title: 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.
abstract: 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.
  
  
  OBJECTIVE
  This study evaluated the dose-response of AVE5026 for the prevention of VTE in patients undergoing TKR surgery.
  
  
  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.
authors.affiliation: Hørsholm Hospital, Spine Clinic, Hørsholm, Denmark. mirula@noh.regionh.dk
authors.forename: M R
authors.initials: MR
authors.lastname: Lassen
authors.forename: O E
authors.initials: OE
authors.lastname: Dahl
authors.forename: P
authors.initials: P
authors.lastname: Mismetti
authors.forename: D
authors.initials: D
authors.lastname: Destrée
authors.forename: A G G
authors.initials: AG
authors.lastname: Turpie
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019645:Arthroplasty, Replacement, Knee / Q000009:adverse effects*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006470:Hemorrhage / Q000139:chemically induced; D006493:Heparin / Q000008:administration & dosage / Q000031:analogs & derivatives*; D006495:Heparin, Low-Molecular-Weight / Q000008:administration & dosage* / Q000633:toxicity; D006801:Humans; D008297:Male; D008875:Middle Aged; D011183:Postoperative Complications / Q000517:prevention & control*; D011292:Premedication / Q000379:methods*; D018570:Risk Assessment; D054556:Venous Thromboembolism / Q000517:prevention & control*
chemical_list: C542814:AVE 5026; D006495:Heparin, Low-Molecular-Weight; D006493:Heparin