Darexaban (YM150) versus enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: a randomised phase IIb dose confirmation study (ONYX-3)

Abstract

This double-blind, double-dummy, randomised, phase IIb study (NCT00902928) evaluated different dosing regimens of darexaban compared with enoxaparin (randomised 1:1:1:1:1 to 15 mg twice daily [bid], 30 mg once daily [qd], 30 mg bid or 60 mg qd or enoxaparin 40 mg qd) in patients undergoing elective total hip arthroplasty. Patients, investigators, pharmacists and sponsor were all blinded to treatment allocation. Darexaban administration started 6-10 hours (h) post-surgery. Enoxaparin 40 mg qd administration started 12 ± 2 h before surgery. Treatment continued for 35 days. Bilateral venography was performed on Day 10 ± 2. The primary efficacy outcome was total VTEs (composite of proximal/distal deep-vein thrombosis, pulmonary embolism) or death, at Day 12. Total VTE rates were similar across all groups. There was no apparent difference in efficacy between once- and twice-daily darexaban (odds ratio [OR] 1.00; 95% confidence interval [CI] 0.71-1.42; p=0.988), or total daily dose (30 mg/day vs 60 mg/day; OR 0.81; 95% CI 0.57-1.15; p=0.244). There was no significant difference in major and/or clinically relevant non-major bleeding between darexaban qd or bid, or between total daily doses of 30 mg or 60 mg, and also for any dosing regimen of darexaban vs enoxaparin. Darexaban was well tolerated, without signs of liver toxicity. In conclusion, darexaban, administered qd or bid, and at total daily doses of 30 mg or 60 mg, appears to be effective for VTE prevention and was well tolerated. Data suggest no significant differences between a once- or twice-daily dosing regimen.

Low molecular weight heparin versus other anti-thrombotic agents for prevention of venous thromboembolic events after total hip or total knee replacement surgery: a systematic review and meta-analysis

“…Enoxaparin was the only LMWH used in the included studies at a dose of 40 mg once daily as subcutaneous injection in 15 studies. However, for five studies, the postoperative regimen of 30 mg of enoxaparin administered subcutaneously every 12 h (30 mg bid) was used as this regimen was approved by the Food and Drug Administration (FDA) [ 21 , 26 – 28 , 36 ]. Zou et al [ 22 ] used enoxaparin sodium as 4000 anti-Xa activity IU (0.4 ml) once daily dose, and Fuji et al [ 29 ] assessed the effectiveness of three different doses of enoxaparin given subcutaneously; 20 mg qd, 40 mg qd, and 20 mg bid.…”

“…Zou et al [ 22 ] used enoxaparin sodium as 4000 anti-Xa activity IU (0.4 ml) once daily dose, and Fuji et al [ 29 ] assessed the effectiveness of three different doses of enoxaparin given subcutaneously; 20 mg qd, 40 mg qd, and 20 mg bid. The length of follow-up period ranged from 12 days (Eriksson et al [ 21 ]) to 90 days (Fuji et al [ 29 ]).…”

“…In Group II (LMWH vs. inhibitor of factor Xa), ten studies, 5 for THR [ 20 , 21 , 28 , 30 , 31 ] and 5 for TKR) [ 22 , 24 , 25 , 27 , 32 ], had complete data for the rate of DVT. A random effects model was used for both THR and TKR due to the presence of high heterogeneity in the data (THR: Q value = 35.701, df = 4, P < 0.001, I-squared = 88.80%; TKR: Q value = 13.523, df = 4, P = 0.009, I-squared = 70.42%).…”

“…In Group II (LMWH vs. inhibitor of factor Xa), four studies [ 21 , 28 , 30 , 31 ] for THR and four studies [ 24 , 25 , 27 , 32 ] for TKR reported the incidence of major bleeding. Fixed effect model was used as low heterogeneity was observed for THR (Q value = 4.236, df = 3, P = 0.237, I-squared = 29.18%) and TKR (Q value = 3.543, df = 3, P = 0.315, I-squared = 15.33%).…”

Nonvitamin K antagonist oral anticoagulants (NOACs): the tide continues to come in

“… 15 , 16 Although full-scale clinical development of this drug was stopped in 2011, darexaban has been trialed in the prevention of VTE after abdominal and orthopedic surgery. 17 – 19 It has also been trialed in acute coronary syndromes, 20 as has rixaroxaban (with successful end point outcomes), 21 although guidelines from the European Society of Cardiology Working Group on Thrombosis recommends the use of newer antiplatelet agents over addition of NOACs in this setting. 22 Thus, although there is a modest amount of promising literature on this drug, any advantage it can bring over its competitors remains to be seen and, should clinical development restart, robust additional data will be sought.…”