Oral direct factor Xa inhibition with edoxaban for thromboprophylaxis after elective total hip replacement

2010 ◽  
Vol 104 (09) ◽  
pp. 642-649 ◽  
Author(s):  
Alexander Cohen ◽  
Bengt Eriksson ◽  
David Puskas ◽  
Minggao Shi ◽  
Tomas Bocanegra ◽  
...  
Keyword(s):  
Total Hip Replacement ◽  
Hip Replacement ◽  
Factor Xa ◽  
Primary Efficacy ◽  
Direct Factor ◽  
Bleeding Events ◽  
Once Daily ◽  
Total Hip ◽  
Efficacy Analysis ◽  
Safety Outcome

SummaryEdoxaban is a new oral direct factor Xa inhibitor. The purpose of this study was to evaluate the efficacy and safety of different doses of edoxaban for the prevention of venous thromboembolism (VTE) in patients undergoing elective total hip replacement. A total of 903 patients were randomised to oral edoxaban 15, 30, 60 or 90 mg once daily or subcutaneous dalteparin once daily (initial dose 2,500 IU, subsequent doses 5,000 IU). Both drugs were begun 6–8 hours postoperatively and continued for 7–10 days, when bilateral venography was performed. The primary efficacy endpoint was the incidence of total VTE, which included proximal and/or distal deep-vein thrombosis (DVT) by venography or symptomatic, objectively confirmed DVT or pulmonary embolism during the treatment period. The primary safety outcome was the incidence of the composite of major and clinically relevant non-major bleeding. All venograms and bleeding events were reviewed by a central independent adjudication committee blinded as to treatment allocation. Of the 903 patients randomised, 776 were evaluable for the primary efficacy analysis. The incidences of VTE were 28.2%, 21.2%, 15.2%, and 10.6% in patients receiving edoxaban 15, 30, 60 and 90 mg, respectively, compared with 43.8% in the dalteparin group (p<0.005 ). There was a statistically significant (p<0.001) dose-response for efficacy across the edoxaban dose groups for total VTE and for major VTE. The incidence of clinically relevant bleeding was low and similar across the groups. Oral edoxaban once daily is effective for preventing VTE after total hip replacement.

scholarly journals A Once-Daily, Oral, Direct Factor Xa Inhibitor, Rivaroxaban (BAY 59-7939), for Thromboprophylaxis After Total Hip Replacement

Circulation ◽  
2006 ◽  
Vol 114 (22) ◽  
pp. 2374-2381 ◽  
Author(s):  
Bengt I. Eriksson ◽  
Lars C. Borris ◽  
Ola E. Dahl ◽  
Sylvia Haas ◽  
Menno V. Huisman ◽  
...  
Keyword(s):  
Total Hip Replacement ◽  
Hip Replacement ◽  
Factor Xa ◽  
Factor Xa Inhibitor ◽  
Direct Factor ◽  
Once Daily ◽  
Total Hip

Prevention of Venous Thromboembolism after Total Hip Replacement with Once-Daily BAY 59-7939 - An Oral, Direct Factor Xa Inhibitor.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 280-280 ◽  
Author(s):  
Bengt I. Eriksson ◽  
Lars Borris ◽  
Ola E. Dahl ◽  
Sylvia Haas ◽  
Menno V. Huisman ◽  
...  
Keyword(s):  
Venous Thromboembolism ◽  
Total Hip Replacement ◽  
Hip Replacement ◽  
Factor Xa ◽  
Study Drug ◽  
Dose Finding ◽  
Efficacy And Safety ◽  
Once Daily ◽  
Total Hip ◽  
Subcutaneous Enoxaparin

Abstract Venous thromboembolism is a serious risk after major surgery, and significant research is underway to develop novel, convenient anticoagulants. Patients undergoing hip replacement surgery are a suitable population for the study of novel anticoagulants because of a high rate of silent deep vein thromboses (DVTs), and the ability to quantify bleeding in a controlled environment. BAY 59-7939 is an oral, direct Factor Xa inhibitor in clinical development for the prevention and treatment of thromboembolic disorders. Dose-finding studies in hip and knee replacement patients showed that twice-daily, oral BAY 59-7939 initiated post-operatively had a wide therapeutic window, with similar efficacy and safety to enoxaparin (30 mg twice-daily or 40 mg once-daily) for the prevention of venous thromboembolism (VTE), and was unlikely to require monitoring. This European, randomized, double-blind, double-dummy, dose-finding study was performed to compare the efficacy and safety of once-daily, oral BAY 59-7939 with subcutaneous enoxaparin for VTE prevention in patients undergoing total hip replacement. Males over the age of 18 and postmenopausal females undergoing elective total hip replacement were randomized to oral BAY 59-7939 5, 10, 20, 30, or 40 mg once daily, or subcutaneous enoxaparin 40 mg once daily. Patients received enoxaparin on the evening before surgery and at least 6–8 hours after surgery, or BAY 59-7939 6–8 hours after surgery. Study drugs were then given every 24±2 hours. Each treatment group was to include 135 patients: a total of 810 patients. Mandatory bilateral ascending venography was performed 6–10 days after surgery; the last dose of study drug was given on the day before venography. Patients were followed for 30–60 days after the last study treatment. The primary efficacy endpoint was a composite of any DVT, objectively confirmed non-fatal pulmonary embolism (PE), and all-cause mortality; the secondary efficacy endpoint was major VTE - proximal DVT, PE, or VTE-related death. The primary safety endpoint was the incidence of major, post-operative bleeding not later than 2 days after the last intake of study drug; secondary safety endpoints included clinically relevant, non-major bleeding, and minor bleeding. An in-depth analysis of the study results will be presented here. Based on the study findings, the potential clinical impact of oral BAY 59-7939 administered once-daily for thromboprophylaxis in orthopaedic surgery will be discussed.

Characterisation of exposure versus response of edoxaban in patients undergoing total hip replacement surgery

2012 ◽  
Vol 108 (11) ◽  
pp. 887-895 ◽  
Author(s):  
Shashank Rohatagi ◽  
Helen Kastrissios ◽  
Michelle Green ◽  
Michelle Green ◽  
Minggao Shi ◽  
...  
Keyword(s):  
Total Hip Replacement ◽  
Hip Replacement ◽  
Oral Absorption ◽  
Factor Xa ◽  
Compartment Model ◽  
Surgical Patients ◽  
Response Analysis ◽  
Total Hip ◽  
Replacement Surgery ◽  
Exposure Response

SummaryEdoxaban is an oral direct factor Xa inhibitor approved for the prevention of venous thromboembolism (VTE) in Japan. The objectives of this analysis were to characterise the population pharmacokinetics (PK) of edoxaban and the relationships between edoxaban exposure and clinical outcomes in a phase IIb study of surgical patients following total hip replacement (THR). A total of 1,795 subjects from a phase IIb study, 10 phase I studies, and three phase IIa studies were included in the PK analysis. The exposure-response analysis included data from surgical patients assigned to edoxaban in the phase IIb study. Edoxaban disposition in healthy and post-surgical patients was well-described with a linear, two-compartment model. Creatinine clearance was significantly correlated with edoxaban clearance and the rate of oral absorption was affected by surgery. The probability of a post-operative VTE was significantly correlated with steady-state metrics of edoxaban exposure estimated for each subject by Bayesian post-hoc methods with age and gender being the significant and expected covariates. The incidence of bleeding was low in these studies and hence no exposure-response relationship could be identified. These analyses suggest that edoxaban has a predictable anticoagulant effect in this patient population leading to dose-proportional reduction in incidence of VTE with low incidence of bleeding.

scholarly journals SR123781A: A New Once-Daily Synthetic Oligosaccharide Anticoagulant for Thromboprophylaxis After Total Hip Replacement Surgery

2008 ◽  
Vol 51 (15) ◽  
pp. 1498-1504 ◽  
Author(s):  
Michael R. Lassen ◽  
Ola Dahl ◽  
Patrick Mismetti ◽  
Dirk Zielske ◽  
Alexander G.G. Turpie
Keyword(s):  
Total Hip Replacement ◽  
Hip Replacement ◽  
Once Daily ◽  
Total Hip ◽  
Replacement Surgery ◽  
Hip Replacement Surgery

scholarly journals Dabigatran etexilate for the prevention of venous thromboembolism in patients undergoing elective hip and knee surgery: a single technology appraisal

2009 ◽  
Vol 13 (Suppl 2) ◽  
pp. 55-62
Author(s):  
M Holmes ◽  
C Carroll ◽  
D Papaioannou
Keyword(s):  
Total Knee Replacement ◽  
Total Hip Replacement ◽  
Knee Replacement ◽  
Hip Replacement ◽  
Meta Analysis ◽  
Dabigatran Etexilate ◽  
Single Technology Appraisal ◽  
Once Daily ◽  
Total Hip ◽  
Total Knee

This paper presents a summary of the evidence review group (ERG) report into the clinical effectiveness and cost-effectiveness of dabigatran etexilate (DBG) for the prevention of venous thromboembolism (VTE) in patients undergoing elective hip and knee surgery based upon a review of the manufacturer’s submission to the NICE as part of the single technology appraisal (STA) process. The submission’s evidence came from three reasonable-quality trials comparing DBG with enoxaparin, and a comparison of DBG with fondaparinux based on the relative efficacy and safety as derived from a mixed treatment comparison (MTC) meta-analysis. DBG (220 mg and 150 mg once daily) is not inferior to enoxaparin (40 mg once daily and 30 mg twice daily) in terms of major VTE or VTE-related events (secondary outcome). Meta-analysis shows that 220 mg DBG is not inferior to enoxaparin (40 mg once daily or 30 mg twice daily) in reducing total VTE and all-cause mortality (primary outcome) in total hip or knee replacement, whereas there is uncertainty around the clinical effectiveness of 150 mg DBG for this outcome. In the MTC analysis DBG compared favourably with the other interventions, with the exception of extended enoxaparin and fondaparinux. The adverse event profile was not significantly different in those receiving DBG and those receiving enoxaparin. The submitted two-phase economic model compares DBG with enoxaparin and fondaparinux in total hip and knee replacement. The model structure is appropriate and the model assumptions are reasonable. The health states, costs, utilities and recurrence rates used are considered to be appropriate for the required analysis. The model estimated that at the licensed dose of 220 mg once daily DBG dominates enoxaparin in both total hip replacement and total knee replacement and that at the lower dose of 150 mg once daily DBG dominates enoxaparin in total hip replacement and enoxaparin dominates DBG in total knee replacement. DBG is less cost-effective than fondaparinux in total hip replacement at both doses; the cost per quality-adjusted life-year of fondaparinux versus DBG is £11,111 and £6857 for the higher and lower doses of DBG respectively. In total knee replacement, both DBG doses are dominated by fondaparinux. For DBG versus all comparators in all cases the cost-effectiveness results are based on small incremental cost and health benefits. Weaknesses of the submitted evidence include that methods used for screening studies, data extraction and applying quality assessment criteria to included studies, as well as key details of trials included in the MTC, were not adequately described. In addition, some input parameters into the modelling process are incorrect. The ERG was unable to correct all of these mistakes and the impact on the model results is therefore unknown. The National Institute for Health and Clinical Excellence guidance issued as a result of the STA states that DBG is recommended as an option for the primary prevention of VTE events in adults who have undergone elective total hip or knee replacement surgery.

scholarly journals PREOPERATIVE IDENTIFICATION OF PATIENTS AT HIGH RISK OF DEEP VENOUS THROMBOSIS DESPITE PROPHYLAXIS IN TOTAL HIP REPLACEMENT

1987 ◽  
Author(s):  
E Rocha ◽  
J A Práamo ◽  
M J Alfaro ◽  
B Cuesta ◽  
J Fernádez ◽  
...  
Keyword(s):  
Total Hip Replacement ◽  
Hip Replacement ◽  
Varicose Veins ◽  
Factor Xa ◽  
Tissue Type ◽  
Predictive Index ◽  
Platelet Factor ◽  
Total Hip ◽  
Vein Thrombosis ◽  
Preoperative Prediction

Preoperative prediction of postoperativevenous thrombosis was investigated in 111 patients undergoing total hip replacement prophylactically treated with aspirin (1 g/d) or a combination of heparin (5000 IU) plus dihydroergotamine (0.5 mg) twice a day during 7 days. The followingpreoperative parameters were determined:age, sex, overweight percentage, previous thromboembolism, varicose veins,heartdisease, malignancy, plateletcount, platelet-crit, mean platelet volume, circulating platelet aggregates, platelet factor 4, β-thromboglobulin, fibrinogen, Factor Xa, VIII:C, AT III, fibrin monomers, FDP,euglobulin lysis time, α2-antiplasmin, tissue-type plasminogen activator (t-PA) and its inhibitor (PAI). Postoperatively deep vein thrombosis (DVT) developed in 16patients was detected by ascending venography. Stepwise logistic discriminant analysis was used to identifyfactors which predicted DVT. Three such factors, FDP, PAI and t-PA, were significantly associated with DVT and used to construct a predictive index. The predictiveindex, I = 2.09 + 0.46 (FDP) + 1.39 (PAI) - 0.24 (t-PA), was 100% sensitive and 95% specific in the prediction of DVT. This index could allow for identification of those patients in whom routine prophylaxis would be sufficient and forselecting those in whom more effective prophylactic regimens would be necessary.

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