A dose-finding study with TAK-442, an oral factor Xa inhibitor, in patients undergoing elective total knee replacement surgery

Summary

This multicentre dose-finding study compared TAK-442, an oral factor Xa inhibitor, with enoxaparin for thromboprophylaxis after knee arthroplasty. In this parallel group study, patients were randomised to oral TAK-442 (40 or 80 mg once-daily [QD] or 10, 20, 40, or 80 mg twice-daily [BID] started 6–8 hours postoperatively), which was blinded as to dose, or to open-label subcutaneous enoxaparin (30 mg BID starting 12–24 hours postoperatively) for 10 days. Treatments were continued until bilateral venography was performed (maximum of 14 days). The primary efficacy endpoint was the composite of any deep-vein thrombosis, non-fatal pulmonary embolism or all-cause mortality, while the primary safety endpoint was major bleeding. Of 1,038 patients randomised who received at least one dose of study drug, 949 completed the study and 730 (76.9%) were evaluable for the primary efficacy analysis. Recruitment into the 10 and 20 mg BID dose groups was stopped early because the incidences of the primary efficacy endpoint were significantly higher than that with enoxaparin. The primary efficacy endpoint occurred in 22.0% of patients given enoxaparin and in 39.0%, 38.4%, 23.5%, 21.4%, 26.8%, and 14.3% of those receiving TAK-442 10 mg BID, 20 mg BID, 40 mg QD, 40 mg BID, 80 mg QD, and 80 mg BID, respectively. The incidences of major and clinically relevant non-major bleeding with TAK-442 were not dose-dependent or different from that with enoxaparin. All TAK-442 doses except 10 and 20 mg BID displayed similar efficacy and safety profiles to enoxaparin.

Keywords

Oral factor Xa inhibitor - anticoagulants - thromboprophylaxis - venous thromboembolism - total knee replacement

• References

• 1 Geerts WH, Bergqvist D, Pineo GF. et al. Prevention of venous thromboembolism. American College of Chest Physicians evidence-based clinical practice guidelines (8^th edition). Chest 2008; 133 (Suppl. 06) 381S-453S.
• 2 Cordell-Smith JA, Williams SC, Harper WM. et al. Lower limb arthroplasty complicated by deep venous thrombosis: prevalence and subjective outcome. J Bone Joint Surg Br 2004; 86: 99-101.
• 3 Lassen MR, Ageno W, Borris LC. et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty. N Engl J Med 2008; 358: 2776-2786.
• 4 Lassen MR, Davidson BL, Gallus A. et al. The efficacy and safety of apixaban, an oral, direct factor Xa inhibitor, as thromboprophylaxis in patients following total knee replacement. J Thromb Haemost 2007; 5: 2368-2375.
• 5 Turpie AG, Fisher WD, Bauer KA. et al. Bay 59–7939: an oral, direct factor Xa inhibitor for the prevention of venous thromboembolism in patients after total knee replacement. A phase II dose-ranging study. J Thromb Haemost 2005; 3: 2479-2486.
• 6 Weitz J. New oral anticoagulants in development. Thromb Haemost 2010; 103: 62-70.
• 7 Kawamura M, Konishi N, Hiroe K. et al. Antithrombotic and anticoagulant profiles of TAK-442, a novel factor Xa inhibitor, in a rabbit model of venous thrombosis. J Cardiovasc Pharmacol. 2010 doi: 10.1097/FJC.0b013e3181e2bfcf.
• 8 Konishi N, Hiroe K, Shinozawa E. et al. Antithrombotic profiles of TAK-442, a novel oral factor Xa inhibitor, in venous and arterial thrombosis models. J Thromb Haemost 2009; 7 (Suppl. 02) PP-WE-400.
• 9 Stringer F, Scott G, Kupfer S. et al. The pharmacokinetics and pharmacodynamics of TAK-442, an oral, direct factor Xa inhibitor following multiple dosing in healthy male subjects. Brit J Clin Pharmacol. 2010 in press.
• 10 Eriksson BI, Quinlan DJ, Weitz JI. Comparative pharmacodynamics and pharmacokinetics of oral direct thrombin and factor Xa inhibitors in development. Clin Pharmacokinet 2009; 48: 1-22.
• 11 Heit JA, Colwell CW, Francis CW. et al. Comparison of the oral direct thrombin inhibitor ximelagatran with enoxaparin as prophylaxis against venous thromboembolism after total knee replacement: a phase 2 dose-finding study. Arch Intern Med 2001; 161: 2215-2221.