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

Abstract

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 concentration-dependent 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.

Current Status of New Anticoagulants in the Management of Venous Thromboembolism

“…Like apixaban and rivaroxaban, betrixaban is a very specific inhibitor of the FXa, both free and bound in the prothrombinase complex [43]. In animal models, betrixaban has a bioavailability of 49% [44].…”

“…Elimination is mostly by biliary excretion with minimal renal clearance, which would allow its use in patients with renal insufficiency, without a requirement for dose adjustment. Because of its independence with major CYP P450 enzyme pathways, betrixaban has a minimal potential for drug interactions [43]. …”

“…The conclusion was that betrixaban demonstrated antithrombotic activity and appeared well tolerated. Further studies are expected to come based on the results of the EXPERT trial [43]. …”

Update on anti-coagulation in atrial fibrillation

“…The anticoagulant effects of betrixaban in humans was initially investigated in the US and Canadian trial, in which it was compared with enoxaparin for prevention of thromboembolism after knee replacement surgery [the Evaluation of betriXaban for the Prevention of vEnous thRomboembolism in daily practice (EXPERT) trial] 81 . In this study, 215 patients were randomized to treatment with betrixaban 15 mg or 40 mg bid, or enoxaparin 30 mg subcutaneously every 12 h for 10–14 days.…”

New anticoagulants for the prevention of venous thromboembolism

“…The oral anti-Xa betrixaban has been compared with enoxaparin, both started postoperatively in patients undergoing TKR 47. DVT on mandatory unilateral venography or symptomatic proximal, or PE was reported through to day 14 in 20%, 15%, and 10% of patients receiving increasing doses of betrixaban or enoxaparin, respectively.…”