Thromboprophylaxis After Orthopaedic Surgery With An Oral, Direct Factor Xa Inhibitor: Pooled Results Of Two Phase Iib Clinical Trials.

Abstract Thromboembolic events, such as deep vein thrombosis (DVT) and pulmonary embolism (PE), are a serious risk after surgical procedures, such as major orthopaedic surgery. BAY 59-7939 is an oral, direct Factor Xa inhibitor in clinical development for the prevention and treatment of thromboembolic disorders. The efficacy and safety of BAY 59-7939 for thromboprophylaxis have been determined relative to enoxaparin in two clinical trials, one after elective total hip replacement surgery, and one after elective total knee replacement surgery. Both trials were multicenter, multinational, double-blind, dose-ranging studies; the hip surgery trial was performed in Europe, and the knee surgery trial in North America. This pre-specified analysis combines data from both trials. Patients (n=1343) were randomized to oral BAY 59-7939 at 2.5, 5, 10, 20, or 30 mg twice daily (bid), or subcutaneous enoxaparin (40 mg once daily starting 12 hours before hip surgery, or 30 mg bid starting 12 hours after knee surgery). Treatment continued until mandatory bilateral venography was performed 5–9 days after surgery. The primary efficacy endpoint was a composite of DVT, PE, and all-cause mortality, and was analyzed in 914 per-protocol patients. The secondary efficacy endpoint was major venous thromboembolism (VTE) - proximal DVT, PE, and VTE-related death. The primary safety endpoint was major, post-operative bleeding, and was analyzed in 1317 patients. Observed pooled event rates are shown in the table. No significant dose-response relationship for efficacy was observed with BAY 59-7939 (P=0.39 and P=0.46 for primary and secondary endpoints, respectively) in logistic regression models using total daily dose and adjusting for study, age and gender effects; this was potentially due to the efficacy achieved with the lower BAY 59-7939 doses. A significant dose-response relationship was observed for major, post-operative bleeding with BAY 59-7939 (P<0.001). In conclusion, this analysis showed that for the prevention of VTE following major orthopaedic surgery, BAY 59-7939 has a wide therapeutic window and, at doses of 2.5 to 10 mg bid, has similar efficacy and safety to the enoxaparin regimens. BAY 59-7939 (mg bid) Endpoint 2.5 5 10 20 30 Enoxaparin DVT, PE, all-cause mortality 36/167 (21.6%) 38/166 (22.9%) 26/161 (16.1%) 38/156 (24.4%) 17/88 (19.3%) 49/176 (27.8%) Major VTE 5/167 (3.0%) 4/166 (2.4%) 5/161 (3.1%) 5/156 (3.2%) 1/88 (1.1%) 8/176 (4.5%) Major, post-operative bleeding 2/232 (0.9%) 3/238 (1.3%) 5/236 (2.1%) 9/232 (3.9%) 10/143 (7.0%) 4/236 (1.7%)