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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

Summary.  Background: BAY 59‐7939, a novel, oral, direct factor Xa inhibitor, is in clinical development for the prevention of venous thromboembolism (VTE), a frequent complication following orthopaedic surgery. Methods: In a multicenter, parallel‐group, double‐blind, double‐dummy study, 621 patients undergoing elective total knee replacement were randomly assigned to oral BAY 59‐7939 (2.5, 5, 10, 20, and 30 mg b.i.d., initiated 6–8 h postsurgery), or subcutaneous enoxaparin (30 mg b.i.d., initiated 12–24 h postsurgery). Treatment was continued until mandatory bilateral venography 5–9 days after surgery. The primary efficacy endpoint was a composite of any deep vein thrombosis (proximal and/or distal), confirmed non‐fatal pulmonary embolism and all‐cause mortality during treatment. The primary safety endpoint was major, postoperative bleeding during treatment. Results: Of the 613 patients treated, 366 (59.7%) were evaluable for the primary efficacy analysis. The primary efficacy endpoint occurred in 31.7%, 40.4%, 23.3%, 35.1%, and 25.4% of patients receiving 2.5, 5, 10, 20 and 30 mg b.i.d. doses of BAY 59‐7939, respectively (test for trend, P = 0.29), compared with 44.3% in the enoxaparin group. The frequency of major, postoperative bleeding increased with increasing doses of BAY 59‐7939 (test for trend, P = 0.0007), with no significant difference between any dose group compared with enoxaparin. Bleeding endpoints were lower for the 2.5–10 mg b.i.d. doses compared with higher doses of BAY 59‐7939. Conclusions: Oral administration of 2.5–10 mg b.i.d. of BAY 59‐7939, early in the postoperative period, showed potential efficacy and an acceptable safety profile, similar to enoxaparin, for the prevention of VTE in patients undergoing elective total knee replacement.