A dose–response study of a recombinant human soluble thrombomodulin (ART-123) for prevention of venous thromboembolism after unilateral total hip replacement

Abstract number: OC330

Kearon^* C., Comp† C., Douketis§ D., Royds† R., Yamada§ K., Gent^* M.

§Asahi Kase, America Inc., USA ^*McMaster University, Canada; †University of Oklahoma, USA;

Background  

Current antithrombotic drugs that are used to prevent venous thromboembolism (VTE) after orthopedic surgery have the limitations that they require laboratory monitoring (warfarin), daily injection (LMWH, fondaparinux), or are not very effective (aspirin). ART-123 is composed of the active, extracellular domain of thrombomodulin. It inhibits thrombosis via activation of Protein C and is active for 5–10 days after subcutaneous injection.

Objective  

To identify an effective and safe dose of ART-123 for the prevention of VTE after total hip replacement.

Methods  

A North American, open-label, sequential dose-ranging study was performed. All patients received a subcutaneous dose of ART-123 (0.3 or 0.45 mg kg^-1) 2–4 h after completion of surgery. Patients who received 0.3 mg kg^-1 on the day of surgery received a second injection of 0.3 mg kg^-1 after 5 days. To ensure that patients were receiving some protection from VTE, intermittent pneumatic compression (IPC) was also used in the first 30 patients that were studied (regulatory requirement). The primary efficacy outcome was all DVT on mandatory bilateral venography 8 days after surgery and symptomatic VTE within 30 days of surgery. The primary safety outcome was major bleeding within 10 days of surgery. An Independent Central Adjudication Committee assessed all outcomes. Decisions to change a dosing regimen were made by the Steering Committee based on regular reviews of observed rates of VTE and bleeding.

Results  

Of 306 treated patients, 223 have completed evaluation for the primary efficacy analysis.

Conclusion  

The observed rate of asymptomatic and symptomatic VTE of 2.1% among patients who received either a single, or two, dose(s) of ART-123 without IPC indicates that soluble thrombomodulin is very effective at preventing VTE. A single large dose of ART-123 shortly after surgery prevented all VTE but appeared to be associated with an increase in major bleeding.