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.
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.
Lassen
M R
MR
Hørsholm Hospital, Spine Clinic, Hørsholm, Denmark. mirula@noh.regionh.dk
Dahl
O E
OE
Mismetti
P
P
Destrée
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D
Turpie
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AG
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*
C542814:AVE 5026; D006495:Heparin, Low-Molecular-Weight; D006493:Heparin