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A randomized evaluation of betrixaban, an oral factor Xa inhibitor, for prevention of thromboembolic events after total knee replacement (EXPERT)

Journal: Thrombosis and Haemostasis
ISSN: 0340-6245
DOI: http://dx.doi.org/10.1160/TH08-07-0460
Issue: 2009: 101/1 (Jan) pp. 1-216
Pages: 68-76

A randomized evaluation of betrixaban, an oral factor Xa inhibitor, for prevention of thromboembolic events after total knee replacement (EXPERT)

Alexander G. G. Turpie1; Kenneth A. Bauer2; Bruce L. Davidson3; William D. Fisher4; Michael Gent1; Michael H. Huo5; Uma Sinha6; Daniel D. Gretler6; for the EXPERT Study Group*

1McMaster University, Hamilton, Ontario, Canada; 2Beth Israel Deaconess Medical Center, Boston, Massachussetts, USA; 3Weill Cornell Medical College, Doha, Qatar; 4McGill University Health Centre, Montreal, Quebec, Canada; 5University of Texas Southwestern Medical Center, Dallas, Texas, USA; 6Portola Pharmaceuticals, Inc., South San Francisco, California, USA

Keywords

Clinical trials, Venous thrombosis, oral anticoagulants, major bleed, betrixaban, direct factor Xa inhibitor, total knee replacement (TKR)

Summary

Betrixaban is an oral direct inhibitor of factor Xa (FXa) being developed for the prevention of venous thromboembolism (VTE). Its antithrombotic effects had not been previously tested in patients. This exploratory clinical trial in the US and Canada randomized 215 patients undergoing elective total knee replacement (TKR) in a 2:2:1 ratio to receive post-operative betrixaban 15 mg or 40 mg p.o. bid or enoxaparin 30 mg s.c. q12h, respectively, for 10–14 days. The betrixaban dosage was blinded, but enoxaparin was not. Primary efficacy outcome was the incidence of VTE, consisting of deep-vein thrombosis (DVT) on mandatory unilateral (operated leg) venography, symptomatic proximal DVT, or pulmonary embolism (PE) through Day 10–14. Safety outcomes included major and clinically significant non-major bleeds through 48 h after treatment. All efficacy and bleeding outcomes were adjudicated by a blinded independent central adjudication committee. Of 214 treated patients, 175 (82%) were evaluable for primary efficacy. VTE incidence was 14/70 (20%; 95% CI: 11, 31) for betrixaban 15 mg, 10/65 (15%; 95% CI: 8, 27) for betrixaban 40 mg, and 4/40 (10%; 95% CI: 3, 24) for enoxaparin. No bleeds were reported for betrixaban 15 mg, 2 (2.4%) clinically significant non-major bleeds with betrixaban 40 mg, and one (2.3%) major and two (4.6%) clinically significant non-major bleeds with enoxaparin. A dose- and concentrationdependent effect of betrixaban on inhibition of thrombin generation and anti-Xa levels was observed. Betrixaban demonstrated antithrombotic activity and appeared well tolerated in knee replacement patients at the doses studied.

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