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AVE5026, a new hemisynthetic ultra‐low‐molecular‐weight heparin for the prevention of venous thromboembolism in patients after total knee replacement surgery – TREK: a dose‐ranging study
Author(s) -
LASSEN M. R.,
DAHL O. E.,
MISMETTI P.,
DESTRÉE D.,
TURPIE A. G. G.
Publication year - 2009
Publication title -
journal of thrombosis and haemostasis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.947
H-Index - 178
eISSN - 1538-7836
pISSN - 1538-7933
DOI - 10.1111/j.1538-7836.2009.03301.x
Subject(s) - medicine , venography , pulmonary embolism , deep vein , low molecular weight heparin , thrombosis , dose ranging study , incidence (geometry) , heparin , surgery , venous thrombosis , complication , knee replacement , venous thromboembolism , arthroplasty , double blind , placebo , physics , alternative medicine , pathology , optics
Summary. Background: AVE5026 is a new hemisynthetic ultra‐low‐molecular‐weight heparin, with a novel anti‐thrombotic profile resulting from high anti‐factor (F)Xa activity and residual anti‐FIIa activity. AVE5026 is in clinical development for venous thromboembolism (VTE) prevention, a frequent complication after total knee replacement (TKR) surgery. Objectives: This study evaluated the dose‐response of AVE5026 for the prevention of VTE in patients undergoing TKR surgery. Patients/methods: In this parallel‐group, double‐blind, double‐dummy study, 690 patients were randomized, and 678 treated with once‐daily doses of AVE5026 (5, 10, 20, 40, or 60 mg) or enoxaparin 40 mg in the calibrator arm. The primary efficacy end point was VTE until post‐operative day 11, defined as deep vein thrombosis (DVT) detected by bilateral venography, symptomatic DVT, non‐fatal pulmonary embolism (PE) and VTE‐related death. The primary safety outcome was the incidence of major bleeding. Results: The primary efficacy outcome was assessed in 464 patients. There was a significant dose‐response across the five AVE5026 groups for VTE prevention ( P < 0.0001), with the incidence of VTE ranging from 5.3% to 44.1% compared with 35.8% in the enoxaparin group and for proximal DVT ( P = 0.0002). Also, a significant dose‐response for AVE5026 was seen for major bleeding ( P = 0.0231) and any bleeding ( P = 0.0003). Six patients in the AVE5026 groups, four in the 60 mg group, experienced major bleeding; none did in the enoxaparin group. Conclusions: The safety and efficacy results of this study suggest that a AVE5026 dose of between 20 and 40 mg presents an adequate benefit‐to‐risk ratio.