Document downloaded from, day 04/11/2011. This copy is for personal use. Any transmission of this document by any media or format is strictly prohibited.
Effects of Raloxifene on Endothelial Function and Hemostasis in WomenWith Ischemic Heart Disease Merce` Roque´Marta Joan Victoria Manuel Morales,Jaume Marrugat,Joan Isaac Subirana,Dolors Ta`Juan Carlos Reverter,Miriam Castro,and Magdalena a Departamento de Cardiologı´a, Instituto del To´rax, Hospital Clı´nic, Barcelona, Spainb Institut d’ Investigacions Biome`diques August Pi i Sunyer, Barcelona, Spainc Departamento de Cardiologı´a, Hospital Universitari Dr. Josep Trueta, Girona, Spaind Unidad de Lı´pidos y Epidemiologı´a Cardiovascular, Institut Municipal d’Investigacio´ Me`dica, Barcelona, Spaine Departamento de Hemostasia, Hospital Clı´nic, Barcelona, Spainf Departamento de Ginecologı´a, Hospital Clı´nic, Barcelona, Spain Received 5 October 2010Accepted 2 March 2011 Introduction and objectives: Modulation of vascular tone is one of the most relevant estrogen effects. A beneficial effect on endothelial function in postmenopausal women has also been proposed for theselective estrogen receptor modulator raloxifene. However, its effects in women with established cardiovascular disease have not been fully elucidated. In addition, recent trials have generated controversy regarding thromboembolic risk with raloxifene use. The aim of the study was to assess the effect of raloxifene on: a) endothelial function and b) coagulation and fibrinolysis pathways.
Methods: The MERCED trial was a prospective, randomized clinical trial. Thirty-three postmenopausal women with ischemic heart disease were enrolled in the study. Raloxifene treatment was administered for a 3-month period, according to a double-blind crossover design. Assessment of vascular function andbiologic parameters related to coagulation pathways were conducted at various pre-established time-points.
Results: Flow-mediated dilatation was severely impaired in the study population, and raloxifene had noeffect on endothelial function. Treatment with raloxifene was associated to decreased levels offibrinogen (3.41 [3.11-3.74] vs. 3.69 [3.40-4.00], P < .05); prothrombin fragments F1+2 (0.93 [0.77-1.12]vs. 0.94 [0.78-1.15], P < .05); and plasmin/antiplasmin complexes (211 [166-267] vs. 242 [199-295],P < .01).
Conclusions: The present study provides evidence that in postmenopausal women with demonstratedendothelial dysfunction and ischemic heart disease, mid-term treatment with raloxifene does not affectendothelial function. In the MERCED trial, no increased thrombotic risk was observed, but a decreasedthrombotic and fibrinolytic activity was observed with raloxifene. Further studies are required todetermine whether thrombotic risk is associated with specific clinical characteristics or subgroups ofpostmenopausal women with cardiovascular disease.
˜ ola de Cardiologı´a. Published by Elsevier Espan˜a, S.L. All rights reserved.
Efecto del raloxifeno en la funcio´n endotelial y la hemostasia en mujerescon enfermedad coronaria Introduccio´n y objetivos: La modulacio´n del tono vascular es uno de los efectos estroge´nicos ma´s relevantes. En mujeres posmenopa´usicas, se ha propuesto un efecto beneficioso en la funcio´n endotelial del modulador selectivo del receptor estroge´nico raloxifeno, aunque sus efectos en mujeres con cardiopatı´a isque´mica establecida no han sido estudiados plenamente. Estudios recientes han generado controversia respecto al riesgo tromboembo´lico del raloxifeno. El objetivo del estudio es determinar el efecto del raloxifeno en: a) la funcio´n endotelial, y b) las vı´as de la coagulacio´n y la fibrinolisis en mujeresposmenopa´usicas con enfermedad coronaria.
Me´todos: El estudio MERCED es un ensayo prospectivo y aleatorizado que incluye a 33 mujeresposmenopa´usicas con enfermedad coronaria. Se administra raloxifeno durante 3 meses, comparado conplacebo, en un disen ˜ o cruzado y a doble ciego, y se analiza de forma seriada la funcio´n vascular y los para´metros biolo´gicos relacionados con las vı´as de la coagulacio´n.
Resultados: Se ha observado una grave alteracio´n de la vasodilatacio´n mediada por flujo a nivel basal y eltratamiento con raloxifeno no ha modificado significativamente la funcio´n endotelial. El raloxifeno hainducido un descenso de los valores de fibrino´geno (3,41 [3,11-3,74] frente a 3,69 [3,4-4]; p < 0,05), los * Corresponding author: Departamento de Cardiologı´a, Institut del To´rax, Hospital Clı´nic, Villarroel 170, 08036 Barcelona, Spain.
1885-5857/$ – see front matter ß 2010 Sociedad Espan ˜ ola de Cardiologı´a. Published by Elsevier Espan Document downloaded from, day 04/11/2011. This copy is for personal use. Any transmission of this document by any media or format is strictly prohibited.
M. Roque´ et al. / Rev Esp Cardiol. 2011;64(7):572–578 fragmentos F1+2 de la protrombina (0,93 [0,77-1,12] frente a 0,94 [0,78-1,15]; p < 0,05) y los complejosplasmina/antiplasmina (211 [166-267] frente a 242 [199-295]; p < 0,01).
Conclusiones: El tratamiento a medio plazo con raloxifeno en mujeres con enfermedad coronariano afecta a la funcio´n endotelial. Adema´s, se ha documentado menor actividad trombo´tica y fibrinolı´ticacon raloxifeno. Sera´ necesario determinar si el riesgo trombo´tico adscrito al raloxifeno en estudiosprevios se asocia u´nicamente a subgrupos especı´ficos de mujeres posmenopa´usicas con enfermedadcardiovascular.
ß 2010 Sociedad Espan ˜ ola de Cardiologı´a. Publicado por Elsevier Espan˜a, S.L. Todos los derechos reservados.
FMD: Flow-mediated dilatationPAI-1: Plasminogen activator inhibitor type-1 The MERCED study was a 2-center, national, randomized, double-blind, cross-over trial. Treatment sequence allocation(raloxifene-placebo; placebo-raloxifene) was randomly assigned SERM: Selective estrogen receptor modulator by blocks of 4 patients for both participating centers. Patients, their TAFI: Thrombin-activatable fibrinolysis inhibitor treating physicians, and the investigators performing endothelialfunction analysis in each center were blinded to treatmentsequence allocation. Study design follows the CONSORT statementfor reporting randomized trials.
Study duration was 28 weeks, divided in 3 phases: a 12-week period during which patients were randomly assigned with the use of a computer-generated table to receive either raloxifene60 mg/day or placebo, followed by a 4-week wash-out period, and Modulation of vascular tone is one of the most relevant effects a final 12-week period in which the patients switched to the of Intracoronary or percutaneous estrogen adminis- corresponding placebo or raloxifene. A balanced permuted-block tration has been shown to restore the vasodilator response to approach (in blocks of 4 patients) was used to prepare the acetylcholine, both in patients with atherosclerotic coronary artery randomization tables for each participating center. Randomization disease and those with angiographically normal coronary arteries tables were provided by the Unidad de Ensayos Clı´nicos of the but with proven endothelial dysfunction.
Hospital Clı´nic, and study medications were provided by the Since the publication of the HERS demonstrating an pharmacy department at our institution. illustrates increased risk in thromboembolic complications and breast cancer in postmenopausal women treated with a combination of estrogen The protocol was approved by the local ethics committee of plus progesterone, there has been growing interest in evaluating each participating center and the Agencia Espan the effects of the selective estrogen receptor modulators in the Analysis of blood samples for biochemistry and coagulation A beneficial effect on endothelial function has also been was conducted in a centralized manner. Endothelial function proposed for the selective estrogen receptor modulator (SERM) analysis was performed at each participating center using the raloxifene.More specifically, a previous clinical study in same study protocol and sonographic equipment and software.
postmenopausal women receiving raloxifene for 12 months Measurements of endothelial function parameters were also demonstrated an increased brachial artery endothelial function as compared with control patients. From a thrombosis point-of-view, raloxifene has been reported to modify coagulation parameters. On one hand, a favorable decrease in fibrinogenlevels has been reported in postmenopausal woon the hand, an increase in procoagulant parameters has been docu- levels < 30 pg/mL and FSH > 40 UI/L), aged 70 years, admitted mented with raloxifene mid-term treatment.No previous to the cardiology department of the participating centers, with studies analyzing coagulation and fibrinolysis pathways in documented coronary artery disease (at least 1 vessel with a stenosis women with established cardiovascular disease have been >70% or history of a previous myocardial infarction) were assessed for eligibility. Exclusion criteria were contraindications to raloxifene The MORE studyhad shown a decreased risk of cardiovascular (previous venous thrombotic disorders, hepatic disease, breast or events in a subgroup of postmenopausal women at increased endometrial cancer), chronic renal failure (creatinine >2 mg/dL), cardiovascular risk. The RUTH study sought to analyze the effect of participation in a clinical trial < 30 days prior to randomization or raloxifene on women with demonstrated ischemic heart disease or having received hormone replacement therapy in the previous 6 at increased risk, but failed to demonstrate any reduction of the months. All patients gave written informed consent. Before risk of coronary heart disease. In addition, an excess of fatal stroke enrollment, patients underwent a thorough gynecological evalua- and thromboembolic events was observed. No assessment of tion consisting of a pelvic exam, pap smear and mammography in all coagulation and fibrinolysis parameters was done in the RUTH patients, and pelvic sonography when indicated.
We undertook the MERCED trial with the aim to study the effects of raloxifene on endothelial function in postmenopausal women with coronary heart disease. In addition, to assessthrombosis risk, a thorough analysis of coagulation and fibrinolysis Endothelial function was studied using high-resolution ultra- sound of the brachial artery, according to a previously validated Document downloaded from, day 04/11/2011. This copy is for personal use. Any transmission of this document by any media or format is strictly prohibited.
M. Roque´ et al. / Rev Esp Cardiol. 2011;64(7):572–578 Assessed for
Gyn screening
Raloxifene n = 16
Placebo n = 16
Placebo n = 17
Raloxifene n = 15
Blood tests
Brachial artery echo-Doppler
Figure 1. Study flowchart. Enrollment strategy for the MERCED trial. Eligible patients had evidence of ischemic heart disease and were required to have a normalgynecological screening. Randomized patients were allocated to receive placebo or raloxifene, in a double-blinded manner during the first phase of the study, andswitched to the other treatment arm for the second phase, after a 4-week washout period. *2 patients randomized to placebo discontinued treatment due tomedication intolerance.
technique.Blind analysis of all images was conducted centrally measurement in our laboratory has been reported to be 0.0002 (0.04% of total variability) and 0.001 (0.22% of total variability), The studies were carried out in a quiet, temperature-controlled room (24 8C) with the patient in the supine position, using a highresolution vascular probe connected to a conventional ultrasound.
All studies were performed at the same time of day, and patients rested for at least 10 min prior to beginning the study.
A longitudinal section of a nontortuous segment of the right Raloxifene effects on the following variables were analyzed: brachial artery 2 cm to 5 cm above the elbow was scanned. The lipid profile (total cholesterol, high density lipoprotein cholesterol center of the artery was identified by obtaining the clearest image [HDLc] and low density lipoprotein cholesterol [LDLc], apo A, apo B, of the anterior and posterior arterial wall layers. Each scan lipoprotein [a] and triglycerides); coagulation (F 1+2, activated consisted of a longitudinal image of the brachial artery and a factor VII and factor XII, and thrombin generation curves); and pulsed wave Doppler spectral display of the brachial artery flow.
fibrinolysis (plasminogen activator inhibitor type I [PAI-1], Endothelial-dependent vasodilation was assessed by analysis of thrombin-activatable fibrinolysis inhibitor [TAFI] antigenic and the brachial artery diameter changes in response to an increase in activity, plasmin-antiplasmin [PAP] complexes, and clot lysis flow. Reactive hyperemia was achieved by the rapid release of a assay). Blood samples were obtained at baseline (time 0), and at pneumatic pressure cuff placed around the forearm, distal to the arterial segment scanned, which was inflated up to 300 mmHgduring 4 to 5 min. A pulsed wave Doppler signal of the brachial artery flow and bidimensional images were recorded 55 s to 65 safter cuff release.
General laboratory work, including hematology and lipid Blind analysis of all images was conducted centrally by a profile, was performed following standard methodology.
blinded investigator. Staff at each participating center wasspecifically trained to perform the endothelial function analysisin a standardized protocol.
Flow-mediated vasodilation (FMD) was used as an index of endothelium-dependent vasodilation and was calculated as the Prothrombin and activated partial thromboplastin times were percentage change in brachial artery mean diameter after reactive determined in an automated coagulometer CA-1500 (Dade hyperemia over that obtained at baseline. Flow was estimated Behring, Marburg, Germany) using standard reagents (Thrombo- from the velocity-time integral of the pulsed wave Doppler signal plastin IS and Actin FSL; Dade Behring) and were expressed as and heart rate. Vasodilation induced by sublingual nitroglycerine ratios (patient time:control time). Fibrinogen level was measured was used as an index of endothelium-independent vasodilation.
by the Clauss’ technique. The prothrombin fragments F1+2 were Using this methodology and a nested analysis of variance, inter- assessed as a thrombin generation marker by ELISA (Enzygnost- observer and intra-observer variance for brachial artery diameter F1+2; Dade Behring). Activated factor XII was determined by a Document downloaded from, day 04/11/2011. This copy is for personal use. Any transmission of this document by any media or format is strictly prohibited.
M. Roque´ et al. / Rev Esp Cardiol. 2011;64(7):572–578 direct immunoassay (Shield Diagnostics, Dundee, United King- dom), and activated factor VII was determined by ELISA (American Baseline Characteristics of the Study Population Diagnostica, Greenwich, Connecticut, United States). Thrombin generation curves were measured as endogenous thrombin potential (ETP) using a chromogenic substrate method (Dade- Behring) in a fully automated coagulometer (BCS-XP, Dade- PAI-1 plasma antigen was measured by ELISA, based on a double antibody principle (Imulyse PAI-1, Biopool, Umea, Sweden).
TAFI plasma antigen was measured by ELISA (Asserachrom TAFI, Stago), and the plasma activity related to TAFI was quantified by a chromogenic method (STA-Stachrom TAFI, Stago). Plasma levels of plasmin–alpha 2-antiplasmin complexes were quantified as a plasmin generation marker by ELISA (Dade Behring).
Clot lysis time was studied in a plasma system in which tissue plasminogen activator-mediated fibrinolysis of a thrombin- induced clot is measured using changes in turbidity at 405 nm (Multiskan Ascent, Thermo Labsystems, Finland). The clot lysis time is expressed as percentage of the normal control.
Samples from the study population were compared with healthy controls, obtained from a representative population sample (n = 99 women, aged 59 Æ 6 years), from which we already have anonymized serum samples in our hospital’s laboratory database.
Assuming a standard deviation of 2.76% and to detect a 2% difference in the dilatation of the humeral artery, 30 patients were needed to achieve a statistical power 1-b = 80%, a = 0.05 in a We assessed the normality of variables by examining the ACEI: angiotensin-converting enzyme inhibitors; AMI: acute myocardial infarction;ARA: angiotensin receptor antagonists; ASA: acetylsalicylic acid; CABG: coronary normal probability plots. The systolic blood pressure at baseline, artery by-pass grafting; CVA: cerebrovascular accident; CVD: cardiovascular reactive hyperemia, prothrombin time, activated partial throm- disease; DBP: diastolic blood pressure; IHD: ischemic heart disease; PCI, boplastin time, fibrinogen, PAP complexes, F percutaneous coronary intervention; SBP: systolic blood pressure; STEMI: ST and glucose were log-transformed to achieve normality.
elevation myocardial infarction.
Data are expressed as percentage or as mean Æ standard deviation.
We used the Student t-test or Mann-Whitney U-test, as appropriate, to determine differences in baseline characteristics.
We checked the possible carryover effect by testing a period-by- Baseline characteristics of the study population are summar- treatment interaction term in the general linear mixed models.
Because the period-by-treatment interaction term was not During the study follow-up, no differences were observed statistically significant in any model, we did not include period- regarding the control of blood pressure, dyslipidemia or diabetes by-treatment terms in the final models used. These models used with raloxifene or placebo. Likewise, no significant differences in the differences between pre- and posttreatment values as the acute ischemic events, angina functional class, or other clinical dependent variables and included independent variables of events were observed between treatment groups.
treatment as fixed effects, and participant number as random All data regarding clinical and biologic parameters analyzed are effect.In tables, the log-transformed variables were reversed to get original values; therefore, differences become ratios and meansare geometric instead of arithmetic. Statistical significance wasdefined as a P value < .050 for a 2-sided test. We performed analyses by using the R software (R Development Core Team 2006;R = A Language and Environment for Statistical Computing.
Baseline median FMD in our study population was 1.81% (95% R Foundation for Statistical Computing, Vienna, Austria).
confidence interval: 1.13% Æ 2.50%).
Among the different parameters analyzed assessing endothelial function, there were no differences between brachial artery diameter at baseline, or after raloxifene treatment. Blood flowduring reactive hyperemia was unchanged before and after In total, 33 postmenopausal women with demonstrated placebo or raloxifene. The percentage of increase in the brachial ischemic heart disease were enrolled in the study. During the artery diameter during reactive hyperemia was higher after study follow-up, 2 patients —randomized to placebo— withdrew raloxifene treatment (2.83% vs. 2.16%), but no significant difference consent due to gastrointestinal intolerance to study medication.
was demonstrated. All data are summarized in .
Overall, raloxifene was well tolerated and no significant side In addition, raloxifene treatment had no effect on endothelial- independent vasodilatation in response to nitroglycerin ).
Document downloaded from, day 04/11/2011. This copy is for personal use. Any transmission of this document by any media or format is strictly prohibited.
M. Roque´ et al. / Rev Esp Cardiol. 2011;64(7):572–578 Table 2Effect of Raloxifene Treatment on Lipid Profile, Endothelial Function, Thrombosis and Fibrinolysis BA: brachial artery; HDLc: high density lipoproteins cholesterol; LDLc: low density lipoproteins cholesterol; NTG: nitroglycerin; PAI: plasminogen activator inhibitor; TAFI:thrombin-activatable fibrinolysis inhibitor.
Data are displayed as the arithmetic mean (95% confidence interval) of the post- and pretreatment values.
Levels of F1+2, factor VIIa, factor XIIa, and fibrinogen were Baseline levels of PAI-1, TAFI antigen and TAFI activity increased at baseline, when compared with healthy controls from were increased compared to healthy controls (50 Æ 23 vs.
our hospital’s laboratory database (1.11 Æ 0.53 vs. 0.76 Æ 0.21 22.8 Æ 12.4 ng/mL; 12.4 Æ 2.6 vs. 11.1 Æ 1.9 mg/mL; and 123 Æ 23 nmol/L; 5.09 Æ 1.8 vs. 2.8 Æ 0.8 ng/mL; 3.1 Æ 1.1 vs. 2.7 Æ 1.0 ng/mL; vs. 111 Æ 10%, respectively, all P < .05).
and 3.75 Æ 0.94 vs. 3.1 Æ 0.9 g/L, respectively, all P < .05).
A decrease in PAP complexes was observed in response Raloxifene induced a decrease in fibrinogen levels compared to raloxifene treatment when compared with placebo (P < .01, ), indicating reduced fibrinolytic activity.
Thrombin generation, explored through F1+2 levels, was decreased by raloxifene treatment compared with placebo(P < .05; The MERCED trial did not demonstrate a beneficial effect of raloxifene on endothelial function in postmenopausal women withischemic heart disease. In addition to endothelial function, as a secondary aim the present study thoroughly assessed the effects ofraloxifene on thrombosis and fibrinolysis pathways, showing a decrease of several thrombotic risk markers.
Endothelial dysfunction is a risk factor for future cardiovascular events. In healthy women without obstructive coronary arterydisease presence of endothelial dysfunction has been shown to Figure 2. Vascular function. Assessment of brachial artery diameter post- predict ischemic heart disease.Improvement of endothelial hyperemia and after sublingual nitroglycerin. Flow-mediated dilatation of the function is one of the most studied mechanisms through which brachial artery after hyperemia in baseline conditions, and after placebo andraloxifene treatment, as well as flow-mediated dilatation after nitroglycerin estrogens and SERMs exert the described beneficial effects on Document downloaded from, day 04/11/2011. This copy is for personal use. Any transmission of this document by any media or format is strictly prohibited.
M. Roque´ et al. / Rev Esp Cardiol. 2011;64(7):572–578 In our study, raloxifene treatment had no effect on endothelial- In our study, a substantial reduction in fibrinogen (0.92 g/L on dependent or –independent vasodilatation.
average) was observed with raloxifene. The pre-established Baseline median FMD in our study population was lower than follow-up of our study was 7 months; therefore, we cannot that observed in previous studies of postmenopausal women with assess whether the observed decrease in fibrinogen levels would coronary heart suggesting a more severe endothelial translate into a reduction of future cardiovascular events.
dysfunction in our population. A high proportion of our population F1+2 levels, an indicator of thrombin generation, were increased had dyslipidemia and hypertension, together with a long-term at baseline in our population and decreased with raloxifene history of coronary heart disease in most patients, a risk profile treatment. Previous studies conducted in healthy postmenopausal that very likely accounts for the severely FMD observed.
women have shown either no change or an increase in F1+2 levels in In regard to the effects of raloxifene on endothelial function, response to The association of high fibrinogen levels previous studies have reported divergent conclusions. In a study with an increased thrombotic risk has been partially related to an conducted in healthy postmenopausal women, with a baseline altered generation of activated protein C.Increased levels of vasodilatory response of 8%, FMD endothelium-dependent FMD of fibrinogen can impair protein C activation and, thus, thrombin the brachial artery increased after 6 months under raloxifene generation. This mechanism may provide a link between the therapy, to the same extent as In contrast to this observed decrease in fibrinogen levels and thrombin generation, previous study, our study population included women with assessed through F1+2 levels, found in our study.
coronary artery disease and a high risk factor burden. A likelyexplanation for the observed differences between both studieswould be that raloxifene is not able to improve FMD in the presence of severe endothelial dysfunction. Similar to our work, astudy conducted in postmenopausal women with known coronary Levels of fibrinolysis regulators correlate with cardiovascular artery disease and impaired FMD (2.84% at baseline), did not find events in patients with risk More recently, the TAFI has any beneficial effect of raloxifene on endothelial been associated with the presence of cardiovascular risk factors, Several findings of this previous study are consistent with ours: raising the possibility that increased TAFI activity or antigen levels short duration of treatment (8 and 12 weeks, respectively), the risk factor burden of the study population, and demonstrated coronary The present study demonstrates the presence of a prothrom- artery disease. In the presence of advanced atherosclerosis with botic and hypofibrinolytic state, at baseline, in this population of demonstrated coronary artery disease, the beneficial effects of postmenopausal women with ischemic heart disease.
estrogen receptor modulation via increase of NO production may Determination of PAP complexes in our study was aimed at be hampered, as eNOS levels are reduced in atherosclerosis.
further examining the fibrinolytic system in the context of Taken altogether, the results from previous and present studies ischemic heart disease. Increased levels of PAP have been firmly suggest that raloxifene is not able to improve endothelial associated with a higher risk of myocardial infarction and function in postmenopausal women with established ischemic cardiovascular death.To our knowledge, this is the first study heart disease. This fact could also explain the failure of to assess the effect of raloxifene on PAP. Treatment with raloxifene replacement therapy and raloxifene in this population in previous resulted in a decrease in PAP complexes. We hypothesize that the decrease in PAP complexes found in our study may not reflect a Linked to endothelial function, in the MERCED study no changes decreased fibrinolytic activity per se, but is more likely a in the lipid profile were observed with raloxifene use. All patients consequence of the decrease in thrombin generation, as it parallels were under statin treatment and mean levels of total cholesterol the observed decrease in F1+2 levels.
and LDLc were within recommended range, suggesting that in apopulation under adequate treatment with statins, raloxifene doesnot induce any further reduction in cholesterol levels. This finding is also consistent with the results from the previously discussedstudy conducted in women with coronary artery disease under Because of the small sample size and short duration of treatment, we were not able to detect changes in clinical variablesduring follow-up. It is possible that the observed effect ofraloxifene is influenced by the concomitant medications the patients were receiving. However, given the randomized, cross-over design of the study, the possible confounder effect of medical The clinical implications of the RUTH trialin terms of treatment is randomly distributed among groups. A longer increased risk of death from stroke and venous thromboembolism duration of treatment and extended follow-up would be needed do not encourage the use of raloxifene, even though it did not result in order to evaluate the long-term effects of the observed findings in an increased incidence of coronary events. No assessment of thrombosis-related biologic parameters was performed in theRUTH trial, as we did in the present study. In our study, no adversecardiovascular events were observed with raloxifene treatment, although the present study had a short follow-up time and smallsample size.
Overall, the present study provides evidence that in post- Different disarrangements of the coagulation/fibrinolysis path- menopausal women with demonstrated endothelial dysfunction ways have been previously described in patients with ischemic and ischemic heart disease, mid-term treatment with raloxifene heart Levels of PAI-1, F 1 + 2, factor VIIa, factor XIIa, does not affect endothelial function. In addition, a decreased fibrinogen, and levels of TAFI antigen and activity were higher in thrombotic activity was observed. The findings of the present our study population when compared to a healthy population.
study are controversial, given the previous evidence on increased Treatment with raloxifene resulted in a decrease in fibrinogen thrombotic risk associated with raloxifene use. Whether throm- levels. Raloxifene has been previously reported to decrease botic risk is increased in specific postmenopausal population plasma levels of fibrinogen in healthy postmenopausal women.
subgroups remains to be assessed in future studies.
Document downloaded from, day 04/11/2011. This copy is for personal use. Any transmission of this document by any media or format is strictly prohibited.
M. Roque´ et al. / Rev Esp Cardiol. 2011;64(7):572–578 8. Walsh BW, Kuller LH, Wild RA, Paul S, Farmer M, Lawrence JB. Effects of raloxifene on serum lipids and coagulation factors in healthy postmenopausalwomen. JAMA. 1998;279:1445–51.
We are greatly indebted to Dr. Magda Heras for participation in 9. Sgarabotto M, Baldini M, Dei Cas A, Manotti C, Barilli A, Rinaldi M. Effects of study design and critical review of the data and manuscript; to I.
raloxifene and continuous combined hormone therapy on haemostasis vari-ables: A multicenter, randomized, double-blind study. Thromb Res. 2007;119: Ramio´ and T. Martorell for assistance in recruitment and follow-up of patients; to E. Martı´ for assistance in the statistical analysis; to E.
10. Barrett-Connor E, Grady D, Sashegyi A, Anderson PW, Cox DA, Hoszowski K, Lilly for editorial assistance; and to L. Gonza´lez for secretarial et al. Raloxifene and cardiovascular events in osteoporotic postmenopausal women: four-year results from the MORE (Multiple Outcomes of RaloxifeneEvaluation) randomized trial. JAMA. 2002;287:847–57.
11. Barrett-Connor E, Mosca L, Collins P, Geiger MJ, Grady D, Kornitzer M, et al.
Raloxifene Use for The Heart (RUTH) Trial Investigators. Effects of raloxifene on cardiovascular events and breast cancer in postmenopausal women. N Engl JMed. 2006;355:125–37.
12. Sorensen KE, Celermajer DS, Spiegelhalter DJ, Georgakopoulos D, Robinson J, This work was funded by the Red HERACLES grant (RD06/0009/ Thomas O, et al. Non-invasive measurement of human endothelium dependent 0008), from the Fondo de Investigaciones Sanitarias, Ministerio de arterial responses: accuracy and reproducibility. Br Heart J. 1995;74:247–53.
13. Senn S. Cross-over trials in clinical research. 2nd ed. Chichester: John Wiley; 14. Matsuzawa Y, Sugiyama S, Sugamura K, Nozaki T, Ohba K, Konishi M, et al.
Digital assessment of endothelial function and ischemic heart disease in women. J Am Coll Cardiol. 2010;55:1688–96.
15. Griffiths KA, Sader MA, Skilton MR, Harmer JA, Celermajer DS. Effects of raloxifene on endothelium-dependent dilation, lipoproteins, and markers of vascular function in postmenopausal women with coronary artery disease. JAm Coll Cardiol. 2003;42:698–704.
16. Saitta A, Altavilla D, Cucinotta D, Morabito N, Frisina N, Corrado F. Randomized, double-blind, placebo-controlled study on effects of raloxifene and hormonereplacement therapy on plasma NO concentrations, endothelin-1 levels, andendothelium-dependent vasodilation in postmenopausal women. Arterioscler 1. Mendelson ME, Karas RH. The protective effects of estrogen on the cardiovas- cular system. N Engl J Med. 1999;340:1801–11.
17. Oemar BS, Tschudi MR, Godoy N, Brovkovich V, Malinski T, Lu¨scher TF. Reduced 2. Roque´ M, Heras M, Roig E, Masotti M, Rigol M, Betriu A, et al. Short-term effects endothelial nitric oxide synthase expression and production in human athero- of transdermal estrogen replacement therapy on coronary vascular reactivity in sclerosis. Circulation. 1998;97:2494–8.
postmenopausal women with angina pectoris and normal results on coronary 18. Ridker PM, Vaughan DE, Stampfer MJ, Manson JE, Hennekens CH. Endogenous angiograms. J Am Coll Cardiol. 1998;31:139–43.
tissue-type plasminogen activator and risk of myocardial infarction. Lancet.
3. Sitges M, Heras M, Roig E, Duran M, Masotti M, Zurbano P, et al. Acute and mid- term combined hormone replacement therapy improves endothelial function 19. Tomiyama H, Kimura Y, Mitsuhashi H, Kinouchi T, Yoshida H, Kushiro T, et al.
in postmenopausal women with angina and angiographically normal coronary Relationship between endothelial function and fibrinolysis in early hyperten- arteries. Eur Heart J. 2001;22:2116–24.
sion. Hypertension. 1998;31:321–7.
4. Herrington DM, Braden GA, Williams JK, Morgan TM. Endothelial-dependent 20. Ta`ssies D, Roque´ M, Monteagudo J, Martorell T, Sionis A, Arzamendi D, et al.
coronary vasomotor responsiveness in postmenopausal women with and with- Thrombin-activatable fibrinolysis inhibitor genetic polymorphisms as markers out estrogen replacement therapy. Am J Cardiol. 1994;73:951–2.
of the type of acute coronary syndrome. Thromb Res. 2009;124:614–8.
5. Hulley S, Grady D, Bush T, Furberg C, Herrington D, Riggs B, et al. Randomized 21. Dı´ez N, Montes R, Alonso A, Medina P, Navarro S, Espan trial of estrogen plus progestin for secondary prevention of coronary heart increased fibrinogen concentration with impaired activation of anticoagulant disease in postmenopausal women. JAMA. 1998;280:605–13.
protein C. J Tromb Haemost. 2006;4:398–402.
6. Sumino H, Ichikawa S, Kasama S, Takahashi T, Sakamoto H, Koizumi A, et al.
22. Schroeder V, Wilmer M, Buehler B, Kohler HP. TAFI activity in coronary artery Effects of raloxifene on brachial arterial endothelial function, carotid wall disease: A contribution to the current discussion on TAFI assays. Thromb thickness, and arterial stiffness in osteoporotic postmenopausal women. Int 23. Morange PE, Bickel C, Nicaud V, Schnabel R, Rupprecht HJ, Peetz D, et al.; 7. Wong CM, Yung LM, Leung FP, Tsang SY, Au CL, Cheng CH, et al. Raloxifene AtheroGene Investigators. Haemostatic factors and the risk of cardiovascular protects endothelial cell function against oxidative stress. Br J Pharmacol.
death in patients with coronary artery disease. The AtheroGene Study. Arter- ioscler Thromb Vasc Biol. 2006;26:2793–9.


Nhs qipp medicines management implementation august 2010

NeLM news service DOH “Quality, Innovation, Productivity and Prevention (QIPP)” 2010/11 report on medicines management Source: Department of Health (DH) Date published: 28/07/2010 16:02 Summary by: Sheetal Ladva In response to the challenges of the current economic climate within the NHS, the Department of Health’s has focussed on identifying areas where it can simultane

Microsoft word - codideon-cast.doc

CONVENIO RELATIVO A LA OBLIGACIÓN DE DILIGENCIA POR PARTE DE LOS ESTABLECIMIENTOS BANCARIOS y DE AHORRO DE ANDORRA 9 DE ABRIL DE 1990 INTRODUCCIÓN, PREÁMBULO Los Bancos establecidos en el Principado de Andorra han adaptado hasta la fecha sus actividades a las normas habituales de la banca comercial, siguiendo los tradicionales usos y costumbres de los Bancos comerciales europeos. D

Copyright © 2010-2014 Online pdf catalog