Dose-escalation study of rivaroxaban (BAY 59-7939) – an oral, direct Factor Xa inhibitor – for the prevention of venous thromboembolism in patients undergoing total hip replacement

Abstract

Introduction Rivaroxaban (BAY 59-7939) is a novel, oral, direct Factor Xa inhibitor in clinical development for the prevention of thromboembolic disorders. The aim of this study was to demonstrate proof-of-principle for rivaroxaban. Materials and methods This was an open-label, dose-escalation study to assess the efficacy and safety of rivaroxaban, relative to enoxaparin, for the prevention of venous thromboembolism (VTE) after total hip replacement surgery. Patients were randomized in a 3:1 ratio to rivaroxaban (2.5, 5, 10, 20 and 30 mg twice daily [bid] or 30 mg once daily [od] starting 6–8 h after surgery) or enoxaparin (40 mg od starting the evening before surgery). Therapy continued until mandatory bilateral venography was performed 5–9 days after surgery. Results A total of 625 patients received therapy, of whom 466 patients were eligible for the per-protocol efficacy analysis. The primary efficacy endpoint – deep vein thrombosis (DVT), pulmonary embolism (PE) or all-cause mortality – occurred in 22.2%, 23.8%, 20.0%, 10.2%, 17.4%, 15.1% and 16.8% of patients receiving rivaroxaban 2.5, 5, 10, 20, 30 mg bid, 30 mg od and enoxaparin, respectively. The dose-response relationship with rivaroxaban for the primary efficacy endpoint was not statistically significant ( p = 0.0504), although major VTE (proximal DVT, PE and VTE-related death) decreased dose dependently with rivaroxaban ( p = 0.0108). Major, post-operative bleeding increased dose dependently with rivaroxaban ( p = 0.0008), occurring in 0–10.8% of patients, compared with 0% in patients receiving enoxaparin. Conclusions This study demonstrated proof-of-principle for rivaroxaban for the prevention of VTE after total hip replacement surgery.