[Translation into French and republication of: "Management of cancer-associated thromboembolism in vulnerable population"]. / Traduction et republication de : « Prise en charge de la maladie thromboembolique veineuse associée au cancer chez les populations vulnérables ¼.

Although all patients with cancer-associated thrombosis (CAT) have a high morbidity and mortality risk, certain groups of patients are particularly vulnerable. This may expose the patient to an increased risk of thrombotic recurrence or bleeding (or both), as the benefit-risk ratio of anticoagulant treatment may be modified. Treatment thus needs to be chosen with care. Such vulnerable groups include older patients, patients with renal impairment or thrombocytopenia, and underweight and obese patients. However, these patient groups are poorly represented in clinical trials, limiting the available data on which treatment decisions can be based. Meta-analysis of data from randomised clinical trials suggests that the relative treatment effect of direct oral factor Xa inhibitors (DXIs) and low molecular weight heparin (LMWH) with respect to major bleeding could be affected by advanced age. No evidence was obtained for a change in the relative risk-benefit profile of DXIs compared to LMWH in patients with renal impairment or of low body weight. The available, albeit limited, data do not support restricting the use of DXIs in patients with TAC on the basis of renal impairment or low body weight. In older patients, age is not itself a critical factor for choice of treatment, but frailty is such a factor. Patients over 70 years of age with CAT should undergo a systematic frailty evaluation before choosing treatment and modifiable bleeding risk factors should be addressed. In patients with renal impairment, creatine clearance should be assessed and monitored regularly thereafter. In patients with an eGFR less than 30mL/min/1.72m2, the anticoagulant treatment may need to be adapted. Similarly, platelet count should be assessed prior to treatment and monitored regularly. In patients with grade 3-4, thrombocytopenia (less than 50,000platelets/µL) treatment with a LMWH at a reduced dose should be considered. For patients with CAT and low body weight, standard anticoagulant treatment recommendations are appropriate, whereas in obese patients, apixaban may be preferred.

[Translation into French and republication of: "Anticoagulant treatment of cancer-associated thromboembolism"]. / Traduction et republication de : « Traitement anticoagulant de la maladie veineuse thromboembolique associée au cancer ¼.

Venous thromboembolism (VTE) is a frequent and potentially fatal complication in patients with cancer. During the initial period after the thromboembolic event, a patient receiving anticoagulant treatment is exposed both to a risk of VTE recurrence and also to an elevated bleeding risk conferred by the treatment. For this reason, the choice of anticoagulant is critical. The choice should take into account patient-related factors (such as functional status, age, body mass index, platelet count and renal function), VTE-related factors (such as severity or site), cancer-related factors (such as activity and progression) and treatment related factors (such as drug-drug interactions), which all potentially influence bleeding risk, and patient preference. These should be evaluated carefully for each patient during a multidisciplinary team meeting. For most patients, apixaban or a low molecular-weight heparin is the most appropriate initial choice for anticoagulant treatment. Such treatment should be offered to all patients with active cancer for at least 6months. The patient and treatment should be re-evaluated regularly, and anticoagulant treatment changed when necessary. Continued anticoagulant treatment beyond 6months is justified if the cancer remains active or if the patient experienced recurrence of VTE in the first 6months. In other cases, the interest of continued anticoagulant treatment may be considered on an individual patient basis in collaboration with oncologists.

Adult breast, lung, pancreatic, upper and lower gastrointestinal cancer patients with hospitalized venous thromboembolism in the national French hospital discharge database.

BACKGROUND: Venous thromboembolism (VTE) and cancer are strongly associated. In France, evidence on patients with pancreatic, upper GI [gastrointestinal], lower GI, lung, or breast cancer-associated VTE and their hospital management is limited. The aims of this study were to provide data on the number of hospitalized VTE events among cancer patients, the patients' characteristics, and their hospital management to estimate the burden of disease and the hospital burden of cancer-related VTE and to provide guidance on research. METHODS: This longitudinal, observational, and retrospective study was based on the comprehensive hospital discharge database (PMSI). Adult patients (≥ 18 years old) hospitalized with a cancer of interest in 2016 and hospitalized (within 2 years with VTE (captured a as a principal, related, or significant associated diagnosis) were included in the study. RESULTS: We identified 340,946 cancer patients, of which 7.2% (24,433 patients) were hospitalized with VTE. The proportions of hospitalized VTE were 14.6% (3,237) for patients with pancreatic cancer, 11.2% (8,339) for lung cancer, 9.9% (2,232) for upper GI cancer, 6.7% (7,011) for lower GI cancer, and 3.1% (3,614) for breast cancer. Around two thirds of cancer patients with a hospitalized VTE had active cancer (with metastases and/or receiving chemotherapy during the six months prior to the index date): from 62% of patients with pancreatic cancer to 72% with breast cancer. Around a third of patients were admitted to the hospital through the emergency room, up to 3% of patients stayed in an intensive care unit. The average length of stay ranged from 10 (breast cancer) to 15 days (upper GI cancer). Nine (lower GI cancer) to 18% (pancreatic cancer) of patients died during the VTE hospital stay. CONCLUSIONS: The burden of cancer-associated VTE is substantial, both in terms of the number of patients affected and in the hospital use. These findings offer guidance on future research on VTE prophylaxis in a very high-risk population, particularly in patients with active cancer.

Twice- or Once-Daily Dosing of Direct Oral Anticoagulants, a systematic review and meta-analysis.

AIM: The direct oral anticoagulants (DOAC) have similar half-lives, but the dosing regimen varies between once daily (QD) or twice daily (BID). For some prescribers, the QD regimen improves compliance. Others prefer BID regimens to promote better stability of plasma concentrations, particularly in the event of missed doses. Limited level of evidence provides guidance about the best treatment strategy. The purpose of this study was to compare the treatment effect of QD vs. BID administration of DOACs in major orthopedic surgery (MOS), non-valvular atrial fibrillation (NVAF), venous thromboembolism (VTE), and acute coronary syndrome (ACS). METHODS: We conducted a systematic review up to April 2020. We included phase II clinical trials comparing DOAC QD vs BID with same daily dose. We extracted data for the occurrence of major thrombosis (proximal deep vein thrombosis, pulmonary embolism, myocardial infarction, ischemic stroke) and major hemorrhage (ISTH criteria and recommendations of the European Medicines Agency for surgical patients). Relative risks (RR) were combined using a fixed and random effects weighted meta-analysis. RESULTS: Twelve randomized, controlled, phase II trials were included (10,716 patients), representing 24 dosing regimen comparisons of apixaban, darexaban, edoxaban, rivaroxaban, letaxaban, and dabigatran. There was no difference for major thrombotic event (RRBID/QD = 1.06, 95%IC 0.86-1.30) nor for major bleeding (RRBID/QD = 1.02, 95%IC 0.84-1.23) between the BID vs QD regimens, without heterogeneity (I2 = 0%). CONCLUSION: Our study does not support a global difference in term of efficacy and safety of the BID and QD regimens of DOAC in MOS, NVAF, VTE and ACS.

Deep Vein Thrombosis in Europe-Health-Related Quality of Life and Mortality.

OBJECTIVES: Deep vein thrombosis (DVT) is a major health-care burden in Europe, but exact estimates are lacking. This study reports results from the PREFER venous thromboembolism (VTE) study concerning health-related quality of life (HrQoL) and mortality of patients with DVT. METHODS: PREFER VTE was a prospective, observational study, conducted in 7 European countries, designed to provide data concerning treatment patterns, resource utilization, mortality, and QoL. First-time or recurrent patients with DVT were followed at 1, 3, 6, and 12 months. Health-related QoL-as measured by the EuroQoL 5-Dimension 5-Level instrument ( EQ-5D-5L)-was analyzed using Tobit regression with repeated measures, assessing the impact of baseline characteristics stratified by cancer activity. Mortality was analyzed using logistic regression. RESULTS: At baseline, patients with DVT had a 0.14 lower EQ-5D-5L index score (0.72 for total sample) compared to the reference UK population (0.85). The EQ-5D-5L index score improved from baseline to 12 months in patients with active cancer (from 0.70 to 0.79) and those without (0.72-0.87); 7.3% died within a year, a 5.2% excess mortality compared to the age- and gender-adfjusted general population. The 12-month mortality rate of DVT varied between 2.9% in the pooled data from Germany, Switzerland, or Austria and 15.4% in Italy. Furthermore, the mortality rate differed between patients with active cancer and those without (42.9% vs 4.7%). CONCLUSIONS: Deep vein thrombosis is associated with a substantial burden of illness in terms of HrQoL at baseline, which following treatment normalizes after 12 months and has a significant mortality rate. In addition, active cancer has a significant impact on mortality and the HrQoL of patients with DVT.

Chronic thromboembolic pulmonary hypertension suspicion after pulmonary embolism in cancer patients.

INTRODUCTION: Chronic thromboembolic pulmonary hypertension (CTEPH) is a severe condition which should be screened in patient with persistent dyspnea after pulmonary embolism (PE). After PE, CTEPH incidence was estimated between 0.1 and 9.1% in overall patients. Although cancer is associated with an increased risk of CTEPH, CTEPH incidence is still unknown in cancer patients with PE. We aimed to estimate the frequency CTEPH-likely patients after PE, in cancer patients. MATERIALS: We individualized cancer patients of a monocentric prospective registry including consecutive patients with symptomatic PE. The primary outcome was the frequency of "CTEPH-likely" patients defined by the European Respiratory Society (ERS) guidelines (an accelerated tricuspid regurgitation more than 2.8m/s and at least 1-2 segmental or larger-sized defects, after more than 3 months of therapeutic anticoagulation). RESULTS: We included 129 cancer patients with PE. Colorectal cancer (19%), breast cancer (17%) and prostate cancer (15%) were the most frequent cancers. PE occurred after surgery or medical immobilization in 17% of patients, while 26% of patients had history of venous thromboembolism. During the follow-up, 2 patients (1.5%) had a clinical suspicion of CTEPH and only 1 patient with ovarian cancer (0.75% 95%CI [0.0%-2.2%]) was classified as "CTEPH-likely", 6 months after PE. CONCLUSION: The frequency of screening for CTEPH seems negligible in PE patients with cancer. Concomitant cancer may affect the clinical suspicion of CTEPH.

Assessment of a flow cytometry technique for studying signaling pathways in platelets: Monitoring of VASP phosphorylation in clinical samples.

A recently released kit (PerFix EXPOSE) was reported to improve the measurement of the degree of phosphorylation of proteins in leukocytes by flow cytometry. We tested its adaptation for platelets to monitor vasodilator-stimulated phosphoprotein (VASP) phosphorylation, which is the basis of a currently used test for the assessment of the pharmacological response to P2Y12 antagonists (PLT VASP/P2Y12). The PerFix EXPOSE kit was compared to the PLT VASP/P2Y12 kit by using blood samples drawn at 24 h post clopidogrel dose from 19 patients hospitalized for a non-cardio-embolic ischemic stroke and treated with clopidogrel monotherapy for at least five days in an observational study. The platelet PerFix method was based on adaptation of the volume of the sample, the centrifugation speed and the incubation temperature. Poor agreement between prevention by adenosine diphosphate (ADP) of PGE1-induced cAMP-mediated VASP phosphorylation and ADP induced aggregation assessed by Light Transmittance Aggregometry was found. We found a significant correlation between the PLT VASP/P2Y12 kit and the PerFix EXPOSE kit. The PerFix EXPOSE kit may also be helpful to monitor adverse effects of second-generation tyrosine kinase inhibitors on platelets.

Incidence and risk factors of major bleeding following major orthopaedic surgery with fondaparinux thromboprophylaxis. A time-to-event analysis.

AIMS: Increased exposure to fondaparinux, as observed in patients with renal impairment, may increase bleeding risk. This study aims to determine the time course of major bleeding after major orthopaedic surgery, identify predictors of bleeding and simulate the effect of a reduced dose of fondaparinux on bleeding for patients with moderate renal impairment (creatinine clearance = 20-50 ml min-1 ). METHODS: Data including fondaparinux anti-Xa activities from two multicentre prospective cohorts were used. In the first cohort, patients (n = 957) received fondaparinux 2.5 mg once a day. In the second, patients with moderate renal impairment (n = 436) received 1.5 mg once per day. The time-to-major bleeding after the end of surgery was modelled using a parametric survival analysis in NONMEM. RESULTS: The observed rate of major bleeding up to day 11 was 5.2%. The time-to-event analysis indicated that the hazard of bleeding was highest in the first days following surgery and then remained low thereafter. Independent significant predictors of an increased hazard of major bleeding were male sex, lower body weight and increased drug exposure. Simulated rates of major bleeding up to day 11 in patients with moderate renal impairment were 6.5% with fondaparinux 2.5 mg once daily and 3.8% with fondaparinux 1.5 mg once daily. CONCLUSION: The hazard of major bleeding is highest in the first postoperative days and increases with fondaparinux exposure. To reduce the risk of bleeding in patients with moderate renal impairment, this study supports the use of a lower dose of fondaparinux 1.5 mg once daily.

Statistical controversies in clinical research: limitations of open-label studies assessing antiangiogenic therapies with regard to evaluation of vascular adverse drug events-a meta-analysis.

Background: Previous meta-analyses have shown paradoxical increased risk of bleeding and thrombotic events in patients receiving antiangiogenics (AA) that may be simply explained by the studies design included. By a meta-epidemiological approach, we aim to investigate the impact of double-blind (DB) and open-label study designs on the risks of bleeding, venous thrombotic events (VTE) and arterial thrombotic events (ATE) in cancer patients treated with AA. Materials and methods: We searched Medline, Cochrane, ClinicalTrials.gov databases and proceedings of major oncology congresses for clinical trials published from January 2003 to January 2016. Randomized clinical trials that assigned patients with solid cancers to AA or control groups were eligible for inclusion. Combined odds ratios (ORs) for the risks of bleeding events, VTE and ATE were calculated for open and DB trials. Estimation bias of the treatment effect was determined by the ratio of OR, by dividing the OR values obtained in open-label trials by those obtained in DB trials. Results: The literature-based meta-analysis included 166 trials (72 024 patients). For bleeding events, comparison of AA versus control yielded an overall OR of 2.41 [95% confidence interval (95% CI) 2.12-2.73; P < 0.001], but this risk was overestimated by 1.68 (95% CI 1.33-2.13) in open-label studies. Concerning VTE, the OR was 1.19 (95% CI 1.04-1.35; P = 0.012) overall with AA, but this effect disappears when considering only DB trials (OR 0.99, 95% CI 0.83-1.17). The corresponding ratio of OR showed a significant overestimation of 1.53 (95% CI 1.19-1.96) in open-label trials. For ATE, an OR of 1.59 (95% CI 1.30-1.94; P < 0.001) was observed, associated with a significant overestimation of 1.65 (95% CI 1.13-2.43) in open-label trials. Conclusions: Open-label studies overestimated the risk of vascular adverse events with AA by at least 50%. Meta-analyses assessing adverse drug events should therefore be restricted to DB randomized trials.

Assessment of clinically relevant bleeding as a surrogate outcome for major bleeding: validation by meta-analysis of randomized controlled trials.

Essentials Surrogacy of clinically relevant bleeding (CRB) for major bleeding has never been validated. Our meta-analysis evaluated CRB surrogacy in trials of new versus traditional anticoagulants. Surrogacy was not validated in orthopedic surgery, venous thromboembolism or atrial fibrillation The difficulty in demonstrating the surrogacy may reflect a lack of homogeneity in its definition SUMMARY: Background Clinically relevant bleeding (CRB), comprising major bleeding and clinically relevant non-major bleeding, has been used as a surrogate for major bleeding in most anticoagulant trials. The validity of this surrogate to estimate trade-off between thrombotic and bleeding events in clinical trials was never assessed. Methods We systematically reviewed randomized phase III trials comparing new anticoagulants with the standard of care for venous thromboembolism prevention following major orthopedic surgery, venous thromboembolism (VTE) treatment, or stroke and systemic embolism prevention in atrial fibrillation (AF), and reporting both major bleeding and CRB rates. The validity of CRB as a surrogate for major bleeding was assessed according to the strength of the association between the relative risks of major bleeding and CRB, measured by the use of R2trial and its 95% confidence interval (CI). Results In the postoperative prophylactic setting (13 studies), major bleeding and CRB rates were 1.12% and 3.56%, respectively, and R2trial was 0.69 (95% CI 0.34-0.93). For acute VTE studies (n = 12), major bleeding and CRB rates were 1.87% and 9.07%; the corresponding R2trial values were 0.28 (95% CI 0.01-0.80) and 0.68 (95% CI 0.09-1.00) when only double-blind studies were considered (n = 7). For AF studies (n = 7; 22 strata), major bleeding and CRB rates were 4.82% and 15.3%, and R2trial was 0.59 (95% CI 0.15-0.82). Conclusion Despite an apparent correlation between CRB and major bleeding in major orthopedic surgery, AF, and double-blind acute VTE studies, the wide CIs suggest that CRB might not be an acceptable surrogate outcome in any of these settings.

Pharmacokinetic/pharmacodynamic model for unfractionated heparin dosing during cardiopulmonary bypass.

BACKGROUND: High-dose heparin is used during cardiopulmonary bypass (CPB) to prevent thrombosis in the circuits used for extracorporeal circulation. The aim of this study was, initially, to develop a population pharmacokinetic/pharmacodynamic (PK/PD) model to assess the variability of PK/PD parameters and their correlation with the results of the routine haemostatic test activated clotting time (ACT) and thereafter to develop a Bayesian estimator enabling an individualized dosing strategy. METHODS: Fifty consecutive patients undergoing cardiac surgery with CPB were included in the study. Heparin was administered as an initial bolus of 300 IU kg -1 followed by additional boluses of 5000 IU to maintain ACT <400 s. In total, 361 blood samples were collected. The PK and PD data were analysed using a non-linear mixed effect model. RESULTS: A two-compartment model with a linear elimination link to an E max model best described heparin anti-factor Xa activities and ACT. Covariate analysis showed that body weight was positively correlated with clearance and central compartment volume. Inclusion of body weight with these parameters decreased their variability by 11 and 15%, respectively. The Bayesian estimator performed well in predicting individual parameters in an independent group of patients. CONCLUSIONS: A population PK/PD analysis of heparin during CPB, using a routine haemostatic test, shows that Bayesian estimation might help to predict ACT on the basis of only one or two blood samples.

Indirect comparison meta-analysis of two enoxaparin regimens in patients undergoing major orthopaedic surgery. Impact on the interpretation of thromboprophylactic effects of new anticoagulant drugs.

Two enoxaparin dosage regimens are used as comparators to evaluate new anticoagulants for thromboprophylaxis in patients undergoing major orthopaedic surgery, but so far no satisfactory direct comparison between them has been published. Our objective was to compare the efficacy and safety of enoxaparin 3,000 anti-Xa IU twice daily and enoxaparin 4,000 anti-Xa IU once daily in this clinical setting by indirect comparison meta-analysis, using Bucher's method. We selected randomised controlled trials comparing another anticoagulant, placebo (or no treatment) with either enoxaparin regimen for venous thromboembolism prophylaxis after hip or knee replacement or hip fracture surgery, provided that the second regimen was assessed elsewhere versus the same comparator. Two authors independently evaluated study eligibility, extracted the data, and assessed the risk of bias. The primary efficacy outcome was the incidence of venous thomboembolism. The main safety outcome was the incidence of major bleeding. Overall, 44 randomised comparisons in 56,423 patients were selected, 35 being double-blind (54,117 patients). Compared with enoxaparin 4,000 anti-Xa IU once daily, enoxaparin 3,000 anti-Xa IU twice daily was associated with a reduced risk of venous thromboembolism (relative risk [RR]: 0.53, 95% confidence interval [CI]: 0.40 to 0.69), but an increased risk of major bleeding (RR: 2.01, 95% CI: 1.23 to 3.29). In conclusion, when interpreting the benefit-risk ratio of new anticoagulant drugs versus enoxaparin for thromboprophylaxis after major orthopaedic surgery, the apparently greater efficacy but higher bleeding risk of the twice-daily 3,000 anti-Xa IU enoxaparin regimen compared to the once-daily 4,000 anti-Xa IU regimen should be taken into account.

[Management of major bleeding complications and emergency surgery in patients on long-term treatment with direct oral anticoagulants, thrombin or factor-Xa inhibitors. Proposals of the Working Group on Perioperative Haemostasis (GIHP) - March 2013]. / Prise en charge des complications hémorragiques graves et de la chirurgie en urgence chez les patients recevant un anticoagulant oral anti-IIa ou anti-Xa direct. Propositions du Groupe d'intérêt en Hémostase Périopératoire (GIHP) - mars 2013.

New direct oral anticoagulants (NOAC), inhibitors of factor IIa or Xa, are expected to be widely used for the treatment of venous thromboembolic disease, or in case of atrial fibrillation. Such anticoagulant treatments are known to be associated with haemorrhagic complications. Moreover, it is likely that such patients on long-term treatment with NOAC will be exposed to emergency surgery or invasive procedures. Due to the present lack of experience in such conditions, we cannot make recommendations, but only propose management for optimal safety as regards the risk of bleeding in such emergency conditions. In this article, only dabigatran and rivaroxaban were discussed. For emergency surgery at risk of bleeding, we propose to dose the plasmatic concentration of drug. Levels inferior or equal to 30ng/mL for both dabigatran and rivaroxaban, should enable the realization of a high bleeding risk surgery. For higher concentration, it was proposed to postpone surgery by monitoring the evolution of the drug concentration. Action is then defined by the kind of NOAC and its concentration. If the dosage of the drug is not immediately available, proposals only based on the usual tests, PT and aPTT, also are presented. However, these tests do not really assess drug concentration or bleeding risk. In case of severe haemorrhage in a critical organ, it is proposed to reduce the effect of anticoagulant therapy using a nonspecific procoagulant drug (activated prothrombin concentrate, FEIBA, 30-50U/kg, or non-activated 4-factors prothrombin concentrates 50U/kg). For any other type of severe haemorrhage, the administration of such a procoagulant drug, potentially thrombogenic in these patients, will be discussed regarding concentration of NACO and possibilities for mechanical haemostasis.

Extended venous thromboembolism prophylaxis in patients undergoing hip fracture surgery - the SAVE-HIP3 study.

There is currently limited information available on the benefits and risks of extended thromboprophylaxis after hip fracture surgery. SAVE-HIP3 was a randomised, double-blind study conducted to evaluate the efficacy and safety of extended thromboprophylaxis with the ultra-low molecular-weight heparin semuloparin compared with placebo in patients undergoing hip fracture surgery. After a seven- to ten-day open-label run-in phase with semuloparin (20 mg once daily subcutaneously, initiated post-operatively), patients were randomised to once-daily semuloparin (20 mg subcutaneously) or placebo for 19 to 23 additional days. The primary efficacy endpoint was a composite of any venous thromboembolism (VTE; any deep-vein thrombosis and non-fatal pulmonary embolism) or all-cause death until day 24 of the double-blind period. Safety parameters included major and clinically relevant non-major bleeding, laboratory data, and treatment-emergent adverse events (TEAEs). Extended thromboprophylaxis with semuloparin demonstrated a relative risk reduction of 79% in the rate of any VTE or all-cause death compared with placebo (3.9% vs 18.6%, respectively; odds ratio 0.18 (95% confidence interval 0.07 to 0.45), p < 0.001). Two patients in the semuloparin group and none in the placebo group experienced clinically relevant bleeding. TEAE rates were similar in both groups. In conclusion, the SAVE-HIP3 study results demonstrate that patients undergoing hip fracture surgery benefit from extended thromboprophylaxis.

Semuloparin for prevention of venous thromboembolism after major orthopedic surgery: results from three randomized clinical trials, SAVE-HIP1, SAVE-HIP2 and SAVE-KNEE.

BACKGROUND: Semuloparin is a novel ultra-low-molecular-weight heparin under development for venous thromboembolism (VTE) prevention in patients at increased risk, such as surgical and cancer patients. OBJECTIVES: Three Phase III studies compared semuloparin and enoxaparin after major orthopedic surgery: elective knee replacement (SAVE-KNEE), elective hip replacement (SAVE-HIP1) and hip fracture surgery (SAVE-HIP2). PATIENTS/METHODS: All studies were multinational, randomized and double-blind. Semuloparin and enoxaparin were administered for 7-10 days after surgery. Mandatory bilateral venography was to be performed between days 7 and 11. The primary efficacy endpoint was a composite of any deep vein thrombosis, non-fatal pulmonary embolism or all-cause death. Safety outcomes included major bleeding, clinically relevant non-major (CRNM) bleeding, and any clinically relevant bleeding (major bleeding plus CRNM). RESULTS: In total, 1150, 2326 and 1003 patients were randomized in SAVE-KNEE, SAVE-HIP1 and SAVE-HIP2, respectively. In all studies, the incidences of the primary efficacy endpoint were numerically lower in the semuloparin group vs. the enoxaparin group, but the difference was statistically significant only in SAVE-HIP1. In SAVE-HIP1, clinically relevant bleeding and major bleeding were significantly lower in the semuloparin vs. the enoxaparin group. In SAVE-KNEE and SAVE-HIP2, clinically relevant bleeding tended to be higher in the semuloparin group, but rates of major bleeding were similar in the two groups. Other safety parameters were generally similar between treatment groups. CONCLUSIONS: Semuloparin was superior to enoxaparin for VTE prevention after hip replacement surgery, but failed to demonstrate superiority after knee replacement surgery and hip fracture surgery. Semuloparin and enoxaparin exhibited generally similar safety profiles.

[New antithrombotic drugs for the treatment of venous thromboembolism]. / Les nouveaux anticoagulants dans la maladie thrombo-embolique veineuse.

Numerous newer anticoagulants are under advanced clinical development for the treatment of venous thromboembolism. These new drugs specifically inhibit activated factors II or X, with predictable effects and no need for dose modification and laboratory monitoring. The main direct activated factor X (FXa) inhibitors are rivaroxaban, apixaban and edoxaban. They are taken orally once or twice per day. Dabigatran is the main inhibitor of activated factor II (IIa) and is administered orally once daily. Dabigatran and rivaroxaban are already licensed for the prevention of thromboembolic events following major orthopedic surgery such as total hip and knee replacement. They will probably soon be authorized for the treatment of venous thromboembolism, if they both confirm their efficacy and safety, and can demonstrate their cost-effectiveness. However, only rivaroxaban has been tested as a stand-alone treatment, whereas dabigatran was compared to vitamin K antagonism after a standard treatment regimen based on heparin or its derivates.