ) . We found a significantly increasing trend of oral contraceptive use in four categories of increasingly sophisticated diagnostic tests that were applied to 1067 women with a suspicion of venous thromboembolism , irrespective of the outcome . Stratified analysis showed the diagnostic level to be a confounder . Conclusion In our population -based study with the possibility of internal comparison , we found clear evidence that diagnostic suspicion and referral bias does play an important role in case-control studies of venous thromboembolism risk among oral contraceptive users . This underlines the importance of making an effort to avoid this bias when design ing a new study Objective To evaluate the effects of postmenopausal hormone therapy ( HT ) with or without the addition of folic acid ( FA ) on serum homocysteine levels in a r and omized , placebo-controlled design . Additionally , a non-r and omized control group with no treatment was included . Methods Forty non-hysterectomized healthy postmenopausal women were r and omly allocated to receive either oral continuous combined HT ( 0.625 mg conjugated equine estrogen with 2.5 mg medroxyprogesterone acetate daily ) and oral folic acid ( 5 mg/day , n = 20 ) or HT and placebo ( n = 20 ) for 3 months . A control group ( n = 15 ) did not receive any study medication and was followed in the same manner . The fasting total serum homocysteine level was measured by fluorescence polarization immunoassay with a sensitivity of < 0.5 μmol/l . Serum levels of folate , estrogen and lipid profile were also followed . Results The mean age of the postmenopausal women was 52 ± 6 years . Baseline homocysteine level was the highest in the HT + FA group ( 9.96 ± 2.82 μmol/l ) , compared to HT + placebo ( 9.64 ± 1.89 μmol/l ) and control groups ( 9.01 ± 1.83 μmol/l ) ( ANCOVA , p = 0.022 ) . Low baseline folate and vitamin B12 levels contributed significantly to the high level of baseline homocysteine in the HT + FA group . The addition of FA to HT led to a significant decrease in the serum homocysteine level from the baseline level of 9.96 ± 2.82 μmol/l to the final level of 8.92 ± 2.53 μmol/l ( p = 0.023 ) . On the other h and , HT alone ( HT + placebo group ) significantly increased the serum homocysteine level from 9.64 ± 1.89 μmol/l to 10.22 ± 1.77 μmol/l without a decline in serum folate level ( p = 0.045 ) . The serum homocysteine level in the control group did not change significantly ( from 9.01 ± 1.83 μmol/l to 9.58 ± 2.05 μmol/l , p = 0.29 ) . Conclusions Three months of oral continuous combined HT  increased the fasting total serum homocysteine level without affecting the serum folate level . Lowering the homocysteine level in postmenopausal woman on HT is achievable by folic acid supplementation OBJECTIVES In this paper , we present the results of changes in risk factors by use of hormone therapy ( HT ) at 18 months in the Women On the Move through Activity and Nutrition ( WOMAN ) r and omized trial . METHODS The trial was design ed to test the hypothesis that aggressive dietary changes and increased physical activity to reduce weight , waist circumference ( WC ) , glucose , insulin , and lipoproteins would reduce progression of sub clinical atherosclerosis , carotid intimal media thickness and plaque , coronary artery calcification , and pulse wave velocity ( PWV ) . The study focused on postmenopausal women ( n = 508 ) , mean age of 57 , who were r and omized to the Lifestyle Change ( LC ) or Health Education ( HE ) group .  RESULTS At 18 months of follow-up , there was significant , 17 lb , weight loss and 10 cm WC decrease in the LC group . There were significant differences in changes in low-density lipoprotein cholesterol ( LDL-C ) , insulin , glucose , large LDL , and LDL particles between the LC and HE groups . Risk factor changes were greater for women in the LC who lost a significant amount of weight ( > or=18.8 lb ) . Participants at 18 months were subdivided into women who had stayed on HT , 125 ( 28 % ) ; stopped HT after r and omization , 145 ( 33 % ) ; and not on HT at baseline but stopped an average of 7 months prior to r and omization , 173 ( 39 % ) . Weight loss in the LC was similar for all three groups , but LDL lipoprotein response was better for women who stopped HT after r and omization or were not on HT at baseline . CONCLUSIONS The trial has been successful in increasing exercise and diet changes and reduction in weight and WC and variables related to metabolic syndrome Background —Although effects of statins on cardiovascular outcomes are well established in men , fewer data exist for women . Furthermore , the effects of statins plus hormone replacement therapy ( HRT ) on cardiovascular outcomes are uncertain . Methods and Results —We examined statin use , cardiovascular events , and total mortality in the Heart and Estrogen/progestin Replacement Study ( HERS ) , a r and omized clinical trial of estrogen plus progestin versus placebo in postmenopausal women with heart disease ( n=2763 ) . A nonr and omized comparison of statin users and nonusers revealed lower rates of the primary outcome , nonfatal myocardial infa rct ion or coronary heart disease death ( relative hazard [RH]=0.79 , 95 % confidence intervals [ CI ] 0.63 to 0.99 , P = 0.04 ) , and total mortality ( RH=0.67 , 95 % CI 0.51 to 0.87 , P = 0.003 ) . Rates of venous thromboembolic events were also lower among statin users ( RH=0.45 , 95 % CI 0.23 to 0.88 , P = 0.02 ) . HRT result ed in a significant increase in early risk for primary events in women who did not use statins ( RH=1.75 , 95 % CI 1.02 to 3.03 , P = 0.04 ) but not in statin users ( RH=1.34 , 95 % CI 0.63 to 2.86 , P = 0.45 ) . Adjustment for postr and omization statin use showed no effect of HRT on risk for the primary outcome ( RH=0.96 , 95 % CI 0.77 to 1.29;P = 0.72 ) . Conclusions —In HERS , statin use was associated with lower rates of cardiovascular events , venous thromboembolic events , and total mortality . These data provide strong support for statin use in eligible women with coronary disease 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 Objectives To derive and vali date a new clinical risk prediction algorithm ( QThrombosis , www.qthrombosis.org ) to estimate individual patients ’ risk of venous thromboembolism .  Design Prospect i ve open cohort study using routinely collected data from general practice s. Cox proportional hazards models used in derivation cohort to derive risk equations evaluated at 1 and 5 years . Measures of calibration and discrimination undertaken in validation cohort . Setting 564 general practice s in Engl and and Wales contributing to the Q Research data base . Participants Patients aged 25 - 84 years , with no record of pregnancy in the preceding 12 months or any previous venous thromboembolism , and not prescribed oral anticoagulation at baseline : 2 314 701 in derivation cohort and 1 240 602 in validation cohort . Outcomes Incident cases of venous thromboembolism , either deep vein thrombosis or pulmonary embolism , recorded in primary care records or linked cause of death records . Results The derivation cohort included 14 756 incident cases of venous thromboembolism from 10 095 199 person years of observation ( rate of 14.6 per 10 000 person years ) . The validation cohort included 6913 incident cases from 4 632 694 person years of observation ( 14.9 per 10 000 person years ) . Independent predictors included in the final model for men and women were age , body mass index , smoking status , varicose veins , congestive cardiac failure , chronic renal disease , cancer , chronic obstructive pulmonary disease , inflammatory bowel disease , hospital admission in past six months , and current prescriptions for antipsychotic drugs . We also included oral contraceptives , tamoxifen , and hormone replacement therapy in the final model for women . The risk prediction equation explained 33 % of the variation in women and 34 % in men in the validation cohort evaluated at 5 years The D statistic was 1.43 for women and 1.45 for men . The receiver operating curve statistic was 0.75 for both sexes . The model was well calibrated . Conclusions We have developed and vali date d a new risk prediction model that quantifies absolute risk of thrombosis at 1 and 5 years . It can help identify patients at high risk of venous thromboembolism for prevention . The algorithm is based on simple clinical variables which the patient is likely to know or which are routinely recorded in general practice records . The algorithm could be integrated into general practice clinical computer systems and used to risk assess patients before hospital admission or starting medication which might increase the risk of venous thromboembolism Abstract Objective : To test whether use of combined oral contraceptives containing third generation progestogens is associated with altered risk of venous thromboembolism .  Design : Matched case-control study . Setting : 10 centres in Germany and United Kingdom . Subjects : Cases were 471 women aged 16 - 44 who had a venous thromboembolism . Controls were 1772 women ( at least 3 controls per case ) unaffected by venous thromboembolism who were matched with corresponding case for age and for hospital or community setting . Main outcome measures : Odds ratios derived with stratified analyses and unconditional logistic regression to adjust for potential confounding variables . Results : Odds ratios ( 95 % confidence intervals ) for venous thromboembolism were : for any oral contraceptives versus no use , 4.0 ( 3.1 to 5.3 ) ; for second generation products ( low dose ethinyloestradiol , no gestodene or desogestrel ) versus no use , 3.2 ( 2.3 to 4.3 ) ; for third generation products ( low dose ethinyloestradiol , gestodene or desogestrel ) versus no use , 4.8 ( 3.4 to 6.7 ) ; for third generation products versus second generation products , 1.5 ( 1.1 to 2.1 ) ; for products containing gestodene versus second generation products , 1.5 ( 1.0 to 2.2 ) ; and for products containing desogestrel versus second generation products , 1.5 ( 1.1 to 2.2 ) . Probability of death due to venous thromboembolism for women using third generation products is about 20 per million users per year , for women using second generation products it is about 14 per million users per year , and for non-users it is five per million per year . Conclusions : Risk of venous thromboembolism was slightly increased in users of third generation oral contraceptives  compared with users of  second  generation products  . Key messages Key messages This case-control study examined risk of venous thromboembolism associated with different types of oral contraceptive Overall , there was a fourfold higher relative risk of thromboembolism associated with current use of any oral contraceptive versus no current use The risk of thromboembolism was 1.5 times higher for third generation contraceptives compared with second generation products Our data indicate the need for clinical prudence but allow doctors and women seeking contraception to exercise informed OBJECTIVE : To examine the effect of raloxifene on major adverse events that occur with postmenopausal estrogen therapy or tamoxifen . METHODS : The Multiple Outcomes of Raloxifene Evaluation , a multicenter , r and omized , double-blind trial , enrolled 7,705 postmenopausal women with osteoporosis . Women were r and omly assigned to raloxifene 60 mg/d or 120 mg/d or placebo . Outcomes included venous thromboembolism , cataracts , gallbladder disease , and endometrial hyperplasia or cancer . RESULTS : During a mean follow-up of 3.3 years , raloxifene was associated with an increased risk for venous thromboembolism ( relative risk [ RR ] 2.1 ; 95 % confidence interval [ CI ] 1.2–3.8 ) . The excess event rate was 1.8 per 1,000 woman-years ( 95 % CI −0.5–4.1 ) , and the number needed to treat to cause 1 event was 170 ( 95 % CI 100–582 ) over 3.3 years . Risk in the raloxifene group was higher than in the placebo group for the first 2 years , but decreased to about the same rate as in the placebo group thereafter . Raloxifene did not increase risk for cataracts ( RR 0.9 ; 95 % CI 0.8–1.1 ) , gallbladder disease ( RR 1.0 ; 95 % CI 0.7–1.3 ) , endometrial hyperplasia ( RR 1.3 ; 95 % CI 0.4–5.1 ) , or endometrial cancer ( RR 0.9 ; 95 % CI 0.3–2.7 ) . CONCLUSION : Raloxifene was associated with an increased risk for venous thromboembolism , but there was no increased risk for cataracts , gallbladder disease , endometrial hyperplasia , or endometrial cancer . LEVEL OF EVIDENCE : Objective To examine the risk of non-fatal idiopathic venous thromboembolism in current users of a combined oral contraceptive containing drospirenone  , relative to current users of preparations containing levonorgestrel .  Design Nested case-control study . Setting UK General Practice Research Data base . Participants Women aged 15 - 44 years without major risk factors for venous thromboembolism who started a new episode of use of an oral contraceptive containing 30 µg oestrogen in combination with either drospirenone or levonorgestrel between May 2002 and September 2009 . Cases were women with a first diagnosis of venous thromboembolism ; up to four controls , matched by age , duration of recorded information , and general practice , were r and omly selected for each case . Main outcome measures Odds ratios and 95 % confidence intervals estimated with conditional logistic regression ; age adjusted incidence rate ratio estimated with Poisson regression . Results 61 cases of idiopathic venous thromboembolism and 215 matched controls were identified . In the case-control analysis , current use of the drospirenone contraceptive was associated with a threefold higher risk of non-fatal idiopathic venous thromboembolism compared with levonorgestrel use ; the odds ratio adjusted for body mass index was 3.3 ( 95 % confidence interval 1.4 to 7.6 ) . Subanalyses suggested that referral , diagnostic , first time user , duration of use , and switching biases were unlikely explanations for this finding . The crude incidence rate was 23.0 ( 95 % confidence interval 13.4 to 36.9 ) per 100 000 woman years in current users of drospirenone and 9.1 ( 6.6 to 12.2 ) per 100 000 woman years in current users of levonorgestrel oral contraceptives . The age adjusted incidence rate ratio was 2.7 ( 1.5 to 4.7 ) . Conclusions These findings contribute to emerging evidence that the combined oral contraceptive containing drospirenone carries a higher risk of venous thromboembolism than do formulations containing levonorgestrel Context Optimal duration of anticoagulation after pulmonary embolism is uncertain , but physicians commonly prescribe 3 months of therapy for patients with transient risk factors for thrombosis and 6 months for patients with continuing or no known risk factors . Contribution After 3 months of successful anticoagulation , 326 patients were r and omly assigned to stop therapy immediately or extend therapy to 6 months or 1 year . Regardless of duration of anticoagulation , 33 patients had recurrent thromboembolic events but only one event occurred in a patient still receiving therapy . Implication s Extending the duration of anticoagulation does not seem to protect against recurrence once therapy has been discontinued . Patients at high risk for recurrence may require indefinite anticoagulation . The Editors Recent studies have shown that patients with a first episode of venous thromboembolism are protected from a recurrence while they are receiving anticoagulant treatment ( 1 , 2 ) . On the basis of differences in the risk for recurrence when anticoagulant treatment is discontinued , different duration s of oral anticoagulation are currently recommended in different patient categories . A shorter period of anticoagulation is recommended for patients with venous thromboembolism associated with transient risk factors than for patients with idiopathic venous thromboembolism or venous thromboembolism associated with continuing risk factors ( 3 - 5 ) . Current recommendations on the duration of oral anticoagulant treatment for venous thromboembolism are based on studies that mostly included patients presenting with deep venous thrombosis ( 1 , 2 , 5 - 7 ) . Only a limited proportion of patients included in these studies presented with pulmonary embolism . Deep venous thrombosis and pulmonary embolism are generally considered to be two clinical manifestations of the same disease . However , patients presenting with pulmonary embolism are reported to have a higher incidence of fatal recurrent venous thromboembolism than patients presenting with deep venous thrombosis ( 8 , 9 ) . We performed a multicenter r and omized trial to evaluate the long-term clinical benefit of extending a 3-month course of oral anticoagulant therapy to 6 months ( pulmonary embolism associated with temporary risk factors ) or to 1 year ( idiopathic pulmonary embolism ) in patients with a first episode of pulmonary embolism . The primary outcome of the study was symptomatic , objective ly confirmed recurrence of venous thromboembolism . Methods Study Patients Consecutive patients ranging from 15 to 85 years of age with a first episode of symptomatic , objective ly confirmed pulmonary embolism were included in the study if they had completed 3 uninterrupted months of  oral anticoagulant therapy without having a recurrence or bleeding . The diagnosis of pulmonary embolism was confirmed by pulmonary angiography or spiral computed tomography or by a lung scan indicating a high probability of pulmonary embolism or a lung scan indicating an intermediate probability of pulmonary embolism in a patient with objective ly diagnosed deep venous thrombosis . Study patients were categorized as having idiopathic pulmonary embolism or pulmonary embolism associated with transient risk factors . Idiopathic pulmonary embolism was defined as pulmonary embolism occurring in the absence of known cancer , known thrombophilia , or any transient risk factor for venous thromboembolism . Pulmonary embolism associated with transient risk factors was pulmonary embolism occurring after recent trauma with or without bone fracture , recent surgery or childbirth , or prolonged immobilization ( that is , lasting > 7 days ) , or occurring during the use of oral contraceptives or pregnancy . Patients with pulmonary embolism associated with permanent risk factors ( known cancer or known thrombophilia ) were excluded from the study . Systematic screening for occult cancer or thrombophilia was not performed before enrollment . Patients who required prolonged anticoagulant therapy for reasons other than venous thromboembolism were excluded from the study , as were patients with major psychiatric disorders , patients with a life expectancy shorter than 2 years , those who could not return for the follow-up visits , and those who declined to participate . The institutional review boards of the participating hospitals approved the study ; all patients gave informed consent . Study Design and Interventions The Warfarin Optimal Duration Italian Trial in patients with pulmonary embolism ( WODIT-PE ) was a multicenter r and omized , open trial with independent , blinded assessment of the outcome events . The study was design ed to evaluate the clinical benefit of extending the 3-month course of oral anticoagulant therapy after a first episode of pulmonary embolism . Patients who had completed 3 months of warfarin or acenocumarol therapy were r and omly assigned to discontinue anticoagulation or to continue it for 3 additional months ( pulmonary embolism associated with transient risk factors ) or 9 additional months ( idiopathic pulmonary embolism ) . R and omization was performed central ly in permuted blocks of six . The dose of warfarin or acenocumarol was adjusted to achieve a target international normalized ratio ( INR ) between 2.0 and 3.0 . The therapy was monitored in anticoagulant clinics associated with the study centers , all in Italy . Outcome Measures The primary outcome of the study was the recurrence of symptomatic , objective ly confirmed venous thromboembolism after the initial 3 months of anticoagulation . The secondary outcome was the cumulative incidence of adverse outcome events ( recurrence of venous thromboembolism , death , or major bleeding ) . The criteria for the diagnosis of recurrence of pulmonary embolism were a new filling defect revealed by pulmonary angiography or spiral computed tomography or a new high-probability perfusion defect revealed by ventilation-perfusion lung scan . Sudden , otherwise unexplained death was also considered a recurrence of pulmonary embolism . The criteria for the diagnosis of deep venous thrombosis as an outcome for recurrence of venous thromboembolism in patients without deep venous thrombosis at baseline were the presence of a noncompressible proximal vein on ultrasonography or an intraluminal filling defect on venography . In patients with deep venous thrombosis at baseline , the criteria for the diagnosis of recurrent deep venous thrombosis were abnormal results on compression ultrasonography ( proximal veins ) or venography in the contralateral leg or , in the ipsilateral leg , an extension of an intraluminal filling defect on venography ; a newly noncompressible venous segment ; or an increase of 4 mm or more in the diameter of the thrombus ( proximal veins ) on ultrasonography ( 10 ) . Bleeding was defined as major if it was clinical ly overt and associated with either a decrease in the hemoglobin level of at least 20 g/L or the need to transfuse two or more units of red blood cells , if it was retroperitoneal or intracranial , if it warranted the permanent discontinuation of therapy with the study drug , or if it required rehospitalization . Deaths were classified as the result of pulmonary embolism , bleeding , or another identifiable cause or as unexplained . All suspected outcome events ( recurrent thromboembolism and bleeding episodes ) and all deaths were review ed central ly by an independent , external adjudication committee whose members were unaware of the treatment group assignments . Follow-up Patients were instructed to return for follow-up visits at 3 , 6 , and 12 months after r and omization and every 6 months thereafter until the completion of the study . Patients were asked to return to the study center immediately if symptoms suggestive of recurrent venous thromboembolism or bleeding developed . For all patients who died during the follow-up period , the date and cause of death were documented . We attempted to gain permission for autopsies of all patients in whom pulmonary embolism could not be excluded as the cause of death . Statistical Analysis The primary analysis of efficacy was a comparison of the rates of symptomatic , objective ly confirmed recurrence of venous thromboembolism in the two treatment groups . The analysis was performed on an intention-to-treat basis . It was assumed that the rate of recurrence of venous thromboembolism would be 12 % in patients assigned to the discontinue oral anticoagulant therapy in the 2 years after discontinuation . We also assumed that the prolongation of oral anticoagulant therapy would produce a 50 % reduction in the risk for recurrence . Given these assumptions , we needed 312 patients in each group to detect a difference of this magnitude between groups with a power of 80 % and a type I error rate of 5 % . To avoid the exposure of the study patients to an ineffective or dangerous therapeutic regimen , one prespecified interim analysis of efficacy and safety was planned after we r and omly assigned 50 % of planned patients . The following criteria for stopping the trial were defined a priori : an overall rate of recurrence of thromboembolic events lower than 7.5 % , an unequivocal reduction in the rate of recurrent venous thromboembolism in the patients assigned to continue therapy ( P < 0.001 by a one-sided test ) , a risk for recurrence in the continued therapy group that was less than 25 % lower than that in the group assigned to discontinue therapy , or a rate of major bleeding higher than 5 % in the continued therapy group . The cumulative hazard of recurrent venous thromboembolism was calculated according to the Kaplan-Meier life-table method ( 11 ) . Rates of recurrence in the two groups were compared with the use of the log-rank test ( 12 ) . Results Patients Patients were recruited between January 1997 and December 2000 when , after 326 patients were included , the results of the interim analysis showed a difference of less than 25 % in the risk for recurrent venous thromboembolism between the two treatment groups . At the time
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 .